Foresight Medicine

About Foresight Medicine

Conversations about the future of preventive healthcare with leading experts. foresightmedicine.substack.com (https://foresightmedicine.substack.com?utm_medium=podcast)

Publisher

Robert S. Rogers

Category

health & fitness · science

Language

en

Explicit

No

First episode

18 Feb 2026

Latest episode

8 Jun 2026

Latest episodes

7 episodes in the feed.

1. 

   8 Jun 2026

   Episode #7: Prevention of Diabetes and Innovation in Metabolic Health with Dr. Robert Gabbay

   Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic framework for leveraging new technology to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. Today we’ll be talking about the foundational topics of diabetes, obesity, and metabolic health. I am very honored to have as my guest, Dr. Robert Gabbay. Dr. Gabbay is an endocrinologist, physician- scientist, and an inspiring leader in diabetes care, research, and prevention. He has served as both chief scientific and chief medical officer of the American Diabetes Association and the chief medical officer of the Joslin Diabetes Institute, and is Associate Professor of Medicine at Harvard Medical School. He has pioneered innovative care models for diabetes and chronic disease more broadly, and he is a major contributor to the important guidelines clinicians use to provide optimal diabetes care, a prolific and insightful analyst on new developments in the world of pharmacotherapy devices and other technologies for metabolic health. Listeners should note we are recording this on Monday, June 1st, 2026, and this conversation is for general informational purposes only and does not constitute individual medical advice. Bob, welcome. Thank you so much for joining me today on Foresight Medicine. Robert Gabbay: Thanks, Robert. I’m looking forward to our conversation. Robert Rogers: So I’m really looking forward to this conversation, and one thing that I know is that you are a guest with whom we could probably cover any aspect of the broader topic of diabetes, metabolism, obesity with and have a really insightful conversation. But that is a very broad topic. Perhaps it’s the most foundational thing to health today and a place where there’s a lot of focus. And to focus our conversation in the spirit of Foresight Medicine and our focus on prevention and early intervention, what I’d really like us to spend most of our time talking about is not healthcare, and medical care for patients with full-blown, well-established diabetes, significant obesity, and all of those attendant complications that come downstream of that. Hugely important topic, really exciting developments now with better tools to treat those patients. But I think a bit of a already emerging care paradigm, that we have that we really, that we’re really knowing more and more what to do with that population. And what I’d really like to focus on is the millions of Americans who have prediabetes or maybe just a little bit overweight, who are at risk of having, those outcomes but aren’t there yet, where I think the terrain is a little bit less settled, maybe you’ll have something to say about that and really focus our attention there. So maybe just to start, you’re a wonderful writer and analyst of new developments in this field, and I recently read a great series you wrote on the state of prediabetes care in the US, and you pointed out big opportunities for improved care. So why don’t we just lay a little foundation for our guests?What is prediabetes, and what is the sort of benefit of recognizing it as its own entity? Robert Gabbay: Great. Thanks for asking that and so a number of years ago, prediabetes was defined as a subgroup of individuals that in essence, have a very high risk of developing diabetes. And the reason to identify those folks is there are things that could be done to help prevent them from moving from prediabetes to diabetes. Robert Rogers: Yeah, and just say, maybe say a little bit more about that. So prediabetes itself is a marker of some level of risk for poor health outcomes, but it also carries with it an attendant risk of progressing to diabetes. And could you say a little bit more about both of those risks and how we sort of think about their magnitude? Robert Gabbay: Yeah. No, absolutely. So first of all, just to give you the sense of numbers, and your listeners, so there are over ninety million people with prediabetes, so really a large part of the US population, and about thirty-eight million people with actual type two diabetes. And so what determines, first of all, someone with prediabetes moving to diabetes, so the state of prediabetes is a marker for having some typically some significant amount of resistance to insulin. And the development of diabetes, type two diabetes, takes two problems, being resistant to the effects of insulin and not being able to overproduce insulin to compensate. So these people with prediabetes already have the resistance, but they’re able to make a lot of extra insulin to keep their blood glucose normal, or in the case of prediabetes, a little bit above normal, and that’s the zone that puts them at risk. Turns out that having prediabetes in and of itself, and more specifically that resistance to insulin, insulin resistance, increases the risk of cardiovascular disease significantly. So it’s really a marker of high cardiovascular risk and at the same time, a marker for people that are at high risk for developing type two diabetes and all of the other complications that go with type two, like, eye disease, kidney disease, neuropathy, et cetera. Robert Rogers: Great. So that’s a really nice foundation, I think, to start for our listeners, and something that I’ve always thought interesting when I think about the challenge of diabetes and how we define it, is that metabolic health really does exist on a spectrum, and there’s a marker that clinicians use a lot, that’s, best thought of I think, as an average of your blood glucose level over a period of time, called the hemoglobin A1C. And it’s very hard for us to practice medicine without kind of hard definitions, so we have to choose specific cutoffs and say, “This person has prediabetes. This person has diabetes.” But the fact of the matter is that risk exists somewhat continuously along this along this spectrum. And so I think as we think about individualizing and personalizing care, it’s okay to share that level of nuance with patients. One thing I’d like to ask your opinion on is there is this famous project called the Diabetes Prevention Plan, something that you know very well, something that you’ve been involved in and it’s actually known to be quite effective. And maybe you could talk a little bit about what exactly it is but also why has it been so challenging for our healthcare system to implement it at scale? Robert Gabbay: Well, it’s an interesting story. So it started with a sponsored randomized controlled trial that asked the question: Can you prevent the development of type 2 diabetes? You can identify people at high risk with prediabetes, but is there anything you can do about it, or is it inevitable? People randomized to different interventions. One of them was a lifestyle program, and that reduced the risk of developing type 2 diabetes by sixty percent. Another arm looked at a drug, metformin, and that was only half as effective. So we have an intervention that can reduce the risk of developing diabetes by sixty percent, which is quite remarkable when you think of a lot of the other treatments that we use for prevention. That led to a lot of efforts by a number of individuals, and the Center for Disease Control and CMS, ultimately to have coverage for the diabetes prevention program. So Medicare covers a diabetes prevention program. A number of other commercial insurers cover it as well. So here’s an intervention that works, and it has coverage. And at the same time, with those over ninety million people with prediabetes that would be eligible, for being in this program, how many do you think have actually over the last… Oh, it’s been out there for oh, probably close to twenty years now, at least fifteen. How many people do you think out of those ninety million have gone through the program over those years? Robert Rogers: A very small percentage. I can imagine that much. If I was gonna guess a number, I’d say it’d be in the low millions. Robert Gabbay: Yeah, less than a million. Robert Rogers: Is that right? Yeah. Robert Gabbay: Wow. Yeah, despite all of the effort, and something that works, and it’s evidence-based and all of that. So the question is why, and there are probably a number of factors. Some of the sort of administrative challenges of being certified to deliver this program, are challenging. Reimbursement happens after you do it, and so small places, community health centers, which are probably the ideal place to do this because if you think about you need something that will be able to reach ninety million people. So that could happen in primary care or honestly, really probably best in a community environment, just to have the reach that one needs. It is a commitment, and it’s — it’s generally an in-person program. Robert Rogers: Just say a little bit, if you don’t mind, just say a little bit about the actual components of this of this intervention, just so people get a sense of how manageable or cumbersome it is. Robert Gabbay: Yeah. So there are a series of classes that occur, initially weekly and then, a bit less often. And part of the power of the program, is not to just do it with one individual, but to have that peer support, to have a group of people together that are learning together. It’s led by a facilitator that can be taught to do this. Doesn’t have to be in general, it’s not a physician. It may be a nurse, but it doesn’t need to be. It could be a community health worker, and there are programs to train individuals to do this. And so it’s a in large part, a weekly program, that guides individuals on the lifestyle changes and the things that worked. So what did they do in that diabetes prevention program that reduced the risk by sixty percent? People, were active, mostly walking five days a week, so thirty minutes, five days a week, which is doable for most people. It’s not any extraordinary amount of exercise. And they lost about seven percent of their body weight. And they had the instructional nutritional aspects. So there’s a teaching component and also a problem-solving component. So here are what the recommendations are. What we know is just telling people, “Here’s what you need to do,” doesn’t necessarily mean that it will happen. And so guiding them as when might you do it, what are some resources, all of that problem-solving is what goes into this program. And so it’s really a behavior change program over that period of time. So it’s a time commitment, and that’s another barrier. Robert Rogers: That’s another barrier, right. Great. So that’s a really, I think, great foundation, for our listeners to understand what has been sort of the pillar of prediabetes care for some time. And you mentioned that there’s this comprehensive program. You also mentioned that there can be the use of metformin, which is a diabetes drug which has been around for many decades. But now in the last few years, we’re in a whole new era with respect to the pharmacologic options for the treatment of diabetes and its attendant, organ damage, and for obesity, with the incretin therapies, the GLP-1s and similar. And I’d love for you to give us a little bit of your perspective of what is a rational approach, a how should a clinician think about using those therapies, specifically in the context of prediabetes, not necessarily someone who full-blown has diabetes and is starting to show already significant organ damage from that where I think the care paradigm is already a bit more in focus? Robert Gabbay: Those therapies have really changed the way we think about managing type 2 diabetes and also obesity in general. One of the big risk factors for having prediabetes is obesity. And so the majority of individuals prediabetes also have obesity, and so treating obesity, also helps with prediabetes. That said, it does so incredibly effectively. And so as an example, one of the one of the medications, Tirzepatide, which is a dual GLP-1 and GIP medication, marketed as Mounjaro or Zepbound, reduced… took people with prediabetes, and 90% of them had normal glucose at the end. Robert Rogers: Wow, that’s astounding. Robert Gabbay: That’s a dramatic, like 90%. Now, you compare that to metformin that well, I mentioned, in the diabetes prevention program, 30%, prevented the development. Here it was 90%, so super effective therapy. Robert Rogers: Yeah. And who would you recommend, which patients would you recommend, use, Mounjaro or a similar, or a similar type of medication, that are… As far as patients that are currently on the pre-diabetes spectrum? Robert Gabbay: Certainly, first and foremost, people, that are living with obesity, would be the individuals, so a BMI greater than 30, and we can talk about BMI versus other, sort of measures, but that’s the standard. I think, I think the challenge with the medications is access and cost. And so if you’re thinking about an individual, you could imagine a large number of people, that would meet the criteria. When you’re thinking about it from a public health point of view, then it’s a little bit of a different, sort of way of well, do you treat everybody, or do you treat people at highest risk? And what is really is emerging right now is to be able to take that large group of individuals with pre-diabetes and in essence sub-categorize them to say, “Here’s… Out of all those people, here are the people that are at highest risk of moving from pre-diabetes to diabetes, and therefore maybe we should have more aggressive therapy for them. Those people that are at a low risk, we might wait and see, about sort of those kinds of therapeutic options.” and so it’s been interesting because this idea that is being termed staging of Type 2 diabetes is following the pattern of what’s happened over the last few years with Type 1 diabetes. Robert Rogers: Yeah. Say a little bit more about that. I think that’s a really interesting parallel. Robert Gabbay: So it’s been interesting that Type II defined prediabetes many years ago. Type I diabetes had not had any kind of staging, but there is a marker for people at higher risk of developing Type I diabetes, and those are autoantibodies, to in essence the cells that produce insulin. You can measure those autoantibodies, and if somebody has those they’re at higher risk of developing Type I diabetes. And so over the years they’ve been able to find subcategories of individuals that have stage one, meaning they just have the antibodies, stage two, they have the antibodies and their glucose are a little bit above normal, but not to the level of Type I diabetes, and stage three, full-blown Type I diabetes. And the reason that’s been important to define those people is there are now, therapies that can be used in individuals, with the earlier stages of Type I diabetes that can delay the development of Type I. Robert Rogers: You’re saying if, that if we can have a similar formality to a staging system for type 2 diabetes, which would certainly encompass this pre-diabetic insulin-resistant state, that would really enable this more, quote, in your words, precise or precision medicine approach to which patients get on therapies and which therapies those are. Is that right? Robert Gabbay: Yeah. And the idea would be that for all these individuals would benefit from some type of lifestyle, adjustment, that could be very helpful. And then certain ones that have a really high risk of moving on to full-blown type 2 diabetes might get pharmacological therapy. Right … and so you subdivide the group and you, and you, based on risk, and you use the right, treatment for the right individuals based on their risk. Robert Rogers: So let me, let me pull on two threads, of something that you mentioned in one of your earlier answers there. Talked about how if someone has pre-diabetes and true obesity, a body mass index greater than 30, that’s a good candidate to put on one of these newer agents. I wanna ask you, what about people who are only perhaps mildly overweight, what the evidence says about that? And a corollary to that question is how should patients’ age, play into this decision? It was interesting in your answer about the Diabetes Prevention Program, you mentioned how Medicare was one of the probably the first insurers to make this covered, and then commercial insurers maybe came a little bit later, and Medicare generally kicks in when people are in their 60s. And it just seems to me, and I’d love to hear your thoughts on this but you take two people who maybe, get to their late 60s and have similar, numbers in terms of obesity, in terms of their insulin resistance and glycemic control at this moment in time, but if one of those people has had several decades prior to that of having been obese and insulin resistant and the other kind of has only gotten there, has only gotten there recently, it stands to reason that those decades do take their toll, and we’re not necessarily gonna expect the health outcomes at age 75 or 80 to be identical for those people. So we’ve sort of missed an opportunity if we let someone go all through early adulthood and early middle age, without sort of treating those risk factors. Robert Gabbay: So ideally, one looks at the risk of developing, and this is just what we do in medicine in general, the higher the risk for something happening, the more aggressive the approach is to those individuals. So we know, and that’s, and that’s the logic behind staging type 2 diabetes, to be able to identify a group of people with higher risk. So there, A1C is a continuum, hemoglobin A1C is a continuum, as you talked about and we make the diagnosis of either pre-diabetes or diabetes on a relatively sharp number. An A1C of 6.4 is pre-diabetes, an A1C of 6.5 is diabetes. Turns out, and not surprisingly, that those that have higher A1Cs close to that 6.5 are higher risk of going over and developing full-blown diabetes. So those might be the individuals that we’re more aggressive to treat. In addition, it we look at we would ideally look at the comorbidities that they may have. Someone with cardiovascular disease already established, well, they would warrant therapeutic options that would address the cardiovascular disease, insulin resistance, and at the same time prevent the progression towards type 2. If they had liver disease, these medications are demonstrated to be effective there. So I think it’s, in the end, the ideal thing would be to look at the whole individual and personalize that therapy based on what con-- what other conditions they have beyond just pre-diabetes, and be more aggressive in those that have more conditions. Robert Rogers: Great. A highly individualized approach. That’s one of the themes we come back to on Foresight Medicine. One more question specifically about pre-diabetes, and then we’ll finish with a few where I get to take advantage of your broader, expertise in this in this area. So there’s now several approved or nearly approved, therapies in this category, incretin therapies, GLP-1 and GLP-1 like therapies. There’s both injectable options and oral options. And when choosing among them, there’s several factors one might consider, and I’m not particularly interested in saying, in having you endorse one over the other, but I just want us to talk sort of philosophically about what are the factors that a patient and a clinician might think about. One is of course the extent of the weight loss. Another is the health benefit that redound beyond the weight loss, itself. The tolerability is really important, the side effects, the cost to the patients, the convenience, and perhaps the risk of currently unrecognized, adverse effects that could happen over very long-term use. And so what I’d really like to get your sense of is how should the weighing of these factors differ for someone who’s pre-diabetic or maybe just, very early diabetes and a little bit overweight, versus those with more severe obesity and quite established health complications who make up the bulk of the patients who have been studied for the longest amount of times in the clinical trials of these medicines? Robert Gabbay: Well, Robert, I think you bring up exactly the right notion that these individuals that have these other conditions are the ones you’re gonna want to be more aggressive about. So and goals will be More aggressive. So for example, someone that has a higher degree of obesity would… One might choose a medication that has a larger percent weight loss. For someone who is very concerned about doing injections and not comfortable with that and that would be a barrier for them to initiate therapy, an oral agent may be a better option. I also think that in the next year or two, we’re gonna see a number of other new treatment options added. So right now we have oral, injectable, and essentially two flavors of each, at different dosages. I think in a very short period of time we’ll see a number of others, and what my hope is there will begin to be some head-to-head trials that will help us really have a precision approach to identifying which therapies would be most effective, which ones have the demonstrated benefit for which comorbidities. So I think it’s gonna be all of those things put together that will help make the decision of which is the right medication for the patient in front of you right now. Robert Rogers: Great. So people are very interested in this topic of de-escalating from these therapies after they have achieved substantial weight loss. And you’ve written about this topic. You’ve written about how we don’t really know how effective lower or less frequent dosing, that does maintain the weight loss will be at maintaining the broader health and organ protective benefits of these drugs. How are we gonna learn the answer to that very important question?Super important, especially as we think about using these at an earlier, point in people’s lives. Robert Gabbay: I mean, number one, I struggle a little philosophically with the notion that medication works, it’s effective, it’s achieved the goal that you started that medication for and then we wanna back off on it. We don’t do that with blood pressure medicine. We don’t do that with statins. We really don’t do that with many other classes of drugs. So altogether, because these drugs do plateau in terms of their weight loss. If one continued to lose more and more weight, then yeah, you would need to back up. But people plateau. They lose X amount, and then they stay at X amount long term. So I struggle a little bit with that notion to begin with. The other interesting thing that we’re learning is that the benefits of these medications on other disease states like cardiovascular disease and liver disease, kidney disease, seem to be not strictly related to weight loss. So there are individuals that have not lost much weight because there’s a spectrum of response, but they see cardiovascular benefit. And so the studies would’ve looked for benefit on these other disease states. They don’t they haven’t used low-dose medication, so we don’t know if the low dose will have those benefits. And that’s a reason to be a little nervous about dropping dose. Certainly one doesn’t wanna lose too much weight, and in fact, that’s one of the interesting things of a recent trial that had the most potent of agents, retatrutide, which is three hormones together. A sizable number of individuals, stopped the medication because they were losing too much weight. And so yes, there is… You can lose too much weight, and that would be a reason for dropping a dose, certainly. Robert Rogers: Yeah. And I think that just makes the larger point that all of these drugs are quite effective at achieving a relatively substantial amount of weight loss. And so when trials are done in patients who are significantly, obese, morbidly obese, that might be a real distinguishing factor between them. But as we think about using them in patients who are who are perhaps only mildly overweight, a little bit insulin-resistant, perhaps other factors really become, more, come more to the fore in terms of how we would choose amongst them. And one that I just, would love to get your take on something that I’ve thought about is if we’re thinking about long-term use of some of these agents, in a pre-diabetic population, perhaps over many years, there probably is something to be said for going with the class of agents that has the absolute longest, track record in terms of safety, and I would say that’s the GLP-1 injectables among the four options in terms of which type of medicine, an injectable or oral. I don’t know if you share that perspective. That’s sort of my working hypothesis when I would think about how to counsel patients right now. Robert Gabbay: I think that’s reasonable. What we do know is that these GLP-1 agents, have been around for 20 years on the market, so we really have a lot of safety data and surveillance on them. The other combination with other hormones, we have far less of a period of time of observation.So having 20 years of data is better than having three to five years of data, certainly, and so I think that makes a lot of sense. Robert Rogers: Let me ask you another question. Now, you and I are both based in the Boston area. It’s hard to walk down the street in Boston, in the summertime and not see people wearing continuous glucose monitors, and it is not because the rates of type one diabetes have soared to 10 or 20% of the population. These are quite the craze, for people who are focused on, quote, “prevention and proactive health.” Tell me about what you think are rational use cases for them. Maybe let’s just break it out among three different groups of patients, someone who’s metabolically healthy, somebody who’s pre-diabetic, and somebody with type two diabetes. Robert Gabbay: So I’ll start with the type 2 diabetes, ‘cause that’s the easiest. So anybody that is taking insulin, really, the studies show pretty resoundingly, and the recommendations are that they should be offered a continuous glucose monitor. For many people not on insulin with type 2 diabetes, they also benefit, and there’s some data there as well. Then you get into that other group of people, either with pre-diabetes or metabolically well without any abnormalities of glucose. I think where those where the CGM devices can be helpful is to learn a little bit more about how what you do affects your glucose. And for people with pre-diabetes, yeah, it’s, there’s more evidence there saying, not having big excursions of glucose, is helpful. And I don’t have diabetes, but I’ve worn them, and then you learn, like, different foods. Like, “Wow, I really jumped up.” there’s certain things that would be obvious, but there’s sometimes things that are not obvious that you… that are part of your regular diet that really impact your blood glucose. So I think that’s helpful, and getting that feedback on behavior. How much of that people need is a question. And I think the greatest successes have been often intermittent use of CGM in these individuals, Where they wear it, they learn the things they need to change, and how different activities and foods affect their blood glucose. They make some changes, and then down the road, they recheck to see where they’re at. And I think that’s where we’ve seen a lot of success. Robert Rogers: Great. Two last questions for you. You’re a major leader in innovation and implementation around new diabetes technology, and I’m curious if there’s any new tools or devices, at any level of diagnostics, therapeutics, even systems-level implementation, that you’re particularly excited about you think are gonna be particularly impactful, in the coming years. Robert Gabbay: Well, I think for people with diabetes, I think the really exciting thing has been and will continue to be is automated insulin delivery. So devices that for individuals that require insulin, which is everyone with Type 1, 1.8 million people in the US, but also for the many people with Type 2 diabetes, about 8 million, that require insulin. These devices use continuous glucose monitor, and they take that information and through an algorithm, instruct an insulin pump to deliver an appropriate amount of insulin to control blood glucose with a feedback loop. The challenge with them up till now has been one still needs to say what you’re eating and when you’re eating, and be able to say, “I’m eating, X amount of grams of carbohydrate.” And that has been… That takes time for people to learn. What we’re on the verge of is a truly driverless car that would essentially personalize the algorithm to the individual. Right now, it’s one algorithm fits all sizes. You can imagine an algorithm learning over time what you eat and how you eat, and being able to adjust the algorithm from for example, you probably eat less than 20 different breakfasts, over the course of a year. Most people eat, somewhat similar things, and it can learn that and now adjust accordingly So that you can really just put this thing on and not need to think a whole lot about it. And that for people living with diabetes, would be a dramatic improvement. Robert Rogers: Dr. Robert Gabbay, a great leader and inspiring visionary and educator in this field of diabetes, obesity, and metabolic health, thank you so much for joining us on Foresight Medicine. Robert Gabbay: Thank you so much. I enjoyed our conversation. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

2. 

   8 Jun 2026

   Episode #6: Prevention and Early Intervention for Kidney Disease with Dr. Katherine Tuttle

   Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine podcast at the Foresight Medicine Substack where we are envisioning the future of preventive healthcare as a comprehensive whole body framework for leveraging new technology to maintain health as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties, and today we will be talking about the kidneys. I am very honored to have as my guest, Dr. Katherine Tuttle. Dr. Tuttle is professor of medicine in the Division of Nephrology at the University of Washington and Executive Director of Research at Providence Inland Northwest Health. She is one of today’s most prolific and impactful clinical and translational scientists in the area of kidney disease. She has led foundational research on the pathophysiology of diabetic kidney disease, and her work has been pivotal in establishing the current pillars of therapy for chronic kidney disease more broadly. Her work is broad, and it spans elucidating the mechanisms of those therapies, the clinical trials that have established their benefit, and the interrelationship between kidney disease and cardiovascular and overall health. She’s a leader in many of the major national and international organizations focused on kidney health that shape the practice of nephrology through guidelines and grant making. Listeners should note that we are recording this on Friday, May 22nd 2026, and this conversation is for general informational purposes only and does not constitute individual medical advice. Kathy, welcome. Thank you so much for joining me today. Katherine Tuttle: Well, it’s great to join you. Robert Rogers: So I’m really looking forward to this conversation, and on the Foresight Medicine project, we’re really going organ system by organ system, disease category by disease category, thinking about the future of preventive and proactive health. And for some of the diseases, the tools that we have both from a diagnostic and therapeutic standpoint are really exciting, but they’re almost somewhat aspirational. And I think one of the really cool things, and I think we’re gonna get into this today when it comes to kidney disease, is that of course, the tools in our toolbox are evolving and expanding, and you’re a major participant and leader in those efforts, but they’re actually already quite good in many ways. And so there’s this additional challenge of how can we deploy optimally what we already have. And so I’m really excited to get into both aspects of that. And so I guess I would just like to start out by saying how did you first become particularly interested among your interests in the early identification and prevention of chronic kidney disease? Katherine Tuttle: Well, thanks for that question, Rob because it really goes back a long time. And before I was a nephrologist, I actually did a fellowship in endocrinology and metabolism. And the focus was really on physiology, glucose metabolism, glucose regulation. And there were people who volunteered for these studies. These were the original insulin and glucose clamping studies done some 40 years ago. Mostly people with type 1 diabetes who would spend eight to 10 hours in a room with multiple lines and blood draws. And we had a machine called the Biostator, which was an artificial pancreas. Today, people wear it on their belt, but in those days, it filled an entire room. And when I was doing those experiments, I got to know the study participants really well. We didn’t have helpers then either. I mean, I was drawing the blood, processing the samples, and staying with the patient the entire time while running the Biostator. And I got to know them quite well. We were all about the same age in our late 20s, and it really stunned me one day when one of our study participants, this altruistic volunteer who signed up for these experiments with the hope that it would somehow help people, crashed into dialysis at Barnes Hospital. We didn’t see it coming. We weren’t even looking for kidney disease. We weren’t even thinking about it. We were focused on the physiology of glucose metabolism, really important. I’m still a physiologist. I still do preclinical research. But it occurred to me that we really need to get much more focused on solving problems that matter to patients, and not-- virtually nothing was being done about kidney disease and diabetes in the mid-1980s. We weren’t screening for albuminuria. We had maybe a serum creatinine, but no one knew what to do with it. And I realized that this was an enormous unmet need, and I just decided that something needed to be done about it. I wasn’t sure what I was going to do but I decided I would do something, and then I pivoted to nephrology and went on to train in nephrology. And then I’ve spent most of my career focused on trying to solve problems related to diabetes and the kidney. And thankfully, after decades of work and along with really an army of other people in the field, we now have truly transformative therapies, so I’m glad I’ve been here for the whole journey. Robert Rogers: I just want listeners to appreciate how unique it is to have fully trained in both endocrinology and in nephrology. But it clearly set you up very well because diabetes which we’ll get into is of course one of the major contributors to kidney disease. And so your own training and career trajectory kind of follows along. So I’d like to lay a little bit of foundation and help people understand the scope of the problem that we care about preventing or intervening upon when we talk about kidney disease. And I mentioned to a few friends who were kind enough to listen to this podcast that I was gonna be doing an episode on kidney disease and the first couple of comments that I got were like, “Oh yeah, ending up on dialysis is really terrible.” And that is of course true. When many people think of kidney disease, our minds immediately go to perhaps the most severe or extreme outcome, which is when your kidneys completely fail and you require dialysis or a transplant. And there’s several hundred thousand people in this country, I think about eight hundred thousand, who are currently on dialysis, tens of thousands more who live with a with a transplanted kidney. And so that is of course a problem of significant scope. But in some ways it’s really only the tip of the iceberg. And so maybe you could explain how is it that decrements in kidney function that are well short of complete loss, end-stage kidney disease, really are quite important, significant and a health burden? Katherine Tuttle: Oh, thanks for that question, Rob. I think it’s been the great under-recognized public health crisis, frankly. In fact, The Lancet published an updated global burden of disease study on CKD in November of twenty twenty-five, coincident with American Society of Nephrology’s Kidney Week with new estimates of the global burden of disease. They’re now estimating eight hundred million people worldwide, and half of it is attributable to diabetes, so some four hundred million people with diabetes and kidney disease in this world. The other thing, too, is they projected the death rate squarely attributable to kidney disease. In 2013, it was the nineteenth leading cause of death. By 2023, it’s now... It became the ninth leading cause of death. And if we don’t change the trajectory we’re on by 2040, they’re projecting it’ll be the fifth leading cause of death in the world. So it is an enormous public health problem. And I think that is really the issue. It’s the mortality associated with this. So nine out of ten people who develop chronic kidney disease, particularly if they have diabetes, will die on the road to kidney failure. And the people who make it to dialysis or transplant to the end of the line are a ragtag survivor bunch because of the enormous complications that are highly fatal, and these include cardiovascular complications. And yes, there’s a high burden of conventional cardiovascular risk factors, but it’s the kidney disease that really accelerates the risk. So if you have low kidney function and you spill protein in your urine, above and beyond diabetes, the risk of cardiovascular death is increased thirty, three zero, fold. We published those data over 15 years ago. And so I think people have not recognized how fatal this condition is. The next leading cause of death is infections due to impaired immune response associated with CKD. And the reason it matters is not just scary to statistics, and I imagine we’ll get to this but we now have therapies that reduce mortality, and mortality from both cardiovascular disease and infections in people with chronic kidney disease. So you’re right, it is the tip of the iceberg, and people are very sick, and many will die and never make it to dialysis. So we can say if you get to the point you need kidney replacement therapy, congratulations, you made it. Wow. Yeah. But then, life on dialysis is also very burdensome. And even today, let’s just talk about survival as the starting point. The median survival of a person with diabetes who initiates dialysis is two years, worse than most forms of bad cancer which we fear because of the death risk. So what I wanna call out is we need to recognize that this is a killer. It’s rising in prevalence, and it’s rising in importance of causes of death as we’ve done better with other causes of death at least historically reducing cardiovascular risk and risk from infections because we vaccinated people at least historically. Now what we have emerging is this other cause which has been left unaddressed. Robert Rogers: Yeah. And so in your very compelling answer there, you mentioned a couple of things that I really want us to take a deeper dive on. One is how now we have medicines that really do impact the mortality of having kidney disease and diabetic kidney disease. But you also mentioned how the presence of kidney disease is a real risk factor for many other forms of death, particularly cardiovascular morbidity. And so you have been I think, one of the leading people from the field of nephrology who’s helped to really set forth a new paradigm in how we think about kidney and cardiovascular care in the past few years. And the paradigm is called CKM or sometimes CKLM, which stands for cardiovascular, kidney, liver, sometimes it’s thrown in there, and metabolic health. And instead of looking at each of these organs in isolation, it sort of appreciates the interrelationship between them. And maybe you could just tell us a little bit about how that paradigm and that lens is a more helpful contemporary way to think about these problems. Katherine Tuttle: Well, it’s much more realistic. It’s integrative pathophysiology. These organs don’t act in isolation. And yes, I was involved with the initial scientific working group for the American Heart Association that wrote the scientific statement, the presidential advisory. The first American Heart Association, American College of Cardiology guideline is set to publish early in June, and I’m an author on that. And I guess one thing I wanna say about liver, it actually is included in the original CKM construct. It is under the metabolic umbrella. So people sometimes misunderstand that. So the liver was always there- M But it really is one of the metabolic organs. When we think about again, integrative pathophysiology, it’s liver metabolism along with fat and pancreatic metabolism. So I always feel like I have to say that because we never left that out, but it really acknowledges the liver as a metabolic organ that also is very important in terms of integrating these risks. And what we know is that dysfunctional adiposity, diabetes, liver disease creates a systemic inflammatory milieu, also particularly from the standpoint of adiposity, increases the burden of conventional risk factors, again, like diabetes, hypertension, dyslipidemia. And those are factors that cause both heart and kidney disease to be accelerated. And then the really bad actor is that once kidney, the kidneys begin to fail, it’s gasoline on the fire of cardiovascular disease because then the sick kidney produces bad humors that accelerate atherosclerotic disease and particularly heart failure, preserved ejection fraction. But then the heart doesn’t behave very nicely either when it begins to fail or become diseased--even, even with coronary disease, there are systemic factors that then cause further kidney injury, so we end up in this vicious positive feedback cycle of spiraling downhill. And with the new therapies, they really address three main pathways: metabolic, hemodynamic, and fibrosis and inflammation. And so I sort of call that the box at the bottom. These are the final common pathways. Irrespective of the inciting injury, these organs sort of collapse into those pathways. And so now what we recognize is while it’s always important to try to treat the original cause, whatever it is if we don’t treat the final common pathways, we still have progression. So a great example of that is back to diabetes. We’ve done studies of intensive glycemic control, trying to reduce cardiovascular and kidney risk in people with established diabetes. It does very little. And it’s because while acknowledging it’s very important to control blood glucose or everything gets worse, it’s because they’re already on a on a downhill train, and you’ve gotta break the cycle at the bottom. So the new therapies then on top of say, good blood pressure, glycemic control, treatment of lipids, then interrupt those final common metabolic hemodynamic and fibroinflammatory pathways. Robert Rogers: Great, and I really wanna get into those new therapeutic options, and modalities in just a bit. But we’ve already talked about it quite a bit, the relationship between diabetes and the risk of chronic kidney disease. There’s also another major risk factor, epidemiologically that accounts for a lot of chronic kidney disease, which is hypertension, high blood pressure. And so maybe just walk us through for both of those two major risk factors, how much do they elevate one’s risk of kidney disease, and how much does aggressive treatment of those risk factors actually reduce the risk? Katherine Tuttle: Yeah, so if we go back to the dialysis population that we’re working with 75% of people on dialysis either have diabetes or hypertension as the primary at least clinically identified cause. Now that said, 95% of people with diabetes and kidney disease have hypertension, so that’s actually half. And then about a quarter are hypertensive people who don’t have diabetes. We also know from studies of hypertension control, while we can reduce the rate of losing kidney function versus uncontrolled hypertension, it’s still really a modest effect compared to the newer therapies. That said, it’s very important to control blood pressure though, because if we don’t control blood pressure, then we have another accelerating factor. But what we’re saying is we’ve done this for a long... We’ve for a long time, controlled blood pressure and controlled glucose, and still have had only an explosion of kidney disease. So there really... It’s important, but by the time people are diagnosed, there’s already been target organ injury, and it will do little other than mildly mitigate the disease just to control the original risk factors. So I hope I’ve answered your question. It’s foundational. Right. ‘Cause if you leave those uncontrolled, it’s just, it’s, it’s another accelerant. But that’s really only one part of it, and actually once the disease is established, probably lesser, it... I don’t wanna say it’s unimportant, but the in terms of driving the disease, there’s gonna be less benefit from blood pressure or glucose control than the highly effective therapies that target tissue-level mechanisms. Robert Rogers: Okay. Great. So I think we’ve now laid enough foundation to go into those highly effective therapies that target tissue-level mechanisms. So say, say a little bit more about what these new classes of therapies are that have really changed the whole care paradigm over the past decade, and that we’re still learning how to use and deploy further. Katherine Tuttle: Yes, and if I could, I’m gonna also speak about heart failure because it is the closest adjacent condition to CKD. And of all forms of cardiovascular disease, the most likely cause of exiting the planet. So and both of them basically have kind of converged into the very similar, treatments. So the first breakthrough... Well, if we go back historically, and again, since your audience is a general medical audience, I would like to acknowledge the importance of the renin-angiotensin system. Robert Rogers: Sure. Say a little bit about what that is for- Yeah... For our audience. Yeah. Right. And how, and how the original, the kind of foundational medications that have been treating that have been around for 40 or more years in some ways, right? Katherine Tuttle: Right. So these are agents... The renin-angiotensin system is a very important physiologic, hormonal regulating system that controls sodium retention by the kidney, vascular function, cardiac function, and kidney function in fundamental ways. And so with overactivation of the system, this is a major cause of hypertension. So originally, targeting the renin-angiotensin system was viewed as a way to treat hypertension and certainly, agents in these in these classes, either ACE inhibitors or angiotensin receptor blockers do that. But for the first... But there was biology mechanisms that in both the heart and the kidney that there were tissue-level activation pathways for these systems, and that there could be benefit beyond blood pressure control. So 25 years ago, after these drugs were first approved for the treatment of high blood pressure, they were studied for heart failure and for chronic kidney disease and diabetes initially. And these were the first classes of agents that beyond conventional risk factor control, beyond blood pressure control, added additional survival benefit. And again for people who aren’t steeped in the specialty, this means that these people had beyond controlling their blood pressure, they were more likely to stay alive, and their organs were less likely to fail. So for about 20 years that is all we had for these conditions. However, the treatment benefit by today’s standard was modest. So let me go to the kidney side of this. So we had two major trials, RENAL of losartan and IDNT of irbesartan. The relative risk reductions for kidney failure or dying were reduced 15 to 20%. But at the time that was really heralded as a major breakthrough. That was in September of 2001. And between, over the next 20 years, though, we saw nothing but the end-stage kidney disease population double. So I mean, it wasn’t really having a huge population effect, although during that time, electronic health records came forward, and when we actually looked at real-world data, we found that only, like, 25% of people who should be on these therapies for CKD were getting them. So it wasn’t entirely, ineffective therapy. It was also ineffective implementation. Robert Rogers: Right. Katherine Tuttle: But be that as it may that was what we had. But that was the first signal that we could interrupt disease risk at the target organ level beyond just treating blood pressure and diabetes. So enter the SGLT2 inhibitors. So this was the first breakthrough class. The signal came from something called the cardiovascular outcome trials. And the story here is that It was-- these were safety trials that were mandated by the US Food & Drug Administration in 2008 for any new glucose-lowering agent that was put on the market. And the reason was that in 2006, there was a so-called rosiglitazone debacle where rosiglitazone was placed on the market for treatment of type 2 diabetes. But within the first year of being on the market, the agency received, the FDA, when I say the agency, received a number of post-market approval reports of major adverse cardiovascular events. So there had been a long signal that glucose-lowering agents could increase cardiovascular risk, going all the way back to sulfonylureas, but nobody was gonna go back and restudy those old generic drugs. Robert Rogers: Right. Katherine Tuttle: But they knew they had a lever with the new drugs. So they said, then if you-- if we approve a new drug for lowering glucose in type 2 diabetes, the sponsor has to do a post-market approval safety study to stay on the market. There was a lot of pushback, but it really became the gift that keeps on giving because not only were these agents safe, they were highly efficacious for reducing major cardiovascular risk. And the really interesting thing was especially with SGLT2, while there was some benefit on a atherosclerotic disease, the big win was on heart failure, particularly preserved ejection heart failure, which had not benefited from the same therapies that were working for reduced ejection fraction heart failure. And that’s important because the majority of heart failure in this country is preserved ejection fraction. Right. Very much like CKD. The major secondary outcomes were kidney outcomes. And remember, the people put in the study weren’t put in for kidney risk. They were put in for heart risk, and most of them didn’t have kidney disease. Yet, we saw a reduction in new onset of kidney disease marked by albuminuria, slowed kidney function decline, and even prevented kidney failure. Interestingly enough, in 1987, one of my mentors, Dr. Ralph DeFronzo, and I gave a derivative of SGLT2 inhibitors to diabetic rats. And that paper was published in the JCI in 1987. And while the intent wasn’t originally about organ protection, we actually knew at that time that there would be reasons to study kidney function because the drug works in the kidney. Robert Rogers: So just to sort of for our listeners, you talked about how there was this longstanding foundation of medications, initially for hypertension, but then showing benefit in kidney disease and in heart failure, the ACE inhibitors and angiotensin receptor blockers. And then you just took us through this really, beautiful history of the SGLT2 inhibitors, this next, this next class. And I think you’re gonna get into the class that people are hearing so much about these days, the GLP-1s, the incretin therapies, the big weight loss drugs in just a second. But as we, as we sit here today, let me just ask you, which patients do we know should be on the SGLT2 inhibitors in terms of it would benefit their kidney function and their health? And are there patient populations where we don’t yet know whether or not, they would benefit, but that’s being actively investigated, and you think we might have additional answers in the in the coming years? Katherine Tuttle: Yeah. So after those initial chronic vascular trials, we had what we called the CKD trilogy. We did three major kidney outcome trials, and these ran in parallel to the big heart failure trials. I do wanna say this was another historic moment. Every single one was stopped early for overwhelming efficacy. Very unusual! In our field, we had stopped... Plenty of studies for futility or safety, but never for overwhelming efficacy. And for those of you who aren’t in nephrology, I would say if you look around in your field, it is a rare moment when something’s stopped for overwhelming efficacy. The bar is very high for that. So that was how profound the effect was. And long story short is originally the first study was exclusively in type 2 diabetes with more severe kidney disease. The next study, DAPA-CKD, and then EMPA-KIDNEY progressively broadened the entry criteria such that in the last study, more than half the people didn’t even have diabetes, and they didn’t even have to have protein in their urine, which had historically been a criteria for our trials. So bottom line to answer your question, these work across most forms of chronic kidney disease, irrespective of diabetes or protein in the urine. So now we have grade 1A guideline recommendations from our major guideline-forming organization, which is called KDIGO, Kidney Disease Improving Global Outcomes, but also endorsed by the American Diabetes Association, the American Heart Association, or the ACC because we have so much overlap that these drugs are indicated for people with CKD with or without diabetes, and with or without albuminuria. These are fundamental therapies. The relative risk reductions are in the range of thirty to forty percent on top of an ACE or an ARB. And the other really important thing is you can’t just look at relative risk reduction. You have to look at absolute risk because the higher the absolute risk, the greater the clinical benefit. So you’re talking about people who in these trials that were cut short because of benefit, only went about two years, primary outcome, kidney outcome event rates approaching twenty percent, and that going down by thirty or forty percent is an enormous clinical benefit. So then the same thing happened with heart failure, and the really interesting thing in the heart failure trials to me anyway, is that they also included people with CKD, and the heart failure patients who benefited most for cardiovascular survival were the people with CKD. So they benefit broadly, back to our call to recognize the mortality risk, is in this high-risk population, especially if they have diabetes, we reduce risk of death, particularly heart failure death, and among the living, markedly preserve kidney function and reduce the risk of kidney failure. Robert Rogers: Great. And now the latest class in the last five years are the GLP-1 agonist drugs like semaglutide, Wegovy, Ozempic, the GLP-1/GIP combined, tirzepatide, Mounjaro. People are very interested in this class of medications. They have lots of benefits. People think of them primarily as medicines that aid in weight loss and control of blood sugar for diabetes, but their benefits really redound ar beyond that.So how are those being, used now in the context of kidney disease and kidney disease prevention? Katherine Tuttle: So GLP-1s really work very differently. Our lab did a lot of the pre-clinical work, again, because we were interested in the effect of metabolic processes to exacerbate target organ injury. But here, these are mostly non-hemodynamic drugs. And at the level of the kidney and blood vessels, they are anti-inflammatory and anti-fibrotic. And so when those drugs were approved for the treatment of type 2 diabetes, they too had to conduct cardiovascular outcome trials for safety. And the second gift that kept on giving. But the really great thing was first off on the heart disease side, while there’s overlap in benefit, the SGLT2s mainly are heart failure drugs, although a slight benefit on atherosclerosis, and it’s the opposite with GLP-1s, primarily anti-atherosclerotic, but with some heart failure benefit. But again, secondary kidney outcomes lined up just as we would have predicted based on the models, less protein in the urine, and preserved kidney function. So we went from the CVOTs to one, and only one, dedicated kidney trial, which was the FLOW trial. And this is number four, stopped early for overwhelming efficacy. And some of us had been involved in the SGLT2 inhibitor trials and knew we would only get one shot at goal with the GLP-1, so the bar was set even higher to stop this trial, called FLOW, earlier than for the SGLT2 trials. And I’ll never forget the day. On October 13th, 2023, we received a message from the Data Safety Monitoring Board, which is our independent review committee who advises us on safety, and they recommended that we stop the trial. And the reason was it would no longer be ethical to keep people on placebo when this drug was on the market So again, four trials stopped for overwhelming efficacy. Again, this is historic. Never happened in our field, and probably very few fields within a five-year period of time. And FLOW was set up very rigorously. It tested semaglutide, and I wanna be clear that this was not a weight loss study. We used the one milligram once weekly subcutaneous injectable dose. We started the trial in 2019, and it ended in 2024. The median follow-up for people in the study was 3.4 years, and they lost very little weight, 4.5%. They came in at a mean weight of 90 kilos, and they went down to 85. This was not a weight loss study, yet we had profound benefits. We reduced the primary. On top of standard of care, ACE or ARBs, and some SGLT2 inhibitor use. So it, SGLT2s were increasing. It was 16% at the beginning of the trial, 33% at the end. But in spite of using SGLT2s and ACEs and ARBs, we had profound benefits, 24% reduction on top of those therapies- Right... For the primary kidney outcome. We had as much or more benefit on cardiovascular outcomes in the cardiovascular trials. And most importantly, 20% reduction in all-cause mortality. So yes, there was a 20% reduction in CV death, but it did not account for all the mortality benefit. And we think this is because these agents also reduce the risk of infection which we monitored very closely because the trial was largely conducted during the pandemic. Robert Rogers: Well, that’s great, ‘cause you’ve given a really... You’ve given a just a beautiful overview of how each of these therapies have developed, how they’ve shown their extraordinary benefit, how that benefit is manifest in several ways, it both through a direct improvement in or a reduction in the amount of kidney mortality and kidney failure, but also these much broader benefits. And so I wanted to sort of sort of ask you— I learned, about a concept from something you wrote, this idea of kidney disease going into remission. Now, we don’t usually talk about the word remission in the context of kidney disease, right? People might think of it in cancer. But I think what you’re trying to get at is this that there is a natural decline that happens in kidney function with aging. It’s probably accelerated by many parts of our modern lifestyle, but there just is an intrinsic aging of the kidney. And so we do expect the amount of what we measure called the glomerular filtration rate to go down as people age, but the rate at which it goes down is of course, quite modifiable. And so you sort of wrote about how now that we have all of these emerging therapies, we could actually hope to get somebody who has kidney disease, whose kidney is aging faster than normal, they’re losing that GFR faster than normal that the slope of that decline could actually converge back to normal, and that would essentially in some sense, be remission. And so what I wanted to ask you was you talked about these three very powerful classes of therapies, and if we start to layer them, how many people can... That currently have kidney disease can we get to remission or pretty close? Katherine Tuttle: So yeah, really important question. And so first, we have to go back to the data to answer your question. But because these agents work by different mechanisms, the combination appears to be additive. Now, the studies of combination therapy are just beginning. We’re doing that. But we can look at for example, in FLOW, all those SGLT2 inhibitor users who were in the GLP-1 study, and we see that they still get additional benefit from GLP-1. So everything points in that direction. So my research group and others have done modeling analyses to project what the expected benefit could be. And as you’ve said, we see that if we optimally use these agents in people with CKD. We could get to the point that the rate of kidney function decline is no different than people without kidney disease, which really is remission of the disease. And with the GLP-1s, and I wanna be clear that this is still in the research realm, but the direction things are going is also not just slowing decline. We actually see signals that kidney function can improve. Restoration of function. I hate to use. Beyond Robert Rogers: Remission. Beyond remission, Katherine Tuttle: Yeah. Regeneration. Regenerativeness. Katherine Tuttle: So with FLOW, we also did a mechanistic companion study called REMODEL which we have presented at two international conferences, American Society of Nephrology Kidney Week 2025, World Congress of Nephrology 2026 in Yokohama, and hopefully the paper will be out soon. But what’s been presented at the meetings I can tell you. So we see something called filtration fraction go up on the physiology on the functional imaging. That’s the proportion of blood that gets filtered into the urine. That is the basis of glomerular filtration rate. The fraction filtered increases. That means increased glomerular filtration rate. And we saw that in the remodel study where we had much more precise measurements than we would have in a big clinical trial in FLOW. So it’s early days, but there is a signal not only based on function, but structurally there can be repair of the glomerular filtration barrier. Robert Rogers: That’s really exciting, and I think we’ve spent most of our time today talking about the therapies, the tools that are really just getting more and more exciting in terms of their power for treatment. But of course, more powerful treatments, one of the things is it does is it really extends the logic of the benefit of early identification and early intervention and prevention if you have better tools with which to intervene. And so I wanted to just have you briefly explain at this point in time, what does screening for chronic kidney disease really entail? What are the what are the components of screening for it, and who do we think should be screened? Katherine Tuttle: Yep. Actually, those are big questions. Well, what I think is well established, and again, guideline recommended by the kidney people, KDIGO, the diabetes people, ADA, and the heart people, AHA/ACC, are all people with diabetes, all people with hypertension, all people with cardiovascular disease, and anybody with a family history of kidney disease. Now that’s probably about 70% of the United States’ population. Right. The other question is should we do population-wide screening? This is just my opinion. Unfortunately, the US Preventative Health Services Task Force did not recommend that. That is their decision. But there’s probably still a lot of kidney disease out there that goes undiagnosed because it’s so common, and they don’t necessarily have those criteria. They don’t know their family history for example. And because kidney disease was so undiagnosed until recently, how would if anybody in your family died of kidney disease unless they were on dialysis? So there are some of us who think that there should be population-wide screening. I happen to be in that camp. There have actually been cost effectiveness analyses done, out of Stanford, for example. Economic analysis showing that if you did population level screening, even the cost of an SGLT2 inhibitor, the return on investment would still be in favor of screening, even, even taking that into account. Robert Rogers: And I’ll just say, I’ll just say for our for our listeners, when we talk about screening for kidney disease, it’s, it’s really not all that cumbersome. We’re generally talking about two very, inexpensive and accessible laboratory tests. A blood test that measures how well your kidney is filtering at any given moment in time, and then, a test of the urine to see if you’re spilling protein into the urine. Really, those two are quite powerful. And we call that measuring your estimated GFR and testing for albuminuria. And I guess, just, just a couple questions on the screening front, though. Is there any recommended interval with which you think it makes sense to screen? If somebody has normal kidney function and no protein in their urine when they’re 40, is that a lifetime warranty? Probably not, right? So how frequently would it make sense to even check these things? Katherine Tuttle: Well, we know most is diabetes. So all people with type one, type two diabetes annually. And type 1, five years after diagnosis ‘cause it usually starts early in life and takes a while to accrue. We would say the same for the other high-risk groups, hypertension and cardiovascular disease. But the other really important thing is once it’s detected, you need to be rechecking more often, just like you do lipids or blood pressure, ‘cause you’re gonna intervene, and then you wanna get to some goals. And actually, the goal that we titrate to is albuminuria, and we want to get albuminuria as low as possible. So after it’s diagnosed, we’ll be rechecking every three to six months until they’re on a stable regimen. And then with established kidney disease, we still recommend every three to six months ‘cause it can take off and get away from you pretty quick, and we need to get therapies on board because to quote one of my colleagues, “Time is nephrons.” So with regard to general population screening, we don’t know ‘cause it hasn’t been recommended. So that remains an unanswered question. But people should at least be screened once in my opinion. Yeah. And then, it’s a subject of research, again to continue to evaluate for example, the cost effectiveness and what frequency of testing would remain cost effective. If you’re not in a high-risk group, it might not be every year. It might be every five or every 10 years, but we don’t know that. Robert Rogers: So those are the sorts of things that are gonna have to be better established with population research. But just a couple more questions now along the vein of balancing the great benefits, both in individual and public health with early detection and early intervention of kidney disease with this risk of over-medicalization and creating, patient, anxiety. And I guess I have kind of just a broad, almost philosophical question about this. We have used the three-letter abbreviation probably 15 times on this discussion already, CKD, chronic kidney disease. And just that labeling, kidney disease, can sound alarming, especially to somebody who has no symptoms of kidney disease, as most people don’t until it’s quite until it’s quite progressed. And I’m just wondering if we’re gonna be entering this world where we think it makes sense for a broad swath of the population to find out about their kidney disease risk through screening where there’s a lot of benefit to using these therapies probably at an earlier point to prevent deterioration in kidney function and also to promote overall health and reductions in mortality. Is that terminology, you think, the most helpful framing? Do we need to help, help explain the issue to patients in perhaps a less alarming way? Katherine Tuttle: Well, a couple things, too. I wanna go back to again where we started- Which was my patient who crashed into dialysis and didn’t think there was anything wrong with her except diabetes. And that’s really the problem. And it doesn’t bother us to screen for cancer, which is asymptomatic, right? Because people know that diagnosis is serious, and they need treatment to stay alive and function. It’s, it’s this it should be the same level of urgency. And I don’t think this is over-medicalization. I think it’s health maintenance. Because the most common question that nephrologists get asked is “Why didn’t anybody tell me?” And these therapies can prevent, what’s gonna, what’s about to become the fifth leading cause of death in the world. I mean, this is right up there with the top leading causes. It doesn’t bother us to screen for heart disease or cancer. I think we should be screening for this and I don’t think it’s over-medicalization. Because whether people know it or not or feel it, many people are hurdling toward the abyss without even knowing it. And I’m on the other end trying to catch them and them saying, “How come nobody told me?” So I’m not saying that everyone needs four drugs. There are probably some people who will do fine just on a good old-fashioned ACE inhibitor. But I guess it’s a matter of what you value and what you choose. But if you have diabetes and you’re not getting tested for kidney disease, I mean, you’re really playing, you’re really playing roulette with your life. Robert Rogers: Yeah. I think something you said at the outset is actually an interesting turn of phrase, health maintenance. It’s part of health maintenance. And perhaps, discussing this as a sort of a very common problem that many people encounter for which there are specific risk factors and for which you can be proactive about maintaining is… Perhaps can be less alarming to people than labeling, labeling them as having chronic kidney disease. Although certainly you don’t want to as you’re saying, underplay it and have people not recognize the degree of risk that they carry, especially if they have diabetes or other high risk factors. Katherine Tuttle: Yeah. And in fact, some people in our field have called that renalism, right? Like avoiding it- Robert Rogers: I haven’t heard that term before. That’s an interesting term. Katherine Tuttle: Yeah. Avoiding it because you don’t wanna know about it. And so I think there’s that part of it, too. I don’t think... People have high blood pressure or heart disease, and they manage it, and I think we can do the same with kidney disease. And then back to what I’ve told you, I mean, our therapies are now showing evidence that kidney function can be preserved. And in fact, I’ve also written about prevention of kidney disease. But it will require some form of intervention. You can’t just think it away. And I would say in the area, area of kidney disease, maybe even more we can do to maintain kidney health than maintain health in some of these other areas. Robert Rogers: Yes. That is that is certainly, an exciting, prospect that it... That finding out, these things is much more actionable with the kidney than in many other areas. A few kind of quicker rapid-fire questions to help us close up here. We’ve spent the vast majority of our time with good reason because epidemiologically it accounts for the biggest proportion of kidney disease, about kidney disease that’s really driven by metabolic disease risk factors, diabetes and hypertension. But there are a couple of other forms. And on Foresight Medicine, we’ve had episodes and we talk a lot about genomics, as a general purpose technology that is going to really expand what individualized, personalized preventive care can look like across a variety of diseases. A healthy person today could walk into a genomic screening clinic or get a commercial test and find out their risk of several single gene, monogenic kidney disorders. And I don’t really in the interest of time and complexity, want us to start going through individual kidney genetic disorders. Would just be curious on your thoughts if there are any that you think you would advise a patient, a healthy person who’s kinda doing this screening to learn their risk for where it would actually be actionable and where the utility of finding out about that increased risk would outweigh any sort of anxiety. Katherine Tuttle: Yeah, genetic testing is becoming important. There are two really, major forms of kidney disease. They’re rare diseases, but two that have become, actionable based on genetics, and one is polycystic kidney disease, and the other is APOL1 kidney disease. I think that one is particularly, exciting because it is a genetic variant that is found in people of recent African ancestry and helps, not completely, but partially explain the excess risk of kidney disease and kidney failure in the African American population. And it now, is becoming actionable. There are actually clinical trials going on targeting APOL1 that look very promising. Polycystic kidney disease is another monogenic form, although there are several different types. But similarly, we’re having some major advances for example, using microRNA technologies to restore kidney health and reduce cyst formation. So I think if you have a family history of polycystic kidney disease, the... You definitely should be screened. And with regard to the genetic testing and interventions that’s really in clinical research studies, so I’d encourage people to consider participating in a trial. And same for APOL1, but there it would go beyond just family history, but somebody of African ancestry. Or sometimes on a kidney biopsy, we see a certain diagnosis that we call FSGS, focal segmental glomerulosclerosis. And irrespective of your racial identity, if you have that we recommend APOL1 testing because can’t tell what... By what people look like. There are people who might not identify as African American who have African ancestry. And that too is becoming, targetable, but still in clinical trials. But genomics is very important in kidney disease. We’re also identifying some disorders where there are polygenic risk scores that may become actionable as well. So you’re right, we talked about big chronic diseases. But the really exciting thing is even in our rare diseases, like IgA nephropathy is one, 70 clinical trials going on. We don’t recommend genetic testing in everyone at this point. But for certain, ancestries, family history, or kidney biopsy features, we will do genetic testing if we think it could potentially be actionable or affect prognosis that might influence, the way people think about themselves or their lives. Robert Rogers: Yeah, and just to very briefly touch on maybe that last major category of kidney diseases, and you sort of alluded to it in your answer beyond, genetically mediated ones are diseases where the immune system attacks the kidney. And there are many, many, many of these and again, don’t wanna get into too much detail on any one of them. But just to make the larger point that we recently had an episode of the show where we talked about the early, early identification and interception of the autoimmune disease rheumatoid arthritis. And this idea that the antibodies in rheumatoid arthritis can actually become apparent as many as five years before people have any joint symptoms. And if you can identify them at a certain stage, there’s a lot of research, I don’t, hasn’t, hasn’t quite, hasn’t quite panned out to a to a clear to a clear, defined clinical pathway of what to do. But there’s a lot of research that we could maybe nip the autoimmune disease in the bud and prevent the downstream damage. And just wanted to gauge your sense here, we’re farther away probably from being able to do that for any individual immune-mediated kidney disease. But what I was gonna ask you is one, if you could just briefly comment on that. But secondly, the general tools of screening for kidney disease by measuring the eGFR and protein in the urine, those are actually quite good and will start to pick up problems at a pretty early stage. And if you can’t explain them by the usual things, are a good reason to start a more detailed, immunologic workup. So I was just curious your thoughts on those points. Katherine Tuttle: No, I’m glad you asked that because it’s really important when possible to identify cause as well. So even in people with diabetes for example, they can get other... It’s common and other diseases are common. So a good example would be type 1 diabetes is an autoimmune disease. So a young woman with type 1 diabetes and a high urine albumin who if she also has blood in her urine might have lupus, might have lupus nephritis, right? So we didn’t get into details about diagnosis, but maybe this is a good chance to say that in the context of doing the urine albumin screening or the uACR test as well as eGFR, there should be a conventional urinalysis done as well. Because you won’t know for example, that people have hematuria or other abnormalities in the urine if you don’t look. And so while we recommend UACR screening, our guidelines actually say there should be an investigation into cause. So if the urine sediment is bland and they have typical features of diabetes, you don’t need to do anything else. But what you wanna pick up is that person who might just happen to have hypertension, diabetes and have an autoimmune disease as well. And that’s where I think the urinalysis is really important because in many of those diseases, it’ll either be hematuria or heavier albuminuria that is not explained by the metabolic condition. And that... Again, that’s a larger conversation. And then I also wanna promote the importance of imaging and kidney biopsy in those individuals. So to diagnose polycystic kidney disease, that’s gonna be an imaging test, usually an ultrasound. And then with regard to the immunologic diseases, it’s biopsy. And we find a lot of unexpected findings at the tissue level that we’re not gonna get any other way. And so many of us have moved to becoming much more tissue-based, more like oncology, that part of our routine workup for kidney disease, if it’s not typical for CKM, it does include a biopsy. And I do think to be honest with you, when we do more-- when there’s more awareness on CKM and albuminuria screening, I think we’re gonna pick up more of these rare diseases that are out in the population that we just didn’t see until it was too late before. So I do wanna encourage people to have their eyes open that other kidney diseases may occur. They’re not that rare, even though we call them rare. They’re not that rare in the world of kidney diseases, and we don’t wanna miss lupus, IgA nephropathy, and other forms of immunologic diseases that have now become treatable. And like you said for rheumatoid arthritis, if we identify these immune diseases early, then there’s a lot more we can do about it. But I will walk back to what we where we started, is we’re gonna treat the inciting factor. So let’s say it’s lupus, or IgA nephropathy. We have highly effective therapies now for the immune side, but they’re still gonna need the kidney protective therapies because by the time they’ve taken a hit in that organ, they’re in the box at the bottom again. And those are the progression factors. And even the guidelines now for immunologic kidney diseases say treat the immune disease plus ACE inhibitor/ARB and SGLT2. Robert Rogers: Great way to tie, tie our whole discussion together. Very last question for today. What is one big open question in the field of kidney disease prevention that is currently being studied that you think will have a much better answer to in say, five years or sooner? Katherine Tuttle: I think we need implementation science, frankly. So you said on prevention, so what is the best approach to screening? Do we need to do population screening or stay focused on high-risk groups? And then on the prevention side, getting to precision approaches, can we phenotype people better so that we don’t necessarily need to use all drugs on all patients? I’d like to see us eventually look more like clinical oncology, right? So for example in breast cancer, there’s, biomarkers, there’s tissue, there’s imaging, and then depending on those features, you might end up in a low-risk category with a lumpectomy and have a nice life or at the other extreme, have a bone marrow transplant and be in a clinical trial at about 15 or 20 variations in between. So I think real prevention will be at the time of identification, getting a proper diagnosis, and then being stratified into the right pathway, which might be diet and exercise for some people. Maybe you’re so low risk that you don’t need to take any drugs. Other people might need the full-court press and some new thing, and other people might need various combinations of our pillars. Robert Rogers: Dr. Katherine Tuttle, a great leader in the field of kidney disease treatment and prevention. Thank you so much for joining us today. Katherine Tuttle: Thank you. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

3. 

   12 May 2026

   Episode #5: Prevention of Autoimmune Diseases with Dr. Kevin Deane

   Foresight Medicine Episode #5 Prevention of autoimmune diseases If you enjoy this interview and want to learn more about the frontier of prevention for autoimmune disease, including how you can become involved in a study of prevention for rheumatoid arthritis, please visit the website of the Autoimmune Disease Prevention Center of the University of Colorado, directed by my guest, Dr. Kevin Deane: https://medschool.cuanschutz.edu/centers/adpc (https://medschool.cuanschutz.edu/centers/adpc) Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a comprehensive, whole-body framework for leveraging new technologies to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. And today, we will be talking about autoimmune diseases. I’m very honored to have as our guest Dr. Kevin Deane. Dr. Deane is Professor of Medicine in the Division of Rheumatology at the University of Colorado. He is a leading researcher in the field of rheumatoid arthritis, where his many high-impact publications, bridging immunology, epidemiology, and clinical trials, have helped define the concept of preventing or intercepting rheumatoid arthritis and other autoimmune diseases before significant damage occurs. Dr. Deane was the principal investigator of the STOP-RA trial, a landmark rheumatoid arthritis interception study that tested whether treatment in high-risk individuals could prevent or delay the development of clinically apparent rheumatoid arthritis. And he’s a major contributor to guidelines on the identification, risk stratification, and management of people at high risk of rheumatoid arthritis. Listeners should note that we are recording this on Thursday, May 7th, 2026, and this conversation is for general informational purposes only, and does not constitute individual medical advice. Kevin, welcome. Thanks so much for joining me today. Really excited to be chatting with you. Kevin Deane: Great, Robert, thanks for the invitation, and happy to be here. Robert Rogers: So, you know, to kick things off here, this is one of the conversations that I’ve been most excited to have, because I feel like it’s one of the furthest out there frontiers for preventive healthcare. There’s a cadre of people who call themselves preventive cardiologists, preventive neurologists. I think there’s many primary care physicians and others who would consider themselves to be quite conversant in screening and early detection of cancer. But it’s not too many people who call themselves preventive rheumatologists, and I think you’re probably one of the leading people who might be able to change that. And so, first question I always just like to start off with is,how did you become interested in this field, in autoimmune disease and rheumatoid arthritis, but specifically this idea of early detection, intervention, and as you’ve termed it, interception? Kevin Deane: Good, good question. I think part of it was my own personal belief that I’d like to catch people before they get too sick. And I think that underpins a lot of my philosophy now and where I’ve gone with trying to help prevent rheumatoid arthritis. In a bunch of autoimmune diseases, in particular the rheumatic diseases, things like rheumatoid arthritis and lupus, we oftentimes wait until people get quite sick before we even see them for the first time in a rheumatologist’s office and initiate treatment. I got tired of seeing that. I thought, why can’t we get to these people earlier? There was another line of evidence, if you will, as I started my training about 20 years ago, that was coming to the forefront, where blood tests for our autoimmune diseases got a lot better, and in particular, a test came on the market, something called the anti-CCP antibody for rheumatoid arthritis, it was highly accurate for disease. That sort of acted as a game changer, because rheumatologists had a phrase, and they still do to some extent, oh, don’t just treat a lab test. And I get that, but when you have really good lab tests, it may indicate that somebody has not only got a disease now, or maybe at high risk for disease, that can change the game. So, and quick summary of that. My personal belief, let’s try and catch people before they get sick, and then some advances in the field where in rheumatic disease, we had really good blood-based biomarkers that could be predictive of future disease. That got me going down the pathway to prevention. I’ll add one other thing to that. Robert Rogers: That’s so super interesting about how the discovery and really the identification of the anti-CCP antibodies as a really powerful diagnostic tool really leveraged your career in this direction, because I sort of take for granted that blood test has existed. As long as I’ve practiced, it’s always something we send when we’re suspecting rheumatoid arthritis in the workup, but as you said, it really, really opened up this field in a very different way. Kevin Deane: Yeah. And the other line of evidence along those… For years, the disease entity type 1 diabetes has been working on early risk identification and prevention. They’re well ahead of us in, actually, rheumatic diseases, but they’ve been using autoantibodies that are related to type 1 diabetes for years, have had for years very good predictive models, but had really advanced their understanding of how you can use antibodies to predict future disease, about the same time I came along into the career of rheumatology, and I was working with people who had a foot in the epidemiology world of type 1 diabetes, and also knew about rheumatoid arthritis and other autoimmune diseases. So that coming together, the knowledge from type 1 diabetes really informed my thinking. And so those three lines of evidence, me wanting to prevent disease, the new tests in rheumatic diseases, and the work that had been done in type 1 diabetes, all those things came together. Robert Rogers: Yeah, there’s a couple of threads you mentioned there that I really want us to go with here, and I think it’s interesting that you’ve brought up early in our conversation, kind of comparing some autoimmune diseases, and as you mentioned, type 1 diabetes is perhaps, among all the autoimmune diseases, the one where the paradigm of prevention is the farthest advanced, in the sense that there’s actually an approved therapy, and I’ll just say briefly for our listeners, you know, for patients who are at have a family member who’ve had type 1 diabetes, and they have the antibodies that are highly suggestive they’re going to get it, there is actually a therapy that can delay the onset of them getting to the point where they actually have full-blown diabetes and need insulin. And you could imagine, especially for a mostly juvenile disease, when you’re dealing with children, being able to delay for a few years when they might need that level of intervention is hugely, hugely valuable. And I’m glad you brought up that comparison, because I don’t want us to go too deep on this right now, but, you know, when we say… when we think of, for example, preventive cardiology, right, we’re talking mostly about, say, coronary artery disease, atherosclerotic cardiovascular disease, and maybe a few other diseases now we can get into nowadays with the valves and stuff. But when we talk about autoimmune disease, I mean, it is so many diseases, right? I mean, medical textbooks will say there’s about 100 of them, and, you know, there’s probably 10 to 15 that constitute the vast majority of what you see in your clinical practice. And I don’t really want to spend a huge amount of time, because I think it’s a really complicated and time-consuming topic. People can do a little of their own self-education with their own LLM of choice, of sort of, you know, how we describe and classify and group together the many different autoimmune diseases. But since we are going to focus on rheumatoid arthritis, I’m just curious. where do you place RA? And we can… maybe we’ll start using that, introduce that abbreviation so people… we don’t have to keep saying all the time, RA. Where do you place RA in terms of the spectrum of autoimmune diseases, in terms of how preventable or intervenable it might be? Kevin Deane: So, yeah, as you state, there’s a bunch of autoimmune diseases. If you look at each one of them, they’re all, as an individual disease, pretty rare. Like, for example, rheumatoid arthritis affects about 1% of the population. Type 1 diabetes actually affects 1 in 300, so, quite rare, but still very impactful. Lupus is about 1 in 1,000. But when you lump them all together, about 1 in 6 people actually have an autoimmune disease. This is counting them all up. Thyroid disease, some of the things I talked about, RA, or lupus, or type 1 diabetes, you lump them all. So that’s a pretty substantial, substantial portion of the population has some form of autoimmune disease. At a very high level, autoimmune diseases are when your own immune system, which should normally help you fight infections, heal wounds, help clear cancers, goes bad, if I can use that term, and starts attacking you. They can either do it in a very targeted way, like, for example, type 1 diabetes, it attacks the cells in your pancreas that make insulin. Only those cells are attacked, but boy, when those are gone. you’re out of luck, because you don’t have any insulin, and you need insulin. Rheumatoid arthritis, on the other hand, is where your immune system attacks, as the name implies, your joints and causes arthritis. It can also affect other things, including the lung, but the joints are the primary target. Other diseases, such as lupus, can affect almost any organ in the body. Another one that’s a little bit more targeted is thyroid disease, where the autoimmune system will just attack the thyroid gland. But anyway, so rheumatoid arthritis in that context. It is quite common in terms of diseases, like 1 in 100 is a little bit more than some other autoimmune disease, so that’s why we sort of focused on that. It’s something we want to first look at in prevention and rheumatic diseases. Once we figure out some things there, we’ll probably work to the more rare conditions. Robert Rogers: Great, so you know, there’s a lot of autoimmune diseases. Collectively, they represent a pretty significant portion of disease, but each one of them is so complicated, each one of them has so much of its own biology, there’s going to have to be so many, disease-specific details for prevention for each, and so let’s go with one of them that’s more common and more defined, and so that’s why you want to zero in on RA. So let’s lay a little bit more foundation for our listeners about the disease, before we get into the idea of preventing it. So you mentioned, really, what RA is, but talk us through a little bit what the current treatment options are, what the current treatment paradigm is. Patient comes to your office with a new diagnosis of RA. Kevin Deane: Yeah. So, usually, by the time somebody gets to the specialist or the rheumatologist, they’ve had probably 6 to 12 months in common care pathways in the United States of aches and pains, stiffness, pain, feeling of swelling in their joints. Their primary care will often see them maybe one or two times, finally recognize that rheumatoid arthritis is driving these symptoms, maybe with blood tests, maybe noticing a swollen joint, then they’ll get to rheumatologist. At that point, we make a diagnosis of rheumatoid arthritis based on what we see on physical examination, whether someone has swelling in a joint that looks to us like that joint is inflamed. We do blood tests that help confirm that. Tests such as the anti-CCP antibody, another commonly used test as a rheumatoid factor, help us confirm that. Then, we initiate treatment, which, because of the immune nature, the inflammatory nature of rheumatoid arthritis, our drugs are basically all some form of an immunomodulatory agent that we try and knock back the immune system so it stops damaging the joints. And typically, once somebody gets their first swollen joint and rheumatoid arthritis, that disease for them is forever, i.e, they’ll be on some immune drug to modulate that for the rest of their lives. Now, whether that’s one drug or two or three kind of depends on the course that they’ll take, but once we get the diagnosis, immune modulation typically for life, to help knock back that inflammation, which is very important, and we do a pretty good job in most people with rheumatoid arthritis now, in dampening down the inflammation and keeping them functional and happy and not destroying their joints. But we’d argue that about half the people who get RA never feel as good as they did before they got rheumatoid arthritis, and certainly meds and all the visits you gotta do to manage disease is painful for people, so that’s why… another reason why rheumatoid arthritis has been something we’ve put at the forefront for prediction and prevention. One of the keys, also, for rheumatoid arthritis, it does have good blood tests. I think I mentioned this earlier. CCP test that is highly accurate for rheumatoid arthritis, to put some numbers on that, it’s about 95-98% specific for rheumatoid arthritis, so if you have arthritis and that blood test, we’re very confident that you have rheumatoid arthritis. That test has also given us insights, because it typically shows up in the blood three to five years before you actually get your first swollen joint. We can then use that to predict fairly accurately who’s going to get disease in the future. And I’ll stop there. Robert Rogers: No, no, that’s great, and there’s a lot of really interesting things that I want to follow up on. Since you started talking about having a good blood test, then that’s going to just be an absolutely essential prerequisite for any kind of, you know, screening or early prevention program in autoimmune disease. So tell us, so the anti-CCP is very helpful. It’s very specific for rheumatoid arthritis. How sensitive is it? Kevin Deane: So, that’s a good question. We guess it’s about 80% sensitive, so of 100 people with rheumatoid arthritis, about 80 will be positive for the anti-CCP test. In the old days, i.e. a few years back we actuallyclassified rheumatoid arthritis as two subtypes. One is what we call seropositive, where they have an autoantibody, and the other group is seronegative. The field is moving towards we’re actually probably going to break RA into subsets. And that there’s maybe more than we want to delve into here. But of the subset that’s seropositive, i.e. there’s a blood test positive, like the CCP, that’s the one that’s particularly prime for early identification and even prediction for the future, and also prevention. The subset of rheumatoid arthritis where there’s no blood markers makes it more challenging to predict who’s going to get it in the future. And that actually informs a lot of autoimmune diseases. Lots of autoimmune diseases, some of them have really good blood tests that are… I think those are the key ones that the field is working towards as the first in line to get prevention. That’s why type 1 diabetes is advanced, because they have very accurate blood tests, and I think they have data, like, if you’re under the age of 25 and you have two blood markers for type 1 diabetes, I think the risk of it is about 100% that that person will get type 1 diabetes within 10 years. That’s very powerful. Robert Rogers: So it’s fair to say… it’s fair to say that among autoimmune diseases, the anti-CCP blood test for RA kind of ranks it at the top of the list, because it’s… it’s quite sensitive, it’s very specific, and like you said, it appears… it can often appear long before symptom onset, which creates this window of opportunity. And so we’ll get into all of that in just a second, but I wanted to come back to this really interesting thing that you mentioned, which is… which gets to the logic of prevention and early intervention in RA. So you said that, you know, most patients will actually respond reasonably well to the immunomodulatory treatments that exist today, but about half of people will never feel as good as they did before they were ever diagnosed. Is that right? And so it sounds to me, and I want to make sure that we sort of spell out, really, what the logic of prevention here, it sounds like prevention could really have sort of two goals, and these aren’t necessarily distinct, they’re somewhat overlapping, but one is this idea that you know, if you could kind of hit the disease earlier and harder, you might, ameliorate the severity of it, so that person who, you know, was maybe destined to have disease that was really hard to control, that left them very symptomatic, well, maybe if you started a treatment earlier, their symptoms would be lower. But even perhaps more powerfully than that, is there also this idea that during maybe a distinct window of opportunity, if you hit the disease in a certain way, you could actually, prevent them from having it going forward. Are those both goals of prevention? Kevin Deane: Those are both goals. That second one you mentioned is… we call that the shoot-the-moon idea, where if you could catch somebody at that right time in the disease development, before they ever even felt sick, you could give them an intervention, like a time-limited intervention, like, here’s a few doses, or maybe 6 months of treatment, and reset their immune system so they would never develop that autoimmune disease in the future. That’s the goal. I think should strive for that. But the second point you also mentioned is also very important. What if we could just catch the disease early enough that there was no joint damage, and you could control it very easily, even if you had to take medicine for the rest of your life, but you didn’t ever have bad disease? That would still be a victory. So both of those are goals in prevention. Robert Rogers: Yeah, and you’ve, of course, been very involved in actually trying to develop strategies to achieve those goals, and I want to delve into that in just a minute, but you mentioned kind of what the general average person’s risk is of autoimmune disease in general, and rheumatoid arthritis in particular, but maybe just walk us through what are some of the environmental or genetic or other risk factors that place someone at increased risk? Kevin Deane: Yeah, I’ll try and speak broadly to autoimmune disease. I’ll then focus on rheumatoid arthritis. Yeah. So there’s a lot of different genes that are associated with getting autoimmune diseases. Turns out that there’s a couple of genes that put people at risk for lots of autoimmune diseases, and then within that, there’s a few genes that are specifically related to autoimmune diseases. The challenge with genes are there’s not one or two or even a set of genes that are strongly predictive, so we haven’t yet been able to use genetic testing alone to predict future risk for rheumatoid arthritis. Some of the closest things we get at in clinical care is if you have a family member who’s a first-degree relative, i.e. a mom, or a dad, or a sibling, or an offspring with an autoimmune disease, your personal risk can go up. But even then, the risks aren’t that high. So, for example, in rheumatoid arthritis, if you don’t know anybody in your family has rheumatoid arthritis, your lifetime risk is about a half to 1%. If you have a family member with rheumatoid arthritis, then your risk may go up to 5-7% in a lifetime, which is increased, but not that strong. So I think we need to look beyond just genes. Then we look at other things, like environment. So, of the the environmental factors, one of the strongest risks for any autoimmune disease is actually exposure to tobacco, and in the form of cigarette smoke. We think that the reasons for that is that insult to the body from cigarette smoke is what can trigger the autoimmune system, and actually drive lots of different types of autoimmune diseases. There’s a bunch of other things, too, that we’re learning more about as we go. Dietary components, other environmental exposures, like exposure to dust, can put people at risk for certain autoimmune diseases. We’re learning now that exposure to forest fire smoke, which the west coast of America now, maybe other parts too, are being exposed to, actually put people at risk for developing disease like rheumatoid arthritis, so combination of genes and environment really drive that forward. We’re trying to understand that better, so ultimately, we could get at what we think is what we call primordial prevention, where you eliminate environmental risks to get rid of disease. I think that’s going to be a ways in the future. So now, what we really do look at is biomarkers, where whatever set of genes you have, whatever environmental factors you have, if you start developing these biomarkers that means that you’ve really progressed down the pathway towards getting an autoimmune disease. That’s working pretty well now for rheumatoid arthritis, as we’ve mentioned, type 1 diabetes. Other diseases are coming around to this as well. They’ve got a good blood test, we’re starting to look at it for prediction and prevention. Things like lupus, which has great blood tests as well, another autoimmune disease called scleroderma. People are working in advancing that. So, a lot of things are coming along. To use blood-based biomarkers, not necessarily genetics, to predict future disease. Robert Rogers: Great, and just at the level of what might be actionable for an individual patient, mentioning both environmental and genetic risk factors, so, you know, avoiding smoking, and then you also mentioned things like avoiding forest fire smoke, but a lot of those things really require, sort of, environmental or public policy at a large scale. Are there any other specific lifestyle recommendations that are actually advisable for a patient to prevent, to lower the risk of autoimmune disease? Kevin Deane: Yeah, I left that out. So, it’s also becoming apparent for a variety of autoimmune diseases that diet and obesity and lack of exercise, those three things, diet, obesity, lack of exercise, are actually strong contributors to dysregulated immune system or autoimmunity. A few diseases are perhaps more related to that. Rheumatoid arthritis, obesity is one of the strongest lifestyle risk factors one can have for getting rheumatoid arthritis. Other autoimmune diseases, including psoriasis and psoriatic arthritis, also obesity is a big driver, so that’s a… that’s a big driver.The recommendation there, then, is to maintain a healthy body weight. So far, no one’s proven a specific diet in particular for autoimmune diseases. However, general information and population-based studies suggest that a Mediterranean-type diet, which is whole grains, fruits and vegetables, minimal meats, minimal fats, and if you want to use a fat, don’t use butter, use olive oil. Mediterranean diet is thought to help reduce risk for autoimmune diseases. And daily exercise is beneficial across the board for a lot of conditions, but also may reduce risk for autoimmune disease. Robert Rogers: Very good. And then on the genetics front, you know, as you mentioned, at a sort of interesting research or population level, we can identify, patients who are at a relatively increased risk for autoimmune disease, but the problem is that as a practical matter, for instance, telling somebody that their general risk of something goes from 1% to 5% to 7% may not be all that useful. But I’m curious, just if you’ve given this some thought, you know, we do have people who are healthy adults who are considering getting whole genome or whole exome sequencing, just to learn about their disease risk across a variety of diseases, and do you think that there’d be utility to learning about their polygenic risk for autoimmune disease, or do you think that could cause more anxiety than is actually useful, or, like many things, really apply a case-by-case basis? Kevin Deane: Yeah, I think at a high level, for most autoimmune diseases now, the broad genetic testing for risk is not right where it needs to be for this to be actionable for all people. That said, there’s a few certain genes that are at higher risk for things like type 1 diabetes, but as a general whole for autoimmune diseases, I think the genetic testing isn’t at the level it needs to be. Now, that may be changed soon, we may have different breakthroughs. But I’ll give you an example, at least for rheumatoid arthritis. The strongest risk factor, genetic risk factor, for rheumatoid arthritis is something called the shared epitope, which is, I won’t go into huge detail, but a marker on chromosome 6 that creates a certain risk. That risk factor is present in about 30-50% of the population, yet only 1% of the population or less get rheumatoid arthritis, speaking to the fact that that gene may show up on a screen as being a risk factor for rheumatoid arthritis, but very few of those people will actually go on to get rheumatoid arthritis. So it’s not quite there yet. Now, if we get better at this and understand what’s the gene, and then what’s the environmental interaction and be able to put that into more actionable prediction, that’ll be something, but we aren’t… we aren’t quite there yet. Robert Rogers: Great. So, that’s a very helpful answer, and so I’m curious, as we now kind of get into the meat and potatoes of prevention here, how much damage to joints and other organs can typically accrue before a patient will actually present clinically with symptoms? And what do we know about, sort of, how long that preclinical phase of RA disease lasts? Kevin Deane: In general from blood bank studies where we’ve been able to actually find people who develop rheumatoid arthritis and go back in time for blood they might have had fortuitously collected and stored before they got diagnosis, we think, on average, the immune markers appear in the blood for rheumatoid arthritis, this is including that CCP test, on average 3 to 5 years before they get their first swollen joint. Now, that’s a range then, right? So people can have these markers for up to 10 years or longer before they get rheumatoid arthritis. Some people have a very rapid course where their biomarkers may be abnormal, their CCP may be abnormal, and they get arthritis within a few months. But the range is 3 to 5 years. The challenge is, is that there’s not probably initially any joint involvement in rheumatoid arthritis. We think that those antibodies and that autoimmunity is being triggered somewhere else in the body. There’s growing insights into that might be in the lung, that might be in the gut, it might be in the cervical vaginal tract in some individuals, maybe the gums and others. So it’s not an arthritic condition at first, but the autoimmunity gets developed, circulates in the body, and then ultimately then targets the joints. Once that joint gets targeted, this is pretty variable, at least in rheumatoid arthritis. You can have some individuals who have explosive onset of disease, where they’ll go from basically no joint symptoms to multiple joints are painful and swollen, and they’re having a difficult time doing daily activities within a week or two of the onset of disease. Some people may have a much slower course, where they have one joint that flares up, and then it settles down, and then another one flares up, and they slowly accumulate. So the range is pretty wide. The other challenge, though, is any kind of joint inflammation can start to damage the joint. And that’s why we’re ultimately going to try and develop ways that we can find people before those joint symptoms even first start, because even once the joint symptom starts, even if it’s mild, damage can occur. And then over time, even if you shut that inflammation off, if that small bit of damage has occurred that can then progress and become disabling for a person down the road, even though the original disease process is shut down. Robert Rogers: Do we have data that suggests that, if you start treatment with our current therapies at an earlier point in the disease, that the chance of success is actually higher, or the chance of getting control of disease and having minimal amounts of symptoms is actually higher? I imagine that’s a very hard thing to study, because, you know, people come in when they come in, and we don’t let them say, well, let’s… you wait a while before we start treatment, so it has to be mostly observational data. But from the observational data that exists, what do we know about that? Kevin Deane: Yeah, so we do know that the earlier you catch rheumatoid arthritis, once it’s crossed that threshold to being what we’re going to call full-blown disease where you have inflammation, the earlier you catch it and start treatment, the better those people do, and the less medicine they need, ultimately, to control disease. So, at the very least, the field needs to find people in an earlier stage of active disease and get treatment started then. We think of it, it’s probably akin to, like, a fire. You have a match that’s lit, let’s say that’s a little bit of inflammation. You can have a campfire that’s a bit more inflammation, and you can have a full-blown forest fire. It’s much easier to control a match being lit. You can pinch that with your fingers and shut it off. Harder to put out a campfire, and almost impossible to put out some big forest fires. So it’s the same thing for rheumatoid arthritis. Catch it early, it’s easier to treat, easier to shut it down, and there’s less damage. So that’s… at the very least, we can catch it at an early stage, that’s gonna be beneficial for the people. Robert Rogers: And that really adds to how compelling the logic is of prevention, because that we already know that if we treat at an earlier point in the course of symptomatic disease, that we have a higher chance of success. It makes sense that if you could extend that back in time, you might have even greater success. Kevin Deane: Yeah, and you mentioned that term, it’s a great term, window of opportunity, which can mean different things, but in rheumatoid arthritis and other autoimmune disease, we think that there’s a window of opportunity even before any damage occurs, where the immune system has become dysregulated, and that’s the time to strike, to helpfully stop it from ever damaging an organ, or even hit the reset, those two branches of what we think would be success and prevention that we talked about earlier. Robert Rogers: And I think that’s a great segue into something that I really want to go a little bit deep with you on, which is the trial that you led, the STOP-RA trial, to really inform what we know in that area. So tell us about that. Tell us about the trial, its rationale, its design, and all its details, because we’re actually quite curious. Kevin Deane: Yeah, so I’ll build on some of the things we’ve talked about already. So, we know that blood markers for rheumatoid arthritis can appear, on average 3 to 5 years before a person gets their first swollen joint. In particular, the anti-CCP antibody is quite accurate for rheumatoid arthritis. I’ll give you some harder numbers for that. If somebody has an elevation of a blood marker for anti-CCP in general, that person has a 30-50% chance of developing rheumatoid arthritis within 3 to 5 years. So we use the CCP test as the anchor inclusion factor, or identification factor, for our study. To put people in the trial. So the requirements were you had to have an anti-CCP test elevated in the blood. We picked a higher level than just your average positive test, because we wanted to make sure that we weren’t getting any false positives in there, so we picked a level that was 2 times the normal cutoff. I won’t go into great details there. And you could not have any evidence of joint inflammation to get into our study. We picked the drug to intervene of hydroxychloroquine, also known as Plaquenil. The rationale behind that was rheumatologists were already using that drug in people who had low-grade autoimmunity, thinking, the drug is pretty safe, and we think it may be effective. So people were already doing it, but we had no data, so we said, let’s use that. Plus, it’s a pill that’s relatively safe. It does have some side effects. Long-term use can cause some eye toxicity. Every once in a while, there’s an allergic reaction, but it’s relatively safe. So we said, let’s take people who are at risk for rheumatoid arthritis and give them this drug that’s a pill, pretty easy to take, usually pretty well tolerated, that should have some immunomodulatory effect. Hopefully that’s going to be enough in this early stage of RA development to alter the course of disease. Turns out that, in our study where we enrolled about 142 people, randomized half of them to get hydroxychloroquine, half a placebo, gave them drug for a year, and then stopped the drug, and then followed them for 2 years after that, and I’ll get back to that point in just a second. Drug didn’t work at all to either make them feel better while they were taking it, so if they happen to have aches and pains, it didn’t help, and it didn’t delay the onset of rheumatoid arthritis at all. I’ll get back to that study design. We gave the drug for a year and followed up for 2 years after that, to that point I talked about earlier, it was a shoot-the-moon hypothesis. We thought if we can catch these people at this early stage of RA before they actually get joints inflammation, wouldn’t it be great if a short-term use of a drug could actually reset their immune system? Turns out it didn’t work in this study, and we can talk about this in the next few minutes. Other studies have also taken that approach for RA prevention. They also have not seen a complete reset of the immune system, but that was sort of the philosophy behind that, the whole, what we were calling the Stop-RA study. Robert Rogers: Right, so it’s a really powerful and beautifully done study, and it’s really informed so much data in this field, and like you said, you really were able to identify these patients who were at high risk. Your hypothesis that the criteria you used to identify patients that were at high risk of developing RA proved to be true, right? Because in both arms of this trial, many of these patients did go on, so that’s a very powerful finding, but the particular intervention that was tested, which is a relatively benign intervention, the medication is well-tolerated and widely used, didn’t really move the needle. So tell us a little bit more about maybe some of the other similar interventions that have been trialed in that particular window of opportunity, how those results may have been similar or different to what you found in the Stop-RA trial? Kevin Deane: Most of the studies that have been done for prevention of rheumatoid arthritis have used that anti-CCP test as the anchor risk marker. And as you said, what we did prove in the Stop-RA study is that that marker is associated with about 30-40% of people developing rheumatoid arthritis within 3 years, so it proved we can predict RA. The drug didn’t work. Other studies have used different drugs. The two studies that use the same drug that is most successful were called the ARIAA, and then the next one is called the APIPPRA study. The ARIAA study is done in Germany, APIPPRA study largely done in the United Kingdom. They use the drug Abatacept, which is a biologic or injectable therapy that targets B and T cell and interactions and T cell, and specifically T cell activation, which was thought to be a key player in the development of autoimmunity, especially at this early stage. It’s a drug that’s been commonly used if you have full-blown rheumatoid arthritis. We thought, let’s just move it earlier into this window of opportunity. So, same study designs in both of these studies, I won’t go into huge detail there. The drug was given for a period of time, either 6 or 12 months, depending on the study, and then stopped. People were followed afterwards. This drug worked extremely well while people were taking the drug in the study, the rates of development of rheumatoid arthritis were exceedingly low. Fantastic effect on drug. However, when they stopped drug, they accelerated, and the people who stopped the drug then started getting rheumatoid arthritis. They still made their primary endpoint, so at the end of the studies, less people had developed rheumatoid arthritis who had been on the study drug than were off of it, but they sort of lost effect after 3 to 4 years afterwards. So it wasn’t a complete reset, but it did demonstrate the right drug at the right time can really develop significant decreased rates of rheumatoid arthritis. That’s informing the field going forward. We may wind up, to prevent RA, just starting treatment earlier, before anybody ever gets their first swollen joint. And that would still be, as we talked about earlier, a victory, because if they never developed that first swollen joint, even though they’re taking drugs, that could still be beneficial. Robert Rogers: Wow, that’s really interesting. So, it sounds like, you know, there is this… this real hope, this real aspiration that you identify these patients who are at really high risk of developing rheumatoid arthritis, you know who they are, you can identify them, you intervene with these different immunomodulatory agents for a time-limited period of time, and then that will have lasting benefits, and the benefits will be durable, and that you might be able to achieve this reset. And that really, unfortunately, hasn’t yet panned out with our existing agents, but the hope still very much remains, based on the abatacept data and perhaps these other clues, that if you just start the treatment earlier and continue it, you could really reduce the, you know, the onset of actual clinically apparent disease and the severity of the symptoms. And so then I guess, it becomes somewhat of a, of a, of a risk-benefit trade-off of, you know, how many, patients are you going to be treating with these agents who perhaps may not have needed it, and not deriving the benefit from it, versus all those patients who… for whom you are greatly controlling their symptoms. Is that the right way to think about the trade-off? Kevin Deane: Yeah, it’s exactly right, and the field is doing exactly what you just said. We’re looking back at this trial data to find, of all the people that were in the trial, who is really most likely to get rheumatoid arthritis? Because those are the people, you’re exactly right, you feel better about the risk-benefit. These people really do need a drug because they’re really gonna progress to disease. That’s underway now. I think lots of diseases actually have that challenge, right? I think I just heard a talk on cardiology where, if I can use the term, the number needed to treat, i.e. the number of people you need to give some kind of intervention to, to prevent one person from developing that disease or that endpoint, I think it’s, like, around 40 to 60 for, like, using cholesterol-lowering medicines to prevent one heart attack. That’s a lot of people being treated to see one person benefit. We’re trying to get those same numbers together for rheumatoid arthritis. Some of the early calculations from the APIPPRA study showed the number needed to treat was 6 people to have one person have a delay of onset of rheumatoid arthritis by about 2 years. That needs to be validated, but that kind… those kinds of things are what the field is going to have to look at going forward. Robert Rogers: Right, and so then, of course, to just carry that idea a little bit further, the logic of prevention here is really dependent on a couple of things. One is how tolerable and what the side effect profile is of the drugs that you’re going to use, especially over a long period of time, but also how likely an individual patient is to have really severe disease. Like you said, a lot of patients, you know,they are well controlled on our first-line agents. And so, I just wanted to take one step back. We talked about this ability to predict, based on sensitive blood tests, which patients will have onset of RA, or onset of other autoimmune diseases, to any extent. But if a patient comes to you for the first time, where is the current state of research in defining who’s gonna have a more severe course going forward, and who’s gonna have a less severe course going forward? How good are we at sort of being able to define that risk right now? Kevin Deane: Yeah, that’s a good question. We’re fairly good at a lot of autoimmune diseases when somebody comes in the door and has full-blown disease, engaging how bad that’s gonna be. In rheumatoid arthritis, combinations of things, number of joints involved, levels of autoantibodies, so it… actually, the levels do matter, like, the higher your CCP, the more likely you are to have persistent and severe disease. Other markers of inflammation, such as just general blood inflammatory markers, something we call the C-reactive protein or erythrocyte sedimentation rate. All those things can be factored in to say, you not only have disease, this is going to be a bad form of disease, and so we should be likely more aggressive going forward. Those are factoring in. Fortunately, those same kind of things are actually also predictive of who’s going to get rheumatoid arthritis in the future if you catch them in the asymptomatic or before the onset of disease. The models, though, that we’re working on are trying to make that really actionable. Because right now, it’s hard in medicine across the board when you start testing multiple blood tests to have all that come down to one easy answer for a person who’s at risk for disease or has a disease themselves to say. You have all these tests, and they tell me that you’re 50% likely to have bad disease, or get disease. So I think the near future is trying to use AI and other approaches to be able to let us use a lot of different blood tests and other factors to give really accurate prediction and prevention for specific individuals. Robert Rogers: How do patients react to learning that they have positive blood tests or autoantibodies that place them at high risk of developing RA if they’re not currently symptomatic? I’m curious what you observe to be the different spectrum of reactions there. Kevin Deane: There’s a lot of variability, and we’re… it’s not my area of expertise, but having talked to a lot of people who are at risk for rheumatoid arthritis, we get to see this a lot, ranging from they’re not worried at all, versus very scared and very worried. Some of it is dependent on their prior knowledge of rheumatoid arthritis. You can envision, if you’re a young female whose mom had severe rheumatoid arthritis, and you saw her be disabled from that disease, and you find out you have that blood marker for rheumatoid arthritis yourself, that’s very different than a person on the street who’s never known anybody with rheumatoid arthritis, and that their blood test is elevated. So it’s a wide range. I think the field is also trying to now understand that, how we incorporate a person’s personal perception of their risk, and their perception about what they would want to do with that risk, and how much they want to know into the whole approach. Again, not my area of expertise, but we think about this a lot. Lots of people now know that they’re gonna get their cholesterol checked at a routine doctor’s visit that’s part of their cardiovascular disease risk prevention, and are sort of aware of that. Less people know about autoimmune diseases, and the autoimmune disease testing can be a little bit more esoteric. And so trying to incorporate what people have learned in other diseases like cardiovascular disease prevention, putting that into autoimmune disease, I think is going to be critical. And having people who really think about how we message risk for autoimmune disease, it’s gonna be important. Robert Rogers: Yeah, one of my major theses in this whole project of Foresight Medicine focused on the future of preventive and proactive care is that population-level guidance is really a little bit less useful, I think, nowadays than a really individualized risk-benefit assessment, and a big part of that goes into an individualized assessment of what a patient’s desire for proactivity is, and like you said, all these important background factors about their own personal experience and knowledge really have to be taken into account. So I’m curious, you know, you have thought about this fascinating field of prevention, interception of autoimmune diseases very deeply for a while. If there was going to be one major development in any of the areas that touch on this domain, could be diagnostics, could be therapeutics, could be kind of systems-level changes of how we take care of patients, what do you think would most move the ball down the field towards this goal of having really effective RA prevention? Kevin Deane: Gosh, limited to one thing. I… Robert Rogers: No, you don’t have to be limited to one thing. You can give a list in each category. Kevin Deane: Yeah, good, part of the challenge, there’s a chicken and the egg problem. To study an autoimmune disease, or any disease, to identify who’s at risk for getting it in the future, you have to test a lot of people, follow them, and see what happens to them, without knowing yet what to do to prevent disease. And so then that puts you in a pickle where you know somebody’s at risk for disease, you can’t give them anything that’s approved by FDA or some other regulatory agency to prevent it, then you just have to follow them. So what I would like to say is we would love to see a breakthrough soon in rheumatoid arthritis, where there’s going to be a prevention that actually works, that we can give in a sustainable way. So we have a goal, then. Aha, here’s a drug that actually works, then we can continue to study that and try and do even better in the future. So we need an agent or an intervention that works, and we’ve proven it to be so, and have regulatory bodies approve that. The other side of that, we also need broad population testing for people who are actually at risk, because those people are going to be able to, if I can use the term, feed the studies that are going to actually get us the answers to finding that drug, or whatever intervention that may be that works. I’ll use an example, type 1 diabetes. They sort of had to do this chicken and the egg thing for years. They had to test a lot of kids with autoantibodies to understand exactly how type 1 diabetes develops, and then had to do, I want to say, more than 10 trials before they finally found a drug that actually worked. And that whole pipeline had to get moving to the point where they now have an approved drug. So to get better soundbites for that, we need an intervention that works, and then we need to have broad population testing to find people at risk. In between that, if we can do the broad population testing that is refined enough that we minimize false positives and really identify those people truly at risk for going on disease, that’s the third thing that we need. I would say right now, even the anti-CCP test is pretty good, because anybody who’s positive for that test. Let me rephrase that. Of people who are positive, 30 to 50% will go on to get rheumatoid arthritis within 3 to 5 years. That’s a very strong predictive marker, and maybe enough to drive certain studies, but if we can even improve that better, I think that would be… that would be more… more beneficial to the field. Robert Rogers: Absolutely. Is there anyone for whom, as we sit here today, in May of 2026, you would recommend getting a screening blood test for RA or other autoimmune diseases, if they currently have no symptoms? Kevin Deane: So, you added a good point at the end there, currently no symptoms. So, this is, again, at the research stage, so this is not yet a public health approved approach. I would say if you have a family member with rheumatoid arthritis, those are the people who should consider having a risk assessment about their personal risk. And that can include testing for the anti-CCP antibody. If that’s negative and it looks like you may not be at high risk, that can be comforting, so I think that can be reassuring to that person. Still not perfect, we don’t have the data to support this. We don’t quite know, like, if you’re negative once at the age of 30, say, for these markers for RA, does that mean your lifetime risk then goes down to zero? We don’t know that. But I think people who have a family member of disease, those are the ones that are the highest risk for disease. Certainly, though, other people who are starting to develop signs and symptoms of autoimmune disease and rheumatoid arthritis, I’ll speak to that, that would be symptoms of aches and pains in their joints, I think they should have a conversation with their primary care provider about that, what their risk may be. There’s a lot of other things that can cause those symptoms, so that has to be done carefully, but if you’re starting to have symptoms, at the very least, if we catch you early, that’s where we have benefit. We’ll have to stay tuned for more public health-based approaches where we can actually start screening people. Robert Rogers: So would it be fair to say that if you fall into that bucket of, you know, having a family member, a close to first-degree relative who has RA, you could consider getting this blood test if you’re asymptomatic. If you’re having things that kind of are a little bit suspicious for the disease, then, you know, go ahead and get tested. But if you’re just the average person out there who falls into neither of these two categories, having kind of a widespread screening program like we do for, say, certain cancers is premature at this point, and it’s not something you would advise, but it’s something that we’re… you and others are studying really hard, so that maybe one day we’ll get there. Is that fair...? Kevin Deane: Yes, that’s exactly right. To get us to the point where we actually understand how to implement in public health care, there’s ongoing research projects, at least around rheumatoid arthritis and other autoimmune diseases that are also doing this as well. But I’m most familiar with the rheumatoid arthritis aspects. So we have at the University of Colorado Center we call the Autoimmune Disease Prevention Center. Within that, we have something that we call Stop-RA National. Stop-RA was the name of our prevention study that we did before, now we added National onto that. This is now a project where you can come and sign up under research now. Get your own blood tested for the anti-CCP, and we explain all that to you, what that means for your health. It’s not just through general healthcare, it’s through research, but people can participate if they’re interested in assessing their own risk of rheumatoid arthritis, and we can… we can walk somebody through that whole process. So, Autoimmune Disease Prevention Center at the University of Colorado, underneath that is the Stop-RA National Study. And that you can participate in understanding your personal risk for rheumatoid arthritis. Robert Rogers: Great, that’s really… that is a great use of this podcast to promote the wonderful research that’s being done at the forefront of preventive care, and I really hope that people, if they find this content and use that as a springboard to engaging with your research center, that would be great. Maybe one last question here. We’ve sort of mentioned this notion a few times, but maybe I would just like to develop it a little bit more, this idea of resetting the immune system. And so, I think that this notion has perhaps gained more credibility in the last few years, but generally, I think, in the context of very severe autoimmune disease that’s very well established. And the reason I say that is because there’s, you know, been patients who have, for example, I think the most well-known example is the systemic autoimmune disease lupus. Really, really bad cases of lupus. They have gone through all of the normal immunomodulatory therapies, and their disease is still raging out of control. And then there was this really brilliant idea to use these very advanced technologies, specifically cellular therapies, to basically wipe out all of their B cells, the arm of the immune system that produces antibodies and is responsible for a lot of autoimmune diseases, and lupus in particular, and this… that technology of wiping out our B cells with with what’s called CAR T-cells, really comes from the world of oncology, where a lot of the hematologic malignancies are of the B cell lineage, and so it was a great breakthrough 10 or 15 years ago when we figured out that you could treat those leukemias and lymphomas with this therapy, and the same idea has been applied now to a much smaller number of patients, but with very promising reports in some cases to patients with autoimmune diseases. And then it’s quite remarkable that, you know, in some of these cases, the patients have been able to come off of their other immunomodulatory drugs, and of course, we don’t have years and years of data here, but at least for several months or years, it looks like when they start to bring back their B cells or reconstitute their immune system, they are not producing those things that attack their organs in the same way, and so their immune system has truly been reset. And so, I guess, I’d love to hear your comments on that, but in the context of prevention, in the context of bringing advanced therapies forward earlier and earlier in the course of disease, do you think that we’re going to have to have very different modalities from that to be able to use at the interception and prevention stage? Is that just too extreme in terms of its expense and side effects profile, that you could bring it into the, into the early disease setting, or not? Kevin Deane: Great, I’m glad you brought that up. This has been groundbreaking for the field of autoimmunity, and as you mentioned, especially in severe disease, where we can basically reset the immune system with these very powerful therapies. I think this has given us great insights that you actually can, in some cases, reset the immune system, even long into disease, with very severe disease. We are looking carefully at now how you might carefully use that earlier and earlier in the period. Currently, the risks of some of these therapies are probably too great to implement in someone who feels well, even if they may have a high risk for developing an autoimmune disease in the future, but the concepts are there. I think as we get better at these cellular therapies and these reset interventions, I think we’re going to really look hard at giving this to people earlier in their disease process. We’ve actually had some people who are at risk for future rheumatoid arthritis actually come to us and say, hey, is this something I could do? Because it’s very appealing to have a one-and-done, shoot-the-moon approach where you could reset the immune system. And if this is how we do it, and we do this safely, I think this is the way of the future. I just look forward to working further and making sure this is refined. We know exactly the right people to do this in and can do this in the safest possible way. Robert Rogers: Dr. Kevin Deane, thank you so much for your time today on Foresight Medicine. We have learned a lot, and I’m really excited to follow the future developments in the field of prevention of autoimmune disease that you’ll be leading. Kevin Deane: Very good, thanks for, having me on. Thank you. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

4. 

   12 May 2026

   Episode #4: Screening for Pulmonary Fibrosis with Dr. Anna Podolanczuk

   Foresight Medicine Episode #4 Transcript Screening and early intervention for pulmonary fibrosis Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic and whole-body framework for leveraging new technologies to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. Today, we will be focusing on the lungs and interstitial lung disease and pulmonary fibrosis. I’m very honored to have as our guest today Dr. Ana Podolanczuk. Dr. Podolanczuk is Associate Professor of Medicine at Weill Cornell, and a nationally recognized expert in interstitial lung disease and pulmonary fibrosis.She is a pulmonologist, critical care physician, a major contributor to the current clinical trials landscape, testing new therapies in interstitial lung disease, and a leading investigator of the earliest detectable stages of this disease. And it is in that capacity that I am most excited to speak with her today. Her work spans imaging, biomarkers, environmental risk factors, and the broader question of how we might identify interstitial lung disease earlier at a stage where intervention could potentially alter outcomes. Anna, welcome. Listeners should note that we are recording this on Thursday, April 23rd, 2026, and as always, this conversation is for general informational purposes only and does not constitute individual medical advice. So, Anna, I’m really excited to have you on today, and one of the reasons is because in some previous episodes of Foresight Medicine, we have had discussions about diseases where there’s really a quite well-established paradigm for what preventive or early intervention care looks like. And when it comes to the lungs and the diseases we’re going to be talking about today, I don’t think there’s an established paradigm, but there’s people who are working on that, and you’re very much one of those. And so this is an exciting new frontier for us. And so, kind of the first question I want to just start out with, and it’s always my first question to our guests is, what inspired you to focus on this area of lung disease? How did you get here? But in the course of your answer, for our listeners, let’s just level set with a couple of important terms. When we say interstitial lung disease, what do we mean? And when we say pulmonary fibrosis, what do we mean? Anna Podolanczuk: Sure, thanks so much for having me, and this is something I feel very passionate about and happy to speak about it. So, let’s start with the definitions. When we’re talking about interstitial lung disease, we are talking about diseases of the lungs that affect the lung parenchyma, the little membranes in the alveoli, where gas exchange occurs. And so that separates those diseases. They’re separate from things like airways diseases, like asthma and COPD, or from vascular diseases like pulmonary hypertension. And so pulmonary fibrosis is a subset of interstitial lung diseases, where there is scarring of the lung interstitium, of the lung parenchyma. And so that makes it really hard for oxygen, to get into the body, and leads to progressive usually progressive symptoms, like shortness of breath and cough,and worsening quality of life for many of our patients. And so, really, it’s that presentation that inspired me to go into this field, because even when I was in medical training as a medical student, as a resident, we saw many patients with pulmonary fibrosis being admitted to the hospital, or I would see them sometimes in clinic, and the thing that inspires me to do what I do now, which is focusing on early detection, is that many of those patients used to present very late in their disease course, and usually by the time they presented to the hospital or to clinic, their disease was very, very advanced, and there was very little that we can do. The thing about pulmonary fibrosis or scarring in the lungs is that it’s not reversible. Or currently, with our current treatments, there’s nothing to reverse it. And so, that makes it very challenging to intervene and to improve quality of life. And so all we can do, if we can diagnose disease earlier, we can hopefully have the biggest impact for our patients in terms of actually improving their quality of life. Robert Rogers: I really like that answer, and there’s two threads in that answer that I want to pick up on. First is you started to already kind of lay the foundation for why we might be interested in early intervention and early detection of pulmonary fibrosis, because when patients present clinically and it’s quite advanced, their prognosis can be challenging. But also, in the course of your answer there, in explaining what interstitial lung disease is, for our listeners, I just want to explain why, among all lung diseases are we focusing on this in this episode of prevention. And I think it’s fair to say, you know, in a pulmonologist’s office, there’s many different diseases you see, but probably the single most common, right, are those diseases of the airways, asthma and COPD. And I think that we sort of have a preventive care paradigm for those airways diseases. For COPD, it is so much dominated by the risk factor of smoking. Really, prevention consists a lot of smoking cessation, and for asthma, asthma is very much a disease where the whole care paradigm is about preventing exacerbations. Another disease that we see a lot in the pulmonary clinic is when people have nodules on their lungs, and we’re concerned if they’re cancer or not. And we had an entire episode of that on episode 1 of this series, and I encourage our listeners to check that out. So I think interstitial lung disease is really, among the pulmonary diseases, one that’s really ripe for our discussion today. So, picking up on what you said there about how, you know, when patients with pulmonary fibrosis present to the hospital, or present clinically, it’s often quite advanced. Let’s just outline a little bit what are the current treatment options, because of course, the logic of intervening early depends very much on what treatments can we offer. Anna Podolanczuk: Yeah, for sure. And so, you know, just to add to a little bit to what you were saying, it’s absolutely right that airways, diseases, nodules, you know, those are common, and those are pretty, you know, significant diseases as well, but what makes pulmonary fibrosis so challenging is that they are some of the sickest patients that we see in pulmonary Clinic are those patients with pulmonary fibrosis. And one of the challenges in taking care of those patients is that treatment options are very limited. Like I said, there’s nothing that reverses lung fibrosis. There are currently, 3 approved, what we call, antifibrotic therapies. And all 3 of those therapies slow disease progression. But they don’t even stop it from progressing. They, you know, at best, they slow the disease, the decline in lung function over time. They have limited efficacy. They don’t make anybody feel better. Two of those drugs have been around since 2014, and the latest drug, was just approved, a few months ago, and all of those drugs have side effects. The newer one has fewer than the older ones, but they all have, you know, they’re challenges with tolerability for patients, they’re difficult to take, they’re pills you have to take every day, and there’s not even a good way of knowing if they’re working, because most patients at some point are going to progress with or without therapy, they just progress a little bit slower without those drugs. And so the only other treatment that we often discuss with patients is lung transplantation, right? And so pulmonary fibrosis is actually the leading indication for lung transplantation. And it’s because it’s such a severe disease with so few treatment options. But lung transplantation is not a cure. Takes care of their fibrosis, when successful, but you’re trading one disease for a set of complications, including the risk of rejection, the risk of infection, and so there’s challenges. And then other things that we use to help patients feel better are things like supplemental oxygen, but again, those are, you know, comes with a quality of life, challenge where patients have to lug oxygen around. It may help them feel better, but it also significantly impacts how they feel and function in the world. And so, it’s just very challenging and we’re constantly doing clinical trials and research to find better treatments for patients, but so far, we have very limited options. Robert Rogers: Yeah, and let’s just double-click a little bit more on those antifibrotic agents, because as you’ve pointed out, they are far from perfect, they are not cures for the disease, they are not medicines that reverse the disease. But they do slow the progression of the disease, but they do that at the cost of certain side effects. And maybe just talk a little bit about, with the current standard of care, how you see the benefits of slowing the disease down versus the side effects you see the patients incurring. Anna Podolanczuk: Yeah, so it’s always a balance, and whenever I see a new patient with a new diagnosis of pulmonary fibrosis, we spend a lot of time talking about those risks and the benefits of when to start therapy. The antifibrotic therapies all have significant gastrointestinal side effects, and so many of them can cause diarrhea, nausea, stomach cramping, weight loss, poor appetite. Again, the newer drug is a little bit better, but none of them are perfect. And so for many patients, they don’t want to start therapy if they’re feeling okay when they still have very early disease. But the challenge there is that if you’re going to wait for the development of symptoms, you can’t go back in time and get that lung function back. And so for me, it’s always talking, monitoring patients very closely, even if they’re diagnosed early, and diagnosed before they have significant symptoms, to see if we can predict when they’re going to start progressing, or if we can find a way to identify early progression, then it might make sense to initiate early therapy to try to preserve as much of the lung function for as long as possible. These antifibrotics generally slow lung function decline by about 50% and so what we can tell, from clinical trials, that on average, the way we measure lung function and progression of disease is through something called FVC, or forced vital capacity. It’s a measure of lung volume on an inhaled lung volume on a breathing test. And so patients with IPF [Idiopathic Pulmonary Fibrosis], on average in trials, tend to lose about 200 milliliters of their lung volume, of their FVC per year. And the antifibrotics and trials have been shown to slow that down by about 50%. So instead of losing 200, you may lose 100 milliliters as opposed to 200 milliliters. And so again, the challenge of when to start that. I tell patients, if we started something earlier it might actually have a benefit and make you lose less lung volume over time, but it comes with the cost of the side effects. And every, you know, every patient’s different, and it’s always an individual decision for when to start these therapies. Robert Rogers: Yeah, and just for our listeners, IPF is the acronym for idiopathic pulmonary fibrosis, which is the single most common form of pulmonary fibrosis, but there are many others. I appreciate you bringing in this important measure that we think about a lot in lung disease into our conversation called forced vital capacity. The way that I tell people to think about this, and actually how it’s defined, is imagine taking in the deepest breath that you can, fill your lungs up all the way, and then blow all the air out as far as you can. And how much air you blow out there, that’s your forced vital capacity. And, so let’s just say, to make an easy round number, what’s normal for a person depends on their age, and their sex, and their height and personal factors, but let’s just use a nice round number. Say a normal person has 4 liters of that, and let’s say if you get down to 3 liters, you might come to your office to see you and complain, and let’s say if you get down to 2 liters, you might be in real trouble, right? You might be really, really sick. And so, what you’re saying is, is that with our current drugs, if people are gonna go down by 200 milliliters per year, they could maybe slow that to more like 100 milliliters on average. And so what you have to spend a lot of time thinking about is how early to start using those treatments, because they have some side effects. And so, the question that I really want to ask you that that brings up is, you know, how much fibrosis can actually accrue to the lung before a patient will present to you clinically, and how long can that period of time be? Anna Podolanczuk: Yeah, so that answer is different for everybody. I give a lot of talks on pulmonary fibrosis, and one of my first slides is always that it’s a disease that develops over years to decades, and it’s not something that happens overnight in most patients. Unless they had some acute hospitalization or something else that caused other types of pulmonary fibrosis, or injury to their lungs. But for most patients, there’s this long subclinical or early preclinical phase, where they don’t really feel any different, but there’s microscopic injury, and scarring that is developing in their lungs. It is slowly progressing over time. And then, when someone develops symptoms, it’s kind of dependent on their general activity level, right? If somebody’s a marathon runner, they may feel some limitations to their exercise capacity earlier on than somebody who’s more sedentary or not very active. I see patients who lose 30-40% of their lung volume, and are not too symptomatic, and sometimes I see patients who lose 20% of their lung volume and start feeling symptoms. But kind of like you said, it’s, you know, somewhere in that, you know, you lose 25%, 30, 35, or 40% of your lung volume, you’re going to start feeling something. But that’s a lot of lung volume to already lose through scar tissue. And again, that’s not something that we can reverse, and so we’re always trying to identify this disease early to try to preserve as much of the healthy lung as possible. Robert Rogers: It’s really somewhat of a blessing and a curse that we are born with much more lung capacity than we need for our daily lives. It’s a blessing because we can lose a lot and still do fine. It’s a challenge because a lot can be gone before you know that there’s any problem, and then you can be in trouble. And so let’s take a step back for a second. How should an average person think about what the overall risk is of developing pulmonary fibrosis? Certainly, it’s a lot less than things like coronary artery disease, but what is kind of an average person’s risk? And then maybe talk us through what are some of the environmental and genetic and other risk factors that increase that risk? Anna Podolanczuk: Yeah, so pulmonary fibrosis, especially the idiopathic pulmonary fibrosis that we just mentioned, which is kind of the most common idiopathic form of pulmonary fibrosis, is a disease that’s related to aging, and so it’s not something that develops in younger individuals, in people in their 30s, 40s. And rarely in their 50s. It’s something that we start seeing as people get into their 60s, 70s, and 80s. Now that people are living longer, in many cases, we are seeing more and more individuals with pulmonary fibrosis, because they are being identified, you know, into their 80s, and sometimes even 90s. So, the average person’s risk really does depend on your age. I do a lot of research, and I study, research cohorts, and we’re generally looking at individuals who are middle-aged and older. And there are some epidemiologic studies and data sets that show that, idiopathic pulmonary fibrosis affects about 1 in 200 individuals over the age of 65. That is from a Medicare data set. So in that population, it’s… it’s kind of rare, but not that rare. 1 in 200, you know, I mean, we all know, a lot of individuals, and so chances are that at some point, you’re gonna meet someone who is affected by this disease, but it’s usually going to be older individuals. Now, that risk, changes dramatically when we are talking about genetics and exposures. So idiopathic pulmonary fibrosis and other types of pulmonary fibrosis, have a very strong genetic risk. The genetics are not sufficient. It’s not like other, like, diseases, like cystic fibrosis, where there’s one gene, and if you have that you’re gonna develop the disease. It’s a multi-genic disease, or polygenic disease, where there are multiple, genetic factors that contribute to disease risk, and there are both common and rare genetic variants that contribute to risk. But there are a set of genes that run in families, and about 20% of the patients that we see have what we call familial pulmonary fibrosis, where there are multiple individuals in a family, that are affected by this disease, and in those cases, there’s often a strong genetic linkage, and some of those genes are related to premature aging and, pathways, things that we call, like, senescence and telomere function, and so individuals with those specific genetic risk factors are kind of one type of individual that suffer from pulmonary fibrosis. And then there are other genetic factors that are much more common in the general population, but are also strongly associated with disease risk. And generally, if you have those more common genetic factors, then there’s a strong link towards exposures, and so you need that genetic factor plus kind of an accumulation of exposures over your lifetime that cause injury to your lungs to develop pulmonary fibrosis. And in those cases, we still think of the disease as being a disease of premature aging, where the lung kind of exhausts its ability to heal itself when it’s exposed to ongoing injurious factors. And so those exposures are things like smoking, air pollution, many other environmental factors. There are some types of pulmonary fibrosis where exposure to things like mold and feathers can trigger a reaction and injury to the lungs that then leads to scarring. And then there are some intrinsic factors. We think that maybe acid reflux, may contribute to ongoing injury to the lungs that then causes pulmonary fibrosis. Robert Rogers: Yeah, and so you’ve brought up the complex nature of the pathophysiology of pulmonary fibrosis, both genetic and environmental contributions, and when we think about the genetic side of things, on foresight medicine, we discuss genomics a lot as sort of this general-purpose technology that’s gonna inform targeted prevention and early intervention across many diseases, and so there are many healthy people who might be considering getting whole genome or whole exome sequencing. How would you advise such a person to think about the benefits versus the costs and the risks of characterizing their genetic risk for ILD? Anna Podolanczuk: Yeah, I think that’s a challenging question, because we know so little still in pulmonary fibrosis, but we also know a lot. Like I said, there are multiple genetic factors that have already been identified, and when I see patients in clinic, I have the option of sending, you know, targeted genetic panels, but there’s also been research studies that have looked at whole genome sequencing and its utility. And there was a really great study that was done by David Zhang and Christine Garcia out of Columbia University that looked, actually, at the utility of whole genome sequencing in patients with both sporadic pulmonary fibrosis and familial pulmonary fibrosis. And they found that in about 25% of patients, you could find actionable or risk-related variants or genetic factors when you do whole genome sequencing that inform their risk for disease, and can tell us, you know, potentially why the patient developed that disease, but may also have implication for those patients’ family members, and can, help inform their family members’ risks. And we know that in families where there are one or more people affected by pulmonary fibrosis, their first-degree relatives have an increased risk of the disease, and that risk is about 1 in 4 individuals, so about 25% of first-degree relatives of patients with pulmonary fibrosis will have some sort of abnormality on their CT scan that may often be an early manifestation of pulmonary abnormality on CT scan. And so, when you take that, and then you think about whole genome sequencing,if you know that a certain genetic factor or certain variant runs in your family that is strongly linked to pulmonary fibrosis, whether you carry that variant or not may inform how closely, you look at your own symptoms, when you get screened, with a CT scan for pulmonary fibrosis, and how you approach some of those medical decisions. So I think there is utility to it. I wish there was more data, or we had better results with using some of those genetic findings to inform treatment decisions, and with that, we’re just not there. Robert Rogers: Right, and we don’t have anything as of now that can specifically mitigate a specific genetic risk factor, it’s more that it would clue you in to be perhaps more vigilant, which we’re going to talk about in just a little bit, how one might be, quote, more vigilant. Perhaps you could say, would it also make you extra motivated to avoid certain risk factors? Like, you would know extra to not smoke, or similarly? So before we get there, though, kind of one last question that I think is a challenge for the idea of early intervention in pulmonary fibrosis, and that is, you touched on this at the beginning, but could you say a little more about what the different clinical trajectories are of patients with pulmonary fibrosis? How some people will really not progress, some people can progress quite rapidly, and there’s really quite a large spectrum in between. And so, how can we think about predicting whose disease will progress and how rapidly? Anna Podolanczuk: Yeah, yeah, so it’s certainly a heterogeneous group of diseases where the trajectory is very heterogeneous, like you mentioned. Some people can stay stable for many, many years. And some people progress very rapidly. And we have very few ways of predicting, who will progress when. This is why we monitor patients very closely with serial PFTs. I see my patients with pulmonary fibrosis in clinic, every 3 to 4 months with pulmonary function testing. We image them at least, every 1 to 2 years. You know, we certainly assess symptoms. There are a few biomarkers that have been looked at, as being associated with progression. I think the one that we are talking about the most currently is something called telomere length, and some of us are sending that blood test that measures the caps on the DNA called telomeres, and patients who have short telomeres have a much higher risk of disease progression. It may actually inform some treatment decisions. They may respond differently to different therapies, like immunosuppressive therapies. And, it also impacts their risk of disease and their risk of progression. That’s probably the most promising biomarker that we have, but other than that, and aside from those genetic, you know, if there are known genetic factors that are linked to familial pulmonary fibrosis, that is also known to be kind of a more progressive phenotype of patients. There’s very little that we can do. So we just, you know, we kind of end up monitoring patients very closely, and what I tell patients that even if you’re stable for many years, you still need to be monitored, because I have patients who are stable, stable, stable. Eventually, patients fall off a cliff, and what I’m constantly trying to do is find patients before they’re falling off that cliff, and then they end up having a very rapid disease progression at that point. Robert Rogers: It’s very interesting the trade-off that you described that derives from the great heterogeneity of how patients can progress, And something that I think back to when I think about screening in the lungs is, you know, go all the way back to the original, that foundational paper called The Principles and Practice of Screening for a Disease in 1968 by Wilson and Junger, right? And it sort of lays out these principles that anyone who’s interested in early early detection and early intervention should take to heart, when does it make sense to screen for something? And one of those principles is that, you know, the natural history of the condition, including its development from latent to active disease, should be adequately understood. And I think what you’re pointing out is that, we don’t have a fine mapped understanding right now, actually, of being able to predict, you know, who’s going to progress. We have some clues, but I wonder if that is a little bit too pessimistic a take on what we really can do in this realm? Because, like you said, you don’t have to necessarily predict at the outset. You can monitor patients over time, right? You can observe these patients every 4 months or every 6 months and decide when an individual patient is progressing. And so that’s a much more answerable and personalized question than this generalized question of, can we predict progressors? Is that how you actually think about it in practice? Anna Podolanczuk: That’s exactly right. I mean, to me, knowledge is power, and knowing that you might have an abnormality where we can be vigilant and intervene if it progresses, even though we can’t predict exactly when it will progress, is powerful, because, we do have drugs that can modify that disease course, even though not perfect, and so, exactly right, we can monitor patients and intervene early, as opposed to waiting for so much of the lung to be damaged, and that symptoms are developing, and we can’t go back in time. Robert Rogers: Great. So, pulmonary fibrosis is a disease that initially is largely diagnosed with CT scans, and tell us about this relatively new entity that you and others have been working on, defining what we call interstitial lung abnormalities. What is that? What does that look like? What does that mean? Anna Podolanczuk: Yeah, so this is an idea that, we can identify early stages of pulmonary fibrosis on CT scans, on imaging, often before they become symptomatic. And this has been looked at in a lot of research cohorts and kind of a lot of, large studies where patients underwent CT imaging, CAT scans for other indications, like to look at their coronary calcium, for example. And many of them, roughly 7% of the middle-aged and older adults, will have these, often early features of pulmonary fibrosis. And many of them will progress, even though they progress very slowly. But, you know, in that context, we call it an abnormality. We don’t know yet if it’s a disease, if it will impact somebody’s quality and quantity of life, and so it’s just something for us to evaluate and monitor over time, and so this has been a concept that’s been recognized for many years now, but we formally kind o defined an approach to evaluation and management of those patients with these incidental abnormalities. In this recent document, we came together with 40 individuals from across the globe to recommend who should be screened for these abnormalities, and how individuals who have these abnormalities should be monitored and evaluated. Robert Rogers: Yeah, great, and so you are, in fact, one of the leaders of that effort, and the first author of that document from the American Thoracic Society about the approach to the evaluation and management of interstitial lung abnormalities, and so I’d love for you to tell us, kind of how you approach both of those questions. What’s the current standard of care for someone who’s found to have these radiographic findings? Anna Podolanczuk: So, what we agreed on in this document is that these individuals should be evaluated for the presence of interstitial lung disease. And so, one of the things we did in this document is try to come up with criteria for what differentiates an abnormality from a disease. And these are things like having abnormal breathing tests, having symptoms that can be attributed to lung disease. Or having certain features on a CT scan that are known to be associated with a high risk of progression, and those are fibrotic features, so things like what we call traction bronchiectasis and honeycombing. They’re just aspects of a CT scan that are known to be strongly, associated with poor outcomes in patients who have these abnormalities. And so, if people have these abnormalities, any of these things, they should be considered to have a disease, often early disease, but a disease rather than just an abnormality, and at that point, they should be evaluated by a pulmonologist, and monitored, and assessed for potential treatment of that disease. If they don’t meet any of the criteria for interstitial lung disease, if they just have an abnormality. They should continue to be monitored, in a pulmonary clinic with, CT scans every 2 to 3 years, and with, mitigation strategies, so things like, risk reduction strategies like cessation of smoking, any other harmful exposures, you know, age-appropriate vaccinations, all of these preventative strategies that we know can help people decrease the risk of progression. Robert Rogers: So that’s great, so there’s a lot of rich material there. So basically, you know, you said if you went out into the community and did these CT scans for whatever reason on 100 70-year-olds, you know, 7 of them, on average, would have these abnormalities, and then if you catch these abnormalities, the standard of care is now to figure out, is this just a radiographic abnormality, or do they actually have disease? And either way, they’re going to be followed now from now on, but the intensity of that following, it sounds like, differs very much between whether it’s just an abnormality or whether they have the disease. Maybe taking one, just pushing that one step further, should anybody currently be screened for interstitial lung abnormalities even before they’re known? Anna Podolanczuk: Yes. So, in the same document, we had a lot of discussions, and we reviewed the current state of evidence for which groups of people are at risk, at higher risk for having these interstitial lung abnormalities. And there’s several groups that we recommended screening in. The first group are individuals who have family members with pulmonary fibrosis. And we specifically said, individuals, first-degree relatives of patients with familial pulmonary fibrosis, where there are two or more individuals with pulmonary fibrosis in a family. Those individuals have a high risk of having an abnormal CT scan. About 1 in 4 will have some abnormalities, and so we recommended a screening CT scan starting at the age of 50 in those individuals, in the first-degree relatives. Two, we recommended screening in individuals who have what is known as connective tissue diseases. These are, autoimmune diseases, so specifically scleroderma, rheumatoid arthritis, mixed connective tissue disease, myositis, and Sjogren’s syndromes. These are conditions that are, have a high risk of also having interstitial lung disease. These individuals, in our, analysis of the existing data, there’s about, somewhere between a 20% and a 40% risk of having an abnormal CT scan when you look at the data. And so we said everybody who has those conditions should get at least one baseline screening CT scan to evaluate for the presence of interstitial lung abnormality. And finally, we looked at smokers. We know that smoking is a risk factor for pulmonary fibrosis. The data on smokers, the prevalence of interstitial lung abnormalities in smokers, is about 7-10% of middle-aged and older adults, so it’s not that different than the general population. And so we said that’s not enough to justify recommending a screening CT scan for all smokers. But, in patients who are a smoker, lung cancer screening CT scans is already recommended. And so those individuals who are undergoing CT scanning for lung cancer screening, those CT scans should be formally assessed for the presence or absence of interstitial lung abnormalities or interstitial lung disease. That should be formally reported on the CT scan. Robert Rogers: Right, so it sounds like there’s evidence to support screening in those three high-risk groups, patients who have a family member with interstitial lung disease, patients who have certain autoimmune diseases that predispose them, and patients who are already getting CT scans because of their smoking history to look for lung cancer. Are there any other groups who were, quote, on the bubble who you considered putting into that group, or who you could see evidence emerging over the next, say, 5 years, that if we had this discussion 5 years from now, they would be included in that list? Anna Podolanczuk: Its that family history. We had two kind of two subgroups. One was where there was two or more individuals, and one when they were their family members, when there’s only one individuals with pulmonary fibrosis. And in that group with sporadic, you know, it’s a patient who has IPF, and their children or their siblings are interested in screening, the data shows that the risk of pulmonary fibrosis is still elevated in that group, but there’s just less data in those patient populations, so we really couldn’t reach consensus for sporadic IPF, or idiopathic pulmonary fibrosis on screening. And so I think many of us are approaching it on a case-by-case basis and individualized discussions. But I think as we see more data emerging in that patient population, we may modify our suggestions. Robert Rogers: And so when we think about the benefits and risks and costs of screening and early intervention, we always have to weigh several factors, and one of those factors is patient anxiety, this worry that now you’ve been told you have an abnormality or a disease, and you may not have any symptoms of that. I’m curious, in your clinical practice, and to the extent that there’s research on this, how are patients reacting to learning that they have what, to them at this time, is asymptomatic interstitial lung abnormalities or disease on their CT scan. Anna Podolanczuk: Yeah, that’s a great question. I haven’t seen any studies in this specific patient population, but it’s certainly a concern. Most of my patients, when they come to see me because they had this incidental finding on their you know, a lung cancer screening CT scan, or their coronary artery calcium CT scan, and they look it up on the internet, they get very scared, they get very nervous, and so I have to do a lot of education to put this in a larger context, you know, this is not the same as being diagnosed with idiopathic pulmonary fibrosis. This is an abnormality, and so the anxiety is certainly real. At the same time, especially for individuals that have family members who have suffered from pulmonary fibrosis, I think there is interest in trying to identify earlier stages and tryto intervene earlier, because many patients have seen their family members get diagnosed late and have to go through a lung transplant, and so I think it can be very empowering to get screened. But it has to be an individual decision, and it has to come with a lot of education to put everything in context, because the prognosis is highly dependent on the disease stage. Patients who are diagnosed with early disease are gonna live a lot longer than patients who are diagnosed with very advanced stages. Robert Rogers: Yeah. So, let’s, imagine for a second, hypothetical situation. Imagine that we had some sort of widespread screening program, to give middle-aged or older middle-aged adults, chest CTs, in the population at large. It extended beyond those, those three groups that you, have already mentioned. What do you think that would look like at this point in time? Would the risks of that, of overdiagnosis and false positives and things, outweigh the benefits? Would there actually be great benefits? How do you think something would pan out if we did that with today’s tools and technologies? Anna Podolanczuk: So it’s interesting, because actually this is done in some other countries, like in Asia, and a lot of the research comes from Korea and some of it from China, where health screening with CT scans is much more common, and so it’s not just a theoretical discussion. I think the approach to education is different in those countries. I think here, there is, hopefully, a lot more education that would happen. Because I think, from my perspective, it has to be a risk-benefit discussion, and it’s not right for everybody. I think patients need to be aware of their choices, they need to be provided with some sort of guidance before they decide to undergo screening, on whether it’s right for them and what to expect from screening. I think the power of CT scans is that there’s so much now that we can detect on CT scans. Obviously, we’re talking about pulmonary fibrosis, but you get a CT scan, you can identify nodules, you can identify, you know, coronary disease that was previously unknown, you can identify things like emphysema, there’s so many incidental findings, some of them are meaningful, some of them are not meaningful, some of them are actionable, and some of them are not actionable, and there’s certainly a risk of a lot of procedures, and there’s a potential for harm with screening if it’s not done in the right context. And so, I don’t know about the role of just widespread screening. To me, screening and targeted population, where we know there’s an unknown risk, an increased risk, where there’s a higher likelihood of having a true positive as opposed to a false positive, makes more sense than just having this broad, broad screening. But certainly, you know, that should be a risk-benefit discussion with individual patients. Robert Rogers: Very good. What is one development or advance, could be at the level of tools for diagnosis, or treatments, or even policy or systems-level changes, that you think would most advance the field of early intervention for pulmonary fibrosis? Anna Podolanczuk: My dream is to have a blood biomarker that would, be a sensitive test that would inform who should then undergo screening. And so having that first tier, kind of, kind of like a D-dimer, you know, I don’t know, are we still doing D-dimers? But, you know, something that… Robert Rogers: We’ll just explain for our listeners a D-dimer is a specific blood test, and the way that it’s used clinically in medicine is to rule out the presence of a blood clot in the lungs. So people come to the emergency room, one of the things, if they’re short of breath, one of the things that could be causing that is a blood clot in their lungs called a pulmonary embolism, but we don’t necessarily take every patient in the emergency room who’s short of breath, and do a CT scan to determine that, because we have this easy blood test that tells us, you know what? This blood test is so low, we don’t have to worry about blood clot, and we can skip the whole CT scan. And so what you’re saying is you want a D-dimer for pulmonary fibrosis, basically, and then you wouldn’t have to screen all 100 of those people in the community to find the 7 that have interstitial lung abnormalities. You could just screen, you know, the.. Anna Podolanczuk: 10 or 20 or whatever, yeah, exactly. I think that would be life-changing. Robert Rogers: And you mentioned one such biomarker that you’ve studied, and that is being used increasingly in advanced clinical practice. Maybe just say a little bit more about that, and what are some other potential biomarkers that might emerge? Anna Podolanczuk: Sure, and you’re talking about the telomere length testing? Yeah, so again, this is not available in every clinic, because it is, a test that is, only run in certain in very limited number of facilities, and is not often covered by insurance, but I find it useful for many of my patients. And again, this is a test that is measuring the caps of the DNA, and as people age, those caps, the telomere lengths, get shorter, and that’s associated with aging, but in people who have extra short telomeres, it’s associated with premature aging and some of those things that are, some of the diseases that go with that, including lung fibrosis, but also liver fibrosis, and also potentially cardiovascular disease. And so I find it useful. It shouldn’t be a prerequisite in screening. We actually addressed this in our document. But it is something that can be an adjunctive test to help make decisions for our patients. Some of the other tests, you know, we’ve published and others have published on monocytes. These are a type of cell in the blood that is an inflammatory cell, and having elevated monocyte counts is associated with interstitial lung abnormalities and progression of those. So I look at those sometimes, kind of, in the overall, my overall approach to the patient. I don’t make any individual decisions just based on the monocyte count, but I take it kind of as in the overall evaluation of the patient. What I’m really excited about in the future is the role of genomics and proteomics specifically, in helping to guide individual risk of progression. There’s some really great work being done by Justin Oldham out of Michigan, looking at proteomic biomarkers. Now you’re taking, a set of proteins in the, in the blood, and he’s developed predictors, classifiers, using, the levels of certain proteins, and, he’s shown that having a certain level of proteomic biomarkers, having a high-risk proteomic signature can discriminate people who are at high risk for progression of pulmonary fibrosis, and so I think that’s, again, that’s still in the research stages, it’s not available clinically, but I’m excited about that potentially being available in the future. Robert Rogers: Great, and final question, on foresight medicine, we focus on having a comprehensive disease-oriented framework for prevention, and I’ve learned from your work recently that you’ve been studying a lot of the shared risk between both interstitial lung disease, what we’ve been talking about today, and also another disease that we’ll talk about shortly in the future, coronary artery disease and heart disease. Tell us what you’ve found so far. Anna Podolanczuk: Yeah, we’re talking specifically about atherosclerosis, or, that’s another name for coronary artery disease or cardiovascular disease. And what atherosclerosis is, is fibrosis of the blood vessels of the arteries, right? And so it’s just another fibrotic disease, and there is a strong link, epidemiologically, between the risk for pulmonary fibrosis and having elevated coronary artery calcium, having a higher risk of things like angina or myocardial infarction, of heart attacks, and so I think there’s a certain, group of individuals biologically are predisposed to scarring in the lungs, as well as scarring in their arteries, and we’re trying to better understand what that predisposition means. Is it genetic? Is it some combination of exposures? The predisposition seems to go beyond smoking, beyond lipids, although lipids seem to, seem to play a role. Like, for example, I found that having high levels of HDL cholesterol, which is the good cholesterol, is protective. It’s known to be protective in cardiovascular disease, but it also seems to be protective against pulmonary fibrosis. And certain protein components of the HDL seem to be the most important and most protective, and that’s something called apolipoprotein A1. And so we’re trying to better understand what that connection is between those two fibrotic diseases to better identify if there are specific drug targets that we can identify that would work, both for pulmonary fibrosis or cardiovascular disease, or if we can learn from each disease and better identify better treatments for them. Robert Rogers: Very fascinating work. Dr. Ana Podolanczuk, thank you so much for joining us on Foresight Medicine. Learned a lot from this conversation. Anna Podolanczuk: Thanks for having me. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

5. 

   31 Mar 2026

   Episode #3: Prevention and Early Intervention in Parkinson's Disease with Dr. Ray Dorsey

   Edited Transcript of Foresight Medicine Episode #3 on Prevention and Early Intervention in Parkinson’s Disease with Dr. Ray Dorsey Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic and whole-body framework for leveraging new technologies to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. Today, we will be discussing Parkinson’s disease. I am very honored to have as our guest Dr. Ray Dorsey. Dr. Dorsey is Director of the Center for the Brain and Environment at the Atria Health and Research Institute, and part-time professor of neurology at the University of Rochester Medical Center. He is a leading Parkinson’s clinician and researcher with numerous very impactful publications that span the fields of epidemiology, clinical trials of Parkinson’s, as well as Huntington’s disease, and he has pioneered new models of care delivery and clinical trial implementation for neurological diseases. He has shaped our understanding of the growing global burden of Parkinson’s disease, including the concept of a Parkinson’s pandemic and has been a prominent voice in highlighting the role of environmental exposures as targets for prevention. He’s the co-author of two highly acclaimed books on these subjects, Ending Parkinson’s Disease and The Parkinson’s Plan, A New Path to Prevention and Treatment. Listeners should note that we are recording this on Tuesday, March 24th, 2026, and this conversation is for general information purposes only and does not constitute individual medical advice. Ray, welcome. I’m really excited for our conversation. Thank you so much for joining me today. Ray Dorsey: Many thanks for having me, Robert. Delighted to be with you. Robert Rogers: Great. So, in the next 40 minutes or so, I want to cover a lot of ground about the frontiers of prevention and early intervention and detection in Parkinson’s disease, but I’d like to spend the first few minutes laying a little bit of a foundation for our listeners, both about Parkinson’s disease, but also just briefly about you. The question I always start off with is, what drew you to study and take care of patients with Parkinson’s? Ray Dorsey: So both my parents were psychiatrists, so I like to say I rebelled and I became a neurologist. And, during the course of my medical training, as you know, you spend time in different settings, and once we made it to the clinics. I had a wonderful grandmother, and I enjoy being around older people, and got to care for people with Parkinson’s disease, it’s very clinical in its orientation, a lot of it’s based on listening and observation, and you can make people better. And so, I thought that would be a great combination and something that mastered a lot of my interests, and I think I chose wisely. Robert Rogers: I would certainly say so, based on the impact you’re having in the field. We’re going to talk about preventing Parkinson’s, but I want us to make sure we understand what is this terrible disease that we care about preventing in the first place. So, say a patient comes into your office for the first time, and sadly you have to deliver them the news that, yes, they indeed do have Parkinson’s. How do you explain, based on what our current textbook model or understanding is of what is Parkinson’s disease? What is its pathophysiology, its symptoms, and its prognosis? Ray Dorsey: Classically, Parkinson’s disease is a neurological disorder that produces at least two of the following four symptoms. One is a tremor, usually in the hands, usually asymmetric, usually at rest. Second is, slowness of movement takes people longer to do almost everything. Third is stiffness or rigidity, and fourth is difficulties with a balance or a gait. When Dr. Parkinson first described the condition in 1817, he said, I’m describing something that’s not been classified in the medical literature, something that’s not in the medical textbooks of the time, he described 6 individuals with this disease based on just casually observing half the people on the streets of London. Two centuries later, it’s estimated that 6 million people had the disease. So you went from something affecting 6 people on the streets of London that wasn’t part of the medical textbooks to one that’s the world’s fastest-growing disease affecting 6 million people around the world. And it begs the question, why? And we know that our genes don’t change that much in that period of time. We know that it’s growing faster than aging alone can explain, and growing far faster than other age-related diseases, like stroke and Alzheimer’s disease, they really lead you to the conclusion that Parkinson’s disease is being fueled by… not by changes in our DNA, not by things that are going inside of us, but things that are going outside of us in our environment. Chemicals in our food, including certain pesticides, water, including dry cleaning and degreasing chemicals. And outdoor air pollution are likely responsible for the astronomical rise of this disease. Robert Rogers: That’s super interesting about how, you know, it was only 200 years ago that the disease became prominent enough to really make it onto the radar, and here we are with a Parkinson’s pandemic. And I’d like to double-click on that, and maybe just take us a little bit deeper into how how we go about studying and identifying what it is in the environment that is driving the increase in Parkinson’s disease. Ray Dorsey: Yeah, so it’s, it’s, it’s hard, So, since you’re a pulmonologist, do you know how they determined that smoking was linked to lung cancer? Robert Rogers: You, you, go, go ahead, you’ll, you’ll teach, you’ll teach me and our audience. Ray Dorsey: In the late 1800s in Europe, lung cancer starts emerging, and lung cancer was extraordinarily rare. And the German pathologists, being German, said, did we miss this? So they went back to their cadavers and, you know, looked at the lungs more carefully and see if they were missing occult or hidden malignancies, and there wasn’t any. And they were wondering what was causing it. In the U.S, it was so rare in 1900. That was considered a once-in-a-lifetime oddity. All that doctors and medical students would gather around when they saw a case of lung cancer, thinking they would never see one again. But lung cancer kept getting more and more common in the early 1900s, and in Britain, they were wondering what was going on. Some people thought, was this a delayed effect of exposure to gases from World War I? Other people, including a physician, Richard Dahl, thought it was due to asphalt that was being, poured to pave the way for roads in early 20th century England, and then some people thought it was due to these new things, cigarettes, that had been recently introduced into Europe and then the US around 1900. And so Richard Dahl and his friend Bradford Hill, a statistician did something called the British Doctor Study. They mailed postcards to all the British physicians, I think they might have been all men, and asked them, do you smoke? Yes or no? And if you smoke, how much do you smoke? And then they, sat around and waited. They waited for all the doctors to die. And then they looked at those who died from lung cancer and those who died from other causes, and it turned out that those who died from lung cancer were 30 times more likely to smoke cigarettes than those who, than people who didn’t. Ergo, smoking is as strongly as associated with, lung cancer. But Bradford Hill was bothered by this. He said, boy, I have an association, how do I know it’s a causation? Maybe all smokers really enjoy drinking coffee, and maybe it’s coffee that’s causing lung cancer. So, Bradford Hill put forth nine criteria by which you could go from an association to a causation. I can’t give you them all, but one is, like, the strength of a relationship. Is this a small, small thing or a large effect size? Is this been replicated? Does the exposure happen before the disease? Do people smoke the cigarette before they get lung cancer as opposed to getting lung cancer, which might make them more prone to smoke. Is there a dose-response relationship? Is the more exposure to the toxicant, the chemical, the exposure, more cigarette smoking associated with a greater risk of the disease? Is this biologically plausible? Does this make sense? Are there animal models that are consistent with this? Can we, reason by means of analogy? You go through all those criteria, and smoking, you know, checks a lot of those boxes. Well, it turns out that my colleagues have applied those same criteria to some of the environmental risk factors linked to Parkinson’s disease. Chief among them is a weed killer called Paraquat.Over 70 countries have banned it because it’s been used to commit homicide and suicide, and it’s associated with a 150% increased risk of Parkinson’s disease among farmers who use it, associated with a 100% increased risk of Parkinson’s among people who simply live or work near where it’s sprayed, and in the laboratory reproduces the features of the disease. You’re starting to check off a lot of the Bradford Hill criteria, and they pointed out that it largely did check off these. So I think we have lots and lots of evidence for some of these toxicants. For some, we have much less, and quite frankly, I think the fact that we have much less is an indictment of science, indictment of scientists, and indictment of funders. I’ve never been on rounds where we saw a patient who had lung cancer who smoked, where we talked about the genetics, the genetic… underlying genetic predisposition that led this smoker to get lung cancer. Have you ever had that? Nope. No. But we spend a tremendous amount of time in Parkinson’s disease trying to find out what the genetic underpinnings of the disease are, when, quite frankly, it’s just not a very heritable disease. We’ve known this for 100 years, that Only 15% of people with Parkinson’s disease have a family history of the disease. We’ve known from twin studies for 25 years that the rates of Parkinson’s are similar among identical twins and fraternal twins, suggesting that genetic factors aren’t, that important to the disease. It’s predominantly due to the environment. And then we had two studies done in 2024 that told us that of people with Parkinson’s, that less than 15% of them in the U.S, in North America, South America, and Europe, and the Middle East, less than 15% of people carry a genetic cause or genetic risk factor for the disease. The vast majority of people around the world and the vast majority of people in the United States who have Parkinson’s have little, if anything, to do with genetic causes or genetic risk factors, the principal causes are not in our DNA. They are outside in our environment, and to our discredit, we have failed to rigorously assess many of these environmental causes. Robert Rogers: Yeah, and I want to, pick up that thread, but since you brought up a really interesting, side note, which is, how was it that the link between smoking and lung cancer was proven as causal? An interesting piece, I think, of epidemiological trivia is that smoking raises your risk of almost every disease that you can think of, except Parkinson’s, where there’s a pretty strong epidemiologic association that it decreases the risk. Maybe you’ll comment on that. And I bring that up not to discuss that epidemiologic association, or even… and of course, not to in any way encourage people to smoke related to Parkinson’s disease, but just to say that defining the specific contaminants in our environment that cause disease is very, very challenging, because there are so, so many toxins in our environment, and a decent proportion of them are actually in cigarette smoke, but presumably, the ones that are driving the incidence of Parkinson’s disease are not the ones found in cigarettes, so identifying what those ones are really is challenging, and like you said, calls for a very large research effort, which it sounds like you think we have to devote more resources to. Ray Dorsey: Yeah, so, we gotta do smoking and lung and Parkinson’s disease. Robert Rogers: Yeah, let’s do it. Ray Dorsey: Study after study has shown that there’s a 40% decreased risk of smoking… of Parkinson’s disease among smokers, so no one should smoke cigarettes. So why is that? Two hypotheses. My colleague Dr. Jeff Bronstein at UCLA, thinks it might be reverse causation. So I said the exposure has to happen before the disease occurs. You have to smoke the cigarettes before you get lung cancer. You can’t get lung cancer and then smoke cigarettes. He thinks it might be the other way around. He thinks that people, we know that pathology of Parkinson’s disease begins years, decades before the disease manifests. He says if you decrease the amount of dopamine-producing neurons in the reward centers in the brain, it might be easier to quit smoking. So it might be that people with prodromal, subclinical, pre-Parkinson’s disease find it easier to stop smoking, and therefore, people with early, Parkinson’s before they are diagnosed are less likely to smoke. So it could be the other way around, that early Parkinson’s disease makes you less likely to smoke. My colleague, Dr. Michael Schwarzschild, thinks this is another thing. He thinks that there are actually, contaminants, chemicals, and cigarette smoke that might, decrease your risk for Parkinson’s disease. Among these things are chemicals that decrease the amount of activity of an enzyme called monoamine oxidase, which is responsible for breaking down dopamine, and that if you slow the breakdown of dopamine, you decrease your risk of developing Parkinson’s disease. So he’s spending a lot of time and energy trying to determine are there, chemicals in cigarette smoke that could be actually beneficial or slow, decrease your risk of developing, Parkinson’s disease? Robert Rogers: And we established that we have strong reason to believe that it’s changes in our environment that are changing… that are driving the increase in Parkinson’s. Challenging to identify all of the specific environmental contaminants. One that you mentioned that there’s very strong evidence for is Paraquat. There’s another one that you’ve written quite powerfully about, it goes by the abbreviation TCE or trichloroethylene. And maybe that, maybe just… I don’t want us to elaborate on every single environmental risk factor out there, but that seems to be one that, along with Paraquat, you’ve paid particular attention to. Maybe just tell us a little bit more about that association. Ray Dorsey: Here’s trichloroethylene, I know your listeners can’t see it, but, it’s a molecule. Your listeners, a little flashback to chemistry. Water’s made up of three atoms, two hydrogens, and 1 oxygen, H2O. Trichlorethylene is made up of a whopping 6 atoms, 2 carbon atoms, in black in this model, 1 hydrogen atom, and 3 chlorine atoms, hence its name, tri. chloroethylene. It’s got a cousin named perchloroethylene, or tetrachloroethylene, that’s got one additional chlorine atom, hence the prefix tetra, meaning four. If you’ve ever dry-cleaned your clothes, you’ve likely been exposed to tetrachloroethylene, also known as perchloroethylene, or PERC. My colleagues, Dr. Caroline Tanner and Sam Goldman, now at UCSF, showed that hobby or occupational exposure to these chemicals is associated with a 500% increased risk of Parkinson’s disease. These are also the principal contaminants at the marine-based Camp Lejeune, which many of your listenersmay be wondering why they hear all these advertisements about Camp Lejeune, because Trichloroethylene’s known to cause cancer, perchloroethylene likely causes cancer, so these, carcinogens are likely carcinogens that cause a lot of disease at this marine base for 25 years, and for the latter years, the Marine Corps knew that cancer-causing chemicals were in the drinking water at a marine base and did nothing. They knowingly let the best and brightest of Americans be exposed to cancer-causing chemicals in the water that they were drinking. And they studied Marines who served there, and they found that Marines who served there had a 70% increased risk of developing Parkinson’s disease. A few things that are really important to recognize is that these Marines were young, their average age was 20, some were teenagers. They were healthy, you know, it’s hard to be a Marine if you’re not healthy. And they were only there for a short period of time, on average just over 2 years, yet 34 years later, they had a 70% increased risk of developing Parkinson’s disease. I think it tells us a few things that are very similar to smoking, that the seeds of, to lung cancer, the seeds of lung cancer, the seeds of Parkinson’s disease, the seeds of Alzheimer’s disease are planted at a young age. You don’t get lung cancer at age 60 because you started smoking at 58. You get lung cancer at age 60 because you were likely smoking when you were 18 or you were 20. Second, that there’s a long lag, so the pathology that underlies lung cancer accrues over years or decades. You keep accruing mutations and the like, and the tumor gets bigger and bigger until it produces symptoms or comes to the attention of doctors, like on an x-ray or something like that. Same thing happens with Parkinson’s disease. It takes a while for the pathology to spread, to get to the part of the brain that classically causes tremor, to kill off enough nerve cells. 60% of the nerve cells are killed off by the time you are diagnosed with the disease. Robert Rogers: you know, I think you’ve laid out in many forms a very compelling case that to make a real dent in this Parkinson’s pandemic and prevent many future cases, we do need to make several changes at the level of public health research and then public health policy and implementation around environmental science. But I am curious. Is there anything that you think a physician can do within the context of the doctor-patient relationship to help patients avoid these exposures that increase their risk of Parkinson’s? Ray Dorsey: Listen, if you’re diagnosed with any condition, one of your first questions should be, why did I get this disease? Diseases have causes. If you want to cure a disease, the prerequisite to curing a disease is to know what its cause is. I can’t think of a medical condition that we can cure where we don’t know its cause. Maybe you’ll help me out. That’s your homework assignment while I speak. I name a medical condition we can cure where we don’t know its cause. Once you know a cause, you can prevent it, you can slow it, you can get better treatments, and you can cure it. So now, since having this realization about 7 years ago, I spend the 10 to 15 minutes with new patients trying to figure out why they got the disease. And I, like, do they get exposed to pesticides as a young child because they live near a golf course or a farm? Do they drink well water? What were their jobs as teenagers? Did they work with industrial chemicals? Did they like to degrease engines? Did they work on cars? And then, because once I find it, I can make sure that they’re no longer still getting exposed. Some people are still living near a farm where Paraquat is sprayed. Some people are still drinking contaminated well water. Some are still living near a superfund site where this trichloroethylene can come into people’s homes and breathe it in. That could still be going on, and that has happened. And then there are also tons of comorbidities associated with it. I mentioned trichloroethylene, you know, I care about Parkinson’s disease, but trichloroethylene causes cancer. It’s been causing cancer for 100 years. Ray Dorsey: It causes, as likely causes, non-Hodgkin’s lymphoma, renal cell carcinoma, prostate cancer, multiple myeloma, liver cancer. So many male Marines developed breast cancer at Camp Lejeune that they create a swimsuit calendar of men, male Marines, showing off their mastectomy scars. I mean, the list of diseases associated with trichloroethylene is enormous, and you know, you and I were probably told nothing about trichloroethylene during our decade of medical training. So I think it’s really important to figure out what the cause is. In our book, we give the Parkinson’s 25, 25 ways to reduce your risk of ever getting the disease. Buying organic produce, washing that produce, because even organic produce can have residues of pesticides on it. Using a water filter and air purifier to reduce your exposure to outdoor air pollution, which was likely, when Dr.Parkinson described the condition in 1817, he did so amidst the London fog. Air quality in 1800 London is akin to what’s in Delhi, India today. So we give you 25 actions to reduce your risk of getting the disease, and 25 actions that might slow your progression of the disease. We know, again, from lung cancer that people who continue to smoke are more likely to have progressive lung cancer than people who stop smoking. It turns out that the same is likely true for Parkinson’s. People who already have Parkinson’s disease, who have, exposure to pesticides after they’ve been diagnosed are more likely to have a faster rate of progression than people who don’t, research done by Jeff Bronstein at UCLA. And we know that people with Parkinson’s disease who are exposed to high levels of air pollution after they’ve been diagnosed are more likely to be hospitalized for their condition. And, you know, asthma, you know, pulmonary, you know, if a child has asthma. Really, really important to stop getting exposure to air pollution so you can prevent asthma attacks. I think it’s the same thing for Parkinson’s disease. I think, quite frankly, it might be the same thing for most chronic diseases, whether it’s high blood pressure, or type 2 diabetes, or asthma, or pulmonary fibrosis, or lung cancer, or Parkinson’s disease, or Alzheimer’s disease. Halting exposure to the contaminants that are fueling the rise of disease might be the first, in some cases, one of the most important steps you can take to changing the course of those diseases. Robert Rogers: I like that. That’s really actionable. You could really imagine integrating that sort of conversation into the doctor-patient relationship, either in primary care or in specialty care when they have the disease. To take a quick backtrack for just a second, we have emphasized, I think with good reason and supported by evidence that you have created and expounded upon, the leading role of the environment in Parkinson’s disease. But it is a complex disease, and in individual patients, we do think of complex diseases as resulting from the interaction of environments and genes, and so the genetic contribution to Parkinson’s risk, while maybe not as large as the environmental risk, is not zero. And just quickly, you mentioned earlier in our conversation, perhaps a number around 15%. I know we can’t be overly precise in our quantitative estimates of these things, but is that the breakdown you would give, that roughly 85% of risk in the population comes from environmental exposures and 15% from genetics? Or, I would just love to clarify that. Ray Dorsey: Yeah, so we have the evidence, it’s not what I think, it’s what we know, and so if you rank order diseases from heritability at the top are type 1 diabetes, schizophrenia, you know, bipolar disease. At the bottom of the list are, Parkinson’s disease and breast cancer and mortality. So we know that the genetic contributions are modest. Now, there are some important things that we should discuss. One, in the United States, 13%, probably smaller, carry a genetic cause or genetic risk factors, so it’s important. There are certain populations, for example, North African Berbers, Basque populations, Ashkenazi Jewish populations where these genetic mutations are more common, so it’s really important. And there are gene-directed therapies, aimed at some of these genetic underpinnings. Second, there are, genetic differences in the way we break down medication. So you might break down, you know, a blood thinner a certain way, and I might break it down more slowly, and therefore, the dose for you might need to be lower than for me. Similarly, there are genetic differences in the way we metabolize pesticides, for example, and we know people who are really slow at metabolizing these pesticides, too, changes in their gene might be at greater risk for developing the disease. But I think sometimes scientists like to say there’s complexity. I think there’s actually some clarity. Robert Rogers: very well said. I want to get out of genetic territory, but I want to ask you one more sort of practical question as it might relate to patients, because in this podcast series, we talk a lot about genetics and genomics as a general-purpose technology that might inform prevention and early intervention efforts for many diseases. Perhaps it might have less applicability in Parkinson’s than others, but if someone decides to get whole exome or whole genome sequencing, and we had a previous discussion about that, they can find out whether they carry variants in about 6 or 7 genes that are known to substantially increase their risk of Parkinson’s disease. And currently, none of these genes are considered what we would call Tier 1 genes in genomic testing, in the sense that they don’t necessarily have a defined clinical action path that one can undertake if you have that genetic risk. So, in contrast, a cancer predisposition syndrome, if you find out about that, you know that you and your family members are at increased risk of certain cancers, and there’s an associated screening and monitoring program for that. For some cardiovascular and some cancer predisposition syndromes, we have such pathways. We don’t for these Parkinson’s genes, and so how do you… how would you counsel a patient? How would you discuss with a patient who’s gonna get… who’s a healthy person, who’s gonna get genome screening, whether they want to find out about their Parkinson’s risk. Ray Dorsey: Yeah, so let’s do a deep dive on genetics. So, the most common genetic risk factor for Parkinson’s disease are mutations in a gene called GBA. If you have two copies of… mutations in both copies of the gene, you get a rare disease called Gaucher’s disease. If you have, mutations in one, depending on the mutation, your lifetime risk of developing Parkinson’s disease is about 10%. Said another way, for the most common genetic risk factor, about 8% of people with Parkinson’s disease, at least in the U.S, you have a 90% chance of never developing the disease, but 10% is still something to be addressed. Research, again, by Dr. Caroline Tanner and her colleague Dr. Ethan Brown at UC San Francisco, showed that people who carry a GBA mutation who are exposed to pesticides might have a heightened risk of a disease. So if I knew someone had a GBA mutation, I would be, like, doubling down organic produce, organic dairy products, because when you eat a cow, you’re not just eating the cow, but you’re eating what the cow ate, and the cow ate fat-loving pesticides, they get magnified, they get concentrated as they make their way up the food chain. I’d be especially careful about well water. About 40 million Americans get their water from well. Many of these wells are contaminated by pesticides. People could be drinking in this pesticide-laden water for years and not know. So if you do carry it, I would be especially concerned about pesticide exposure, regardless of age. LRRK2 the most common genetic cause of Parkinson’s disease affects about 2-3% of people with the disease, and these studies have been done in large parts of the world. But those who carry a LRRK2 mutation, only about 40%, the lifetime risk of Parkinson’s is only about 40%. Said another way, most people with the most common genetic cause of Parkinson’s disease will not develop the disease. Now, the gene-environment interactions have not been worked out well, at least to my knowledge, on that. My colleague, Dr. Brian and Dean Miranda and others are looking at this. But it turns out that trichloroethylene, that dry cleaning chemical that I talked about earlier, it mimics the biological effects of LRRK2 mutations. A little bit of science for your listeners. Genes encode proteins, which are the workers of cells. Not surprisingly, the LRRK2 gene encodes a protein called LRRK2 kinase, and it increases the activity, that mutation increases the activity of LRRK2 kinase. Turns out that trichloroethylene actually does the same thing, it increases the activity of LRK2 kinase. So we know from the genetic research, which is important to have been done, and it’s very helpful for us understanding the pathophysiology, and it’s perhaps easier to study, that the environmental risk factors are often mimicking the pathophysiological changes that we see in the genetic forms of disease, and, you know, as you mentioned at the outset before we got on the air, you know, you study mitochondrial function, and almost all the environmental causes of Parkinson’s disease, almost all the genetic and environmental causes of Parkinson’s disease lead to dysfunction of the energy-producing parts of cells called the mitochondria. Robert Rogers: So, that’s a really great overview, and it sounds like what you’re saying is, perhaps it, like on all questions around diagnostic testing and genomic testing, it is an individualized decision. There are benefits to perhaps knowing that you carry this increased genetic risk in terms of your ability to modify your exposure, be extra diligent about modifying your exposure to certain environmental variables. But on the other hand, that has to be weighed against any increased anxiety that it might cause in a person when, ultimately, even the most penetrant of these genetic mutations, actually, you still have a less than 50% chance of developing disease. Ray Dorsey: There’s a great study called PD Generation, led by the Parkinson’s Foundation. Huge call out to Roy Alcalay, Dr. James Beck and others. Offers free genetic counseling and genetic testing for people with Parkinson’s disease, and they… they looked at the results of the first 8,000 people that they did genetic testing, and only 13% of them carried a genetic cause or genetic risk factor for the disease. And so we can answer these questions definitively because we’ve done research. And because organizations like the Parkinson’s Foundation has invested money and time and energy into addressing these important questions, we now need to just turn the page and invest even more money, time, and energy toward investigating the more important environmental causes of Parkinson’s disease and many other brain diseases. Robert Rogers: Great. Let’s switch gears for a second and talk about this exciting new era we’re in of new tools and procedures to detect very, very early, perhaps even totally preclinical Parkinson’s disease, because these technologies, I think, are going to allow us to have a more precise approach to early intervention. You mentioned this very interesting statistic that you said, on average, when somebody presents clinically with Parkinson’s disease, by that point, about 60% of the relevant neurons are already gone or significantly damaged, and so it seems very intuitively appealing that if you could pick off the process before it gets to that point, you could really make a difference. So, could you give us a little bit of an overview of, kind of, the current state of that exciting field, the current techniques that have been developed and are being developed to detect very early or preclinical Parkinson’s? Ray Dorsey: Yeah, so there’s been a lot of headway in this. There’s some great research done by my colleague, Dr. Andrew Siderowf, and his colleagues working on the Michael J. Fox Foundation’s PPMI study. Parkinson’s Progression Markers Initiative, and they found that there’s a marker in the spinal fluid of this misfolded protein called alpha-synuclein that can help identify people with Parkinson’s disease and give you an objective finding to help differentiate those who have Parkinson’s disease from those who don’t. There’s, increasingly available skin testing, so we know that Parkinson’s disease doesn’t actually begin in the brain, it actually begins outside the brain, at least for the vast majority of individuals, either in the gut or in the nose, and some of the pathology can spread to the skin. And there is a company that’s developed a skin test that finds misfolded proteins of people with misfolded protein of alpha-synuclein in individuals with Parkinson’s disease and some other Parkinsonian disorders. Now, how soon they can find that hasn’t been well established, but that’s out there. Are there imaging tests that can identify loss of dopamine-producing nerve cells in the brain? There currently are, to help differentiate whether people have Parkinson’s disease or a different other tremor disorder. Those tests might be helpful for identifying people before they have the diagnosis. There might be blood-based biomarkers that in the future could do so. You can imagine AI being really good at helping identify some of these early subtle features of the disease. But more fundamentally, this is fundamentally a preventable disease, and the way to address lung cancer, the way to address Parkinson’s disease, is to stop smoking and to stop getting exposed to these environmental toxicants. We can just create worlds without these diseases. Parkinson’s disease was extraordinarily rare for 99.9% of human history. Two centuries of Parkinson’s disease is enough. It’s time to say goodbye to Parkinson’s disease. Robert Rogers: Very, very compelling rallying cry, and I really like in your books and in your writing, you know, really identify Parkinson’s as this terrible enemy, and really that we have to have multiple, multiple layers of defense, and by far the most important is changing and modifying our environment and our risk of exposure to the things in the environment so that we prevent the initiation of the Parkinson’s pathology in the first place. But then, for the unlucky percentage of people in whom the beginnings of this pathology starts to take hold, there have to be interventions to identify that at an early enough stage, and then add interventions to retard the progression or one day halt it. And I just want to ask kind of one more question about, compare, really, how we can make more progress along this early intervention and early detection front. And maybe a helpful point of departure is a little bit of a comparison to where we are in that prevention and early detection and intervention landscape with Alzheimer’s disease, right? So Alzheimer’s is, I believe, epidemiologically the number one most common neurodegenerative disease, Parkinson’s number two. They share these similarities in that, you know, they’re both named after a very astute doctor who lived somewhere between 100 and 200 years ago, and noticed very distinct things in the first patients who they wrote about. And both, even before we’re in this current modern era of molecular biology and genetics had these pathological hallmarks that skilled people could see under the microscope. And you mentioned the Lewy bodies, these alpha-synuclein inclusions in Parkinson’s disease, and perhaps the equivalent, so to speak, it’s an imperfect analogy, in Alzheimer’s disease are these plaques composed of beta amyloid. And in the case of Alzheimer’s disease, and I don’t want to get too detailed in that discussion, because in short order, we’ll have a dedicated episode to Alzheimer’s, but basically, there were many false starts in developing therapies that sort of blocked or reduced the burden of these beta amyloid plaques, but then after many years of trying, there are now approved therapies that help to clear out some of those plaques, and they were first shown to have some clinical benefit in people with early stages of Alzheimer’s disease, so people that had symptoms but were not fully, fully gone. And then, as that was shown, you’re able to kick off clinical trials that pull those therapies earlier and earlier into the disease course. So now, people with the very earliest stages of mild cognitive impairment, and in fact, there’s even studies that are ongoing of people that are completely asymptomatic, but you can detect radiographically a burden of these amyloid plaques in their brains. They’re people who are at high risk. And I don’t think we’re at quite the same point in Parkinson’s, in that we don’t yet have an approved disease-modifying therapy that acts on that pathologic hallmark of disease that we can then bring forward into early intervention. So I would just love to hear, sort of, your own roadmap or overview of what’s going to have to happen and how we get to that similar place. Ray Dorsey: So… a lot to unfold, So, Parkinson’s described in 1817, Dr. James Parkinson, Dr. Aloise Alzheimer, a psychiatrist with a penchant for the microscope, describes Alzheimer’s disease in 1906. It’s kind of odd that the disease that affects 7 million Americans wasn’t described until just over 100 years ago. Did we miss a lot of Alzheimer’s disease, or is Alzheimer’s disease a new disease, and I… we probably missed some, but I think that it certainly wasn’t as common 200 years ago. George Washington, John Adams, Thomas Jefferson, Ben Franklin, none of these individuals, as far as we know, had Alzheimer’s disease, and even though almost all of them lived to over their 60s and some into their 90s. In 2003, a really smart German pathologist named Heiko Brock, who’s studied the pathology of both Alzheimer’s and Parkinson’s disease, put forth a new hypothesis for Parkinson’s disease. He says that the pathology… that Parkinson’s disease is not primarily a brain disease. Parkinson’s disease has its roots not first in the brain, but outside the brain. He said, when I look at the brains of people with Parkinson’s, I first find the pathology in the smell center of the brain. And in nerves that go to the gut, called the vagus nerve. And he thought that the pathology of Parkinson’s disease might begin in the gut, much like polio, and that it could be due to neuroinvasion of some kind of infectious particle. He thought a virus, which likely is not the case, at least for the vast majority of individuals. But that this pathology could spread like a fall of a row of dominoes up the vagus nerve, the pathology spreads to the vagus nerve, then up to the parts of the brain that control sleep. Then up to the parts of the brain that control movement, and up to the parts of the brain that cause thinking. As the dominoes fell, new symptoms would develop. Constipation, sleep disturbances, acting out your dreams, REM sleep behavior disorder, Parkinson’s disease, dementia. Well, it turns out that the pathology of Parkinson’s disease is not the only one that begins in the nose. He made less out of the nose, but in 2019, a really smart Danish scientist, Per Borghammer, said there’s two forms of Parkinson’s disease, one that begins in the gut, he calls that a body-first form. And then a more common form that he says begins in the nose, the smell center, the olfactory bulb that he called a brain-first form of the disease. And we know that for both Parkinson’s and for Alzheimer’s disease, one of the earliest features of the disease is loss of smell, and that one of the earliest places you find the pathology of both diseases is in the smell center. And we know that, air pollution plays an enormous role in Alzheimer’s disease, and a more modest role, but important role in Parkinson’s disease. So I think both these diseases, in many cases, begin in the smell center. And they’re both exploiting the front door to our brain, which is our nose, which doesn’t have the normal protective blood-brain barrier. And allows chemicals and pollutants, some really small one-third of the width of the width of our hair, to penetrate the nerve responsible for smell, called the olfactory nerve, hanging up in our upper nasal passages. And with it, it brings in dangerous hitchhikers, like toxic metals, lead from gas, iron from brakes, platinum from catalytic converters, and setting up the disease. What separates these two diseases right now is that we have great markers of Alzheimer’s progression. My friend, my colleague, my classmate, Dr. Dan Skovronsky, and others developed imaging of amyloid plaques. He did so when we were still in training. He created one of the first imaging companies for amyloid called Avid Radios Pharmaceuticals that was later bought by Eli Lilly. And now he’s the Chief Medical and Scientific Officer for Eli Lilly. And because we have these great imaging markers for amyloid or beta amyloid in Alzheimer’s disease, we can more readily determine whether new medications, including medications that target that misfolded protein can reduce the amount of amyloid in the brain, and whether those reductions in amyloid in the brain can be associated with clinical improvements. And we have a whole new class of medications that can lower the levels of amyloid in the brain, and appear to have a clinical benefit, and have been approved by the FDA, and have benefit to people with Alzheimer’s disease. We don’t have such, great imaging markers for, Parkinson’s disease. My colleague, Dr. Ken Marek, has developed a little bit… has developed an imaging modality, but it’s a little bit less sensitive than the amyloid, compound amyloid imaging, in part because the concentrations of the misfolded protein in Parkinson’s disease are much lower than that in Alzheimer’s disease. So if we want to get highly effective treatments, I think we need an objective marker of the disease. Imaging could be one way to do it. Markers in the spinal fluid, the skin, the blood might be others, but that will be the way to get us better treatments. But I still say an ounce of prevention is worth more than a pound of cure, and we can just create a world without these diseases, just like we can create a world without lung cancer, a large portion of lung cancer. We can create a world without Parkinson’s disease, a large portion. We can prevent the vast majority of ALS, we can prevent a lot of intellectual disabilities, we can prevent a lot of Alzheimer’s disease. Robert Rogers: An ounce of prevention is worth a pound of the cure. Words of wisdom from an inspiring scholar and innovator in the field of Parkinson’s disease. Dr. Ray Dorsey, thank you so much for joining us. I really learned a lot from our conversation. Ray Dorsey: Thank you very much, Robert. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

6. 

   18 Feb 2026

   Episode #2: The present and future of genomic screening with Dr. Michael Murray

   Foresight Medicine Episode #2 Transcript Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic and whole-body framework for leveraging new technologies to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. I am very honored to have as my guest today Dr. Michael Murray. Dr. Murray is Professor of Medicine at the Icahn School of Medicine at Mount Sinai, where he is Chief of the Division of Genomic Medicine and Clinical Director of the Institute for Genomic Health. He is a foremost expert in and a true pioneer of the field of genomic screening and integrating the burgeoning science of genomics into actual clinical practice. In addition to being a leading researcher in applied genomics, he has shaped the field as an architect of genomic education for medical professionals, journal editor, a key contributor to task force guidelines and policy statements in the area of genomic medicine, and as founding director of Mount Sinai’s Genomic Health Clinic. I also want to add that Dr. Murray is the senior author of a beautiful review of this topic, entitled DNA-Based Population Screening for Adults, published January 27th in the New England Journal of Medicine Evidence, which frames the topic we are discussing today, and I encourage all of our listeners to read it, and hopefully our conversation can lead to even greater understanding of this topic. Listeners should note that we are recording this on Wednesday, February 11th, 2026, and this conversation is for general information purposes only and does not constitute individual medical advice. Michael, welcome, really excited to have you on and to be talking with you today. So, one of the many reasons I’m very, excited to chat with you and have you as a very early guest in this podcast series is that the goal of this whole project is really to envision the future of preventive health across different organ systems and categories of disease. And I believe that advances in genomic screening are the foundation of this whole enterprise. It’s really the general-purpose technology that’s opening up new opportunities to identify disease risk at a personalized level. So, let’s start with a pretty general question. What is genomic screening, or as you’ve recently termed it, DNA-based population screening for adults, and how did you get drawn to the field? Michael Murray: Yeah, so, so we’re trying to get people to adopt, the term DNAPS, D-N-A-P-S, just because saying the longer things is a mouthful. But, I got interested in screening, in, the early 2000s. I had left, internal medicine infectious disease practice to become a, a geneticist and refocus my career, and I was at Brigham and Women’s Hospital, and taking care of adults, with rare genetic disorders, but particularly interested in, in bringing the information we were learning to the, to the greater population. And at that point, it was, it was theoretical. There were a few companies that launched in the early 2000s, Navigenics and, 23andMe, and they were starting to, to think about this from a business perspective, but it was really the ClinSeq project at the NIH in 2007-2008, led by Les Biesecker, that was the first to, to do this at scale. They came out with a paper showing that they were identifying cases of BRCA in patients that had no no personal or family history, that would go along with that, and, got very interested in their paper, and left Harvard a couple years later to go to a cornfield in Pennsylvania, where Geisinger Health System is, to really, launch a large-scale project in screening. Robert Rogers: Very interesting on multiple levels, including how you, early on, saw the power of this field and sort of reoriented your career. Just for our listeners, BRCA is a gene that confers increased risk for multiple cancers, and something that actually has come up on another one of our podcasts when we talk about multi-cancer early detection. So. Nowadays, that’s… it’s actually quite striking to think that these key efforts that enabled this new field are only about 15 to 20 years old. But nowadays, when somebody thinks about DNA-based population screening, tell us what… what are the tests? What is the tests that are available? What is the actual information, the genes and the variants that they contain? Michael Murray: So, there’s a couple different technical processes that can be used to create the dataset for an individual. The two, most common are what’s called a whole exome sequence, or a whole genome sequence. And the reason why, projects are deciding one versus the other is still mostly around cost. A whole genome sequence gives you all the information in between the genes. You have 20,000 genes, and they only make up about 1-2% of all the data. Everything else is in between the genes, and a lot of that is regulatory information, regulating the genes to turn on, turn off. Turn up, turn down. And so with, with an exome, or a whole exome, you can just get the 1% to 2% that has the gene data, which is where most of current efforts are focused. You can do the whole, genome and get all the data, but right now, you basically ignore 98 or so percent of that data, just because we don’t know what to do with it. Robert Rogers: And, at your own clinic, can you tell us a little bit about what’s actually offered? Michael Murray: Sure, so, so at the Genomic Health Clinic, we, we have people that come in, sometimes referred by providers for an indication, meaning that, you know, they, they have a family member with a genetic problem, and they want to be tested for it. So we call that, diagnostic care or indicated care. Others come in for screening. They, some are, very educated about it. You know, we have scientists and geneticists that come in, and doctors, and others just have this correct notion that they could learn more about their health risks if somebody looked at their DNA and screened it for common risks. So, we… the most common test we do there is called, well, it’s a 163 gene panel. I mentioned that we have 20,000, and it just picks out 163 genes that are the ones we know the most about, and that we can do something with the information if we find a problem. So, about 80% of those 163 genes are either for cancer risk or heart disease risk. That’s really where we have the biggest area of knowledge. And then the third category is just miscellaneous. There’s a number of different, conditions that we know enough about to look for a problem and then address it if we, if we find a problem. Robert Rogers: Yeah, so I really want to double-click on that, because I think that’s so interesting. As you said, there are about 20,000 human genes, and the report that a patient gets back, or that someone who’s interested in screening gets back, contains information on 163 of them. So, could you say a little bit more about the criteria that are used to determine if a gene and a variant should be included in the report to patients? Michael Murray: Yeah, so the, you know, the, the data, that can be generated through these processes, doesn’t change. This is called our germline data, so it’s different than some of the other conversations you’re having about, about cancer genes that have, have a mutation. So this is the germline data in an individual, and that can be looked at to see if there is a disease-associated or a pathogenic change that can be recognized within the code of the gene of interest. So, I’ll borrow the, explanation from my genetic counselor, who gives a great, description of what we do. So, a gene is like a paragraph of, letters, and what we do is go through and do a spell check, and we might find a change that changes the meaning or breaks the function of the gene. Or we might find a benign change, meaning, the example I always give is, like, spelling the word gray, G-R-A-Y, versus G-R-E-Y. It’s a different spelling, but it sounds the same and it means the same thing. We’ve got lots of those changes in our genes, and it’s the ones that actually break the function of the gene that we’re interested in. Because then we can predict the risk that’s associated with not having that gene function. Robert Rogers: Right, so there’s at least two important elements, it sounds like, to deciding the genes that comprise the test. One is being able to assess the pathogenicity of a given variant, and another is how actionable, or not actionable that is. And, let’s… talk a little bit more about both of those aspects. So, first of all, in terms of determining the significance or the pathogenicity of a variant. So, the DNA sequencing machine, it reads all the letters of someone’s DNA, but then to determine if that is relevant to health or associated with the disease, we need to have a system for describing that variant, and you’ve written a lot about this. Can you describe a little bit about the system that’s used to grade variants in terms of being benign or pathogenic? Michael Murray: Yeah, so in, about 15 years ago, there were a number of diagnostic labs, and they had their own internal databases that they used, and sort of one of the reasons to use one lab versus another is whoever had the most data about what were the problematic changes in a particular gene. So you had… you had labs built just to look at one gene, and they were the experts in that. As the data set started growing and the interest started growing, it was recognized that there needed to be a common repository for that information. So, rules were set up on what causes a change to be pathogenic, or likely pathogenic, so disease associated. What information you need to categorize something as benign or likely benign, so just, a incidental change that doesn’t matter. And then there’s a vast middle where, we don’t have enough data to interpret a gene change. Those are called variants of unknown significance. And if we sequenced, 100 people, we’d probably find variants of unknown significance in common genes in at least, 10 or 20% of them. So it’s… it’s… we’re still in the days when, when we have data that we just can’t interpret. And so, we don’t focus on that when we’re doing screening, because giving somebody back information that you can’t interpret isn’t very useful. For a screening effort, we focus on the pathogenic and the likely pathogenic, because those are the ones that we know are disease-associated, and there’s something to do about it. Robert Rogers: And as you said, you know, if you take 100 people, somewhere between 10 and 20% of them might have a variant of uncertain significance in a common gene. Where does that compare to, say, 5 years ago, and where do you think that will be 5 years from now? Michael Murray: Yeah, great question. So, the, the repository, at one point, I, I did a little, It… day-by-day analysis, this is probably 5 or 10 years ago, in the, looking at the BRCA genes, to see how quickly the information was moving. And there was a pathogenic, variant per day being, being, put into the repository. So, that gene, because it’s probably the most tested gene clinically. That data set is growing, and continues to grow on a daily basis. Other genes, for conditions that are, that get less attention or are less common, they grow much more slowly. And the way that the data grows generally is through clinical experience. So if we have a family with a genetic condition, and we figure out, the change in the gene that’s causing that condition in that family, then we… we get enough information and work together with the lab to, to classify their variant as pathogenic. So it’s… it’s sort of families and individuals where variants are seen multiple times that starts to give us confidence that a gene change is pathogenic. There are some genes where there can be a laboratory test where you can figure out the genes broken when you look at it in, in a cell culture or in a, in an experimental way. So data comes that way, too. But it’s a slow-moving task. There’s a lot of people that are interested in, supercharging this by coming up with better systems for moving something from unknown to either benign or pathogenic. Robert Rogers: So, let’s switch to the other half of the equation of what determines whether a gene is sort of included in the report that a patient might see, and that’s its actionability. And I’m quite curious about this topic, because to me, defining actionability is not so straightforward, and I’m curious, sort of, what the current criteria is, and your thinking, but also going forward, how do you think we can account for variation in patients’ preferences, and perhaps an individualized desire to tailor the amount of information to their own notion of what actionability means? Michael Murray: Yeah, so, I don’t like the term actionability, but I don’t have a better one. Okay. So, I think of it more, being more close, to what, what people have called clinical utility, so… Robert Rogers: I will update to using clinical utility. Michael Murray: Yeah, no, actionability is stuck, and we live with it, but it’s a little vague, and so clinical utility in my mind, and I’m sure there’s a bunch of different, definitions out there, but that’s the idea that, you know, if I screen you and find a change in a gene of interest that I can then offer you, some action or set of actions, whether they’re changes in behavior, or medicine, or surgery, something I can offer you that will either prevent you from getting the problem or attenuate the problem if it occurs. So I’m sort of, on the more classical idea about what actionability is, or what you do with results. For a long time now, there’s been a lot of people that have said, well who are you, or who is the medical establishment to tell me whether it’s actionable or not? What if I want to know the information in order to plan my retirement years, or just make personal decisions? And people often call that personal utility instead of clinical utility. And those are obviously important things, but those are also measurable things, so we could set up studies and designs to, you know, kind of gather the information. If we give somebody a result back on whether they might get a disease or not, and they’re less depressed, or they, or they make life changes that are important. You know, that’s… I would consider that clinical utility, too. But, you know, when we’re in these early days and we’re deciding what to prioritize, I, I don’t see that rising to the top of the list of things that we, we really need to do first, when you figure… You know, we could be preventing, heart disease or cancer in a large, portion of the population. That seems, that from a medical point of view, is probably, the top-tier set of tasks, and, would… one of the interesting things about genomic data is once you have the… once you have the data set, you can use it for all kinds of things. So we’ve been thus far in a… in a world in which the data sets are expensive, especially to do them at scale for a group, and so we’ve focused on these, classical clinical utility idea. But, we right now, in our clinic, run a genome or an exome on people, and, they often ask for their data back. And I always encourage that, at least to save. You never know. But one of the questions I always ask, just out of curiosity, is what do you think. Robert Rogers: And just so I understand, when you say they ask for their data back, meaning they ask for data beyond the 163 genes that are included in the report? Michael Murray: Yeah, so I failed to mention that we do the 163 gene most commonly. But we also do whole exome and whole genome for people, and we get a report that we give them back that has, you know, genetic risks. It matches that 163 gene panel, and then it goes beyond it to talk about things like carrier status for recessive conditions, which have no direct, effect on the person’s health, but… but is… they’re important in, family health and reproductive health, Robert Rogers: We’ll go to carrier stuff in a little bit. We can bypass that for now, yeah. Michael Murray: All right. Yeah, so, when we do the whole exome or the whole genome, people have much more data than has been interpreted, and some of them want a copy of it. So, we work with a laboratory that will, give them their entire file. And so you know, I think over time, more and more people will want that, and more and more people will have options to do something with that data, all kinds of things. Ancestry is a simple thing to get to. We know people have been doing that with genetics for a while now. But also, you know, even making new discoveries that science and medicine haven’t made, I think will have, sort of, people looking at their own data and making observations that then become important for everybody to know about, not just them and their family. Robert Rogers: Yeah, and that kind of leads into another thing that I think is quite interesting, and something that I know you’ve given a lot of thought to, which is how our notion of what is clinically useful, or what has clinical utility, will continue to increase over time, for at least two reasons. One is that as we obtain more genomic information, the number of variants that we learn this might actually be important, this might be pathogenic, will increase, and will decrease the space of those that are of unknown significance, but also because there’s new treatments and new therapies being developed all of the time, and what a few years ago completely lacked clinical utility might today have a clinical trial, and tomorrow have an approved therapy. So what’s our current framework for reassessing information and expanding the notion of what’s clinically useful in a genetic report? Michael Murray: So, a couple ways to think about that. One is, in the, in the large, cohort, projects that I’ve been involved in, there, they’ve all been associated with a research element, so there are people that get access to the data, and participants agree to this. Their identities aren’t revealed, the data is not shared beyond the team. : But they’re going into the data and looking for, new, new things in the data that are important, related to human health. So there’s that research going on. And the idea is that some of that research that might come out of a big project might be important enough that, that we bring it out of the research realm and give it to the patient, to then take to their, doctors and get treated. So the idea that you could, participate in one of these projects, and it might, help us all learn, and then bring important information back to you is possible. The other less cutting edge, but just as important, way in which reviewing the data periodically can help is, for the reasons that you said, that we’re learning about new variants in common genes, that if I analyze your data now in February of 2026, a year from now, two years from now what we called, unknown significance might now be known to be significant, and we might give that back to you to let you go get targeted care. Robert Rogers: It’s also interesting to think about the different care system frameworks that have been set up to do DNA-based population screening, you’ve written about how there’s at least three kind of major paradigms. You can think of the public health paradigm, where a governmental or health authority of a country or a region will offer DNA-based population screening the way that there are blood pressure screening fairs, right? It’s a public health good. There’s the one that I think people are actually most familiar with, which is direct-to-consumer. 23andMe, which started with a heavy ancestry focus, but now many companies say, you know, swab your cheek and send this off, and then we’ll send you the report. And then there’s really integrating it into a healthcare system and care delivery the way that you do at the Genomic health clinic. Did those three approaches tend to have significant differences in the type of information that they are including. Michael Murray: Yeah, so the, the public health idea. A lot of people that, are familiar with that on the healthcare delivery side are most familiar with the newborn screening approach. So, every baby, when born, gets a small blood sample taken and looks for up to 40 different conditions that they might have, many of them, genetic conditions, and so that evolved slowly from the 1960s till now, and it found its way into state departments of public health in the United States. So each state kind of, operates that program, within the United States. In other countries, it’s done differently. Some, it’s through the central government. To do that now, is something that people have discussed, but I’m not sure that, we’ll align all the right parties to… to make that a publicly funded project, in the near term in the U.S. On the other hand, Australia has, has at least done this at at an initial scale, a public health funding and organizing of genomic screening, and they just recently published their data, so a lot of people are watching that closely to see how that goes. The direct-to-consumer idea is now, you know, at least 25 years old with the genetics. And the worry there, has not been, so much about the deliverable back to the patient, but more whether that information that goes back to the patient ever makes its way into the health system to deliver the good that, was… is promised by… by the results. So, 23andMe, in a blog post said that they, they have 20,000 people with BRCA results. And… It’s not clear how often that gets back to, you know, people take it to their doctor, and sometimes their doctor’s an expert in it, they know exactly what to do. Other times, they’re just not familiar enough with it to kind of take whatever the next steps are. So the concern there is that that extra step might be a barrier to optimal treatment. And then the, you know, the integrated programs that we have, I think, you know, this idea that an entire health system would be bought in, and they’d create a process for doing this, is probably the model that, we’ll end up being the most used, unless there’s a change in, in the funding structure, because right now, those health systems are motivated to do extra care for their patient, and right now this is considered extra care. And so, we have a growing number of health systems that are supporting this, but it’s still an expensive thing for a health system to take on, and there’s not really a reimbursement model that works yet. Robert Rogers: Yeah, that is a major challenge, and I would love to touch on that a bit at the end. But since you brought up healthcare systems concerns, I’m curious what your assessment is of how prepared the healthcare system is to monitor people who have been identified as increased genetic risk for a disease. You talked about the issue of sort of inaction around BRCA findings, but I imagine among genomic findings, the hereditary cancer syndromes have a somewhat established pathway for care in terms of increased screening and patients for whom even prophylactic surgeries are offered. But outside of cancer, if you go to your cardiologist, or your nephrologist or your hepatologist and said, I did a genomic screen and I have increased risk for this, how prepared are they to monitor you on a long-term basis? Michael Murray: So as you might guess, it’s all over the map. There’s some people that are very prepared, some people not prepared at all. The, the thing that, that cancer screening has, evolved to, provide is there is a, a national organization, NCCN, that, creates guidelines for cancer management. It also creates guidelines for cancer screening. And so they get very detailed and frequently updated, sort of step-by-step processes for what to do if somebody has a positive screening test for a cancer risk. So in a lot of ways, they are leading the way in how we’re going to need to do it as this becomes more and more common. There are some areas that it might be very valuable to get information back, but it’s still going to be hard to find the specialists that have, sort of, the pathway that needs to be followed. So we’re right… right now working on, the American College of Medical Genetics recommendations for population screening. They should come out later this year, but one of the questions that we’re, we’re really, digging in on is, if we support a list of things to be screened, they not only have to have clinical utility or actionability, but the health system has to be ready to handle this at scale. So if you have a genetic risk that requires a follow-up of a colonoscopy, systems are set up to increase their numbers of colonoscopies per year. But if you have a health risk that requires a subspecialty cardiologist, an electrophysiologist to handle your risk for an irregular heartbeat, then the health system may not have the workforce standing ready to expand in that way, so… so we have to make sure that anything that we’re screening for, we have systems in place and workflows in place that can manage the follow-up, or else there’s no point in doing the screening, to find something that people wouldn’t be able to get the right next steps for. Robert Rogers: Got it, got it. Yeah, that seems like it’s going to be one of the major challenges, but also opportunities for the healthcare system over the next decade or so, and that’s one of the things we’re really interested in exploring as part of this Foresight Medicine project. So, there’s one more key concept that I think’s important for our listeners to understand when we talk about DNA-based population screening, and that’s the concept of penetrance. And for most of these diseases that you would report back in a genetic test, it’s not as if having the variant of concern leads to a 100% deterministic certainty that you are going to get the disease, right? There’s a degree of uncertainty, and maybe just talk through how you think about that concept, and more importantly, explain it to patients, and how they receive that concept. Michael Murray: Yeah, so… so penetrance and variance of unknown significance are things I think about all the time, because they’re the trouble spots. Yeah. So, penetrance, you know, the idea that I have a risk, but might never have the bad outcome associated with that risk is something that we have to continue to work on and address. In my talks, I often show a picture of a 100-year-old woman, with a cigarette that she’s lighting off her 100th birthday cake. And, she… her name is Winnie Langley, and she was… she made the press about 10, 20 years ago, because she was still smoking at 100, and I always… show that slide right after I introduced the idea of penetrance, because within healthcare, we’ve been telling… making recommendations in every area of healthcare, some of which we identify risks that don’t ever become relevant for that person. So I always say that Winnie Langley probably outlived most of the doctors that told her to stop smoking, it’ll shorten her lifespan. Robert Rogers: Almost certainly, yeah. Michael Murray: But on a serious note, the thing that we have to do is if we’re giving people back risk. We have to help them to understand what’s going to happen next, and how we’re going to manage the situation if they get evaluated and they don’t have the disease that we say they’re at risk for. And it’s going to be different in almost every gene, certainly in every category of genes. So, BRCA testing is now 30 years old, and what’s happened there is that periodic evaluations, mammograms and MRIs are done to address the risk of breast cancer in someone that has a BRCA risk variant. It’s not a one-time-and-done situation, and 30% or more of women that find out they have that risk will never get breast cancer. And so we have to prepare people for that situation and help them to understand that we have a plan. If the risk is for something like alpha-1 antitrypsin, we know that there are specific environmental triggers that can be avoided. And so, obviously, coaching them towards that, because that’ll increase the penetrance of the, of the gene risk if they’re smoking. There’s not a whole lot of those very specific, sort of, do’s and don’ts, once we give a monogenic gene risk, because these monogenic single-gene situations are very highly penetrant, that some of the lifestyle measures that we’re used to for lots of risks might not impact it greatly. So we have to help people to understand, you know, you’re going to need to undergo periodic screening, or this is where the data’s at with each situation. One of the things that’s been interesting in doing screening is we can identify a risk in an individual. I’ve seen a bunch of cases of this, and that individual who’s participated in screening in the clinic or screening in a big project does not have the disease or condition that they’re at risk for. But what we always encourage is what’s called cascade screening, so screening out to their brothers and sisters, their children, potentially their parents. And we, we know that if it’s an autosomal dominant condition, that 50% of those siblings or children will have the same genetic risk, and we find lots of situations where the first person doesn’t have the disease, but their sister might, or their brother might, or one of their children might. So, why is it penetrant in the brother and not the original person? We don’t have a deep enough understanding of the biology to answer that right now. But we know that it happens. So you can, from screening, identify a risk that’s actually a family risk that might bring benefit to your family But maybe not directly a health benefit to you. Robert Rogers: Yeah, that’s a really interesting side part of this whole effort, this notion of cascade testing, and who is the patient. It’s not only necessarily the patient who first comes to you, but the larger family. And along those lines, I’m curious if there are big lessons that we can draw from the large-scale efforts that have been done to date, so I think you wrote that there’s something like 5 million or so people around the world who have now participated in large-scale DNA-based population screening efforts, either through a large healthcare system or a regional health authority type of program. And when you take a step back, are there kind of common lessons and themes that you can say, we’ve really learned that we can do these things well from the study of that many people, and other things where you say, these are really the big unanswered questions that still remain after having, processed that many people through those sorts of programs. Michael Murray: Yeah, so, we have a lot of programs going on, but there’s no, sort of common list of ways to do it. So, in a sense, each one of them is learning things that, that could become valuable lessons for other programs. So one of the things that we need is we need to get, these programs to… tell the world about their, their lessons learned as they go through it. Both genetic lessons, as well as just operational lessons about how to do this at scale. So the thing that we don’t have is a common set of rules, and it’s because, all these different programs acting in good faith are doing the best that they can. They’re learning sometimes from things that are published, other times they’re learning from experiences of rolling out screening for other things within a health system. So the gathering of the evidence for how to do this best is something that, we’re probably going to need organizational help on, meaning that, you know an authority like what was created in the U.S. government, to start to advise the 50 different newborn screening programs around the country what a standard practice should be and what conditions they should look for as a minimum list and how to do it. We have to create an infrastructure that’ll do that for population screening with DNA. Robert Rogers: One thing that I think is kind of interesting that’s come out of that work is some reasonable estimates of just the global prevalence of serious monogenic conditions that we can pick up through DNA-based population screening, but it looks like for the cardiac types of things and the cancer syndromes, as many as 1-2% of people are carrying these variants that put them at greatly increased risk, and if we expand our purview to some other diseases and other organ systems, I imagine it would double or more from there. And so, it’s a pretty significant chunk of our societal burden of disease, actually, that’s lingering there. Collectively, these things are… even though each individual one is quite uncommon, collectively, they’re… they’re not rare. Michael Murray: Right, yeah, just the, there’s what’s called the CDC Tier 1, the Center for Disease Control did some work, 15 years ago looking at conditions that have a genetic basis that are common enough that if you screened for them at a population level, you could bring a population benefit. And, those conditions are driven by just 9 genes. If you looked at those 9 genes across every population that’s been looked at so far, so it’s not just certain ethnicities or ancestries, but every population seems to be 1 in 75. That number keeps coming up. Sometimes it’s 1 at 70, sometimes 90, but yeah, it seems that way. And, you know, when that data first came out, Geisinger was one of the first places to have the data, and we let people know that, and people said, well, you know, the population you serve is almost exclusively European ancestry in that part of Pennsylvania. And will this work in other places? And we didn’t have a good answer for that, but now there’s been, large projects that have included, significant, number of people with, Mexican ancestry. In New York, it’s been done with people of all kinds of ancestry, and the number keeps coming up at about 1 in 75. So, that’s a lot of people. Robert Rogers: So I want to switch gears just slightly, although we did allude to this earlier in our conversation. So, we’ve been focusing on identifying and talking about genetic variants that directly affect the health of the person who gets the test. But DNA-based population screening can, of course, also be used to identify genetic carrier status. And for our listeners, I think when many people think of a, quote, genetic disease, they’re actually thinking about these sorts of recessive conditions that are sort of the… what comes to mind when you think of genetic diseases. Cystic fibrosis, sickle cell disease, where people almost never have a, quote, family history of it, because by definition, your parent… one parent carries one mutation, your other parent carries the other mutation, and then statistically, one out of four of their children will be affected by the actual disease. And then there’s also, I suppose, the X-linked recessive diseases. So how is genomic screening handling carriers status? Michael Murray: So, about 5 years ago, somebody showed me a, a publication that showed, which specialist within healthcare are doing the most genetic tests? And, you know before, they showed this in an auditorium full of genetics and public health people, they asked the audience to guess who’s doing the most, and people guessed geneticists, they were wrong. They guessed oncologists, they were wrong. They guessed cardiologists, they were wrong. The group that’s doing it the most are, obstetrics and gynecology, and it’s because now, 7 or 8 years ago, the professional group, in OB-GYN they told their, their professional audience that carrier screening should be routinely offered to all women who are pregnant or considering pregnancy. And so what’s evolved very quickly over a 5-10 year period is this is routinely offered in the obstetrical setting, and the way that it goes forward is there’s a full sequencing of different numbers of genes by different labs, but about 700 genes, that are associated with autosomal recessive risk. And they’re analyzed, and, if the, prospective mother is, positive for recessive risk, then her, partner is, offered the test, and if the prospective father is positive for the same thing as the prospective mother, then there’s a 1 in 4 chance of a recessive disease occurring in any child that they parent together. And so, that’s full-on screening that’s being done in a specific setting for a specific reason. It’s really the example of one of the ways that I think this will grow in other areas of medicine. So that’s being done there. In our screening setting, for instance, in our genomic health setting, we give back the, all the recessive risks to people that get that whole genome or whole exome test, so they get that extra test. And often they get back a short list of, of risk factors that they don’t necessarily have a lot to act on. Many of them have already had their children, but we always encourage them to pass that on to their children, because when they start thinking about having a family, they’ll be of specific benefit. And so, recessive screening right now is mostly in the reproductive area, and it’s moving fast. And it’s really set up a model for just frontline clinicians ordering the test, managing the test, and calling in expert geneticists only when there’s a rare, finding or a problem that, that needs subspecialty attention. I think that’s all medicine will go. Robert Rogers: I’m a little bit curious that, as a system, we’ve settled for the obstetrical office to be the frontline provider there, and not moving it a little bit earlier in people’s lifespan from a public health standpoint. Because if you think about it, genetic carrier screening programs have been around for a long time. I believe that one of the first was for the Tay-Sachs gene in Ashkenazi Jewish communities. That goes back to the mid-1980s. I think, actually, for many years in several Middle Eastern and Mediterranean countries, upon receipt of a marriage license, it’s common to do thalassemia screening, a blood hemoglobin disorder. And to my knowledge, although I’m certainly not an expert here, I think they’ve been relatively successful. Those programs are thought to be successful. And the reason that they were limited to focusing on a single gene that was relevant to the population in which those programs were conducted was mostly one of expense, one of logistics. You couldn’t sequence the whole genome. But now you can, and it just seems to me like it would perhaps be a higher public health priority to move this information to people at an earlier point in their life. Do you think we’re going to move in that direction, or no? Michael Murray: One of the areas of screening that’s moving the fastest is genomic sequencing for newborn screening. So right now, it’s essentially a non-genetic test, the newborn screen. And there’s a lot of conversation I’m in on some of them, it’s not my area of focus, but once you do that genomic screen for a newborn, which is, of course, looking for serious disease in the newborn period, but then that child has that for their entire code, is what are you going to save it for to eventually give back other results that are not related to newborn disease? And one of them is autosomal recessive risk for the next generation. So, I think, we’re limited by, funding and maybe a little bit by imagination about how to do this, best. But as sequencing becomes cheaper and more, sort of, large pilots have been tried for all different, in all different kinds of settings for slightly different reasons. I think and I’ve predicted this in writing, I think what we’ll eventually get to, is that everyone will have their entire genetic code generated at birth, and that will be linked to their electronic medical record. At different points in their life, depending on their gender or their age, it’ll be screened for certain things that are relevant to them at that age and time. And, it’ll also be available to delve into for diagnostic reasons. So, Why don’t we have that yet? Just because nobody’s set up the system and been able to pay for it, but there’s no reason why it couldn’t be. That every child get their entire code, and it follows them throughout their life, and it gets…interrogate it periodically based on either some health concern they have or… or some need to be screened. So, I think we’ll get there. Everybody says, how long? Michael, how long? How long? I don’t know that answer. Robert Rogers: Yeah, well, no, I think that’s a very compelling vision of healthcare delivery going forward. So, just to switch gears once again a little bit, we’ve talked now for over 45 minutes, and we’ve discussed genetic disease really as about monogenic disease, right? But, of course when we think about most of the common human ailments that afflict adults, it’s the combination of the effects of many, many different genes combined with environment, and so that has given rise to a deeper understanding of what we call polygenic risk. Just briefly, talk a little bit about your assessment of the current state of what we call polygenic risk scores, what they are. They have generated a lot of enthusiasm, a little bit of skepticism. I think they’re constantly improving. So, as of now, where do you see their real clinical utility, and where do you see them heading in a few years? Michael Murray: So, polygenic risk scores, like you said, is this idea that instead of finding a single gene that, if not working, puts you at risk for a disease, that you’d look at hundreds or sometimes thousands of small changes across, dozens of genes, that contribute to that risk. One of the things that I think is most exciting about that is that, the way that the results will be reported from those tests. It’s easy for any provider to understand. So right now, one of the factors that’s a barrier to implementation across health systems is that the genetic reports come out, and sometimes you gotta be, gotta have a lot of insider knowledge to even understand what the report is saying. But polygenic risk scores are coming out, and they’re essentially a bell curve that puts that person at the highest percent of risk, the lowest percent of risk, most of us in the big middle for any and every condition. Risk for heart attack, risk for high cholesterol, risk for dementia, risk for less common things like multiple sclerosis or whatever. So, these results will be easily understandable by providers and by patients, and lots of people have started to give them back, and they’re… that barrier of needing insider knowledge is gone. The thing that we don’t have about polygenic risk scores that we need to get is the, clear plan for next steps. So… and that’s going to come through clinical research. So, a lot of people tend to forget that, I keep going back to the example, but it’s the prominent one. BRCA gets discovered in the mid-90s: And, it… there was 10 to 15 years of really intensive research, looking at prophylactic surgery, other interventions to show that they had real value to do those things. So when we come up with the polygenic risk score for breast cancer, and there are examples of that, it doesn’t mean that we can take all the same steps as we do with monogenic risk, because that… that came as a result of, important research, that proved it was valuable in that setting. So one of the stumbling blocks right now from just going out and giving everybody their polygenic risk scores for any condition they’re interested in, is that we don’t have the clear workflow of management that comes from that. So, that’ll come a lot quicker than it has in the past, but we need to work that out for each one. One of the most exciting things in polygenic risk scoring came out last year in the New England Journal of Medicine, it was the Barcode study. This study, took older men, and compared a polygenic risk score to the PSA test, which is a test that looks for increased, risk for prostate cancer, or even early evidence of prostate cancer being present. And everyone in medicine knows that, it’s… It’s the only test we really have for that, but it’s not a great test. There’s a lot of false positives and false negatives. The polygenic risk score outperformed PSA and MRI in screening men for this common cancer, and also in helping their providers know which ones need surgery or chemotherapy versus which ones can be slow-growing and just observed over time. So that kind of, specific use of polygenic risk scores is going to be sort of the leading edge of really getting this into practice, getting specialists and and generalists used to using it, and giving clear benefits. So I’m looking for more examples like that to really be the leading edge for polygenic risk scores to get them into common use. Robert Rogers: Right, so right now it sounds like their actual clinical utility for many conditions is not quite ready for prime time until we’ve defined the follow-up care pathway. Michael Murray: Yeah, and one other thing that I’d throw in is that we also have to prove that it’s giving us something different than what we already know, right? Right. So there’s been, lots of ways to figure out if somebody’s at high risk for a heart attack. If we’re going to add in a polygenic risk score, then there has to be data that it improves the prediction somehow. So, otherwise, why do the test? I think that data’s coming in a lot of important areas, Probably in the next 3 to 5 years. Robert Rogers: So, for the sake of completeness, I just want to make sure that you have a chance to briefly describe, kind of, the one other, or one other type of useful information that comes from genomic tests, and that relates to pharmacology. I don’t want to spend a lot of time on this, but this is how someone’s own individual genetic makeup determines their metabolism of drugs, and that could be very useful information in terms of choosing between classes of drugs, dosing drugs, if somebody needs a specific medication for something that they develop. What’s the current state of pharmacogenomics? How useful is it currently? Michael Murray: Yeah, so great question. Pharmacogenomics is something that’s generated a lot of excitement for at least two decades now, and because it’s so easy to understand, you know, the general population understands that, you know, I took this medicine and I got a better effect than my neighbor, my blood pressure went down, theirs didn’t go down, they had to get a new medication, or…I got a side effect, and they didn’t. So people understand that there’s something about their biology driven by their genetics that’ll cause them to react differently to drugs. So the concept is there, it’s easy to understand. The value of looking for certain gene-drug pairs, as we call them. So, a certain change in a certain gene leads to a different reaction to a drug. The most valuable ones, are limited at this point in time, so there’s a lot of observations on things that while, they, they may have a small effect, don’t have clear clinical utility, to go back to that term. There are a few that that absolutely do. I think the one that people got excited about was the use of this pharmacogenomic approach to decide how to dose warfarin. And a lot of attention and research went into that. But then you know, the pharmaceutical field moved on. They came up with better drugs than warfarin. Robert Rogers: Right, that would have been very useful in 2005, less so today. Michael Murray: Right, and in 1995, even more useful. So there’s a couple really high-value ones right now, and there’s a lot that are, probably useful, and some people, But, but not really driving excitement across healthcare. I think the ones that I look to as being most exciting is there are changes in, in a gene where the gene loses its function, and a drug known as clopidogrel, or Plavix doesn’t become activated in the system, so it’s essentially the same as taking a sugar pill if you have changes in that gene. And then you don’t get the anti-platelet, anti-clotting effect that you’re being given the drug for. So that’s one that’s a clear value in patients that are going to be getting those medications. Another one is there is a gene that can be changed in a way that can cause a very rare, but sometimes fatal reaction to a chemotherapy agent that’s been around for decades called 5FU. So, the difficulty with that situation is that it’s rarely used, and when it’s used, there’s often not enough time to wait around to get a test result for whether you’re going to have a reaction to the drug. Sometimes the chemotherapy gets instituted rather quickly. So we… what we haven’t done is come up with rapid tests for some of these things that we’re going… Until we screen everybody, which is my dream, of course, but until we get to that, we need to have, for pharmacogenomics, we have to have rapid tests that could be done in a time frame before the provider institutes the use of a drug, and that’s been a hobbling, or a barrier to, to, implementation for some of the really interesting and important, gene-drug pairs. The other thing is there’s hundreds, perhaps thousands of drugs that we don’t have that knowledge of pharmacogenomics on. So, we offer pharmacogenomics within our, within our clinic, and, people get back a 32-page report, that, that has all kinds of, important and interesting drug gene effects, but it doesn’t cover every, drug in the, in the pharmacy. So there’s limitations in the knowledge, and then there’s limitations in the implementation, but we need to get there. Robert Rogers: A few rapid-fire questions to bring us home. As we sit here in February of 2026, are there people for whom you would actively advise for or against doing genomic screening? Michael Murray: Screening is always voluntary. We’ll point out to people. You know, if you… if you screen an adult with that 163 gene panel, 4-5% of them will have a positive that they didn’t know about, and they could do something about. So, anybody that’s interested, and unfortunately, anybody that has the you need to have the money to pay for it, because right now, screening is not covered by any insurance, that kind of screening. So, some of the big programs are no cost, so participating in those programs if you’re interested, or getting screened at a clinic like we have if you’re, if you have the money to pay for it. And the cost, a lot of people want to know the number, so that test that I’ve referred to a bunch of times is about $300 out of pocket if you had to pay for, the 163 gene panel right now through a certified clinical lab and delivered through a healthcare system clinic like ours. I’d recommend to anybody that’s, thinking about building a family that they get the recessive carrier screen. About 1 in 50 couples, I’ve read, will get back a screen, where both, both of the prospective parents, have a positive that matches and need to do something about it. Robert Rogers: Is there an age limit past which the utility of genomic screening goes way down? I imagine you’re not gonna… you’re not gonna do much for an 100-year-old. What about 80? What about 60? Where’s the inflection point? Michael Murray: Great question. Honest answer, we don’t… we don’t know. But… Right now, there is data being built around people getting screened when they’re 20 to 30 in the adult realm. Because then you can do a lot of the prevention of cancer and heart disease to really bring measurable benefits across a large group. But there, you know, there are other conditions that are later onset, and so, you could learn things in your 50s or 60s that would still be valuable to you right now. And I imagine, you know, if this, recording lasts 100 years, they’ll be laughing at me for whatever I say, because when everybody’s living to be 130, there’ll be reasons to screen people later in life, too. So, I think, right now, if you said we’re gonna screen everybody in New York City, or everybody in the country. Pick an age that you want to do that at. The number would be 20 to 30 year old. Robert Rogers: That makes a lot of sense. Robert Rogers: People who come to your clinic who are not referred because of some specific medical concern in themselves or their family are not a random sample of the population. These are people who are especially motivated, and I’m just curious, are there common profiles, common motivations that you see in, quote, early adopters of genomic screening. Michael Murray: I think they are people that are, are, motivated to stay healthy and live long. And so, you know, there’s a lot of, different personality types that are motivated by that, but that seems to be the motivation by… by most everyone. There are others, and I think this is important, older adults that are motivated by learning about their risks so that it can benefit their children. A lot of people say, you know, if I find something out here, one of the most important things to me is then to pass that on to my adult children. So I think that’s an important motivation. Robert Rogers: Describe a little bit the patient experience at the Genomic Health Clinic at Mount Sinai. So, genomic information, it really sits at the crossroads of genetics, primary care, multiple specialties. So, how are results typically delivered, and tell us a little bit about the infrastructure that you think is required to do this effectively and responsibly. Michael Murray: So, so we have a, a two-visit, plan for each individual, and that can be telemedicine or face-to-face. The first visit, it surprises some people, but we actually take a detailed family health history as part of that first visit. And the reason is, people come in, sometimes saying, you know, there’s nothing that runs in my family that motivates me to come here, I just, you know, I just want to be screened to be healthy. And yet, when we take a detailed family health history, we can find, reasons to do specific tests in about, 5% of people. 5-10% of people, probably, that come in for screening and don’t. Robert Rogers: That’s a lot. Michael Murray: Yeah, and it’s not that they’re ignoring it, or they’re… or they’re not…healthy, motivated, it just has never been pointed out to them that this story on your dad’s side or your mom’s side, you know, might be important to your health. So, we do that as part of the intake. We talk to them about their current health and their past health, and their goals, and then we spend a fair amount of time talking about the test, what it accomplishes, what it doesn’t accomplish, the limitations of it, because a lot of people think you know, I’m getting my 100,000 mile checkup, I won’t need one for another 50 years. But given the limitations of our knowledge, we tell a lot of people that maybe, in 2 years, when polygenic risk scores are becoming important, or in 5 years or 10 years, they might want to revisit this question again of what can I learn from my genetics? So we always kind of give people that idea. We send it off to a laboratory, we don’t do any of the sequencing at Mount Sinai. Most academic centers don’t do that anymore. There’s reference labs around the country that everybody trusts. And it takes… it’s the slowest test in medicine still. It takes about 2 to 4 weeks to get a result back. And then we schedule a follow-up with the person, no matter what the results are, to, you know, even if there are no findings, we still meet with them to tell them. A lot of times they have the question, well, how is it that I have so many people in my family with X, Y, or Z, and I don’t have the gene that seems to be associated with that? So then we talk about polygenic risk scores and other risks for disease. So we have a good conversation, at the end when we have results in hand. So it’s that two-part interaction. Robert Rogers: Dr. Michael Murray, Chief of the Division of Genomic Medicine at Mount Sinai. It’s been a real privilege to talk to you. You are a pioneer in this field and really pushing it forward, and I’m excited to revisit this conversation in a few years as the field advances. Thanks so much for joining us. Michael Murray: Thanks for having me. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

7. 

   18 Feb 2026

   Episode #1: Multi-Cancer Early Detection with Dr. Betsy O'Donnell

   Foresight Medicine Episode #1 Transcript The present and future of multi-cancer early detection with Dr. Betsy O’Donnell Robert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic, comprehensive, and whole body framework for leveraging new and emerging technologies to maintain health for as long as possible. In this podcast series I interview leading experts at the forefront of prevention and early intervention across medical specialties. I am very honored to have as our guest today Dr. Betsy O’Donnell. Dr. O’Donnell is Associate Professor of Medicine at Harvard Medical School. She’s an oncologist and a clinician and researcher who’s making big contributions across multiple fields, including multiple myeloma, nutrition, and exercise for cancer survivors. And in recent years, in the burgeoning field of multi cancer early detection. And it is in that capacity that I am most excited to speak with her today. She’s the director of the Multi Cancer Early Detection Clinic at Dana-Farber Cancer Institute, and an innovative thought leader in this field. Betsy. Welcome. Listeners should note that we are recording this on Monday, January 26th, 2026. This is a field with new data being published all the time, and this episode will not air for a few weeks. So if we say something that becomes slightly outdated, we’ll note that in the show notes, but the audio will stand and this conversation is for general information purposes only, and does not constitute individual. Medical advice. Throughout this conversation, you’ll hear us use the word MED, spelled MCED, which is an abbreviation for multi cancer early detection. Robert Rogers: So Betsy, thank you. I’m really excited to have this conversation. Thanks so much for coming on today. Betsy O’Donnell: Thank you so much for having me. It’s truly fun to get to talk about this and, and really go back and forth about such an exciting topic. Robert Rogers: For our listeners, I’ll just give them a little bit of a guide to this conversation where I’d like to take it. In the next 45 minutes or so, we’re gonna do a little bit of a, the sandwich technique. So we’re gonna end with our destination being some of the really new and exciting stuff that’s at the forefront of this exciting field of multi cancer early detection, the data that’s driving the field, what you see coming down the pipeline. But before we get there, I want us to build a little bit of a foundation in understanding the principles of cancer screening and early detection, early intervention. But I would like us to start out with understanding what it is that, that, that we’re gonna really be talking about today. So tell us what is multi cancer early detection, and how did you get interested in, drawn to this field. Betsy O’Donnell: Absolutely. So multi cancer early detection is really an evolving field, trying to think of means by which we can screen for multiple cancers at once. So if we start with what is the state of cancer screening currently? So right now the United States Preventive Task Force Service recommends screening for breast cancer, colorectal cancer, cervical cancer and lung cancer in smokers. So that’s four cancers. But we know that about 70% of the cancers that are diagnosed don’t have screening tests. And so multi cancer early detection is really aimed at trying to find cancer screening tests that can screen for many of the cancers that don’t currently have existing screening tests with a goal of finding more cancers earlier. And one of the challenges - there are many challenges to cancer screening, but one of the important ones is. As we think about screening and the number needed to screen to find a cancer, the more rare it is, the harder it is to justify screening thousand, a thousand patients to find one cancer if you’re that primary care doctor. And not only that, we don’t have good modalities to find those cancers, but if we aggregate cancers into one test. We need to screen fewer people to find a cancer. And the major goal of multi cancer early detection testing again, is to think about novel ways to find more cancers, but also to find them earlier. And so there are a lot of different ways in which people are exploring early cancer detection. I focus primarily on blood-based screening, and the reason I do this is for multiple reasons actually. One, I think most patients are accepting of blood tests as something they’re willing to do. And also they really offer the ability to be done anywhere, any point of care, location. And one of the major goals that I have when I think about the work that I do in multi cancer early detection, is not only. Bettering cancer screening, but making it more accessible. So when I think about multi cancer early detection tests, I’m thinking about it not only for finding more cancers early, but thinking about how that can affect the population and how we can better medical care nationally, potentially globally, um, through enhancing access. You asked me how I became interested in this. So, Robert Rogers: and lemme lemme just say for, for our listeners, you, said that your focus within multi cancer early detection is on blood-based tests. And, implicit in that is in contrast to these whole body imaging approaches, which are another modality. Let’s put a pin in that because that is a, an interesting kind of side story to the, to the MCED [Multi Cancer Early Detection] world, which maybe we’ll get into maybe how that could be combined with blood tests at the end. But I’d love to hear a little bit about your personal history and interest getting into the field. Betsy O’Donnell: Thank you so definitely put a pin. So as a person in general, I’m a very proactive person. I think most of us in our, in our lives are always thinking ahead, um, trying to figure out what we can do to achieve our goals or to prevent things from happening that we don’t wanna have happen. Oncology in general has been primarily been a reactive field. So a lot of that is history. There’s history and so much of what we do in medicine. But you know, I think about when I started my career in 2001, I was a clinical research coordinator at Dana-Farber, and that was really at the start of targeted therapy. All of the cancer therapies that we had historically really targeted the cell cycle, mitosis, cell division, and we had a limited number of chemotherapies that we combined to try to increase the efficacy, but using all of those same drugs in different cancers. And what’s happened over the past two decades is this dramatic revolution of cancer therapies, targeted therapies, small molecule inhibitors, CAR T cells, bispecific, T-cell engagers. I could go on and on. And what we’ve done is we’ve become much better at treating cancers and keeping people alive with cancer, but we really haven’t got it at the front end of the problem, which is finding cancer when it’s earliest, when it can be cut out, when it can be treated, look as a localized process, and that’s when it’s most curable. And so I worked as the director of inpatient operations at MGHI was very involved in just thinking about how we can operate most efficiently. And as you recall, in 2020, you know, the world was shut down by COVID. And what that did to the hospital that you and I were both at, is we had to allocate most of our resources to treating patients with COVID, which meant we stopped doing elective procedures, things like colonoscopies. We put them on hold so we could manage the pandemic. The original publication, the Pathfinder publication of Grail’s Galleri test was presented ASCO in 2021. And this was at a time where our hospital was really trying to get back in action, trying to get back on its feet. But things like, because we had stopped doing elective colonoscopies, there was a backlog. And it was just tremendously challenging in the healthcare system to just get fundamental things done, like colonoscopies for patients who needed them. And so when I first heard about the data. From the Galleri study, which is a multi cancer early detection test. What really excited me as someone who is doing operations, who’s someone who’s forward looking, who someone believes in preventive medicine, is this is something that could be, you know, a win across multiple fronts. We can find cancer early, we can find multiple types of cancer, but maybe also we can mitigate the burden on the healthcare system. And what do I mean by that? I mean that we can keep patients out of chairs. It’s great. That we can treat cancers for longer, but that’s not what people want, and that’s not what the healthcare system needs. We need cure. And so that keeps people out of chairs, that minimizes the burden of resources needed, like blood products, like experts to give these novel therapies. And then also just the economic cost of ongoing cancer care for these very expensive but miraculous drugs. So not only did I think it was a twofer, I thought it was a lot more than that. This idea. That cancer screening could address a very specific problem, but have a lot of downstream impact on the entire operation of medicine. Particularly excited me. Robert Rogers: Wow. That’s, that’s great. Well, we definitely can hear the passion in how you describe it, and I think that’s sets up, the rest of our conversation really well. So I think when you mentioned how there are guideline recommended single organ cancer screening tests, and I think most people are basically familiar with the concept of how those work, what you’re looking for in a mammogram, what they’re looking for in a colonoscopy. Let’s talk a little bit about what the actual tests are when we talk about multi cancer early detection. Generally speaking, the idea here is that cancer cells are different than normal cells and they leak into the bloodstream things that are different than what normal cells would leak into the bloodstream and that those can be detected. And maybe walk us through a little bit what the different categories are of things that one could conceivably make the basis of a multi cancer early detection test. But then what’s actually being used and kind of showing most promise. Betsy O’Donnell: Yeah. so what’s really remarkable is just the different types of technologies that are being explored in trying to find cancers early. And so you talked about fragments of DNA that break off. So if we think about cancers that are growing, these are not normal healthy cells, often, they’re growing more rapidly, they’re unstable, they’re chaotic, and so. I once heard the analogy of, of a, a flaky loaf of bread, you know, where little crumbles are, are breaking off in the blood. And these are the DNA fragments that we can potentially detect and some cancers break off more flakes than others. And that can be one of the limitations. But what can we look at in that will help us distinguish those DNA patterns from healthy ones. We couldn’t do this 20 years ago, not at scale, not fast, and not at a cost that would allow people to actually purchase it. But some of the different technologies that are being explored and, and probably at the forefront right now is methylation. And so methylation is when we think about having genes have on and off switches. And so there are patterns by which every type of cancer has its own barcode, so to speak. And then when genes are turned on or turned off, there’s kind of an on and off switch. So when we look at methylation, which is really a tag. It’s put on that on off or dimmer switch. It’s turning it off and regulating gene expression. And what’s neat about this type of technology is that it’s uniform. You don’t need a lot of DNA to see the pattern. It’s pattern recognition. And so what’s amazing about. You know, just from thinking about, we first just sequenced the human genome just over 20 years ago, and now not only are we able to sequence the human genome, but we can also create libraries of what normal DNA looks like versus abnormal DNA. And that enables us to distinguish when we look at the blood or potentially other types of body fluids, normal DNA from abnormal DDNA, and that becomes the basis of screening for cancer. Going beyond methylation, though there are other ways in which we’re looking at sometimes those abnormal cancer, DNA have specific mutations, mutations that distinguish those again from healthy cells so we can look at mutational status. DNA is like a blueprint. It’s finely spliced following directions that are set out. And so sometimes there are fragments that can be identified of DNA and those fragments in and of themselves are abnormal, and we can recognize those fragments as abnormal DNA versus normal DNA fragments. And so these are some of the different technologies that are being explored. One of the other more, novel strategies now is looking at immune signatures. How is the body reacting to the presence of something abnormal? Are there specific proteins or meta metabolites, or even just t-cell repertoire that are altered in a predictable pattern in individuals who have cancer. So there’s actually a really broad array of ways in which people are exploring, trying to find cancer. Robert Rogers: Yeah. It’s so interesting that, what seems to be the single most advanced modality in terms of what’s being used is based on the DNA methylation signature. I think if you said to someone, you know, 10, 12 years ago before this field really took off, um, what do you think is gonna be the best modality you might say. Well, cancer is a disease of mutations we will directly detect the DNA mutations, you produce therefore mutated RNA, mutated proteins, different metabolites and all of those things. And you wouldn’t necessarily I think from first principles seized on, on the methylation signature as the thing. Could you just say a little bit more about why you think it is that that has for right now shown the single most promise? And then the follow up to that is, you mentioned how when you think about cancer therapy, now we’re combining all these different modalities. Where are we in terms of being able to combine these different aspects of what cancer cells secrete that’s abnormal into a single test? Betsy O’Donnell: Yeah. So two great questions. I think methylation, so when we think about. Finding cancers. Remember we have tons of cells in our blood. And so, first of all, you have to find these abnormal DNA. And so there are challenges in, in and of that just the types of cancers, the amount of shed they have. So these are things that are not part of the question you just asked me, but very important in terms of multi cancer early detection. And so when you are looking for a specific mutation, it’s like looking for a needle in the haystack. Whereas when you find an abnormal cell that methylation pattern can be recognized in that small amount of DNA that you have. And the methylation patterns are unique to the different types of cancers. Like I mentioned, it’s almost like a barcode. Some mutations are shared mutations too. You can see, you know, KRAS in a number of different types of cancer cells. And so I think where methylation has been, particularly useful is that potentially don’t need as much DNA to find it. And also the signatures allow for the next step, which is identifying where that cancer is coming from. And so, I think that’s probably one of the specific benefits of methylation that makes it attractive. And we can talk about later why signal of origin or tissue of origin can be very important when we think about the broader application of cancer screening. You also asked me about combining modalities. And so I do think it’s very analogous to the way in which we’ve combined chemotherapies to improve the sensitivity of MCED tests. And there are currently a lot of different companies using these different techniques, but there are really a couple that have gone a little bit further. And what we see is the emergence of different strategies. Some focused on methylation, some focused on multianalyte modalities combining methylation with proteomics, with these other patterns, with the goal of increasing our ability to detect cancers. I do think that that makes a lot of sense. Intuitively, you’re trying to broaden the net, so it’s almost like, using a hook and line versus a net approach for phishing for these cancers from the bloodstream. So, I think that’s the very common sense application that’s being applied to the evolution of these tests. Robert Rogers: That’s great. So I think that’s a really nice place to take a step back now before we then turbocharge ahead into what the leading tests are in MCED and how they’re being used and what that data is, and really start to lay a little bit of foundation, about the problem that this tool is trying to solve. And that problem is of course, cancer, which is a big problem. And so I’m curious, when a healthy patient asks you, what is my risk of getting cancer? How, how should they think about that? How can they quantify that? Betsy O’Donnell: Yeah, so I think this is really the companion science to multi cancer early detection is evolving from a one size fits all screening model. So when we think about how we screen for cancer now, it’s really based on age for the most part. And there’s some nuance to it, which we can dive into. But the single greatest risk factor for cancer is age alone. And starting at age 50, our risk of cancer goes up 13 fold. And so really that’s just again, a common sense if we’re going to employ screening on a large population scale, trying to find the people who are most likely to have those cancers. And that’s an age related phenomena, but we know anybody who practices cancer, that there’s a lot of variability and we’re seeing a shift, on a population level to earlier cancers. So how do we evolve from a one size fits all model based on age to being a little bit more nuanced? There are a lot of other companies, and this is not something that I’m an expert on in terms of polygenic risk. So incorporating someone’s personal genetics with other risk factors. So when I talk about high risk, when our clinic sees patients who are quote, high risk, what does that mean? And what are for patients who are really trying to understand their risk, do they have strong family history? Do they have a familial cancer predisposition center? Things like BRCA, Lynch, Li-Fraumeni syndromes, which are small numbers within our population, maybe 2% of individuals. But knowing your family history is critical. Not only knowing if people had cancer, what type of cancer they had, at what age they were diagnosed with that cancer. But then there are other high risk features that patients can have. Smoking historically was and is the number one leading cause of cancer. People are smoking less than they used to. Obesity is the second leading cause of cancer. And as we know, it is a huge problem in the United States. Something that we aren’t necessarily addressing within oncology, but that we’re also seeing and a change in that. So there are a lot of smaller factors as well that can influence one’s personal risk. Having had certain chemical exposures like our veterans in Vietnam, and pesticides in in large quantities, and then chemotherapy cancer survivors who’ve had, are at risk for second cancer. So, these are some examples of people who might get a higher risk. But I think what would be really exciting just to close out, is if we were to be able to evolve more refined cancer risk strategies in parallel with better tests. Robert Rogers: I wanna double click on both aspects of your answer there, both, how we actually quantify risk for those who are considered average risk, as well as the people who are currently identified as being higher risk because of hereditary cancer syndrome. So, just stick with the average risk for a second. There are branches of medicine where clinicians actually use formal risk calculators that say something like a 10 or 30 year risk, for example, for cardiovascular disease, for example, for fractures with osteoporosis. But to my knowledge, there’s no sort of analogous, 10 year or 30 year risk calculator, across the serious cancers. And it’s kind of interesting that there isn’t, because we actually have remarkably good epidemiology on cancer relative to other diseases. Right. We have the SEER database covers a large portion of the country, and so, you could actually probably aggregate, you could say, given a person’s age, sex, race and region, kinda what their risk is across all these cancers. And then perhaps, bring in some of these other factors that might make them higher risk for particular cancers and give a little more quantitative detail. But that’s not something we actually do. Is that, is that, is that feasible or am I being seduced by the delusion of false precision. Betsy O’Donnell: No, we don’t do it. Yeah. I think it’s a low hanging fruit, just like I think multi cancer early detection is a low hanging fruit. I wonder now with the use of so many people on an electronic medical record, everybody using Epic, these are other opportunities to do large scale data analyses. So is there a future state where you log in and and a risk score is calculated through your EMR. These are things that should happen that could happen, but have not yet happened. Robert Rogers: Right. And then you also mentioned how there are these well-defined syndromes that we learn about in medical school and in our medical training, even if we don’t specialize in oncology as you have, where, generally these are genetic mutations where the gene is responsible for repairing or responding to DNA damage. And there’s, there’s like 80 or more of them. And collectively, maybe 1- 2% of the population has them and it puts them at high risk of multiple cancers. And before we jump too far ahead, are we using MCED specifically in those populations who are at risk of multiple types of cancers? Betsy O’Donnell: So I think it’s really important to understand that the data and the research that have been done thus far, it’s very limited. And I think it would be important in our conversations to talk about the difference between a lab developed test and FDA approved drug. So there have not been to date studies in high risk populations. People are using it. And we, specifically at Dana-Farber have a study looking at the use of MCED tests in high risk individuals because we don’t yet know what the best application of the current test is. And so intuitively it makes sense. If you are at high risk, how can we augment your screening? So we’re doing a thousand patient study right now looking at GRAIL’s Galleri test in 500 individuals with a germline predisposition and 500 individuals who have strong family histories sufficient to warrant germline testing because that’s another population too. These people who have clearly some strong familial predisposition but don’t have one of the known mutations that we associate with cancer risk. Robert Rogers: Great., I think at a high level you described the fundamental promise of cancer screening and of multi-cancer early detection. But maybe just one more time so that our listeners really understand. When we talk about cancer screening, early detection, early intervention, there are benefits and risks. I wanna kind of elaborate on the risks in a little bit, but I want us to kind of clearly state what the potential benefits are. So the benefit of catching cancer early is... Betsy O’Donnell: The benefit of catching cancer early is that we can cure it. And so we know, and I’ll use the example of colorectal cancer, that when we find cancers at stages one and two, the survival rates are upwards of 90% versus when we find it late, when it’s spread to distant organ stage four disease where the survival the is much lower on the order of below 15%. And so, you know, the goal is to find cancers when they are most curable and eradicate them and cure patients. Robert Rogers: Great. And some cancers inherently by their biology seem more amenable to screening than others. And colon cancer is perhaps one of the best examples because it’s slow growing. When you have a colonoscopy, you can actually remove the pre-cancerous lesion. And then there are other cancers that seem by their biology just to be fundamentally more challenging and what makes them more challenging? And what’s maybe an example of that end of the spectrum? Betsy O’Donnell: Yeah, you use the perfect example of colorectal cancer where you have a pre-cancerous lesion, like a polyp that can be removed. The cancer in and of itself sheds a good amount of DNA, so that’s the other thing. It’s leaving lots of crumbs. We can pick it up. And there are other tests besides colonoscopy that are FDA approved for colorectal cancer screening. Um, and you know, there’s usually kind of this latency period where you can find it and treat it. The more challenging cancers are the ones that don’t leave these little breadcrumbs. They’re not high shedding tumors, and also they grow rapidly. Things like pancreatic cancer, ovarian cancer, some of our most lethal cancers. You know the other thing about colorectal cancers that may have symptoms early, you may have blood in your stool, for example, that can be either visualized or detected versus something that’s growing in an open space such as our pancreas or our ovaries where they don’t create focal symptoms. But I think in terms of screening, ideally a great screenable cancer is one that if you find it early, you’re going to impact survival. And that it has enough in the case of multi cancer early detection tests shed so that it can be DNA shed, that it can be detected. Robert Rogers: Got it. Alright. Now, I don’t want anyone to think that the relative amount of time we spend on benefits versus risks says anything about the relative level of benefits versus risks. But it’s kind of, I think, more intuitive to understand the potential benefits of multi cancer early detection are, and cancer screening is that, like you said, if you catch it early, you can cure it. The risks are not necessarily intuitive to people if they haven’t spent a little time thinking about this field. But there are, there are some. I tend to think of them in a few different buckets. False positives, false negatives, and potential for overtreatment. And I would love for you to maybe walk through how you think about each one of those in the context of MCED. Why don’t we start with false positives first. Betsy O’Donnell: Yeah, so false positives are probably the greatest fear of the healthcare system, I would say. Right? And why is that? So let’s think about where cancer screening lives now and where MCED would live in the future. It’s in primary care, and if you don’t know, primary care doctors are about the most busy doctors that there are out there. And so if you’re asking people to administer a test and it has a lot of false positive meaning the test says abnormal signal detected, but someone doesn’t actually have cancer, then that requires a series of tests to adjudicate that result. And those can be quite complicated. The person though, at the center of false positives is the patient. So what does it do to a patient to have a false positive? So you take a blood test. It’s not a diagnostic test, it’s a screening test. And it comes back positive meaning an abnormality is detected that can cause anxiety. The patient then has to go on this diagnostic odyssey to determine whether or not they truly have cancer. All of that can be stressful. If you don’t have a cancer, then you’re paying for copays and other expenses associated, whether it be time off work to have tests to determine whether or not you actually have a cancer on a systems level, that can be quite burdensome. When we look at the specificity, which is really how we look at false positive rates, most of the companies are erring on the side of having high specificities. To address this, it comes at the cost of sensitivity, which we can talk about also. But even if it’s 99.5% specific, if you’re doing this in thousands and thousands of patients, the concern is that they start to rack up the number of false positive workups you have to do. But to be fair and to balance that, we have lots of screening tests now, mammography, for example, where we get abnormal responses that have to be adjudicated. So it’s a balance of understanding the limitations of these tests, recognizing that there will be some false positive, but a very small amount and, and entrusting the companies to focus on that as one of their primary endpoints. Robert Rogers: And one of the things that I think is so interesting is which of these risks you most prioritize depends somewhat on your perspective. I think as you said, from the healthcare systems perspective, we are really, worried about false positives. But you wrote pretty eloquently about the development of these tests. And you cited some studies where you asked the people that have actually been the early pioneers, healthy people signing up for these MCED tests, and they’re remarkably tolerant of false positives. You ask them something about how many scares that didn’t turn out to be cancer would you be willing to accept to catch one cancer that was real? And the ratio is like remarkably high, right? And so that tells me something about the difference between thinking at a broad one size fits all systems level to how do we individualize this for an individual patient’s risk tolerance? Is that right? Betsy O’Donnell: So yeah. Two things on that. You know, when we think about anxiety and distress, which is something I’ve written about, I specialize in multiple myeloma, which is an incurable blood cancer. You know, anxiety and distress of a potential screening test versus anxiety and distress of having an incurable cancer.[00:29:00] Those are very different things. And so I have spent a decade trying to mitigate the distress associated with caring for patients and their family members who really are along for the hard ride of a cancer diagnosis. I think it is individualized. People have a choice in terms of the cancer screening. We make recommendations all the time. But there are people who really want cancer screening who have distress because they’re worried about having cancer. They go to their mammogram religiously, they get their colonoscopy ‘cause they wanna do everything they possibly can to mitigate their own anxiety around a potential cancer diagnosis. So. I don’t think we should make generalizations about what people want and what the population wants. I think we should allow people to have the opportunity to decide and to learn from those people. We have to study this on every level, on a systems level, what it costs, and on a patient level, you know, how do] they feel about these tests? Let’s not make assumptions. Robert Rogers: Right. Right. Okay. Let’s move to false negatives. Betsy O’Donnell: Yeah, so that’s the greatest challenge because when we look at what’s been done in terms of the study so far, we’re not randomized. We don’t have a gold standard test for cancer detection. And you mentioned whole body MRIs. You know, there are tests that we use to stage patients who have cancer, things like PET-CT, but those aren’t part of our cancer screening processes currently. So when you look at the studies that have been done, there is no gold standard control arm. Something that will absolutely find cancers. So the false negative rate, meaning you have a screening test, you get a result that says no abnormal signal detected, but actually do have an occult cancer is underestimated or it’s not well characterized by the prospective studies that have been done thus far. Robert Rogers: Do we know anything about the level of distress in addition to the underlying cancer diagnosis for patients who have undergone something, kind of gotten the reassurance, like everything, I’m in the clear, I had this, and then subsequently find out they have a cancer diagnosis. Does that impose a significant additional level of emotional stress on them? Betsy O’Donnell: It’s a great question and I don’t think anything’s been done study-wise to address that question. We don’t know. And I think where you might be able to do something is in longitudinal studies where you’re screening annually and incident cancers are then found in those intervals, but that work, there is a longitudinal study going on right now, the NHS Galleri study in the UK that is doing testing once a year for three years and, and they are baking in some of these quality of life assessments to their analysis. Robert Rogers: Great. And now let’s talk about something that, that doctors also worry about, which is overtreatment, right? The detection of cancers that may have been indolent or lied rather dormant in a patient, or maybe they would’ve ultimately succumbed to something else and this cancer never would’ve caused a problem for them in their, in their lifetime, but now we’ve discovered and we have to do something about that. How do you think about and advise about that risk in the context of MCED? Betsy O’Donnell: There are a couple different cancers that I would say fall into that category. Prostate cancer being one of them, right? There’s some thyroid cancers, some indolent lymphomas, multiple myeloma. The cancer I treat has a precursor condition. Not everybody’s gonna evolve for that. The other half of my research focuses on this. So, you know, this is something I’m very attuned to in my own oncology practice. It used to be that we screened for prostate cancer. There were several large studies on a population level, and what we found was that we were overtreating, this is not using MCED, this was through PSA. That we were overtreating, meaning there were some people who had prostate cancer that would potentially never have caused them symptoms or never have been life limiting in terms of their overall survival. And that’s a morbid surgery. To remove someone’s prostate causes a lot of symptoms and side effects. So does radiation. And so what you don’t wanna do is overtreat and create worse symptoms treating something that would never have been a problem. But I think we really have to look at the broad range of cancers that this includes. Look at the different types of cancers being targeted by these tests. So multi cancer early detection testing is not a one size fits all. A lot of this is company-driven focus on different cancers. Some are really focusing on the low hanging fruits like pancreatic cancer, ovarian cancer, esophageal cancer. But you know, you can pick up some indolent diseases that then need to be monitored, and you do have to think about what the anxiety is for those individuals. What’s interesting in the example of multiple myeloma, there’s a screening study going on in Iceland right now. Population-based 80,000 people have been screened for multiple myeloma and finding the precursor condition MGUS [Monoclonal Gammopathy of Unknown Significance] is actually not associated with long-term increased anxiety. So I think that’s something I do wanna underscore, just the importance of research. Let’s not jump to conclusions that are not based in actual research. Robert Rogers: Yeah. And it sounds like it’s a topic that needs a lot more research and also, again, a case for individualization. What is an individual patient’s tolerance for, say, monitoring? And now I want us to jump back now to the exciting stuff going on with, with MCED, the current studies and what you’re looking forward to. But I just wanna make one more point there ‘cause I, I think it was an important one. Cancer screening is within medicine, a somewhat controversial area in the sense that people have strong opinions about it. There’s people who think it should be much more widely deployed, and there’s people who are skeptics of even what’s what’s currently done. And I think that centers a lot on the story around prostate cancer. Many studies, but I think there was one that was particularly, well known and cited that came out about 10 years ago from the Harvard School of Public Health that showed when they looked at autopsies of thousands of men, many, most, the vast majority of whom died of something completely different from prostate cancer and some large percentage of them, they found histologically confirmed prostate cancer. And that’s sort of cited as a blow against widespread cancer screening because those cancers were obviously indolent, but prostate cancer is perhaps the exception more than the rule, right? I mean, we don’t have massive autopsy databases, and I don’t think anytime soon the NIH is gonna do the, the random million autopsy study. So I don’t think we have perfect data on this question, I think what we do know is that for, for most of the deadly cancers that we’re most concerned about, it doesn’t seem like there’s large numbers of indolent ones lying around. Right? So prostate cancer is an interesting exception, but it’s not the norm. Okay, great. Betsy O’Donnell: It’s not call prostate cancer either, Correct. It’s, it’s a very small subset. Yeah. Robert Rogers: Right. Okay. Alright, so you’ve mentioned a few times the studies, the big clinical trials that have been done and that are ongoing, that are shaping our evidence base for this evolving field of MCED and I’d like to get into that a little bit now. First, maybe just talk us through this general framework of how companies tend to develop new tests in this space where I think generally what they do is they look at first some patients who they already know have cancer and then patients that don’t have cancer, and sort of define the test characteristics of how their test does, and then they move into prospectively looking at patients and seeing how many cancers they pick up. Maybe just describe that framework and then take us through a couple of the major studies that you referenced when thinking about the evidence base for this. Betsy O’Donnell: So I think that this is critical talking about evidence. As alluded to on numerous occasions, this is an exciting area of technology. Lots of companies wanna go into this space. These are lab developed tests or LDTs, and they have a separate pathway for being able to reach patients or people versus a drug that has to be studied, that has a very set pathway from phase one to phase two to phase three to demonstrate evidence that it, it does what it says it’s going to do and to get FDA approval. And so what we see is that companies are developing tests and going direct to consumers. And that is not something that happens when we have new drugs. And so there are companies though that are doing evidence and even the companies that have already gone straight to individuals without doing validation studies that you just talked about are doing what are called case control studies, just as you said, where you have cases of people who have lung cancer, for example, and those who do not, and you test your tests to see how good it is at correctly identifying those who have lung cancer versus those who do not. If you think you have a good signal, then you might move into a prospective study. So you administer this test into individuals who you don’t know what their cancer state is as a screening study to see what you pick up. And so there are very few companies who have actually moved this far into the process of validating their tests. So the two best examples thus far that have published data are GRAIL’s Galleri test that was published in Pathfinder 1 and now Pathfinder 2. And then what is now called Cancer Guard, which is Exact Sciences multi cancer early detection test that was evaluated in the Detect A study. There are a number of ongoing studies, but I think it’s really important to understand that these have to be tested prospectively in asymptomatic individuals. Right now there is bipartisan legislation suggesting that if an MCED test gets FDA approved, that they’re trying to create a Medicare pathway for reimbursement. So right now, a pathway for Medicare reimbursement for MCED tests does not exist. But as we think about the importance and the promise of MCED, this is necessary because these tests are quite costly right now. And so in order for patients to have broad access, which is critical to me, you need to do the work. To do the studies that demonstrate the efficacy lead to an FDA approval, and you have to have, even if you do have an FDA approval, a pathway for reimbursement so that people can actually get these tests and not have to pay out of pocket for them. But when we think about the difference between phase one, two, and three studies, what we often see with drugs is that what looks really good in phase one and two doesn’t pan out in a randomized trial. So I really believe it’s important that we do the work, we do the clinical trials, and we evaluate these tests the same way we would cancer therapies. Robert Rogers: Pathfinder is a major touchstone in the field. What did we learn from it? And what questions has it left not yet answered. Betsy O’Donnell: So the Pathfinder study was originally presented ASCO, as I noted in 2021, it just gives you a sense of, of just chronology of how these things are moving along. This test can screen for up to 50 different types of cancer. It gives a result that says positive or negative. So a screening test saying yes, abnormal signal detected, no abnormal signal not detected, and then it gives a CSO, a cancer signal origin. So it uses DNA methylation, which you talked about earlier, as the main modality for finding abnormal signatures of cancer in the blood, and then using that barcode that we talked about, tries to pinpoint where that abnormal signal is coming from. And so when you look at the data from the Pathfinder study, it had a very high specificity over 99%, and then the sensitivity varies by the cancer. It’s better at some cancers than others, but perhaps the most important kind of focal point for many people is the positive predictive value. And what does that mean? That means if you get a positive result, how probable is it that you actually have a cancer? So in that study, the positive predictive value was about 40%. Meaning if 10 people had a positive signal, four of them actually had cancer. In October of this past year, Pathfinder 2 study was presented, and here we saw that with changes and improvements to the assay. positive predictive value was closer to 62%, meaning that six out of 10 individuals who had a positive test had a cancer result. So those are the kind of most important data to date. The other piece is looking at were these early versus late cancer, so let’s call early stage one and stage two and late stage three and stage four. In both Pathfinder 1 and Pathfinder 2, over half of the cancers found were early stage, stage one, stage two, and very importantly, over 90% of the cancers found did not have recommended screening tests. So these are all real, these are not meant to replace the screening modalities we talked about. This is to complement. And so I think that’s one of the most important things is what cancers did they pick up over and above what screening tests did. And so they demonstrate efficacy in finding early cancers and a broader range of cancers. Robert Rogers: And that’s a really nice recap of the data. I’m curious what sort of upcoming studies or data readouts you’re watching most closely that you think will give us the next batch of evidence to see how these tests really perform. Betsy O’Donnell: The study that I’m watching most closely is the NHS Galleri study. Robert Rogers: Yeah. Tell us about, tell us about that and take a little time to describe it in detail, ‘cause I think this is gonna be a very important evidence base for the field. Betsy O’Donnell: Yeah. So this is a large population-based study that’s going on in the UK right now using GRAIL’s Galleri tests and it’s a randomized trial. Looking at the use of the Galleri test at annual intervals for three different testing time points. So once annually for three years versus just standard of care screening. And I think this should read out this spring. I think that this is really going to be, um, what a lot of. GRAIL’s, FDA approval prospects hinge on which will be very meaningful not only for that company, but also for the entire field, just in terms of creating a pathway and for others who want to seek FDA approval and for understanding at a larger scale, the benefit or lack thereof. It’s hard because tests will continue to evolve. They’re using a specific test and, and if this is positive, fantastic. If it’s not, what lessons can you learn from these in terms of is it the test not being sensitive enough? So I think this is a really important readout. Robert Rogers: Just tell us a little bit more about the specifics of the endpoint that they’re looking at in that NHS study, ‘cause I, I think it was actually very thoughtfully designed. Betsy O’Donnell: Yeah, so again, this is a randomized controlled trial. It’s about 140,000 individuals, ages 50 to 77, and the primary objective is to assess whether adding the Galleri test to standard screening reduces late stage, stage three and stage four, cancer diagnoses compared to usual care. Robert Rogers: Got it. And so that sounds like a very reasonable way to do the study because of course, if you were gonna have to run the study all the way until it could detect a mortality difference, that could be a very, very long and expensive study. But I think it’s basically making the assumption that if you prevent cancers from being diagnosed at stage four or late stage, then that’s probably gonna be correlated with actually improving morbidity and mortality. Is that the underlying assumption? Betsy O’Donnell: That’s the underlying assumption, and that’s one of the biggest challenges of cancer screening and evolving technology, is that the gold standard is mortality and mortality takes years, decades even to read out. And the rate at which our science is evolving is so fast. So how do we find an endpoint that keeps pace with the changes in technology, but still honors the importance of understanding that screening tests are of greatest benefit if they actually change your ultimate outcome, as has been defined historically by cancer screening tests. Robert Rogers: Right. And you’ve made the point that baked into the design of these tests is a preference for high specificity, perhaps at the expense of early stage sensitivity. And for example, in some of the precursor work before the Pathfinder study, where they looked at several thousand patients who had a known diagnosis of cancer and several thousand healthy people, and they said, how well is this test doing? A positive test really correlated very much with stage, right? So it was very good at finding patients who had known stage three and stage four cancer, 70%, 90%. Stage two was about 40%. Stage one, it was about 15%. And I guess I would just be curious, this is really an opinion question: how do you think that performance is? I think you could look at the only 15% pickup of stage one cancers in one of two ways. One is that, that’s really lacking. That’s not quite where we need to be. I suppose the other way to look at it is that maybe that’s a feature, not a bug, right? We’re gonna kind of wait until the cancers cross, at least that stage two threshold and then catching 40% is actually, pretty good. That’s maybe how I look at it, but I’d be curious how you look at it. Betsy O’Donnell: Yeah, I think it’s a little bit like looking at the iPhone 1. It’s a starting point, We are at what the iPhone 18 at this point, you know? And so I think you have to have a certain benchmark to start from and build from. I like the perspective that you have. I haven’t heard it ever stated like that. Where we’re our starting point is we accept that stage two, but I don’t think that’s the ultimate goal. Tying back to what we talked about earlier with, with evolving technologies beyond just looking for DNA shed. Can we increase our ability to find things earlier? Can we, and, and also something that’s talked about, which we haven’t brought up, is longitudinally following individuals. So do we see changes in the patterns of people’s protein expression and their immunophenotyping over time? So that it’s not just about finding something that is already specifically there, but can we identify signatures of things that are evolving? I mean, there’s a lot of exciting science that’s going on in this area, but I think. We need a starting place. You always need a starting place. I have a story I always tell about STI571, which was Gleevec, which is one of our first targeted therapies that we were studying and everything, just like we had any alkylating agent and studying in prostate cancer was the study I was assigned and obviously it’s not a drug we now understand that worked for prostate cancer, right? But it was a starting place. So I really look at where we are in MCED similar to what I looked at in STI571, when it was assigned to me back in the early 2000s. It’s somewhere to start, and I believe that these will get better, they will get more sensitive as we learn, as the technologies evolve, as more interest grows in this area. But hopefully we will do better than just finding stage two disease. Robert Rogers: Great. Couple of rapid fire questions, and then I just wanna end with talking about the experience you’ve had directing this extraordinarily innovative clinic at Dana-Farber. So, you’ve touched on this, but how will the optimal frequency of testing be established here? Betsy O’Donnell: You have to have longitudinal studies where you demonstrate it. And so, companies are going to want you to do it more frequently, of course. Right. But you have to demonstrate that there’s benefit. We don’t do colonoscopies annually. We do do mammography annually. You have to have evidence. These studies have to have multiple time points. And I think again, that’s why the NHS Galleri study is important. You can’t make up a number that sounds good. It has to be evidence-based. Robert Rogers: Got it. Where do you see whole body imaging - Usually MRI based - fitting into this ecosystem. Could it be complementary or is it really it’s kind of own thing for now? Betsy O’Donnell: Yeah, I think it could be. We have different reasons we do things and as I noted, I’m really interested in helping healthcare systems operations and also broadening accessibility. And so whole body MRI are incredibly sensitive. They pick up, they have the potential to pick up cancers early. They can pick up a lot of other incidentalomas, incidental findings as well. So you really need to evaluate if you’re thinking about that as a screening modality in the general population. Do you have enough MRI machines to screen the population? A lot of people are claustrophobic. What percent of the population is going to want to have an MRI? Um, and then when you do have incidental findings, do you have the resources to properly evaluate them? And so they’re very sensitive. I’m not the only physician doing this type of work. In fact, just two weeks ago we had a meeting, a kind of a consortium of doctors who are interested in MCED, practicing and studying them. 25 doctors on a call. Some people are looking at randomized studies of blood tests versus whole body MRI, and I think it’ll be very interesting just what we can learn about the sensitivity of MCED tests from these tests. MRI is exciting. I think for my practice, so my number one priority, and I hope I’m betting on the right horse, but is really thinking about accessibility and, and really trying to get at how do we get more people screened. Robert Rogers: Got it. A quick prediction here. Forever is a very long time, but let’s say in the next 20 years, do you think it’s feasible that MCED could ever replace the existing single organ screening tests, or is its future gonna be an additional layer for selected patients? Betsy O’Donnell: I think it’s hard to imagine replacing those modalities not where it is currently. Maybe 20 years from now, potentially. 20 years is a long time. Long time. So that would be amazing. But I think it will take a lot to displace and should take a lot to displace our currently well adjudicated means of, of screening for cancer. But, for now, the current state, this is a complement not a replacement. Robert Rogers: Got it. A few closing questions about building this MCED care model that you are building. Tell us a little bit about the impetus for creating a dedicated clinical home for this kind of testing. And if you don’t mind, walk us through kind of the patient experience of coming to the MCED clinic. Betsy O’Donnell: Yeah, so this program really started to kind of emulate or model what we’ve done for drug development. So it’s a research platform where we really try to, anybody who’s coming in, these tests are very costly, several hundred dollars, close to a thousand dollars. So we try to offer these tests in clinical trials so that patients are not paying for the cost of the test. But patients are getting these tests, they’re buying them off the internet. They’re getting ‘em from doctors who are prescribing them, but then may not necessarily know how to work up the cancer that’s suggested. And so we created a clinical home for these patients, especially when we’re looking at a Pathfinder 1 data where the positive predictive value is 40%. What do you do with a patient who has a positive test and a negative workup? They need a home, they need to be followed because I think that’s the population for whom I think there is greatest anxiety. And so our clinic is both a research program, but also really focused on those patients who have positive tests, trying to do an expert evaluation. We get them through the diagnostic procedure as quickly as possible. And a lot of patients we found don’t necessarily easily identify providers when they’ve gotten, when they’ve purchased their tests or had them through means other than a providing physician. So it’s been interesting. We’ve seen just over 20 patients with positive tests since we’ve been open and we screen many, many more through clinical trials. 69% of those that we’ve seen have had cancers. Takes us about two weeks to do a diagnosis. We employ the retest in our patients and about a three month follow up, and that really helps us adjudicate the false positives. I love it. I see all the patients myself. I think it’s really important to practice this medicine to understand the limitations, to have to talk to the patients about the tests we’re gonna do. And, in the situations of false positives, how do you reassure those patients? Robert Rogers: I think that’s amazing and really speaks to extraordinary clinical innovation on your part that you can get them from test to diagnosis in a short period of time. Because when we talk about the anxiety around a positive test, part of that is the amount of time you’re lingering with the uncertainty, right? And if you can cut that down, that’s hugely valuable. So the amount of anxiety patients experience is not just some property of the universe. It’s determined by the care system that they have access to. So I think that’s really cool. Betsy O’Donnell: Thank you. Robert Rogers: So as we sit here in January of 2026, is there anyone for whom you would definitively recommend MCED, or anyone who you would definitively recommend against it? Betsy O’Donnell: That’s a great question. So I would recommend the study of MCED. I would recommend participation in a clinical trial. Robert Rogers: So if you’re gonna do it, do it through a clinical trial so that it’s done in a very rigorous way and it contributes to this knowledge base that’s evolving. So that’s an important caveat. If you’re gonna do it, if you’re curious to do it, do it through a clinical trial, that’s one message you wanna get across. Is that right? Betsy O’Donnell: That’s my number one message, I think because, for a variety of reasons. Let’s understand these tests so that we can be authorities and so that I can confidently say, you should or should not do these tests. We need that evidence. I think for individuals who are high risk, who have significant anxiety, these tests are there. You have to, if you understand the properties of the test, you understand exactly what you’re signing up for, then that’s an individualized decision. And we have the resources, not just at Dana-Farber and a number of institutions too, to support people who want to take on. You know, exploring other types of cancer screening. Robert Rogers: Excellent. Dr. Betsy O’Donnell, thank you for coming on today for sharing your immense expertise with us in this area. I think you are really practicing at the forefront of one of the most exciting areas of preventive medicine, and I’m excited to see where this goes and, and maybe redo this conversation in a couple of years and see what more we’ve learned. Thank you so much for joining us. Betsy O’Donnell: Thank you for having me. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe (https://foresightmedicine.substack.com/subscribe?utm_medium=podcast&utm_campaign=CTA_4)

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