Foresight Medicine

Edited Transcript of Foresight Medicine Episode #3 on Prevention and Early Intervention in Parkinson’s Disease with Dr. Ray DorseyRobert 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 dowith 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. This is a public episode. 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Foresight Medicine Episode #2 TranscriptRobert 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 nono 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. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit foresightmedicine.substack.com

Foresight Medicine Episode #1 TranscriptThe present and future of multi-cancer early detection with Dr. Betsy O’DonnellRobert 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. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit foresightmedicine.substack.com