268 ‒ Genetics: testing, therapy, editing, association with disease risk, autism, and more

1. 0:00 – 0:38

   Intro

   1. WCWendy Chung0:00

      There's a big difference, and not all genetic testing is the same. Um, and I'm not being critical of any of the companies or, or that do this, but just to realize they're trying to serve a different purpose. So 23andMe as an example, um, or Ancestry.com, uh, as another example. Those are more things that are not medically sort of targeted. They're not trying to answer a specific medical question of, do you have an increased risk of breast cancer? Do you have an increased risk of heart attack? They're really not getting at that level of detail.

   2. PAPeter Attia0:29

      [upbeat music] Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:38 – 3:25

   Wendy’s interest in genetics and work as a physician-scientist

   1. PAPeter Attia0:39

      Hey Wendy, thanks for making time to, uh, to chat today. This is an especially busy day as I learned you're literally in the process of moving from [chuckles] New York to Boston later today, no less. So, um, [chuckles] we'll try not to, uh, to get in the way of that transition, but that's probably a good intro to kind of explain what it is you do. You're moving from, um, one prestigious institution in, uh, New York to another in Boston. Uh, tell, tell us where you're going.

   2. WCWendy Chung1:08

      Sure. I'm gonna be the chair of pediatrics at Boston Children's Hospital and will be at Harvard Medical School.

   3. PAPeter Attia1:13

      You're both an MD and a PhD. Uh, how do you balance your time between, uh, I guess let's not include the new responsibilities that will be administrative, but up until now, how have you balanced your time between, uh, the lab and, uh, clinical practice? How, how do those split?

   4. WCWendy Chung1:30

      So they split about twenty percent clinical, eighty percent research, but truth be told, they're really together. Um, so when I think about things, I always say it starts with the patient and ends with the patient. So it starts with the patient to me in terms of clinically seeing them. Um, many times the answers aren't obvious, and so it becomes a research question, and, uh, at the end of the day, though, it has to go back to the patient. So within this, that split I think just signifies how much we have to learn and, and why we-- why research is so important to improve clinical care.

   5. PAPeter Attia2:01

      Now did you-- You didn't do a combined MSTP or MD-PhD program. You did your PhD first and then went to medical school or were-- did you do the combined program?

   6. WCWendy Chung2:10

      Yeah, I did a combined program between Cornell and Rockefeller, and since Rockefeller doesn't have a medical school, we do that with Cornell.

   7. PAPeter Attia2:17

      I see. And, um, so, so presumably you knew you wanted to be a physician scientist as you went through training.

   8. WCWendy Chung2:23

      Yes, that's right.

   9. PAPeter Attia2:24

      What, what drew you to your current field of genetics, and how, how would you describe to somebody what it is you do in the lab?

   10. WCWendy Chung2:32

       I'll give you the short version of this, but I was fortunate enough early in my career to be exposed to the National Institutes of Health and was able to spend as an undergraduate, uh, summers there. And that was really when I-- I was a biochemistry major as an undergrad, but had the ability to work on phenylketonuria and, um, although it was mostly in the laboratory, was able to spend time at NIH at the hospital and seeing patients and realize this whole paradigm, which to this day is really how I do things about thinking about how these pieces fit together. And I couldn't really think about the science without thinking about the patients, and I couldn't move forward and fill the gaps in our knowledge for patients unless I did the science. Um, I happened to, I think, be good at both, and so it was a natural to me to do both. And I was young and not so worried about the number of gray hairs that I would, uh, have by the time I finished. And so, uh, set out on this, uh, relatively long training path, but one that suited me extremely well.

3. 3:25 – 17:28

   The genetics of phenylketonuria (PKU), a rare inherited disorder

   1. PAPeter Attia3:25

      Let's talk a little bit about PKU. It's maybe a good introduction to a, uh, a genetic disease. So, um, maybe tell folks what it is and how frequently it occurs.

   2. WCWendy Chung3:35

      Yeah, great question. Uh, so phenyl-- PKU stands for phenylketonuria. Uh, we may come back to it a little later in the show, but, um, it was actually how we started newborn screening. Um, it was to me a paradigm in terms of, um, patients and families really working together to improve care and being very much partners in that. And so that was even true for a condition that I started studying. Uh, as a biochemistry major, I was interested specifically in the, um, biochemistry of that, but I realized, and this was in the late eighties, that a lot of what I was do was doing genetic sequencing to understand the genetic basis of this, um, what we call Mendelian or, or single gene condition. Um, in this particular case, we did know the gene for this condition, but there were so many other things that I was seeing that we didn't yet know the genes for these underlying conditions. And it was coincidental, but really just I, I would say fortuitous for me that the year I started my MD-PhD program was the year the Human Genome Project was announced in terms of going forward. And I had, um, I think the, I don't know, maybe foresight or good luck to be able to see that it was going to be a brand new future when we would have that entire encyclopedia of information to be able to think about human disease differently and thinking about opportunities in the future and one what could-- one, what one could do with the information when we had it. And so I really planned my career in thinking about what I'd be able to do ten or twenty years after I started, and that ended up proving well. Um, and so I've spent a lot of my time using that information and, and trying to apply it to health.

   3. PAPeter Attia5:11

      So what's the clinical manifestation of PKU?

   4. WCWendy Chung5:15

      Yeah. So phenylketonuria is a, um, bittersweet condition in the sense that, uh, it can be associated with intellectual disabilities if not treated, but if caught early and, um, if treated with a diet that is restricted in phenylalanine, one of the amino acids that we see in proteins. If we restrict that, then even though individuals with PKU can't digest that and get rid of the toxic byproducts, we can prevent those toxic byproducts from building up in the body and essentially poisoning the brain. Um, I say tragic because, and again, we may get to it, I've identified individuals who weren't picked up through newborn screening and picked up through some of my research studies, for instance, as teenagers and had irreversible intellectual disabilities. But yet we can prevent those types of problems if these children are identified as newborns. And so that's what our whole newborn screening program was originally predicated on is that early diagnosis, early intervention, changing lives, improving lives. Um, and in fact, uh, we do that extremely well for most individuals with PKU.

   5. PAPeter Attia6:17

      Is PKU, um, a dominant gene, and is it fully penetrant, or is there any variability in that?

   6. WCWendy Chung6:24

      That's a great question. So it's a recessive condition, meaning it takes two to tango. Uh, both your parents are carriers for that condition. Um, within this, there is a spectrum. Um, so we have individuals that are what we call hyperphenylalanine anemic, so they don't technically have PKU. They're not symptomatic. They wouldn't have problems with intellectual disabilities. But it's a spectrum of severity. So, uh, beyond a certain threshold, you have too much of the toxic buildup, and that's when you end up with the problems in terms of brain function. But there are some individuals who have what I'll call subclinical phenotypes. That is, I could see it if I measured, if I bothered to measure the amount of phenylalanine in their blood, but they have enough of the enzyme to be able to clear the toxic byproducts. So, um, that becomes one of the tricky things for us to do in screening newborns is to decide where that threshold is to, to adjudicate this and figure out who needs treatment.

   7. PAPeter Attia7:17

      So is the screening that's done on newborns an, a genetic screen where you're looking for two copies of the gene?

   8. WCWendy Chung7:23

      That's a great question. Um, the traditional way we do this in the very old days, believe it or not, was based on, um, looking at bacteria and how they would grow on an agar, uh, that was depleted in phenylalanine. And we would take a heel prick from a baby and put a little dried blood spot, um, punch of that dried blood spot onto a bacterial lawn and see again where the bacteria would grow. So in the very old days, in the late '60s, early '70s, we did the screen in that way. Um, we got more sophisticated and had ways of being able to directly measure phenylalanine, and we now do it with a process called tandem mass spectrometry, but we still use that dried blood spot to be able to do it. Um, interestingly enough, uh, with a program that we've recently started called GUARDIAN, we also have an orthogonal way of being able to screen, which is based on looking at the DNA, um, so that we've got two different essentially data streams coming in to help us with the adjudication of what I was describing before. Who really needs treatment? Where's that threshold? And being able to be, hmm, better in terms of our test parameters, both sensitivity and specificity, so that we can really identify with greater certainty the babies who need treatment.

   9. PAPeter Attia8:36

      That's interesting. So just to make sure I understand, the reason you don't just rely on, say, a, a genome sequence at the moment, even though you know what gene to look for, it would be targeted, you wouldn't need to do a whole genome sequence, is because that wouldn't tell you about the phenotype fully, and the phenotype is just as important as the genotype, maybe more important as you make a clinical decision about dietary restriction?

   10. WCWendy Chung8:58

       So it's very insightful, and I'm gonna repeat it back just because it might be a, a subtle thing for some, uh, people. So reading out the DNA sequence, we're good at, we're not perfect at. And so being able to decide based on your DNA sequence alone for phenylalanine hydroxylase, the relevant gene, we're not able to perfectly make that one-to-one correlation about whether or not you'll be beyond a threshold of disease in terms of phenylalanine levels. So we do need in this case, I'll call the phenotype the level of phenylalanine levels in the blood. We do need to have that phenotype before we get to the phenotype of intellectual disabilities, which is what we're trying to prevent. So you're right that in this case, we use two different data streams to come in. Um, the other reason why the phenotype alone is imperfect is you can imagine depending on what you've eaten, your phenylalanine levels fluctuate during the course of the day. And so we do it as a cross-sectional one time, and you might happen to get a baby at just the wrong time or just a, you know, sort of higher level. And so being able to have both of those data streams come in allow us to be even better in terms of the accuracy.

   11. PAPeter Attia10:07

       Now, it's interesting. Um, if you, if you look at a can of soda or anything that has aspartame in it, it always presents this warning and says, you know, "If you have PKU, beware." I always find that kind of interesting because the absolute amount of phenylalanine in a minuscule amount of aspartame, which is found in a Diet Coke or something, seems really small. Is that clinically significant? And if so, wouldn't that suggest that even milligrams of this amino acid could be problematic to those afflicted?

   12. WCWendy Chung10:38

       So for those afflicted, they have to be really careful. So if you actually have PKU, then we have a very special diet for you. You're not taking diet sodas. You're not doing anything with aspartame. In fact, we may have you on what's effectively a pretty not-so-fun diet to be on. Um, and in fact, um, many people don't wanna be on that diet for life because it's not the tastiest diet. But for women in particular, when they become pregnant, it becomes not only their own body they're influencing, but that of the fetus developing inside. And so we have to be quite careful with women with PKU when they're pregnant as well. And because of that, um, from a labeling point of view, we wanna make sure they're aware of what's in different food products that they might be eating, 'cause they won't feel the effect right away. It's not as if they get a headache or something like that, and we don't wanna see the effects on the developing fetus later on.

   13. PAPeter Attia11:29

       You know, given that amino acids, uh, sort of show up in all sorts of places, I mean, and, and it's not just like, well, I'm eating eggs so therefore I'm just eating methionine. I mean, are there actual protein sources that are completely void of phenylalanine? I mean, there must be if you're able to subside on, on some sort of phenylalanine, uh, free diet. What, what, what types of foods are excluded completely from this diet?

   14. WCWendy Chung11:56

       So, uh, we don't exclude 100% phenylalanine, so it's a low protein diet in general. Um, so we still need some protein, and you still have some essential amino acids for your body to be able to grow. You need to make muscle, especially as a developing child. There's a lot of growth that's there. So we don't completely restrict. Um, and it's actually a titration if you wanna think of it that way. That is that we make dietary interventions and we check, and then we go back and we diddle, and we go back and forth to be able to get it just right. So it's a lifelong treatment in that way, and it becomes even more critical for young children as both their brain is developing, their body is developing. Uh, we have to get it just right. So, um, not trivial to do, but on the other hand, when we're, when we're good about it, um, children grow up very healthy.

   15. PAPeter Attia12:40

       But it is lifelong treatment. In other words, just getting through adolescence is not enough. If you, um- quote, you know, come off the diet later in life, will you still suffer cognitive changes, or are you most sensitive to those during development? Uh, and by development, I mean sort of adolescence and childhood.

   16. WCWendy Chung12:56

       Yeah, you're most sensitive during childhood, uh, for sure when the brain is growing and when you're making those synapses and connections and being able to develop those, um, all of the things you're learning to do. You're definitely most sensitive then. Um, I find that some people, adults in particular, will tell me about differences that they have in terms of clarity of their thinking and other things if they're, you know, just totally off the diet and not, not restricted whatsoever. Um, but it is different in the sense that you don't crash and burn instantaneously. Um, it's more subtle in terms of what you, what you feel, how your body feels.

   17. PAPeter Attia13:28

       You know, there are certain diseases, we'll probably talk about them, like sickle cell anemia, where, um, they're recessive conditions, but having one copy of the gene and therefore not having the full phenotype poses an advantage, and that's at least in some part explains the propagation of the gene. Is there any such analogy to be made here? Are there benefits in having one copy of this gene? Uh, and obviously there are huge detriments to having two copies.

   18. WCWendy Chung13:56

       So not that we know of. I will say that I don't think that we know everything, but it's not so obvious in terms of the frequency of these mutations. Um, there are, I think, historical reasons why we see it more in certain parts of the world versus others. Um, but, uh, as far as we know, no selective advantage.

   19. PAPeter Attia14:12

       And is there an ethnic distribution?

   20. WCWendy Chung14:14

       There are. So we do tend to see this, for instance, more in, for instance, Ireland. It tends to be more frequent than we see in other parts of the world. Sub-Saharan Africa is an example. And, you know, that has to do with historical reasons in part and where variants occurred, uh, migration patterns of how peoples migrated around the world. Um, but we do see it really for all, all four corners of the world. PKU is seen everywhere and, in fact, in newborn screening, uh, pretty universally screened throughout the world for places that have newborn screening programs.

   21. PAPeter Attia14:44

       Uh, and just to paint the, uh, you know, contours of it, in, in Ireland, what's the frequency that, uh, a child is born with this?

   22. WCWendy Chung14:52

       It's a good question. I, I'm gonna hazard a guess, although I'd have to say I'd need to fact-check myself. We're probably in the order of one in five thousand or so.

   23. PAPeter Attia15:00

       Okay. And in the US, less than that, but by what mark?

   24. WCWendy Chung15:02

       A bit less than that. Maybe one in ten thousand.

   25. PAPeter Attia15:05

       Okay. So still pretty common condition, relatively speaking.

   26. WCWendy Chung15:08

       Yep. Yep.

   27. PAPeter Attia15:10

       Uh, I suspect we're gonna talk about this in much greater detail as we go on, but before we do, I'll want to build up a foundation so people understand the basics. But, but just before we leave PKU, is this something that you think in your career will be a target of gene therapy?

   28. WCWendy Chung15:24

       It's a great question, and I have to say something I think a lot about. Um, I think we have yet to see. Certainly many inborn errors of metabolism, so things that are conditions like phenylketonuria, but other things that have to do with the way the body digests, processes, metabolize foods, uh, are, some would say, easier targets for gene therapy. And we can go into more or less detail about this. But in part, many of these genes are expressed in the liver, so the liver is kind of the, if you wanna think about it, the metabolic brain of the body or the metabolic clearing house. The brain-- or rather the liver is a relatively easy place to target in terms of gene therapy. There are ways that the liver is clearing things, and some of the vectors and the delivery systems we use are relatively easy to get to the liver. And for certain conditions where these are recessive conditions with loss of function, you have to add back the missing enzyme or protein, but you probably don't have to get to a hundred percent. And just for some of your listeners will be astute, um, you had alluded to carriers for these conditions, recessive individuals who have one copy of the gene that's working just fine but one copy of the gene that's not. They tend to be fine. That was the point essentially of what you were saying. Do carriers have any advantage or disadvantage? And, and basically, they're, they're indistinguishable is what I would say, which means for us, in terms of a gene therapy or gene addition or gene replacement strategy, you don't have to be perfect. You have to get some in there. You have to get enough in there, but you don't have to get a hundred percent. And so for all those reasons, um, these types of conditions are interesting in terms of gene therapy targets. And as you alluded to, given that the treatment is lifelong, that kind of stinks. And so for something that could be transformational in terms of quality of life, many of these metabolic disorders certainly are interesting in terms of genetic therapies. So, um, we may come back to it, but, uh, I will not be surprised if within our lifetimes, uh, people will be trying gene, genetic therapies for PKU.

4. 17:28 – 28:43

   The evolution of genetic research: from DNA structure to whole genome sequencing

   1. PAPeter Attia17:28

      Well, I, I definitely wanna come back to this, both from a historical concept, uh, uh, context and then also to talk about the future. But before we do, it might make sense now to pause and kinda go back to some of the basics. I, I know that our listeners are quite sophisticated in general, but I always think it helps to just put some foundational knowledge in place. So, um, you talked about how you began your PhD. I'm just doing the math, but it sounds like you began your PhD in the early nineties. And, um, this was about a decade before the human genome was sequenced. So at that time, you know, obviously, we understood the structure of DNA. Uh, we understood that it was, uh, a double helix. We understood, uh, that DNA was a template that was used to make RNA and that RNA was then used to make protein, and that's, you know, essentially the axiomatic, uh, principle of life, although there, uh, maybe we can talk about, um, some edge cases there. Um, how back in that era, like how did you do genetic work? Uh, maybe explain the differences between sequencing, protein gels, and what the state of science was a decade before the human genome was sequenced. And also, if you, if you can remember, speculate on what was believed to be the outcome of the human genome sequence and how that differed from what was actually found.

   2. WCWendy Chung18:49

      So I'll give you a couple examples, um, that'll bring a smile to some graduate student's face out there somewhere. Um, so when I first started my PhD, um, eventually PCR, which people know about, polymerase chain reaction, is a molecular Xerox machine that we use to amplify DNA and use it for sequencing and other things. We, uh, relatively soon after I started graduate school, had automated thermocyclers, but within PCR, one had to change the temperature for different stages of this amplification process. We had some where you'd have to denature the DNA, so you'd heat things up. Others where the enzyme, the polymerase, would work at a different temperature, so you'd have to bring the temperature down. Um, and so there were three different temperatures it should cycle at. In the very early days, we didn't have machines that would cycle between these three different temperatures or go through 30 f- uh, different cycles of this. So you can imagine, uh, the cheapest labor is a graduate student, so you'd have an ice bucket, you'd have a heating block, and you'd have a, you know, sort of a, a bath, a water bath in terms of a different temperature with a timer in which you'd be literally moving samples, and you'd be essentially a robot being able to do this, uh, in the early days. And we'd work with radioactivity to do the DNA sequencing. We'd have these gels. We would be reading out these ladders of sequence. It was all very manual and not very high throughput. Um, and certainly I did that, as I said, reading out the phenylalanine hydroxylase gene to be able to see all of this. And those were the early days. But if you think about scale and what was necessary to do this for three billion base pairs, there was no way that that could be scaled. And so whole industries evolved in terms of being able to do this, uh, in a more automated, uh, way to be able to do this. And, and really the whole world organized itself around ways to do this massive project. Um, in the early days, we had different chromosomes that were designed to different areas. So Columbia used to be the chromosome 13 center of the universe in terms of being in charge of that. And, uh, that meant that, uh, chromosomes are ordered by largest, uh, with the smallest number. So chromosome one is the largest chromosome. So you'd have some groups that had bigger jobs than others. But we would spread these around and, uh, different groups would come together from around the world for a chromosome 13 meeting, for instance, and try and compare notes. We would have things that we called yeast artificial chromosomes in which we'd literally under a microscope dissect out these chromosomes and put these into these constructs so that we could make more of the DNA and be able to go through and sequence these. Um, but it, there, there have been transformational technologies that have allowed us to go through in terms of higher throughput, greater processivity. Um, but one of the things that the Human Genome Project did that I think was really important was, um, in the early days, data sharing, data access, um, really being able to make the world come together by allowing, um, large groups of people to work together. It wasn't every person for themselves. It really was a scientific enterprise, uh, collectively, and that's, I think, a fundamental principle in which many of us as genomicists believe very firmly in, in terms of data sharing, privacy, and protecting individuals, individual patients, individual participants, uh, but yet being able to make data freely available as immediately as we can so that we can all use it and get smarter together and learn from each other and be able to, um, advance science as quickly as possible.

   3. PAPeter Attia22:08

      I just can't help but want to go back even a little bit further. And, um, I remember one of the most interesting books I read, oh, probably in medical school, was The Double Helix, uh, which of course the, the, the, the relatively short but completely fascinating and gripping story of the discovery of the structure of DNA. Do you want to just briefly explain? 'Cause I, I sort of think right now we are so far removed from how, how much ingenuity was required to figure out that structure and how that laid the foundation for all that came. It, it-- and, and refresh my memory, but, but so, so this was what, 1953? Is that right?

   4. WCWendy Chung22:52

      Yeah, I think that's about right.

   5. PAPeter Attia22:53

      Yeah, in that ballpark. So up, up at that point, did we understand that there were 23 pairs of chromosomes? We already knew that, correct?

   6. WCWendy Chung23:02

      So, um, believe it or not, there were arguments in the early days about whether it was 46 or 48 total chromosomes, uh-

   7. PAPeter Attia23:09

      Okay

   8. WCWendy Chung23:09

      ... in pairs, and it was hard to visualize. Eventually, you know, we got the counting down. We were able to separate them out enough by size and eventually banding pattern. But, um, in the early days, even controversy about that.

   9. PAPeter Attia23:20

      Okay. So what was it that the, the four individuals, which it typically just gives credit to Watson and Crick, but really there were four people that played a pretty pivotal role in this. Um, what was the breakthrough that they had that allowed them to understand the structure of this molecule?

   10. WCWendy Chung23:39

       So I won't say that this is my super subspecialty. Um-

   11. PAPeter Attia23:41

       Mm-hmm

   12. WCWendy Chung23:42

       ... but in terms of the crystallography structure, being able to do that, get, uh, high enough resolution and really have, I think, the insight in terms of being able to imagine this was, uh, all of these things coming together. Quite technical, but, uh, also, um, as you said, I think some unsung heroes in this story as well.

   13. PAPeter Attia24:00

       Yeah. And, and really it was this remarkable ability to look at 2D images that were captured and understand the mathematics and the picture that this had to be a double helix. Um, and it's interesting when you go back and look at some of the other proposed ideas. Each one of them had a shortcoming. Each one of them made sense until you realize, nope, this wouldn't project in this way or that way. So, um, what was the first human gene that was identified? How long after the structure of DNA? I'm curious as to what the gene was and, and more importantly, I guess, what were the methods used to identify a gene, you know, long before we had sequencing?

   14. WCWendy Chung24:44

       So, um, there were biochemical things that were done. So you, you mentioned sickle cell disease as an example. So we had proteins, we knew about proteins, protein electrophoresis, being able to see that. Um, and so conditions like sickle cell disease and hem-- other hemoglobinopathies, we knew at the protein level well before we knew at the DNA level. Um, so that was something pretty characteristic. Other cases we knew based on enzymatic activity, and so we could see biochemically in a test tube, if you will, what the reaction that was run. So we knew about many of those things before we ever knew the exact DNA sequence or exactly what the genetic variants were that caused those conditions.

   15. PAPeter Attia25:22

       And by the time you were a graduate student, so still pre-human genome sequence, so right around the time that, you know, Rudy Leibel is figuring out what leptin is and things like that, um, how much resolution did you have into what a gene looked like at, at that time?

   16. WCWendy Chung25:39

       So it was pretty painful at the time. Uh, we would use these things called linkage maps to try and figure out what chromosome something, a condition was on, be able to get closer through linkage analysis to the right neighborhood, the right zip code, eventually the right address. Uh, when we did this, we didn't have great signposts to be able to even figure out where we were within this. Uh-

   17. PAPeter Attia25:58

       Yeah

   18. WCWendy Chung25:58

       ... we didn't have things like structures of genes, references. Um, so as you were doing this, you were sequencing not just one person with the disease, but also you had to sequence, uh, quote-unquote, normal people or average people for comparison. We didn't have that as something you could just look up online. Uh, we didn't have the internet, as an example, at the time to be able to see, um, you know, have investigators work together from around the world. It's what's much more sort of old school passing papers back and forth and, you know, meeting, uh, in various locations. So it was a lot slower, a lot more laborious. Um, and with this, I have to say, uh, and you had mentioned Rudy Leibel, um, he, he did have this big, bold idea in terms of cloning a gene for obesity, and it's the first time he put in a grant. So putting out that idea, you know, people thought it was just totally ridiculous. The idea that you could, we called it positional cloning, but identify a gene solely based on its position within the genome, um, understanding and not requiring any understanding of the biology or physiology, but just purely based on genetics and genetic mapping. People thought it was impossible to do. So, and of course, uh, subsequently, you know, a whole generation of disease-- or a whole generation of scientists found diseases that way, so. But you know that it, if you can imagine, that process was often a decades-long process or longer. I mean, this was not something you did, um, you know, very quickly. So I, I often tell people, you know, the first gene that I cloned took eight years, um, and you know, the last gene I cloned took eight hours. So, you know, this is just absolutely astronomically different in terms of how we now find disease genes.

   19. PAPeter Attia27:35

       Yeah, it's very interesting. I, I looked at a, a graph and, um, the speed that you're describing even exceeds Moore's law, um, because of, you know, it's sort of-- it's on a Moore's law trajectory with an enormous step function when high throughput sequencing came along, which we can probably get to later 'cause I, uh, I, I think it's, it's important for folks to understand that. What was the first organism, uh, for which we had a, a whole genome sequence?

   20. WCWendy Chung28:00

       Within that, it was certainly a microorganism. I don't remember if it was E. coli or something similar in terms of a bacteria, but definitely a very small organism. Uh, yeast were another important part of our library. Uh, and so being able to understand those small organisms, certainly much easier. Um, you know, even when it comes to the complexity of the human genome, some of us would, you know, say that, well, it's been announced repeatedly that y- the Human Genome Project has been finished, but it's only been recently even that, uh, as we say, telomere to telomere, we've been able to see the sequence, really the, uh-

   21. PAPeter Attia28:33

       Yeah

   22. WCWendy Chung28:33

       ... entirety, including some of the cryptic portions that are hard to read through. So there's still things we have to discover even, you know, even within the human genome.

5. 28:43 – 35:09

   Insights and surprises that came out of the Human Genome Project

   1. PAPeter Attia28:43

      So before the human genome was sequenced, which I think was around two thousand?

   2. WCWendy Chung28:49

      Uh-

   3. PAPeter Attia28:49

      Is the year-

   4. WCWendy Chung28:49

      The first announcement, yes.

   5. PAPeter Attia28:51

      Yeah. Um, there was an expectation that humans would have how many genes based on the understanding of how many genes these far, far simpler organisms had?

   6. WCWendy Chung29:01

      So there were estimates for some people, as many as a hundred thousand genes. By comparison, I think current estimates are about twenty thousand genes in terms of the complexity of people, humans, that is. Um, and but yet the complexity at the individual gene level is probably more complicated than we appreciated. Our ability to have different, what we call isoforms or versions of the way genes are cut and pasted together or how they're utilized in different ways over time and space by different organs or cell types. Uh, any one gene could be made into a dozen or more different gene products. And so some of that complexity was not at the level of the individual gene, but how that gene is, uh, reused in, in slightly different ways. Um, and so anyway, it was shocking the first time, I think, we appreciated that it was about twenty thousand genes in the genome. There were definitely people that were surprised by that.

   7. PAPeter Attia29:58

      Yeah. It seems like such a small number given the variation between individuals. In fact, right, outside of identical twins, we have, you know, what? Eight billion people on this planet, all with distinct genomes. Um, and yet the homology b-- the homology between us is how strong? Like, in other words, how similar are we all genetically?

   8. WCWendy Chung30:19

      Right. So we're all ninety-nine point nine percent the same. Um, about one in a thousand base pairs is what you and I probably differ, uh, by on average. So as, as humans, we're, we're, we're pretty similar to each other. And most of the genetic variants, differences that we have are not meaningful. Um, you know, they don't cause any differences in terms of the way our bodies function. Um, but, uh, on the other hand, you know, as something as subtle as one in three billion base pairs, uh, can be the difference between life and death, can be the difference in terms of the way the body or the brain functions. So, um, you know, small nucleotide differences profou- can be profound depending on what they, what genes and when those genes work.

   9. PAPeter Attia31:00

      So basically, three billion base pairs- 20,000 genes, 46 chromosomes is sort, is sort of the, is, is sort of the, the, the hierarchy of organization. Um, at what point-- Well, maybe just explain to folks the difference between coding and non-coding portions of the gene.

   10. WCWendy Chung31:21

       Sure. Um, so when you think about all of those A's, T's, G's, and C's that you talked about, uh, it's a relatively small portion of that information that gets moved from the DNA to the, eventually the protein. So the portions of that that are made into the, the proteins are about, I don't know, let's say for round numbers, about a percentage and a half of all of that DNA sequence. Um, that other, say ninety-eight and a half percent, uh, there's a lot of it that, to be honest, we have no idea what it does. Um, there are certain portions we do understand. They're very important for regulation to know where and when and how much that gene is expressed. Um, there may be other things that are subtle in terms of being able to attract binding factors, transcription factors, other things that may modify the, the DNA, um, biochemical changes to the DNA itself, which may affect expression. Um, and there are also what people have called junk DNA as th- as well in there, um, repetitive sequences that, uh, probably don't do anything positive for us, um, but, you know, get carried along in the ride. Um, but there's a lot that we also don't know. Um, the-- We don't know everything clearly about this, and there may even be disease-causing variations that are in that space that we haven't even recognized yet, so. Um, but the, to, to your point, uh, it's a small minority that actually encodes ultimately what we think of as most of, um, what the b- what forms the body, physically forms the body in terms of proteins.

   11. PAPeter Attia32:50

       And in 2000, when the, uh, Human Genome Project results were announced, what fraction of those three billion base pairs were identified?

   12. WCWendy Chung33:02

       Oh, so within that, um, I don't know, we'll say round numbers, about seventy percent or so.

   13. PAPeter Attia33:08

       Interesting. And did that include all of the coding segments, or was it not yet understood at that time what fraction of those were coding and non-coding?

   14. WCWendy Chung33:17

       I'd say eventually we f- uh, the majority of the coding was identified at that time, uh, to answer your question. Um, there were a few portions of the genome that were hard to read out for various reasons or hard to map and put the pieces together. Um, one of the things just for the listener to realize is that there was a bit of a jigsaw puzzle. Uh, when we did the, when we did and when we do do the sequencing in many cases, we're not sequencing, I use the term telomere to telomere or end to end along the chromosome. So it's not as if we get one continuous strand of the DNA sequence that comes off the sequencers where we can just read through it and know it comes together. Um, in many cases, we have pieces of it, and we have to informatically put the pieces back together and put it back into the right order. In some cases, that's because we have overlap between those pieces, and so we can see based on overlap, this is the first piece, that must be the second piece, that the third piece based on the overlaps. And so we make these things called contigs or contiguous sequences of DNA and put the puzzle and the pieces together in that way. Um, there are certain regions of the genome that are complicated. They're, they're what we call repetitive sequences, and so they may not be unique, and it may be hard to even sequence through those regions. And so putting those pieces back together in the right order, um, in some cases has been challenging to do. And so sometimes you'll hear some of us as geneticists say there's a dark matter or there's some cryptic regions of the genome that we haven't been able to really dig into, and that's because of some of these complexities of the sequences there and our ability to sequence through them. So even despite what you're saying in terms of knowing the genes or even knowing portions of the sequences, we didn't necessarily know that it was all part of one gene or that we had all the pieces or put it all together yet. And so some genes and some diseases were easier to crack than others as a result.

6. 35:09 – 40:50

   Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more

   1. PAPeter Attia35:09

      So today, if somebody goes out and gets a commercial, uh, genetic test, what's the difference between someone who goes out and gets a whole genome sequence and, say, someone that, you know, goes to one of the over-the-counter, uh, sequencing services like a 23andMe? What's the difference in the analysis and what's the difference in the information?

   2. WCWendy Chung35:33

      This is an important question, and if people are listening, uh, this is time to perk up and listen closely. Um, so there's a big difference, and not all genetic testing is the same. Um, and I'm not being critical of any of the companies or-- that do this, but just to realize they're trying to serve a different purpose. So 23andMe as an example, um, or Ancestry.com, uh, as another example, those are more things that are not medically sort of targeted. They're not trying to answer a specific medical question of do you have an increased risk of breast cancer? Do you have an increased risk of heart attack? They're really not getting at that level of detail. Uh, just as an example, Ancestry.com is very good at being able to understand your heritage, your, your literally where your family is from, where your ancestors are from. It's quite detailed at this point in terms of being able to say what part of the world your family comes from, if you might, uh, be adopted as an example, not know about your heritage or your ancestry, be able to give you some of that. And I'll also say, for better or for worse, if you're trying to find this out, you may identify some of your blood relatives, um, some people who, uh, you would know from a family reunion and some people you might not know for some reason, and people sometimes find out about that. Uh, uh, like I said, even people who are adopted, I've, I've known to find some of their, um, actually their birth parents that way. So that's one type of thing, but that's not really for the intention of identifying information for a medical purpose. Um, and so I just wanna warn the listeners that if you get something, uh, back, or more importantly, if you don't get something back from those tests, it doesn't mean an all clear for your health. It doesn't mean that you're free of cancer or won't have any increased risk. On the other hand, there are other tests that are really designed for a medical purpose to answer a question. Um, and you didn't ask about this specifically, but many of the listeners will know that they would have gotten a test, for instance, if they were thinking about having children, uh, plann-planning a family, wanting to know if they are children or if they were at increased risk of having a child with something like Tay-Sachs disease or cystic fibrosis, one of those other recessive conditions, uh, that we alluded to. And so that's not what the attention, uh, for personal health so much as, as I said, thinking about future children or families. And, um, l-let me be clear, this is not necessarily about abortion, but this is about being able to care for a child long term and think about, uh, reproductive options. So that's another use case and a very common use case in terms of what people will do. Um, another common use case is for thinking about cancer risk, and so some people may have a family history of cancer. Some people may say their particular heritage is such that, uh, for instance, if they happen to be of Jewish ancestry, they may be concerned because they know there's a higher chance of having a BRCA, uh, so called Breast Cancer one or BRCA one or two mutation. And so some people will do a very targeted test, and, and I'm emphasizing targeted, very specific clinical question. And again, it's answering that question. It's not necessarily giving a genetic clean bill of health for everything. It's, it's very focused. On the other hand, you alluded to what I'll call a genomic test, and, and I'm gonna make a distinction between genetic and genomic. And what I mean by genomic when I'm saying this is it's really including, as we talked about, all genes. So it's not focused on just a handful of genes. It's really focused on the genes in the genome, those twenty thousand genes. Um, you can look at just the coding regions that we talked about before, those looking at the protein sequence that we call that in the aggregate an exome, because those little pieces that code the genes are exons, E-X-O-N-S, and when you put them together in the aggregate, we call it the exome. Other individuals are interested in knowing all three billion of their base pairs, their entire genetic sequence, and we call that a genome, and that will include everything, both the coding and the non-coding regions. I think of that in terms of genome sequence as being in some ways the, T-H-E, genetic test, right? It's all-encompassing. One can blind yourself to look at very focused, uh, subsets of genes based on a clinical indication, or you can look at everything because you wanna look at everything about your health or because maybe you don't know all of the genes for your particular symptoms, and you have to be all-encompassing in terms of that. And we may get to some of those use cases, but there are many conditions that are genetically heterogeneous or have many different genes that can cause them. And so we want to be all-encompassing in terms of looking at that. Even though we can sequence all that data right now, we can't interpret it all. So as an example, out of those twenty thousand genes, we have now assigned functions with disease for about seven thousand. But that still means that for over fifty percent of those genes, we don't know of a gene disease association. And s-- and even, I will say, 'cause this happens to me with fair frequency, even when I think I know about an association of a gene with a disease, if we study it further, we'll realize that they don't map just one to one. There may be more than one disease associated with a gene, and so there's still things that we're figuring out about what those genes do.

   3. PAPeter Attia40:49

      So

7. 40:50 – 46:59

   Whole genome sequencing

   1. PAPeter Attia40:50

      Wendy, let's just talk technically about those different options that you laid out, and let's start with the most comprehensive. So, um, I-I've had a whole genome sequence done, and I th-- I believe it was done off a couple of tubes of blood, maybe even just one tube of blood if I recall, but no more than two, so ten cc of blood at the most. Um, what did the-- So I sent that over to, you know, it was a university that did it. It was part of a clinical trial. Um, what did that university do with those two tubes of blood to extract the insight to read the three billion base pairs that, uh, make up my whole genome?

   2. WCWendy Chung41:28

      Yep. So I'm guessing, uh, but, but I'm guessing that what they did is, um In the white blood cells in that tube of blood, they open those up to extract what we call the genomic DNA, so the DNA included in each of the nuclei of those white blood cells. From that, they, uh, depending on how they did this, they, uh, may have captured out specific fragments and then read through all of that using what we call short-read sequencing. Again, my guess in terms of this. That short-read sequencing was probably less than 100 nucleotides for each little fragment. As they did that, they then had to do that, uh, informatic computational step of putting all of those pieces together, and in most cases, they were probably able to do that because they had a reference sequence. They knew what the average person looked like, and they put your sequence right on top of that. And to the extent that those mapped uniquely, they could put that all together. There may have been, though, some of your sequence where they didn't know where it fit, and so it got p- sort of put aside in an area that they didn't even analyze, but there were some of your sequence that probably got put aside that they didn't know where it fit, how the pieces fit together. And in fact, the reason I say this, and this is very, very highly technical, is that we're not perfect at doing this, and so there's times when there's information over here at the side where we haven't used. As they did that, they're then able to read out, and depending on the purpose of what your analysis was, they could read out and they could say, "Well," for instance, if you were interested -- I don't know anything about your own medical situation, but if they said, "Uh, well, we're interested in knowing whether or not you have PKU," they could look at your phenylalanine hydroxylase gene. They could read out all the sequence and warn you, as I said, one in 1,000 base pairs, there's gonna be a difference in this. And so they see a difference, then they have to do an interpretation, and the interpretation is actually, um, a lot more sophisticated than one wi- might imagine because, again, there are literally tens of thousands of genetic variants in your genome, and what they mean and whether or not they do anything whatsoever is hard to know. Each of us has mut- what people think of as mutations or genetic variants that are associated with disease and cause a problem. Each one of us has those, some that are very, very powerful, some that are kinda wimpy, and they infer some very small risk. But in the aggregate, you put together a lot of these little wimpy genetic variants, and it may amount to something more substantial. So depending on when your genome was sequenced, when it was most recently interpreted, you might have gotten really profound, powerful information in terms of taking care of yourself, or you might have gotten the sort of, "Eh, we don't see much here."

   3. PAPeter Attia44:07

      Mm-hmm.

   4. WCWendy Chung44:07

      Um, you know, sort of you go on your merry way. And for the average person, my guess is if you were middle-aged when this was done, for the average middle-aged person, it's mostly, "Eh, we don't see much here," because you've survived, eh, hopefully as a relatively healthy person to this point, that you've, uh, essentially, uh, made it through some of the most devastating things we can see in the genome.

   5. PAPeter Attia44:29

      One more question before we leave the whole genome sequence and talk about the, uh, whole exome sequence. Uh, one thing that they learned in me that, uh, was quite interesting was that I was mosaic for a certain gene. Uh, this was only realized because as part of this clinical trial, everyone in my family was sequenced, and, uh, one of my children, uh, had a full copy of the gene, which they got from me, but I was mosaic for it, so I didn't have very much of it. Can you explain what that means?

   6. WCWendy Chung45:00

      Yeah. So this can come up in a couple of different ways, and, um, I can talk more or less about this if you're interested. But, um, y- you would think we're the same, every cell in our body exactly the same, but in fact, that's not true, and the, the, your viewers or your listeners rather will realize this when we think of cancer. Uh, our genomes are not stable over our life course from the point of conception to the point of death. Uh, and when you think about every cell division, if you have to copy over three billion letters, we're not perfect, and we have spell checkers to try and catch these things, but our body doesn't always catch them. And over time, mutations can accumulate in the body, and of course, as they accumulate, this may lead to aberrant cell growth, which is essentially what cancer is. And so cancer is at the heart of a genetic disease, but oftentimes not from the genes you're born with, but for the changes that happen over your life course. Now, in certain individuals, and, and I'm guessing this was the case when you just described your family, um, this will be true not just of your skin cells, for instance, if there's too much UV damage to your skin in the summertime, um, but this can happen in your germline as well. So it can happen in the egg and the sperm, and when this happens, again, as what we call somatic mutations or mutations over the life course, again, if they're in the germline, they can be passed down to the next generation. And so you can be what we call a germline mosaic. You can be a mosaic. And mosaic, just like a tile pattern that you see in, you know, a bathroom or something, right, where you have some color tiles, um, one color and some other tiles another color. They're a different pattern because some cells have the mutation and some don't. And so in the same way, you can have, uh, what we call gonadal mosaics, meaning that the germline is affected. In some cases, you can see those gonadal mosaicism, uh, that mosaicism in the blood as well, so what you were talking about in terms of getting a blood sample. You might see that a certain fraction of the cells have those mutations in the blood. And then if you see them in the next generation as well, you'll know that it was transmitted through the germline. Um, I'll te-

8. 46:59 – 52:31

   Germline mutations and the implications for older parents

   1. WCWendy Chung46:59

      share an interesting factoid, um, for individuals. Uh, the number of those mutations in the germline actually increases over the life course. And so in particular, uh, if you think about the biological process for spermatogenesis with men, um, those sperm continue to divide over the life course, and those mutations can continue to accumulate over the life course. And so, in fact, some of the conditions that are associated with de novo mutations or new mutations, uh, we see the frequency of that being greater for parents, for instance, who are older parents at the time of conception than for parents who are younger at the time of conception. And it's not, you know, that it's, like, astronomically exponentially higher. It's a linear process for those, uh, those types of mutations, but we do see those increasing over the life course.

   2. PAPeter Attia47:48

      Historically, we would assume that women are more susceptible to that via age. I mean, it-- the, the rate of either aneuploidy or mutation seems to rise more sharply with women earlier, uh, starting probably in mid to late 30s. Um, you're pointing out that the same is true of spermatogenesis. Am I correct in saying that the egg seems more impacted by the sperm, and if so, why is that? Is it a more complex division?

   3. WCWendy Chung48:15

      So what you're bringing up is that, um, meiosis in the two sexes is different, and it is susceptible to different underlying biological processes. So as you're saying, for women, um, the-- if you look at the curve in terms of problems, aneuploidy or sex chrom-- or not sex, but rather chromosome differences, namely Down syndrome is what many people think about, increases with advanced maternal age, and that has to do essentially with the stickiness of the chromosomes at meiosis and the ability to separate, um, or not. And so the curve that is associated with that, which, um, many people learned at some point, is that, um, there's an inflection. There's-- It's not a linear relationship with maternal age, but, uh, as you said, in the mid-thirties it starts to increase more significantly. And as a result of that, there's a whole, um, sort of medical way that we can follow women when they're pregnant to try and pick up, if they're interested, those particular chromosome issues. Um, the difference when it comes to, uh, what we call DNA sequence differences, so again, not whole chromos-chromosomes, but single letters, is that that process of being able to have the cell divide and replicate and copy over that information happens at every single cell division, and there's a certain probability that that will happen. And so that's a linear, linear relationship in men. And based on the biology, men obviously from a reproductive point of view may have, uh, children over a larger period of time, so we can see greater differences across men, uh, as they're, uh, reproducing. So biology's a little bit different between the two sexes.

   4. PAPeter Attia49:55

      Do we have a clear sense, um, why you see more of these, um, meiotic differences, uh, with age? In other words, what is the fundamental characteristic of aging that is driving that? I, uh-- Is it sort of like evolution says, "Well, I don't care because I don't want you to reproduce after a certain age, so I'm act--" You know, again, not to anthropomorphize evolution, but, "Therefore, I'm not going to preserve the integrity of your genome beyond a certain age"? I mean, I, I just-- I'm curious as to-- See, to me, that strikes me as the explana-- like an explanation, but not the reason, right? The reason must be something more fundamental at the level of, you know, an aging hallmark process.

   5. WCWendy Chung50:40

      I, I hadn't thought of the question quite that way, but, um, I do think if you think about throughout all of human history, the age at which people were having, reproducing and having children, um, has skewed much younger than it is in terms of current society. So I think we have pushed the boundaries to a certain extent in terms of what the biology historically has been. I don't know if we had a, you know, use, use before date, uh, in terms of ovaries and, and s- and, uh, gonads before. Um, but that I think just historically has been what's happened. Um, so within that, you know, the, the fundamental biology for women has been proteins that are responsible, as I said, in terms of meiosis and separating of the chromosomes and being able to have... If you remember when meiosis starts in females, it actually is starting way, way early in gestation, so even during fetal life. And so those proteins have to be working and intact from before a, a fetus is, you know, even born, before a child is born, lasting all the way through whenever that, you know, pregnancy is conceived, essentially, when those gametes are finally dividing. So that could be, you know, thirty, forty or more years for that process to have to work, and that's kinda asking a lot when you think about the biology. Um, for men, I'll just throw in another interesting factoid that for some of these mutations that arise during the process of, uh, gametogenesis, there are even what we call selfish sperm mutations. That is that certain mutations may even give a selective advantage, uh, to those spermatocytes, where they may have a reproductive division advantage, for instance. And so we may see more of those in terms of the biology of what we see in the next generation because of the effect they have, even in terms of on, directly on the sperm. So lots of biology at the root of that.

9. 52:31 – 56:21

   Whole exome sequencing and the importance of read depth

   1. PAPeter Attia52:31

      So let's go one step down from the whole genome sequence to the whole exome sequence. So if, if, if as part of my blood test I only wanted the whole exome sequence, are they actually doing the whole genome sequence and just reporting out the exomes, or are they actually doing something technically different?

   2. WCWendy Chung52:48

      So to answer the question, you have to read the fine print on your genetic test report or your clinical trial consent or, or whatever it is. Um, so I don't know the answer, uh, you know, without knowing that. It certainly was the case that a few years ago, not that long ago, it was so expensive to sequence a genome that we rarely did it. It was really just cost prohibitive. The exome was a really good shortcut because we didn't know what a lot of the other information meant anyway, so we were kinda-- it would've been just throwing it away. Increasingly, we have a better sense of what the non-coding regions do. Uh, we have better ability to interpret and recognize genetic variants. And so I would say as the sequencing costs have been coming down, there's more of a shift to going to genomes rather than exomes. But truly, most of what is medically used at this point, um, is in the coding space. So even if you're sequencing a genome, it's still focused on the coding regions. On a research, um, basis though, very different. Um, and of course we have to do research before we can apply it clinically. A lot of the research now is understanding what all of those regions do and being able to eventually use that information clinically. So I do think within the next decade we're gonna see a shift, and we may even shift from this, what we call short read sequencing of these hundred base pair fragments, even to things that are much longer in terms of accuracy, able to read through some of the greater, the areas that are more complex and probably that we've been missing out on before.

   3. PAPeter Attia54:15

      And a short read you said is about a hundred base pairs?

   4. WCWendy Chung54:17

      Plus or minus, yep

   5. PAPeter Attia54:19

      So what's the technical limitation for making that longer?

   6. WCWendy Chung54:23

      As you do this, there's just lower and lower fidelity for each base pair that you do. And so at some point you start getting errors within your readout, and you don't want to have too many errors because you can't distinguish between what are true biology versus what are artifacts of what you're doing in the laboratory.

   7. PAPeter Attia54:40

      How are you correcting the errors? Because if you're getting even one error every-- in one short read sequence, that would-- I mean, given that we s- we're-- we only differ from each other by one and a half percent of those base pairs, that, that would be... You know, for example, you wouldn't be able to use this information in court. Let's-- H-How do we preserve the fidelity of this to make such bold claims as, "Hey, we found this blood at the scene of the crime, and we absolutely know dispositively it belongs to this individual"?

   8. WCWendy Chung55:09

      We do it not just once, is the answer. So in fact, when we read this out, we have a term called read depth. It's how many times we look at any one nucleotide in the genome, and we don't look at each position just once. Uh, depending on how much we want to spend doing it, we might look at the read depth of thir- 30X. So we might look at every one position on average thirty times. And if you see out of the thirty times, twenty-nine of one allele, you know, one nucleotide, one of the other, you say, "Oh, that one, the oddball there, that's probably just a sequencing error. That's an artifact-

   9. PAPeter Attia55:41

      Yeah

   10. WCWendy Chung55:42

       ... of our method in the lab." The other twenty-nine are the ones that we want to pay attention to. Um, in some cases, and again, I bring in cancer, it becomes very important to know for those somatic mutations that won't-- weren't there from birth, that they may be there in a small number of cells, but cells that can be very, very dangerous for cancer. And so we may increase the read depth to be very, very high. We may go up to 1,000X in terms of read depth to make sure we've got the accuracy, um, to see something reproducibly, even in ten percent of cells. But again, we're ten percent. You need ten percent of a large number to have the assurance that what you're seeing is in fact representative of the underlying biology, not an artifact.

10. 56:21 – 1:04:12

    Genetic testing for breast cancer

    1. PAPeter Attia56:21

       Let's talk a little bit more about an example there. So you brought up, um, BRCA1 and BRCA2. So typically the genetic tests, that would be done off a whole genome sequence, uh, or even a targeted sequence, because let's say a person says, "I want specifically to be tested for breast cancer genetics." Um, but you're still testing on the actual DNA taken from white blood cells, correct?

    2. WCWendy Chung56:45

       So these days we do things lots of different ways. Um, and just again, for some of the listeners, we've tried to make everything we do more accessible. Um, this is a fundamental sort of core value for me. So as an example, we can even now do things from cheek swabs-

    3. PAPeter Attia56:59

       Uh-huh

    4. WCWendy Chung57:00

       ... from saliva samples, from blood samples. So again, we try and make it less invasive, uh, easier to do, even potentially from home. And so for some people who have done something like 23andMe, they may have even done it that way.

    5. PAPeter Attia57:11

       Let's pick one of those examples, a cheek swab or a, a, a blood test. You're-- And you're going to do this enormous depth of readout to really make sure that there are no copies of the BRCA gene or any of the other genes that you're looking at. How many genes, by the way, when we do, uh, a breast cancer genetic screen, how many known genes are we looking for?

    6. WCWendy Chung57:33

       So interestingly, uh, it's a little bit of a la carte. So what I mean by that is it's the-- your choice. It's your choice either as a doctor ordering the test, it's your choice as a patient that's getting the test. In some cases, you know you have a family history of a BRCA mutation. And so within that case, we may know the exact address to go to, and it's a very simple plus/minus readout. And we don't have to do a whole genome sequence for that.

    7. PAPeter Attia57:57

       Mm-hmm.

    8. WCWendy Chung57:57

       We just need to look at one gene and say yay or nay, it's there or not there for that particular variant. Um, beyond that, there are even-- I alluded to this before, but there are certain, uh, variants that are seen in certain communities. So as an example, if you happen to be Ashkenazi Jewish, there are three different spots in BRCA1 or 2 that account for the vast majority of all mutations in those two genes. And if you know that, we can take a shortcut, and we can basically say for literally a small fraction of the cost of sequencing a genome, boop, boop, boop, we look at those three spots, we get yay or nay, and you've got most of the information that you need. Um, to your point, uh, there are some people who come in with a family history of breast cancer, and they say, "But I want to be careful." And so in that circumstance, we may do a panel of fifty different genes, five-oh different genes-

    9. PAPeter Attia58:44

       Mm-hmm

    10. WCWendy Chung58:44

        ... that'll cover most of the genes that we see for hereditary, not just breast cancer, but ovarian cancer, colon cancer, the most common cancers that we see that are driven by germline or inherited genetic factors. So for round numbers, fifty is a good number when you're trying to be really comprehensive. If you said, "Just give me the focused breast cancer things," it might be more like ten.

    11. PAPeter Attia59:07

        Yeah. And again, you, you've said this twice now, but I think it's, it's helpful for folks to listen. When last I checked, maybe five percent of cancer was accounted for by germline mutations. Ninety-five percent of cancer is accounted for by somatic mutations. Is that still accurate, would you say?

    12. WCWendy Chung59:26

        I'd say I'm going to modify that just a little bit, not to be a contrarian. Um, but w- for the genes that I'll call monogenic, highly penetrant. Let me unpack that a little bit.

    13. PAPeter Attia59:35

        Yep.

    14. WCWendy Chung59:35

        Monogenic-

    15. PAPeter Attia59:36

        Good, good, good point

    16. WCWendy Chung59:37

        ... monogenic, single gene, highly penetrant, high probability that over the life course you'll develop cancer if you have this particular gene-- genetic variant. So when you limit yourself to that, yes, about five percent of cancers are due to those powerful single genes, high probability of cancer. Now, on the other hand, over time, we've realized that there are additional genes that I'll call moderate risk genes. Many of those genes may confer something like a two to threefold increased risk, as opposed to something like a tenfold increased risk. So there's another probably five percent or so that are due to those. And then there's this other thing that we call polygenic risk. Poly meaning multiple, genic, genes, polygenic, multiple genes. And the number of genes we oftentimes look at in those circumstances may be anywhere from a hundred to hundreds or even in some cases thousands of genetic variants, all mathematically summed together to understand what the risk is associated with that package. All of us have genetic variants that go into that polygenic risk. And part of the question is along a distribution, are you at the high end of that risk curve, or are you at the low end or at the average end? And so within that, um, this is now something that is not clinically being utilized routinely, but we are, on a research point of view, trying to understand clinical implementation for now those polygenic risks for cancer.

    17. PAPeter Attia1:01:06

        And, um, so, so assuming that that amounts to, I don't know, we'll figure it out, but that might amount to ten percent of cases. You'd say, "Well, look, twenty percent of cancer has a genetic component as opposed to..." And it's broken down into those three categories of, you know, monogenic, highly penetrant. Uh, I think the second category, was it monogenic, not highly penetrant, or not monogenic?

    18. WCWendy Chung1:01:31

        I'd call it monogenic moderate risk.

    19. PAPeter Attia1:01:33

        Moderate penetrant, and then polygenic.

    20. WCWendy Chung1:01:35

        Right.

    21. PAPeter Attia1:01:35

        And those would be the three. A- and then going back to this case of, say, the breast cancer example, right? So a woman says, um, "I just want to do a deep dive on breast cancer. I don't know which genes it is because all my family's deceased, but, you know, four women in my family have died of breast cancer. We're gonna do this cheek swab, and you're gonna look at ten genes that are associated, plus whatever the polygenic genes are." Um, why is it that you don't need to look directly at breast cells?

    22. WCWendy Chung1:02:07

        Mm-hmm.

    23. PAPeter Attia1:02:07

        Why is it that we can infer that what we see in a cheek cell, an endothelial cell, uh, or an epithelial cell rather in the cheek or in a monocyte in the blood, is also captured in, uh, in mammary tissue?

    24. WCWendy Chung1:02:23

        Good question, and the answer is it's probably not. Um, so what you're doing when you're doing the cheek sample, the blood sample, is you're really getting at the germline. So you're mostly getting at what you were born with, uh, what that inherited, uh, susceptibility is. As we talked about, though, your genes are changing over your life course. Your cells are changing over your life course. And cancer doesn't happen overnight. You don't go from a normal cell to a cancer cell overnight. There's a progression in terms of going through this. And so, uh, there are other ways that people have thought about that I'll call it a liquid biopsy. So this idea that you might be able to-- And it's a slightly different test than what I was describing before. But where you would look for these somatic mutations, you described this before, but when you're looking for that needle in a haystack, if you've got a tumor that's going to slough off some of that DNA into the circulation, you might be able to see some of that fragmented DNA floating around, and you might be able to pick up some of those mutations that might be reflective of that mammary cell that's either gone awry and is a cancer, but maybe not something that you're detecting on mammography or something else. And so this has in some ways been the holy grail of being able to do cancer screening. It's not quite ready for prime time yet. Um, and people think about it more, I would say right now, for thinking about recurrence of cancer. So how do you monitor someone who's had a previous cancer diagnosis, you think they're all clear, and seeing whether or not they've had a recurrence? Um, the other use case people have thought about is someone who might be at high risk of cancer, so someone who's identified in whatever reason based on an exposure, based on a genetic profile. But it's not ready yet for population screening in terms of being able to pick up cancers at an earlier stage. We're still relying on other things to do that.

11. 1:04:12 – 1:09:42

    What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)?

    1. PAPeter Attia1:04:12

       So let's now talk about what happens at the, the level of the, the 23andMe's and the Ancestry, Ancestrys, uh, and companies that are obviously doing something far less than a whole genome sequence or even a whole exome sequence, just on the na- basis of the cost at which they can offer these things. What are they technically doing with the epithelial cell of your cheek or the saliva or the white blood cells that they get?

    2. WCWendy Chung1:04:40

       So again, and I'll say read the fine print of what you sign on the consent form. Um, number one, it may change over time, and I don't represent any of those companies, so I don't want to misspeak in terms of what they're doing. They are in general, though, number one, not trying to detect cancer. So any of what I talked about-

    3. PAPeter Attia1:04:56

       Yep

    4. WCWendy Chung1:04:57

       ... not the purpose of what they're doing. They're in general not trying to read out the genome, at least not for the purpose of getting you medical information for what I call news you can use to manage your own healthcare. They're largely doing it in a way that I'll call more recreational. And so with doing that, for any of you who have done 23andMe, you may find out something about, for instance, uh, if you were to eat asparagus, what your urine might smell like or what your ear wa- wax might be like or if you're, uh, lactose intolerant. They are things that are related to how the biology of your body works. They are related to genetic variants, so those two things go together. But they're not telling you based on your ear wax if you're gonna have major problems with hearing loss down the road or, you know, cancer risk or things like that. So that's why I use the term recreational in that way. Um-

    5. PAPeter Attia1:05:43

       But what are they technically doing? Like to-

    6. WCWendy Chung1:05:45

       So they are-

    7. PAPeter Attia1:05:45

       Yeah.

    8. WCWendy Chung1:05:46

       Yep. So, uh, depending on the company and depending on what they're doing, they're oftentimes reading out what we call single nucleotide, uh, polymorphisms or so-called SNPs. So they're not reading out the entirety of your genome. They're not reading out all three billion base pairs. They are selectively going in and saying, "At this exact address, do you have an A or do you have a G? At this other address here, do you have a C or do you have a G?" And based on that, they may selectively look at those particular variants and say, "With your profile, I know that your family, you know, originally came from Egypt," uh, or wherever it is, you know, in terms of being able to look at ancestry. Or they may say, "Based on looking at this, I know this particular genetic variant may predispose you to be lactose intolerant. I would expect that you're gonna have problems in terms of eating ice cream for dessert tonight." Um, so, you know, that's generally the type of thing they're reporting out. Um, depending on, again, the company and the terms of the agreements, there may be differences. But generically, that's what all, many of them are doing.

    9. PAPeter Attia1:06:46

       And so if a gene differs by more than one nucleotide, a SNP is not of much use. I mean, you, unless you sample two SNPs in the same gene.

    10. WCWendy Chung1:06:57

        Gets tricky. Um, so technically, a single nucleotide polymorphism could be a genetic variant that has a big, big effect on a gene and could, from a medical point of view, be very, very impactful. So it's not just the size that matters. It's, you know, as some people would say, location, location, location. It's like real estate. So, um, it, it all matters which variant we're talking about. But in general, the ones that they're looking at are not the ones that are medically impactful. They're just normal variants that are innocent bystanders, but help us understand where our ancestors came from. For the most part, that's what the companies are doing.

    11. PAPeter Attia1:07:31

        Although they do comment on some important ones. So you mentioned isoforms as normal variants. So the APOE gene has three isoforms, the two, three, the four isoform. All are relatively common. I mean, the three being the most common, then the four. The two is not that common, but, but all would be considered, quote-unquote, "normal variants." One obviously comes with a much higher risk of neurodegenerative disease. Um, a 23andMe test does read out that prediction. Um, so presumably that tells us that those genes only really differ by one base pair, correct? The two, the three, the four only differ by one base pair. That's therefore the only place they need to sample. Um, but I've seen in ten years several instances of a miscall, meaning-

    12. WCWendy Chung1:08:27

        Hmm

    13. PAPeter Attia1:08:27

        ... the SNP read ends up not matching with the more rigorous, uh, exome sequence. Uh, why do you think that's the case? Is, is that, does that surprise you?

    14. WCWendy Chung1:08:39

        So I, I will say that, you know, in doing this, I'm not someone, you know, that has been asked to go in and QC or do quality control or anything like that for the laboratories. I have known of things as simple as, um, these are done in plates that oftentimes are twelve by eight plates, and if you flip the plate the other way, you can have sample switches-

    15. PAPeter Attia1:09:02

        Hmm

    16. WCWendy Chung1:09:02

        ... and you've got a different person being read out for a different thing. It can be something as simple as a logistic like that, and I have-

    17. PAPeter Attia1:09:07

        Right

    18. WCWendy Chung1:09:07

        ... seen that lab error before. Um, there can be sample switches at multiple places, and at the end of the day, I will say that if you are doing something from the recreational side to something where you are gonna make a major healthcare decision, you are, as in a woman, for instance, gonna go through and have a mastectomy-

    19. PAPeter Attia1:09:25

        Hmm

    20. WCWendy Chung1:09:25

        ... get a second opinion, right?

    21. PAPeter Attia1:09:27

        Yeah.

    22. WCWendy Chung1:09:27

        Like, be sure that this is really you and it's really the result you think it is before you do anything irreversible or, you know, go out and buy that big life insurance policy. Um, 'cause, you know, I w- and I would say that in general, you know, if you were getting a second opinion about cancer diagnosis, so.

12. 1:09:42 – 1:21:57

    The GUARDIAN study and newborn genetic screening

    1. PAPeter Attia1:09:42

       You mentioned the GUARDIAN study earlier. Can you, can you say a little bit more about what that study is?

    2. WCWendy Chung1:09:47

       So the GUARDIAN study, um, as you can imagine based on what I started out the conversation with phenylketonuria, is, um, uh, I've always been, uh, wanting to be able to get information that people could use to be able to maximize health and being able to just be the best person they could be. And I started out in 1996. I, again, had started out in the space of PKU decades ago and, um, had been studying a disease called spinal muscular atrophy for about a decade with colleagues of mine. And this is a neurodegenerative condition, and used to be the most common genetic cause of death for children less than two years of age. And I realized, um, starting in 199- uh, rather, uh, um, starting in 2016, that we were just at the cusp of potentially a treatment that might slow down or stop the neurodegeneration, yet tragically, if we didn't identify babies before they started showing symptoms, it would be too late. That is, we'd have this window of opportunity. So we started out a newborn screening program for SMA, and then babies that were identified through that had the option, if they wanted to, of going into a clinical trial. That ended up being quite synergistic in the sense that we did identify babies who would have been predicted to have the most severe type of SMA. They did get into early clinical trials right away. They did benefit from those. That helped in terms of the ultimate evidence that was necessary to show the efficacy of those treatments. And because of that, um, and because we were able to show that we could do it technically and that people wanted it, um, SMA has been added to the recommended universal screening panel for babies across the United States. And so now four million babies born each year in the United States are screened for SMA, and we have three FDA-approved treatments, including a one and done gene therapy. So babies can now be identified within the first week or two of life, get a one and done IV infusion of the gene, and, uh, go on to have, uh, a much, much better life, if not, uh, you know, be, quote-unquote, "normal," at least as far as we can see so far. So that got me thinking about, um, sort of doing this on larger scale. We've since done a newborn screening study for Duchenne muscular dystrophy, and just recently actually was FDA approved a treatment for, uh, for DMD, Duchenne's muscular dystrophy. Um, but I'm, I don't know. I'm getting older, and I'm getting more impatient, and I didn't want to do these one by one. I started thinking about how could we do these at scale for population health, but not just for one condition at a time, but how could we do it for dozens or hundreds or, uh, potentially even more conditions. And so, uh, the GUARDIAN study actually stands for something. It stands for Genomic Uniform screening Against Rare diseases in all Newborns. And if you put the letters together from that, it spells out GUARDIAN. And the idea behind that is to take that same newborn screening dried blood spot that we use already for PKU that we talked about, sequence the genome We don't need to read out everything in the genome. We only read out the genes that we consent people to read-- to that, that they consent to in the study. And those genes are genes that have, I call it news we can use, information that has treatments immediately available. And in planning this study for almost, uh, four years or, uh, just over four years with families, we had many, many iterations about what they wanted, what they wanted us to screen for, what should be-- what should enable them to be the best parents and give their children the best, uh, chance at a healthy life. And we thought about also this dynamic change in what we'd have treatments for, the fact that the world is changing rapidly, and we wanted the flexibility that if a new treatment became approved tomorrow, [snaps fingers] boom, we could instantly change the screen and be able to implement that. We wouldn't have to wait a decade to gather the evidence to do that. We wanted to be nimble and flexible. So the reason for using the genome as the backbone is it gives us that infinite flexibility to be able to adapt and to be able to move the field forward. So we've been doing the GUARDIAN study in New York City since September 2022, and right now have screened just over three thousand babies. And it really has been remarkable to me in terms of being able to see, um, just the broad support from our community in doing this. In New York City, uh, you should realize, you pro-- most of the listeners probably do realize the wonderful diversity we have in New York City. That is that of the people who participate, um, it's not just, uh, white folks. It's not just people who are from Ireland. We were talking about Irish, um, uh, individuals in PKU, but it's people from around the world. We have, um, about a quarter, a quarter, a quarter, a quarter of people of European ancestry, of Latina ancestry, of Black ancestry, of Asian and other ancestry. So it becomes really, I think, representativeness or representative basically of the world. Um, and it also is geared to leave no baby behind, um, because newborn screening is kind of this one universal thing where everyone goes through the health system in the same way. And by making this free and being able to, uh, allow everyone to enter if they so chose, uh, we can really see also what people, what people-- information people want and what they don't want. Um, within this, I guess one of the things that's been refreshing to me is to see that about seventy-four percent of parents that we approach and offer this to decide they want to do this. And that's an important number to me. When we did this for SMA, the number was ninety-three percent. When we did this for Duchenne muscular dystrophy, it was eighty-four percent. And so within this, it's not a hundred percent of people who want any of these genetic screens, and that's perfectly fine. I'm not trying to force anyone to do anything. But it's also not ten percent. Um, the majority of parents are saying, "Yes, if there's something I can do to ensure that I have a healthier child, like, impa-- like, give it to me. Like, help me be a better parent. Why would I not wanna do this?" is mostly what we hear. Uh, within this, I also appreciate, and we do this with regular newborn screening, just the traditional newborn screening, and we realize that traditional newborn screening isn't perfect. I never thought it was. Nothing ever is. But we realize that adding this additional dimension, and we've even done it for PKU within this study, this, an additional dimension helps us to do a better job. And so just as an example, uh, we've also identified part of newborn screening identifies some children with severe combined immunodeficiency, um, a problem where you can have an overwhelming infection and die from this. But, uh, treatments is available, including a bone marrow transplant. And so because of that, we have as part of newborn screening, um, a way to screen and identify some but not all children that have that. We've added this now genome sequencing to enrich and improve that, and in fact identified a baby that was missed by our traditional newborn screening for SCID, um, yet is at increased risk in terms of this overwhelming infection, but yet with the opportunity to intervene at an early stage when a bone marrow transplant will be most effective. Um, and so there are numerous examples where we've identified whether it's Wilson's disease, whether it's severe combined immunodeficiency, whether it's achondroplasia, but other conditions that are treatable that we just needed to identify those babies. And as we've done that, the number of children that... And I just know because I've been practicing in New York City for twenty-five years, I know sort of how people navigate the system and, and how they get through, and we've been able to really get to many of the people who are usually, um, unfortunately left behind, either because they're immigrants, they don't speak the language, they don't have the same health insurance. Uh, but individuals that we're seeing come out positive for this are very, very different in terms of reflecting our community than the people who navigate the healthcare system and get in to see us. And we realize based on other studies that we've done that most of the children that would have been diagnosed, if ever they were diagnosed, on average aren't diagnosed until somewhere between eight, nine, ten years of age. And so we're intervene-- or we're able to identify them literally a decade earlier, uh, before a lot of damage has been done to their body. So it's just the beginning. You know, three thousand is great. I think it demonstrates that we can do this. I think it tells us what our community wants out of this. Um, it shows us some pitfalls in terms of how it's hard to do and what we need to do to do it better. But I do fully believe that this both de-risks this in terms of being able to also have, um, groups that are working on therapies, uh, be able to realize that this is something. There's an opportunity now for treatment for this and is a powerful way of moving forward health equity, at least for children for the next generation.

    3. PAPeter Attia1:18:25

       Is this something that's done only at Columbia, or is it a multi-center New York, uh, hospital endeavor?

    4. WCWendy Chung1:18:31

       So right now, this is done through our New York Presbyterian Hospital system, so it's not just Columbia, but it's through, um, this hospital network. Uh, it's only so far in those hospitals, but based on our success for this, we are figuring out how we can be able to expand this, uh, more broadly and really think about this, as I said, as integrating within the public health infrastructure. Not trivial to do. Uh, not trivial to do this on scale. As an example, doing this in New York State, if we were to do this for every baby, we'd need to do it for about two hundred and ten thousand babies a year. So, um no small feat, but something that we're, we're gaining the experience to know what the pain points are and how to solve for them.

    5. PAPeter Attia1:19:09

       Is this all funded by NIH?

    6. WCWendy Chung1:19:11

       So within this, as you can imagine, this is not inexpensive to do. So in fact, none of this is funded by NIH. Um, NIH, I won't go into all the details, but NIH is able to fund programs that are about this big. People may or may not see this if they're just listening to me, but a very small amount. Uh, this ends up being about two orders of magnitude larger in cost than anything that NIH can fund. And so it's a challenge in terms of as you think about big, bold, new transformative ideas, how do we as a scientific community accomplish these? And so, uh, we've done this by putting together many different stakeholders. And I, I don't think any one group could be able to take this on. And truth be told, we're not completely there with the funding. I think we needed to demonstrate that we actually could do this in this first feasibility stage, uh, before gaining the resources to do this with what I hope will be at least a hundred thousand babies to get to the sample size we need to see some of these rare conditions and to know what the outcomes are and that we really can screen for them.

    7. PAPeter Attia1:20:10

       So what's the, um, actual cost of doing the sequence for each of the, uh, for each baby, so to look at those two hundred and fifty some odd, uh, conditions? What's the, what's the bench cost?

    8. WCWendy Chung1:20:24

       So as we started out doing this, a round number, a thousand dollars per baby.

    9. PAPeter Attia1:20:28

       Okay.

    10. WCWendy Chung1:20:28

        So thinking about generating the data, interpreting the data, getting it back to folks, cost of about a thousand dollars per baby. Um, the goal is to be able to do this and get it down by the order of magnitude. Can we get it down to a hundred dollars per baby, as an example? And in doing that, can we think about the economic impact? Mo- most importantly, the health impact for the baby, but as we think about as a society how to be able to, you know, afford doing this, we are doing the economic analysis to understand. But the good thing is sequencing costs are decreasing, analysis interpretation costs are decreasing. More of this can be done in automated ways as we understand what normal variation is for people around the world, and that's one of the critical factors is doing that around the world.

    11. PAPeter Attia1:21:12

        Now, that thousand dollars is a fully loaded cost. That's the interpretation, that's the overhead, that's the PI time and such, right? The sequencing cost must be significantly less than that, given that a whole genome sequence can be actually seq- Illumina could do a whole genome sequence for a thousand dollars now, right?

    12. WCWendy Chung1:21:27

        So, uh, even over the course of this study, the sequencing costs have come down, if you can imagine it.

    13. PAPeter Attia1:21:33

        Okay.

    14. WCWendy Chung1:21:33

        And we just started it, like I said, September twenty twenty-two, less than a year ago. But already the sequencing costs have come down. I expect they'll continue to come down in terms of this. And so, uh, data generation certainly can be done for well less than a thousand dollars now. Um, but as you said, part of it is the interpretation, and we have study staff that explain the study to everyone, explain-

    15. PAPeter Attia1:21:54

        Yep, yep

    16. WCWendy Chung1:21:54

        ... you know, results to families. So yep, includes

13. 1:21:57 – 1:26:28

    Treating genetic disease with gene therapy

    1. WCWendy Chung1:21:57

       multiple pieces.

    2. PAPeter Attia1:21:58

       So at the outset of this discussion, you mentioned that SMA actually has a successful gene therapy. I was not aware of that.

    3. WCWendy Chung1:22:04

       Yes.

    4. PAPeter Attia1:22:04

       Um, how many of these, um, uh, single gene, highly penetrant conditions that, that, you know, children are born with, be it inborn errors of metabolism or neurodegenerative diseases, et cetera, how many of them have FDA-approved gene therapies already?

    5. WCWendy Chung1:22:22

       Not very many of them. So really the shining example is SMA or spinal muscular atrophy. Um, there are very few gene therapies that are now approved. Um, there are now, uh, for instance, I mentioned Duchenne muscular dystrophy, um, you know, hemophilia. There are a few other conditions, but it is still a h- literally a handful for, for gene therapy, literally gene therapy. Others have treatments available.

    6. PAPeter Attia1:22:47

       Yes.

    7. WCWendy Chung1:22:47

       And I think for many of those, um, I'll just give one example that we've had t- through the, uh, GUARDIAN study, a condition called Wilson syndrome, for instance, that leads to ultimately liver failure and need for liver transplant. Um, the treatment that we give children for this is zinc. So it's something that it doesn't require gene therapy. It doesn't need anything that fancy. We can simply use zinc to outcompete copper and make sure that we don't end up with a copper overload situation, and we have treatments that are very well tolerated, pennies a day in terms of doing this, we hope, uh, extremely effective long term. So although gene therapy is wonderful, I want to underscore we don't always need gene therapy, so long as we have that early diagnosis.

    8. PAPeter Attia1:23:30

       If there were three diseases today that you see in a pediatric practice that would be most amenable to gene therapy in terms of some aggregate score of the technical nature of doing the gene therapy and the lack of alternative therapies elsewhere and the number of kids afflicted, if you were sort of to take that as your triple proxy, what would be-- if you could wave a magic wand, what would be the three diseases you would want to put high on the list of gene therapy targets?

    9. WCWendy Chung1:24:03

       Hmm. That's a great question. I don't think I've ever thought that through exactly in that way. So, um, I guess what I continue to come back to in many cases, um... So there are a lot of neurological conditions, let me start with that, in terms of places that we are, uh, woefully behind in terms of treatments, and I'll give you one shining example of Tay-Sachs disease as an example. Um, many individuals, uh, the way they've dealt with this because there's no treatment is simply not having children or not having children, uh, together or, um, you know, going through other reproductive options. But things like, uh, Tay-Sachs disease is just a terrible condition because you, your ba- and it has relatively high population prevalence, uh, to one of your points, and has really nothing available in terms of treatment today. Um, and so those children are bo- born healthy, normal children and, and die within the first few years of life with a degenerative, uh, course oftentimes associated with epilepsy. So, uh, a condition, Tay-Sachs, or a condition like that I think, uh, fulfills all the criteria that you're talking about. Um- Other similar conditions like that, um, although I'm-- You know, I think we still need to understand treatability or things like fragile X, uh, another condition that we see, uh, in this case, X-linked, um, by the-- You can tell from the name fragile X, similar in terms of high frequency. Um, really nothing in terms of treatability at this point, and perhaps the ability. It's a-- We can get into it or not, but the gene therapy for this is a little bit trickier. Um, different strategy from a technical point of view than what one, one would take for Tay-Sachs. So whether it's gene therapy or gene editing or other types of things, there would be a different technical strategy. Um, and then I would say, uh, I kn- They're just a large group. I, I won't pick one, but large groups of inborn errors in, in terms of liver disease, uh, or that it primarily affect the liver. So whether you're talking about something like maple syrup urine disease, uh, propionic acidemia, but something like that, that we have good programs in place to identify those childrens and our treatments, um, hmm, they're just not up to snuff yet. They're not quite as good as they should be.

14. 1:26:28 – 1:33:05

    How gene therapy works, and the tragic story of Jesse Gelsinger

    1. PAPeter Attia1:26:28

       Well, let's talk about how genetic therapy works. So, um, God, probably twenty-three years ago, we had, uh, uh, uh, a tragedy in one of the most, um, uh, highly publicized examples of, of early gene therapy. Uh, the, the tragedy, of course, really didn't have to do directly with the gene therapy. It had to do with the vector that was used to deliver it. And, um, the, the young man who received that gene-- I can't remember what it was for. It was for an inborn, inborn error of metabolism as well, wasn't it?

    2. WCWendy Chung1:27:02

       Uh, a urea cycle defect called ornithine transcarbamylase deficiency.

    3. PAPeter Attia1:27:07

       Yeah. And, uh, Jesse, what was his last name?

    4. WCWendy Chung1:27:10

       Jesse Gelsinger.

    5. PAPeter Attia1:27:12

       Gelsinger, yeah. And this was at Penn, at CHOP, right?

    6. WCWendy Chung1:27:14

       That's right.

    7. PAPeter Attia1:27:16

       Uh, about the year two thousand, if my memory is correct.

    8. WCWendy Chung1:27:18

       I think that's about right. Mine may be off by-

    9. PAPeter Attia1:27:20

       Maybe ninety-nine. Yeah, yeah.

    10. WCWendy Chung1:27:21

        Yep.

    11. PAPeter Attia1:27:22

        And so let's talk about that. Uh, again, I'm-- Let's talk technically about that, right? So what, what was the-- So they used an adenovirus, but explain what that means and what, you know, what was the state of the art twenty-five-ish years ago? And, um, and, and let's contrast that with what's being done today.

    12. WCWendy Chung1:27:43

        Sure. Um, so for those of you who are listening, adenoviruses obviously causes the common cold. And so whether it's adeno or adeno-associated virus, we oftentimes use that as the vector or the delivery vehicle to deliver genes. Um, within this, uh, the viruses are manipulated. They're engineered, so to speak, so that they're not gonna be contagious. So even though you might get a cold or pass it along to someone, you're not gonna do that with gene therapy. Yet there are problems with this because the common cold is common, and so people may have been infected with adenoviruses, and their body may try and mount an immune response when it's infected, uh, as it would be with a cold. Um, and that's where a lot of the mischief comes in. And unfortunately, it hasn't ended with Jesse, um, and Jesse's death. Uh, there have been other deaths in the gene therapy space with others that have had a response to the vectors, uh, oftentimes an immunological response to that. Um, in Jesse Gelsinger's case, it was, um, it-- the vector and the gene therapy was targeted at the liver. We've talked about a little bit of that already. Um, but sometimes there can be an overwhelming response from the liver, um, where the liver starts to fail, um, where there's an immune response, uh, that goes on. And so, as I said, this has not been solved completely at this point. There have been other genetic therapies, other diseases, not just liver diseases, but where there have been similar responses. And I think one of the things that we've learned from this is we have to be very careful with people with underlying liver disease when it comes to this because the f- a fragile liver can get tipped over, uh, especially with adenovirus. We also have to be careful about who's been exposed to those viruses. So sometimes we do screens to be able to see who might have one of these responses. Um, but ultimately, and partly because of that, people have also been trying to figure out other delivery systems, other vehicles, other ways of being able to get those genes into cells that may not be as toxic or problematic.

    13. PAPeter Attia1:29:44

        So help me understand a little bit. You know, so an adenovirus is very common. So presumably, in the case of Jesse, he'd already been exposed to some antigen that relate-- was related to this. And so he already had memory B cells and memory T cells that were ready to mount a healthy immune response should he have been exposed to that, uh, very common adenovirus again. Does that imply-- The fact that he had such a harsh response to the gene therapy, was that because of the dose of adenovirus that he received? Or does that imply that he would have had some sort of catastrophic multi-system organ failure had he just had another exposure to that exact adenovirus as a cold and that it, as you said, was a function of his underlying liver health?

    14. WCWendy Chung1:30:31

        So it's a very tricky situation, and I say this because there will be some either patients or doctors advising patients about genetic therapies or genetic, uh, therapy trials in the future. It's tricky in the following sense. Um, you're right that there's a dose response in terms of the immunological response, and so you don't wanna go too high on the dose because you don't wanna have too big a response. On the other hand, with these gene therapies, you oftentimes get one chance at this in terms of doing this because once you've given the therapy, um, the body is going to mount a re-- an immune response to that and would neutralize that same therapy if you were to give that again. And so the tricky thing about this is you don't wanna go too high, and you don't wanna go too low 'cause if you underdose it and if you don't get enough in and that's your one shot on goal, you've burned it. And so within this, it's a tricky situation to figure out how to get it just right. And as it is with many clinical trials, when you're first in human, you don't know, right? It is first in human. Oftentimes, there are non-human primates in terms of trying to figure out as much as you can, but it's still not a person, and each person is unique. And so as you're doing it, um, it is a tricky situation in terms of getting it right. When you do the first person, you learn, and you figure out from there whether you're gonna go higher or lower, but there is someone who's gonna be the first person.

    15. PAPeter Attia1:31:50

        And there's no way to engineer the adenovirus to make it invisible to the immune system while still able to insert its DNA package into the cell?

    16. WCWendy Chung1:32:01

        So there's certainly things that we do to try and do this better. As I alluded to, one of the advantages for someone, uh, for instance, with SMA where we're dosing them at a week or two of life is they're, they haven't had the common cold. They haven't been exposed to these things. They've got a fresh immune system, so the likelihood they're gonna have a response like this is much lower. So we haven't been seeing those types of things with newborns that we've been treating with SMA. Um, there are other vectors that-- or not just vectors, other delivery vehicles that we use that are not viruses, and so that's something else that in terms of developing new technologies, um, things that may not pose the same problems. I, I don't wanna guarantee that that's gonna be the case, but certainly, uh, with the experience we've had even from the COVID vaccine, from mRNA vaccines and having delivery systems that were basically lipid nanoparticles to deliver nucleic acids to cells, we've learned a tremendous amount from millions of people who have been treated with that, and some of those technologies may prove to be helpful, um, with other delivery systems.

15. 1:33:05 – 1:43:03

    Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more

    1. PAPeter Attia1:33:05

       Maybe this is a good time to explain what CRISPR is and how it factors into gene editing. Although I guess before we do that, m- it-- m- maybe one thing to do before that is to explain what is required to change a gene. So, um, like, I don't know, pick, pick someone with, um, [lips smack] uh, sickle cell anemia. So if you wanted to use gene therapy to fix, quote-unquote, "sickle cell anemia," my vague recollection from high school or from, uh, rather medical school biochemistry is that was a one amino acid change, correct?

    2. WCWendy Chung1:33:53

       Correct.

    3. PAPeter Attia1:33:54

       Is it a-- Was valine one of them? Was I can't-

    4. WCWendy Chung1:33:56

       Yep, so the eighth amino acid, exactly, in hemoglobin beta is that, um, there are two different sort of variations or flavors at that amino acid you can change, but that causes sickle cell, cell disease, yes.

    5. PAPeter Attia1:34:08

       Okay. So if you want to permanently change that, it's not enough to do it in the red blood cells that are floating around in the bloodstream, 'cause they're gonna be trashed in the spleen a couple of months from now.

    6. WCWendy Chung1:34:21

       Yeah.

    7. PAPeter Attia1:34:21

       You must change the DNA of the stem cells in the marrow, correct?

    8. WCWendy Chung1:34:26

       That's exactly right. You have to get those progenitor cells from which the future generations of red cells will be derived.

    9. PAPeter Attia1:34:34

       And let's assume you had the correct gene sequence. That's not hard to do. We know what that is, and we can put that into a virus. And maybe just explain to people why viruses are great vehicles. What, what is it about a virus that makes it an ideal candidate here?

    10. WCWendy Chung1:34:50

        Well, the nice thing about a virus is it was designed by Mother Nature to infect our cells, right? So it's pretty good at being able to do that. Um, the viruses that you're talking to and the way that I think about them are often helpful for gene addition. So where you've got a protein product that hasn't shown up for work, it's not working, it's a loss of function, it's not present, you need to be able to deliver or add back that gene. It may not be integrated into your genome, and in fact, there are probably some advantages if it's not, but the virus can bring that in and bring it into the cells. And to your point, and this is important, many times that means bringing it into stem cells, so that they can have the longevity of continuing to populate the body over time.

    11. PAPeter Attia1:35:33

        And so is it safe to say that the real challenge is that step? It's not just putting the corrected version of hemoglobin, the gene for the corrected version of hemoglobin into the v- the virus of choice. It's figuring out how to get that to selectively infect a progenitor stem cell within the bone marrow. Um, is that presumably why we don't yet have genetic therapy for sickle cell anemia?

    12. WCWendy Chung1:36:01

        Well, sickle cell is, um, interesting in that there are a couple different strategies people think of. So one is gene editing is the term-

    13. PAPeter Attia1:36:09

        Yep

    14. WCWendy Chung1:36:09

        ... I'm gonna use. Um, so it's fixing the gene-

    15. PAPeter Attia1:36:12

        Mm-hmm

    16. WCWendy Chung1:36:12

        ... in, in, in sort of where it is, uh, uh, not adding a gene, but actually fixing the gene that's present. Another strategy that people think about, um, and again, for the aficionados who are thinking about that, as I mentioned, hemoglobin beta, uh, in terms of the adult form of hemoglobin. There's also fetal hemoglobin that's made in utero. And so with that, that actually has a very tight binding of oxygen because the fetus needs to be able to get oxygen from the maternal blood, and it can substitute for adult hemoglobin actually quite efficiently. And so one thing one can do is actually turn up the amount of fetal hemoglobin expression and essentially be the in situ version of your gene therapy. It's, it's just manipulating the gene expression, but for a gene-

    17. PAPeter Attia1:37:00

        Hmm

    18. WCWendy Chung1:37:00

        ... that's already present in those individuals. And so there are ways of manipulating gene expression, in that case, for fetal hemoglobin. So there are multiple ways to skin a cat, so to speak. Um, very technically different in terms of what we administer to people and what we're changing in terms of the gene therapy. But I wanna pick up on what you were talking about with gene editing because that's yet something else. That's really in situ.

    19. PAPeter Attia1:37:24

        Yeah, and I wanna, I wanna come back to that.

    20. WCWendy Chung1:37:26

        Okay.

    21. PAPeter Attia1:37:26

        Let's go back to one more thing on the gene addition. If you were to add a gene for a corrected version of beta hemoglobin, would you actually run into a problem now where you're making too much hemoglobin and half of it is appropriate and half of it is sickle and therefore not? And you could argue you're creating more problems 'cause you've doubled the hemoglobin, but you still have the issue where the cells sickle and create all of the distal ischemia that the person has. So is that the real reason that nobody's interested in doing an addition, uh, therapy for sickle cell anemia?

    22. WCWendy Chung1:38:04

        So that's exactly right. Just for the listeners, we don't use the gene addition strategy for sickle cell anemia because we'd have to dilute out, so to speak, so much of the hemoglobin with the sickling that physiologically we run into other problems.

    23. PAPeter Attia1:38:20

        Okay. So gene editing would hands down be the best solution for certainly a situation like that, and probably many cases could it be done with high fidelity and ease. So, um, I, I guess let's talk about gene editing in any way you see fit, in, in whatever way you want to tell the story. I mean, gene editing in and of itself is a whole podcast, I suppose. But, uh, but, but what's the, you know, what's the, the medium version of that story?

    24. WCWendy Chung1:38:50

        Yeah. So from a simplistic way of thinking about this, it's going in and in situ being able to correct the genetic variant. Now realizing we've talked about single nucleotide variants, those are the easiest ones to edit. There's just one single base pair that needs to be flipped. Uh, it actually matters what that base pair is. If you have to change an A to a G or a C to a T, believe it or not, there are different base editors that can do different types of nucleotide switches. Um, but there are many mutations that are not just single nucleotides. There may be multiple nucleotides. There may be multiple repeats, so these sort of complex things that we talked about with fragile X. There may be entire chunks of chromosomes. They get very complicated. And furthermore, it may be, when you think about population genetics, um, you may have a mutation distribution across a gene that may be quite heterogeneous. Sickle cell is an easy one in the way that you mentioned. You're talking about the same position for everyone with sickle cell disease. Couple different nucleic acids, but it's the same position essentially. Whereas other genetic conditions, it may be that almost everyone has a different mutation, so you have lots of different things you need to edit, and that may be easier or difficu- more difficult to do. So there are some nuances in terms of that. Um, you mentioned CRISPR. So CRISPR-Cas9 is something that many will know because, uh, Nobel laureates were awarded, um, for this amazing discovery, which was, by the way, I will say, um, just really good science with creative women who were thinking about other ways to use it. Um, it wasn't fundamentally, uh, the discovery was not made with the intention of doing genetic engineering or ge- you know, genetic manipulations, but, uh, really smart people thinking about it. Um, the CRISPR-Cas9 system has - I think of it as an Achilles' heel of a double-stranded DNA break. So it fundamentally, in terms of being able to make the correction, has to cut the DNA, cutting the two strands of the DNA to make the correction, and that fundamentally leads to some instability as the cell repairs that process, which you use the word fidelity, which I like the use of that term because it really is all about fidelity and potential off-target effects, where you inadvertently introduce other than the intended correction, other genetic changes, and sometimes those other genetic changes can cause mischief. We call them off-target effects. So things where they may, um, inadvertently destroy the gene, cause other changes to the gene, cause other changes to other genes that you weren't even trying to target, but it can lead to problems of essentially promiscuity or inaccuracy or low fidelity. This is, to me, in my opinion, the Achilles' heel in terms of that particular system. So there are others, um, in terms of thinking about other technologies, other strategies that, in terms of doing a double-stranded DNA break, will do a single-stranded DNA break. So it'll nick just one of the two copies, which in terms of the process that the cellular machinery has for the repair of that, ends up being a much higher fidelity system. So there are lower off-target, lower error rates. Um, it tends to be a more robust system. So this is still very, very early. I want to underscore this, very early in terms of doing this. There are lots of other complexities besides the machinery of, uh, what I just described was prime editing, but other complexities in terms of the machinery to go in and make the changes, uh, what types of mutations can be repaired. Prime editing has strategies to be able to do just not single nucleotides, but much more complex mutations to be able to fix. Um, but ultimately, it's a vehicle for delivery. It's getting in early enough before the damage is done to the body. It's being able to get to the part of the body safely that you need to. Um, so there, it, it's sort of multiple pieces of the puzzle that have to all be solved simultaneously to get the whole package to work. So we're not quite there yet, but I'm optimistic that we're, we are, as a lot of scientists working together, realizing that this may be one sort of solution eventually when all the components are there that may be scalable to deal with many different types of genetic conditions.

16. 1:43:03 – 1:47:40

    Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome

    1. PAPeter Attia1:43:03

       You were alluding to the differences in strategies between Tay-Sachs and fragile X syndrome. Do we have enough information now in this discussion for you to explain the different strategies there?

    2. WCWendy Chung1:43:15

       Sure. Um, I think so. So let's start with Tay-Sachs. Um, Tay-Sachs is due to an enzyme that's missing. Um, we talked about recessives. It's a recessive condition. Uh, this is a degenerative condition, and so you want to be able to get in early for all the reasons that we've talked about, and you could do a gene addition. The gene, the enzyme is missing, so you can just pop it back in. Doesn't have to integrate. You just need to get it early enough to do its job and not to, uh, cause any mischief along the way. So that strategy would be a good strategy. The tough part is you need to get it into the brain. And as you get it into, uh, you know, as you're thinking about the delivery system, um, brain is a complex organ, so you want to be able to get it throughout the brain, uh, for, for function. Fragile X is more-

    3. PAPeter Attia1:43:58

       So what does that, what does that mean, Wendy? That means you'd have to introduce a, like an intranasal virus that can... Uh, is this, is this something in glial cells, in neurons? Where does this enzyme normally get made?

    4. WCWendy Chung1:44:10

       Yep. So, uh, within this, as you said, um, there are multiple ways to access the brain. It's obviously a protected space in terms of the blood-brain barrier. Um, I doubt we're gonna be able to do it with intranasal, although, you know, there is some that you can get, um, by putting this, uh, in that way. Um, some cases we do intrathecal, so for women who've had an epidural, it's basically the same way that we access the space for an epidural. In some cases, um, for anyone who's thought about chemotherapy that we give for brain cancer, sometimes we actually have to do it, uh, into the ventricle, and we-- sounds a little bit barbarica, but we go through the skull and being able to do the injections there. Um, but, you know, there, it, it's not as simple-- My point is it's not as simple as a simple intravenous infusion. It's not like we can just give it peripherally and get it to the brain where we need to. Um, so it's challenging in that way, and as we think about it, in some cases, we need to get throughout the brain, even into deep nuclei or different parts of the brain. So as y- as an example, if you were to inject it, and you had a high concentration on the left, but it didn't get to the right, that would be a problem, right?

    5. PAPeter Attia1:45:16

       Mm-hmm.

    6. WCWendy Chung1:45:16

       You need to be able to get, uh, even distribution as we're doing this. So, um, anyway, with, with Tay-Sachs, though, it is the case that, as I was alluding to before, you probably don't need to get to a hundred percent of the protein or the enzyme that's there. Even fifty percent I'm sure is enough, and it's possible you could get down to twenty percent, and that would be just fine. Um, and so that's one strategy. Fragile X is a little bit more complicated. The actual mutation itself is what we call a, a trinucleotide repeat, um, a repeat that's too big, and so we need to be able to make it smaller, uh, within doing this. It also has the same problems in terms of being in the brain, but it's not just simply adding back some additional fragile X protein. So we can't just make it a gene addition strategy. We've got to really think about the gene editing that I was alluding to, where you're fixing, uh, shrinking the size of that repeat back down to the normal size. Um, what's unknown, uh, and I think one of the things we don't know until we do it in people, is what is that window of treatability? And, uh, just to be provocative, to let the, the listeners think about this, is that window, even if GUARDIAN worked perfectly, and we could identify these babies with this within the first week of life, um, is that early enough? Uh, of course, my hope is that for many conditions, that will be. Um, it's possible that we'll need to go even earlier, and so there are some people that have thought about even in utero gene therapy or genetic treatments for some conditions, not all of them, but for some conditions where it might be necessary to get even during development, fetal development to have the maximal effect. So I'm not saying we're going there anytime soon, but just to sort of think through that, um, there may be imperfect solutions unless one gets to the right time and the right place and, to your point, the right cell type even.

    7. PAPeter Attia1:47:04

       And, and fragile X is also a recessive condition, so it can only impact women presumably because you would need both copies of the X?

    8. WCWendy Chung1:47:13

       So, uh, fragile X is, uh, we do call it an X-linked recessive, but what that also means is that it's mostly males who are affected because males only have the one X. If they have-

    9. PAPeter Attia1:47:23

       Mm

    10. WCWendy Chung1:47:23

        ... that repeat expansion, uh, the males will be, um, affected. Females can be affected, although it's much more unusual, um, in terms of-

    11. PAPeter Attia1:47:31

        Because they would need to have got the X from their father as well.

    12. WCWendy Chung1:47:34

        That's it, yep.

    13. PAPeter Attia1:47:37

        Um, I want to come back and talk

17. 1:47:40 – 1:55:55

    Exploring obesity as a polygenic disease: heritability, epigenetics, and more

    1. PAPeter Attia1:47:40

       more at the end of our discussion, uh, about kind of the future of gene editing and the ethics around it and things like that, which I'm sure is something you've thought a lot about. But before we do that, I want to talk about some of the more complex diseases that, um, clearly have a genetic component, um, but, but they're probably much more polygenic. So, um, let's start with what, you know, your colleagues down the hall are doing, uh, with respect to obesity. How much do we understand about the genetics of obesity, and does genetic therapy, therapy play any role there?

    2. WCWendy Chung1:48:16

       So I'll start out about talking with obesity, but I may switch gears, uh, at some point soon after that. So obesity, we have ways of calculating heritability. Um, it's to give us a scientific insight of how genetic is a certain condition.

    3. PAPeter Attia1:48:31

       Mm-hmm.

    4. WCWendy Chung1:48:32

       So you can do this by looking at twins, for instance. You can look at identical twins. You can look at fraternal twins, and you can see how similar they are in terms of body mass index, adiposity, things like that as measures of obesity. Um, and it does end up being highly heritable. It's not the most heritable factor, but it is highly heritable. So that sort of points in one direction that genes are important.

    5. PAPeter Attia1:48:54

       What's the heritability of obesity, by the way?

    6. WCWendy Chung1:48:56

       So the heritability running somewhere around fifty percent for round numbers, um, or point five. Um, other conditions that are extremely heritable, of course, are closer to one. So type as an example and by comparison, type 2 diabetes or non-insulin dependent diabetes, more heritable, more strongly genetic in terms of that.

    7. PAPeter Attia1:49:15

       And type 1?

    8. WCWendy Chung1:49:16

       Type 1 diabetes, less, uh, heritable. Um, a complex interaction both of your immune system and the genetics that govern your immune system, but also what you're exposed to early on and, and sort of the cross-reaction your immune system has-

    9. PAPeter Attia1:49:31

       Right

    10. WCWendy Chung1:49:31

        ... between self and non-self. So, um, a little bit different model. Um, on the other hand, uh, clearly there are, are, I'll call them environmental differences, right? And so you can look at what's happened to the average body mass index of the average American over the last generation. Our genes haven't changed, right? But on the other hand, um, by most measures, you can see that we're, uh, more prosperous. Uh, in general, the average body mass index has increased. And there have been some interesting studies looking at, uh, particular, um, groups of Pima Native Americans, for instance, that have genetically the same genes. They come from the same original community, but they live in different environments, one in which it's more sort of a traditional environment in terms of, um, the amount of access to calorically dense foods and the amount of physical energy that's expended on a day-to-day basis. And those same original groups, but in two different environments, you see much more obesity in the one group, uh, that has ready access to, again, obesogenic foods versus the o- the other that, um, doesn't. So a- again, s- strongly suggesting that it's not just the genes in terms of this. Um, now on the other hand, uh, and this goes back to you were describing Rudy Leibel and his original work in terms of identifying leptin and the leptin receptor through positional cloning methods. Um, leptin and the leptin receptor in terms of mutations in those genes do not account for the vast majority of obesity. Very rare. I, I've certainly had patients with these conditions, but that's just because of the nature of who I am, but very rare, and most people would not have seen this. On the other hand, understanding the fundamental biology of how body weight is regulated and governed, critical in terms of understanding those two molecules. And my point in this is, I don't know if it's gonna be for obesity, but it may be for other conditions like myocardial infarctions or coronary artery disease, that knowing about the biology and sort of the final common mechanism or the final common pathway through which the biology is regulated, one may have ways of either pharmacologically or some will say in terms of gene therapy being able to make permanent manipulations. So statins as an example, in terms of treatment for hypercholesterolemia. There may be various different genetic mechanisms by which one has an increased risk for a heart attack, yet statins seem to work for a lot of different people. And some have thought that, for instance, rather than using that as a medication, would there be a way of genetically making a manipulation so it's kind of a one time and not having to require continued ongoing therapy. So I, I'm not saying, you know, that this is exactly where obesity treatment is going to be going. Um, and I am in a good way excited that, um, we certainly have better treatments for the first time, I think, for obesity now than we had five or 50 years ago. So we may be going in a better direction.

    11. PAPeter Attia1:52:33

        We didn't really talk about epigenetics, but I think obesity might be a good time to do a little bit of backtracking and explain what the epigenome is and how it changes not just over a person's life, but perhaps more importantly from one generation to the next. And the reason I'm asking the question is I wonder if it's playing a role in the propagation of obesity across generations, even though, as you pointed out, we're not really experiencing much genetic drift in the period of time that we're seeing an explosion in obesity. And so with all of that said, my question is ultimately, do you think epigenetic changes could be increa- could be explaining the increase we see in obesity, um, as a susceptibility to obesogenic environmental factors?

    12. WCWendy Chung1:53:28

        I think the bottom line is we don't know. Um, but for those who don't know what the term epigenetics is, um, break it down, epi above and then genetics, the genes. And so there are chemical modifications that happen to the genome which are used to affect gene regulation. Some of those, uh, chemical modifications include methylation, and those are dynamic. They can change over the life course. They can change by cell type, and there are ways to be able to coordinate regulation of potentially groups of genes. They're tricky to analyze from a, a methodological point of view. Scientifically, they're tricky because they do vary over the life course and they vary by cell type or tissue. And so, um, using, for instance, we've talked about this a lot, but using a blood sample, uh, as a matter of trying to get the epigenetic profile for what's going on in your brain or your pancreas doesn't always work. And it's hard to even know whether or not it works 'cause it's not as if we're going in and doing pancreatic or brain biopsies on most people. So, you know, you can do things in animal models. You can get some indirect evidence, but it's hard to know for sure whether or not this is truly answering the question you're trying to answer. So I'll say there's a lot of conjecture in the area of epigenetics and hard to know for sure exactly what that is. On the other hand, um, I will say that we've known about something called the agouti mouse, um, which is a mouse model for obesity. And depending on how much folate you give that mouse, for instance, uh, while the, um, the dam, the mother mouse is, uh, carrying her pregnancy, her, her, uh, her little mice, uh, depending on the amount of folate in her diet does affect the epigenetics. Uh, folate is used in terms of methylation for the DNA, and so you can see a readout of the effect. And depending on that, you can see a change in the coat color. You can see a change in the obesity for these agouti mice and for their progeny. Um, and there are things in terms of, as you said, transgenerational potentially. Uh, I-- we don't entirely know the mechanism of how that might be occurring, whether it's epigenetics or other things. Um, but there are things that we can see. But these are complicated, so I'll, I'll just say I personally don't feel like scientifically we have all the evidence to make definitive conclusions at this point. Um, but, but one wonders about what many different contributors could be, although I have to guess that this is not gonna be the major, major driver.

18. 1:55:55 – 2:10:24

    The genetics of autism

    1. PAPeter Attia1:55:55

       Let's pivot to autism now. Um, autism is in the news all the time it seems, and, uh, it certainly appears as though it's increasing in, uh, frequency and it's unclear how much of that is due to an increase in diagnosis, uh, and recognition versus how much of that is triggered by other environmental factors. But, uh, there doesn't seem to be much, um confusion around the fact that there's a strong genetic component to it. So let's start with that. Uh, based on all of the twin studies, uh, what is the heritability of autism?

    2. WCWendy Chung1:56:33

       Yep. So the heritability-- I, I will say to your point, um, autism is, even within the name, a spectrum. Um, so it's not just one condition, it's a spectrum, and it goes from, uh, severe, um, what some people will call profound autism, um, and can be associated with intellectual disabilities to other individuals at the mild-- quote unquote, "milder end," um, who are-- have, have-- are quite talented in many ways, yet have social challenges. So within that entire spectrum, if one includes everything within that, the heritability is estimated to be approximately point eight, although some individuals will say even as high as point nine. Um, the point within that though is that it's not a hundred percent, and in fact, we do know of, um, times over the life course, in particular prenatal and early childhood, that are important to, to the developing brain, and where, uh, changes in exposure beyond the genes can play a role. So as an example, prematurity is one of the more common, if you will, exposures, um, but in terms of what happens to de-developing brain, and if you are born when you're twenty-six weeks old, um, much higher probability of autism than if you're born at term at forty weeks. And so, um, there are other factors beyond just the genes that are involved. But clearly, um, the other point that I'll make about heritability is one calculates heritability as a measure of the inherited genetic factors. Um, but you've mentioned it once already. One of the factors in autism is that there are de novo or new genetic variants that occur for the first time in the individual with autism, and those individuals aren't captured in that measure of heritability, 'cause heritability is fundamentally trying to get at transmitted genetic variants that are going from parent to child, and those de novo genetic events are new in the child. And so they're genetic aspects not included in heritability, if that makes sense.

    3. PAPeter Attia1:58:30

       Yep, yep. So what are the genes that seem to be responsible for autism?

    4. WCWendy Chung1:58:36

       Uh, so depending on who you ask and how you wanna define this, there-- I think everyone would agree there are at least one hundred genes that have been identified with high confidence as being associated with autism. Um, depending on how rigorous you wanna be about this process, then, you know, some people would say that we estimate that there are at least a thousand genes, and we probably, you know, are about a third of the way there in terms of, uh, having some sense of those genes. Not surprisingly, those genes are genes that are in the brain. They're expressed in the brain. They function in the brain, not surprisingly. And many of those genes are especially early or active i- during development. And so what I mean is intrauterine fetal, uh, development within the brain specifically.

    5. PAPeter Attia1:59:20

       And what do they code for? I mean, how many of those genes would be genes in the exome versus the intron?

    6. WCWendy Chung1:59:27

       So, um, most of the ones we recognize, underscore the ones we recognize are in the coding sequence, but that's a limitation of what we recognize. Um, we do realize that statistically, we see that there is a signal in the non-coding space, but we have less evidence to implicate specific genes or specific genetic variants individually in the non-coding space because the effect size or how powerful they are is somewhat, somewhat reduced compared to those coding sequences. Um, the other issue is not just where in the genes, uh, but what genes are involved. And so the genes that are involved, uh, fundamentally can be genes that function at the synapse, so the connections between brain cells and communicate between brain cells. That happens to be one thing that's quite important. Um, they can be cells that are, are rather genes that are important in regulation of genes and gene networks, so many of them are transcription factors, histone modifiers. We talked even about epigenetics, some of those genes that may be responsible for those epigenetic changes. But they often, I think of them as having multiple downstream genes that they affect. So it's not having a very, you know, sort of focus. It's more a universal effect that they have. Those genes that have that more global effect oftentimes have a more global effect on brain function and cognition. So it may not be that it's autism only, but they may also be associated with intellectual disabilities. They may be associated with epilepsy. They may be associated with more sort of global effects in terms of brain function. And to the extent that that term autism is used across the spectrum, there are oftentimes those individuals described as profound autism. So there can be different things. There can also be-- I, I'll just put as an example, um, we mentioned-- I'll go back to PKU, believe it or not. So I, I happen to run a very large autism study called SPARK. Uh, and within SPARK, we identified a teenage young man who actually has his autism as responsible of undiagnosed PKU.

    7. PAPeter Attia2:01:34

       Hmm.

    8. WCWendy Chung2:01:34

       So even, even autism can be caused by, you know, full circle, uh, an inborn error of metabolism, where there are toxic things that build up in the brain and then cause that dysfunction of the brain. So, uh, not everything is a sort of primarily in terms of the brain, but things that can diffuse to and have an effect on the function of the brain.

    9. PAPeter Attia2:01:55

       But to be clear, autism is a clinical diagnosis in the same way that, you know, familial hypercholesterolemia is a familial-- uh, is a phenotypic diagnosis. It's a diagnosis in the case of FH, where LDL cholesterol has to be above a hundred and ninety milligrams per deciliter off treatment. And it's incredibly heterogeneous in terms of the genes that are responsible. To my last count, I think there were more than thirty-five hundred genes that could produce that phenotype of high LDL cholesterol. So autism is the same, right? The diagnosis is clinical. It's a phenotypic dis- defined disease, and maybe up to a thousand genes involved in, in that. Or a thousand different ways to get there or more, right?

    10. WCWendy Chung2:02:40

        Exactly right. So it is a DSM diagnosis in terms of clinical behavioral criteria. Um, I know this gets confusing for people, but one can have a gene that's identified as causal, but the diagnosis is still a behavioral diagnosis, um, simply a gene associated with that. And as you said, not just one single gene. It doesn't map one-to-one. In fact, no one gene or genetic factor accounts for more than one percent of individuals who have that clinical diagnosis of autism, so incredibly heterogeneous.

    11. PAPeter Attia2:03:09

        And what's the approximate prevalence of autism today?

    12. WCWendy Chung2:03:14

        So round number's two percent. Uh, you were alluding to it before, but this number f- has fluctuated over time, whether it's for all the reasons you said, but about two percent today.

    13. PAPeter Attia2:03:24

        Does it just seem like it's more, or is this really a function of greater awareness?

    14. WCWendy Chung2:03:29

        So I think it's a function of several things. Um, it doesn't help that the definition has changed over time, so literally the DSM diagnostic criteria have changed over time, and so for that, not surprising, the, uh, prevalence has changed over time. Um, in a good way, the-- there is greater recognition and diagnosis, as you alluded to. We've seen this in particular for underserved individuals that are more frequently diagnosed now, so I think the disparities are decreasing, and I think that's a good thing. Um, but there are, um-- Also I'll, I'll say, you know, maybe there are things that are changing in terms of society, um, changing the biology. I don't know. Uh, we haven't been able to put our finger on that, but there are possible contributing factors with that. Um, and then there's also a motivation to a certain extent in terms of the way our society works to be able to access resources. And so people that may not have been motivated to get a label per se, they may still have known it. They may have, you know, thought it to themselves, but they didn't necessarily seek a diagnosis or a label, um, except that there were resources, educational resources, support resources that were important, and we want to make sure those individuals get those resources.

    15. PAPeter Attia2:04:37

        So what are some other both neurologic and non-neurologic sequelae of autism, or call it comorbid conditions with autism?

    16. WCWendy Chung2:04:46

        So I think that's a good way to phrase it. Comorbid conditions is one of the things that, um, I think about. So as an example, some individuals will have epilepsy associated with their autism. For some individuals, that epilepsy will be recognized very early. For some individuals, it won't come until the teenagers or adolescents, but that can be incredibly important. Um, within this, there are behavioral, uh, uh, co-occurring diagnoses, for instance, of anxiety is quite frequent, uh, ADHD or attention issues, uh, again, quite frequent. Um, and I think some things we're just beginning to understand, although I think it's incredibly important, is that most of what we know about autism is based on individuals below the age of twenty. Um, those are the individuals who've been studied most. And I think there's a whole lot we don't know about adults with autism, and I can say I do know some conditions that are associated, um, as degenerative conditions as well, that when people are adults, there may be particular subtypes of autism that are neurodegenerative because the genes that are involved are responsible for neural maintenance, being able to sustain the brain and continue functioning, and when they're not functioning at some point, uh, start having things associated like Parkinsonism. Um, some subtypes that may be associated with increased risk of, we mentioned obesity, but be-believe it or not, some of these same genes may also predispose to obesity, and especially with some of the medications we use to treat some of these behavioral conditions, uh, even increase the effects, the metabolic effects and weight gain and, and diabetes associated with that. Um, and there may be other things as well. But to a large extent, um, I would say it's under-recognized and, and we have a lot of more gaps in our knowledge. But many people who continue to need those-- that understanding, and I think earlier you used the term of precision medicine. I, I don't mean it to sound like a cliché, but you can imagine that it's a large percentage, two percent of the population, great heterogeneity. Everyone doesn't need to have the same sort of rules that they're following, the same rule book or the same management guidelines, and how do we get greater specificity to not overburden people, but yet to be able to also, um, you know, allow them to be their, their full pot-- uh, to achieve their full potential and lead their healthiest lives.

    17. PAPeter Attia2:06:57

        You mentioned that most of what we know about autism is based on studying people who are up to but below typically twenty years old. Does that suggest that prior to about the year two thousand there was nobody really studying this? Because presumably if we were, we would know about what people look like later in life today.

    18. WCWendy Chung2:07:16

        Yep. So many of the adults with autism, number one, were not diagnosed as having autism. They may have had, you know, some of these challenges, but things have just changed over time. Um, and so having a label, having a diagnosis has changed with society. Um, other individuals who were studied twenty years ago have not been followed longitudinally, and that's hard. Um, you know, there-- although there have been some epidemiological studies like Framingham, uh, that have followed individuals over long periods of time, it's hard to be able to do that. People move. People-- You know, investigators lose funding. Um, people die. I mean, you know, lots of things that happen. And so just knowing what someone looked like at two and that same person at twenty-two, there are very few studies, uh, in terms of in children what that looks like. And so I think that's been a large part of the problem as well.

    19. PAPeter Attia2:08:07

        Uh, I mean, I'm shocked to hear that the heritability is as high as it is, point eight to point nine. Um, what is it for other DSM conditions such as bipolar disorder and schizophrenia?

    20. WCWendy Chung2:08:20

        Yeah. So bipolar disorder, uh, and schizophrenia certainly much lower, um, uh, especially, um, in even things like depression, major depression lower still. Uh, so this is actually one of the highest heritable factors in terms of behavioral health or psychiatric conditions.

    21. PAPeter Attia2:08:39

        And, and just approximately what are the heritability factors for those other conditions you just mentioned?

    22. WCWendy Chung2:08:44

        So more in the neighborhood of .5 to .6, or for something like major depression, even lower, maybe more like .3.

    23. PAPeter Attia2:08:51

        What is the implication, by the way, um, if, if the heritability is .8 to .9, that almost implies for certain that an autism person-- a person with autism will have an autistic child, doesn't it?

    24. WCWendy Chung2:09:08

        That's only half the equation, right? [chuckles] So, you know, it takes two to tango in terms of making a child. So both individuals are contributing genetic factors as we're thinking about this. And so, um, and it's the combination of those factors together within that, you know, that combination, um-

    25. PAPeter Attia2:09:24

        E-even if we're not talking about polygenic, uh, combinations. So in other words, of those, I think you said hundred to a thousand genes that seem to be implicated in autism, some individuals with autism may only have one of those genes, correct?

    26. WCWendy Chung2:09:38

        Oh, absolutely. So some of them may have only one gene that's the predominant, um, sort of contributor in terms of this. Some will be more of that polygenic, uh, combination-

    27. PAPeter Attia2:09:48

        Yeah

    28. WCWendy Chung2:09:48

        ... of factors.

    29. PAPeter Attia2:09:49

        But a single gene individual has a fifty percent chance of passing that gene onto their offspring, and assuming it's fully penetrant, that they would have effectively a forty to fifty percent chance of transmitting autism to their offspring?

    30. WCWendy Chung2:10:03

        That's correct. Now, for the types of genes that you mentioned, many of those individuals actually won't go on to have their own families. And so one of the factors within this is that those highly penetrant single gene factors, um, many individuals, for instance, you can imagine if they're not living independently, if they're not-
19. 2:10:24 – 2:15:28

    The genetics of cardiovascular disease

    1. PAPeter Attia2:10:24

       Let's pivot for a moment to cardiovascular disease. Um, there are a couple of things that stand out from a genetic perspective. One I've already mentioned briefly, which is FH. Um, the other is Lp (a) , uh, attached to the LPA gene. I, I believe that, uh, Lp (a) is the most, uh, prevalent, uh, atherogenic condition that is genetically associated. Roughly one in ten people have an elevated that. That would be another great example of how gene addition therapy would be of no use because you'd want to be gene editing that. Um, what else do we know about cardiovascular disease beyond those two special cases of elevated Lp (a) and familial hypercholesterolemia? How much of the rest of ASCVD, uh, appears to be heritable?

    2. WCWendy Chung2:11:15

       Well, the interesting thing is, um, and we alluded to this a little bit. When we think about myocardial infarctions, hyperlipidemia in that sort of cardiovascular health, um, there may be genetic factors that are numerous, but from a therapeutic point of view, we may not target all of those genetic contributors. There may be final common biology.

    3. PAPeter Attia2:11:38

       Yeah.

    4. WCWendy Chung2:11:38

       And so I think that's a theme that I see most in terms of thinking about coronary artery disease, myocardial infarction, things like that. Within the cardiovascular disease space, though, I do think they're interesting. I'll just give one other example in terms of a relatively common but rare disease, that of cardiomyopathies. And so when you think about genetic cardiomyopathies, they affect on average about one in five hundred individuals. And so that's not one in a million. It's also not ten percent of the population, right? We're somewhere in the middle. Um, and I will say that I've been-- I was waiting to see the data come out, um, but we've known about many of those genes for a long time. We've known about the mutations. We've known about, uh, frequency. We've known about natural history, and waiting to see whether or not genetic therapies would be effective for those conditions. And it's not yet in people, but I will say the early data are looking promising in terms of animal models to be able to reverse this or prevent this. Um, I still think the heart-

    5. PAPeter Attia2:12:36

       Hmm

    6. WCWendy Chung2:12:36

       ... is a tricky organ to be futzing with. I'll just put it that way. It always makes me a little bit nervous because, you know, electrical things can happen very suddenly, and it's going to be quite dangerous. So, you know, that always makes me a little bit nervous to think about genetic therapies for the heart.

    7. PAPeter Attia2:12:51

       Mm-hmm.

    8. WCWendy Chung2:12:51

       Um, but like I said, some of the early data from the Seidmans in particular, um, look like there could be promising, uh, roads ahead. And like I said, it's a, it's a common condition that, you know, otherwise oftentimes we treat with transplant, um, you know, when we-- when the heart finally fails. And so it'd be, be lovely if we didn't have to wait for hearts, uh, for transplant.

    9. PAPeter Attia2:13:12

       Yeah, it's interesting. So going back to what you said about the, the ASCVD side, it, it almost sounds to me like you're saying that if genetic therapies and treatments are going to be deployed against conditions, uh, especially like FH, you would really do it to more mimic the drug than you would to try to correct the defect. And that makes a lot of sense in the case of FH because of the heterogeneity, right? There's no-- You know, to have five thousand different gene therapies for the five thousand different genes that can be altered in the result of, of, of hyperlipidemia is, is a bad idea. Whereas if you can simply knock out PCSK9 as a gene, you basically take care of everyone. Um, and so let's talk about what that means technically. So presumably there are genetic therapies that are already in the works at looking at targeting PCSK9. PCSK9 inhibitors as a class of drug have been perhaps the most exciting drug class introduced in the last decade. Um, and the results have lived up to the hype. I mean, when Helen Hobbs first made the discovery of the individuals that were both hyper and hypofunctioning PCSK9, I s- I still remember reading those papers fifteen years ago thinking, "This is too good to be true. This will not pan out," was my-

    10. WCWendy Chung2:14:41

        Mm-hmm.

    11. PAPeter Attia2:14:42

        That was my dumb prediction. "This will not pan out." Um- And I was wrong. Del- I'm delighted to be wrong. Um, so what does that look like now? What does the, what does the gene therapy look like to, uh, to, to go after, to silence a gene in this case, but without creating some unintended consequence?

    12. WCWendy Chung2:15:03

        You know, it, it's going to start out with not just, you know, the average person who might have a higher risk. It's gonna start out at the extreme-

    13. PAPeter Attia2:15:10

        Yeah

    14. WCWendy Chung2:15:10

        ... for someone, we talked about Jesse Gelsinger, who's gonna be willing to be the first in and try this and be that brave first person. And so I, I haven't s- I won't claim that I've designed the clinical trial that goes with this, but just to say it's gonna start, uh, at that extreme. And there are gonna be a lot of complexities. Um,

20. 2:15:28 – 2:21:37

    The financial costs and economic considerations of gene therapy

    1. WCWendy Chung2:15:28

       I, I will say, and I'm sure many listeners are thinking of this, the cost with gene therapies is prohibitive right now, right? It's not as if we could-- If any single gene therapy were three million dollars, which is not uncommon for current gene therapies, we can't afford to spend three million dollars per person, uh, with the number of people who are at risk in the U.S. population.

    2. PAPeter Attia2:15:47

       Wow. So, so that, that SMA single gene therapy is about a three million dollar treatment?

    3. WCWendy Chung2:15:52

       So I'll say the range of genetic therapies right now runs between about one and three million dollars.

    4. PAPeter Attia2:15:57

       Wow.

    5. WCWendy Chung2:15:58

       So depending on which ones are out there. Um, and it, it gets complicated.

    6. PAPeter Attia2:16:03

       Sorry, just to say one thing about that. You know, it is worth keeping that in perspective, right? So I, I'm not gonna sort of advocate one way or the other, but it's not uncommon to spend a million dollars on chemotherapy at the end of life for a year's worth of life extension. And if you contrast that with a million dollar gene therapy in infancy that gives eighty or ninety years of life extension, it at least puts those two treatments in context.

    7. WCWendy Chung2:16:36

       So I agree with you a hundred percent. Um, uh, health economists have been trying to get at that in terms of the value. Um, you know, if we're talking about true value in terms of this, and, and I'm not gonna pit one against the other in terms of this, but you do have to think about, and I would argue not just the healthcare system cost to the person, but it's the societal cost to the family, to the community. Uh, you know, there's a lot of cost that goes into this if you do the, the economic analysis accurately. On the other hand, um, it, you know, to say that that might be worthwhile in one case, you do have to think about scaling, and I'll just throw out a number for you. Ten percent of the U.S. population has a rare genetic condition. They may or may not know it, but that's just true in terms of these monogenic factors that we've been talking about. So that's ten percent of the population.

    8. PAPeter Attia2:17:26

       Wow.

    9. WCWendy Chung2:17:26

       If you now think about the, you know, percentage of the population that's obese or that has obesity or Type 2 diabetes or some of these other common conditions that someday might be treated by these one and done types of things, then it becomes in terms of a society, what can we afford to do? What are the competing other healthcare costs or other societal costs in general that we have? And, you know, how are we gonna rightsize these? I will say that I'm, I'm confident that, um, as we have more ability to understand how to do this, you know, the, the, there's a lot of fixed costs, but the marginal cost is not nearly as high. I think you know what I mean by that in terms of, you know, both what it takes to design the clinical trials, to do the manufacturing, to do the monitoring, you know, all of these things. Uh, they won't scale linearly. Um, and so I do think we'll have some cost realization that we can recoup. But it's, um, you know, I think those are the big questions that we think about is how are we gonna afford this, and what are the key things that we need to do to enable doing this on scale? Um, but, you know, to your point, you know, what are the competing alternatives if it is, you know, a medication that you're taking every day, if you can't really get, you know, to a good point in terms of the, um, MI risk or, uh, anything in terms of heart health or stroke health or other things. Um, so, you know, I, all of those will go into it, and eventually a health economist will price this out and figure out, you know, what a reasonable fee is to charge for such therapies.

    10. PAPeter Attia2:18:54

        Well, you know, again, just going back to what it costs today on the gene therapy side, it still seems like-- I, I don't say this to be disparaging of the field at all 'cause the field is remarkable, but I just say it as more of an observation of where we are relative to, say, gene sequencing. We're still in its infancy, aren't we?

    11. WCWendy Chung2:19:13

        Oh, absolutely. I mean, uh, as sad as it is to say, given what you said about Jesse Gelsinger's case was more than twenty years ago, we are still at our infancy, um, in terms of being able to realize all the potential. I don't even think we have all the technologies or the vehicles or delivery systems that we're gonna eventually be effective.

    12. PAPeter Attia2:19:33

        So, so again, thinking it through that way, in the year two thousand, it cost one billion dollars to sequence a human genome. Today it costs one thousand dollars. So that's a six log reduction in cost, um, in part through Moore's law, in part through the step function change of high throughput sequencing. We don't need a six log reduction in the cost of gene therapy to make it readily available. You know, quite frankly, a two log reduction would make this a game changer. Does that strike you as something that's feasible in the next two decades?

    13. WCWendy Chung2:20:18

        So I s- I would say yes, there are gonna be certain catalytic transformative breakthroughs that will make and enable those changes that you're talking about. So again, I'll go back to what we did with the COVID vaccines, right? Those were, uh, you know, it was incumbent upon everyone to be able to come up with solutions, and the solutions that allowed for the adaptability and even changing the vaccine on the fly were remarkable to me, at least scient- from a scientific point of view. And I know some people may push back on me, but I-- that is my true belief. If you could think about the same way with delivering an mRNA vaccine and doing the same thing and, uh, realize that it's different for genetic gene addition in doing it, but it's not entirely different in terms of how to do this. And so as you're talking about, um, I call it rinse and repeat, but it's being able to do this and having the infrastructure, the delivery system, the regulatory system, the manufacturing process, all of those things. Once you get this and get this down, there are ways to scale this and to be able to, you know, if the gene fits, if it's a certain size, if there's certain mutations, to be able to do this repeatedly. So I do have that hope, but there are gonna be the, the function I think we're gonna see, I call it a step function, right?

    14. PAPeter Attia2:21:32

        Yeah.

    15. WCWendy Chung2:21:32

        So you're gonna see it's not gonna be linear, it's not gonna be-

    16. PAPeter Attia2:21:34

        That's right. Yep.

    17. WCWendy Chung2:21:35

        Right? So that's what we'll see.

21. 2:21:37 – 2:31:55

    The ethics of gene editing

    1. PAPeter Attia2:21:37

       So last year I read Walter Isaacson's biography of Jennifer Doudna and the story of the discovery of CRISPR, and, um, I thought it was a fantastic book. I can't recommend it highly enough to people who are listening or watching. I'm sure you've read it. Um, but there was, there was a fantastic discussion of the ethics of this. And once you realize the power of gene editing, you very quickly start to pivot away from the discussion we're having today, which is a child is born with Tay-Sachs disease. This child is going to be dead in a couple of years, and it's a very ugly death. There's really nobody in their right mind that wouldn't be in favor of a therapy there. We could go through all the examples we've talked about, and there's nobody I can imagine that's going to say if a woman is born with a BRCA mutation and she has the choice between a gene edit to fix it or a mastectomy to remove her breast, we'd probably prefer the former, if for no other reason than it ends the gene there and her daughter won't get it or her son won't get it, et cetera. What do, what do you think? How, how can people think about the next layer of complexity, which is, well, should we be able to take a person who has an APOE4 isoform and turn that into an APOE3 isoform, uh, or an APOE2 isoform, which would actually come with significant protection against neurodegenerative disease? That's a slightly different case because, of course, the penetrance and the, uh, risk profile is different. So h-how do you as a scientist think about this? Because I, I think that boast-- both ethic-ethicists and scientists need to be a part of this discussion.

    2. WCWendy Chung2:23:32

       So I agree completely. Um, and it's, um, I have to admit, so one thing I think we universally agree on, I hope, is that we're not doing gene editing, gene manipulation to affect the next generation. So we're not looking for things that are transmissible in the germline. We're not trying to create a superhuman where we're trying to, you know, fiddle with the genes to either correct them or to be able to enhance them, is the term that I'll use that's transmissible. I think that's a line, um, scientists and ethicists-

    3. PAPeter Attia2:24:03

       But sorry, would that be true even with something like Tay-Sachs or cystic fibrosis or things like that?

    4. WCWendy Chung2:24:09

       That's what, uh, the consensus among the scientific community is, is that again, that you would treat the soma or the body of the person that might-

    5. PAPeter Attia2:24:18

       Mm-hmm

    6. WCWendy Chung2:24:18

       ... be at risk or have those diseases, but you wouldn't try and do manipulations that would be transmissible to the next generation.

    7. PAPeter Attia2:24:25

       I see. So my argument for BRCA is only partially correct.

    8. WCWendy Chung2:24:29

       That's correct.

    9. PAPeter Attia2:24:29

       I argued that the gene therapy would be favorable because it would spare the woman a mastectomy and spare the risk of transmission. You're saying no, you would only do it in the somatic cells, not the germline. She could still transmit that gene to her daughter.

    10. WCWendy Chung2:24:44

        That's correct. That's the, that's the current consensus scientifically. Um, the other part of it is this tricky thing that you're talking about, which is enhancement, right? In terms of it's not correcting something that's problematic, it's enhancing the body the way it is or trying to, um, in some sense prevent a disease process. But, you know, this-- I, I will say the enhancement, once you get to the point of enhancement, that's a trigger word for we, we shouldn't go there. And part of this is that we're not as smart as we think we are. Um, you know, we can think that something's not gonna have off-target effects, that it's not gonna disrupt a gene inadvertently. But I think in the short term, what saves us is that, um, the risk profile, given the uncertainty in the long term, is so high that there aren't gonna be either scientists or people, I think, who are gonna, I hope, uh, go for things that are trivial in terms of enhancements. I, I'd say that's the first part of this. But, um, to your point in the APOE two, three, four situation, I think is one that people think about. I also think that although probably the average listener here is more sophisticated about this, I think the average person, you know, walking down Broadway here is not gonna think about this in quite the same way. And so they're gonna think about things that will be enhancements, whether it's being able to increase your earning potential, being able to be taller, more athletic, you know, funnier. You know, what-- there are multiple dimensions in which people would, um, and people have been surveyed to figure out, you know, how they would value certain attributes. Um, you know, would definitely be thinking about doing that. I think at this point, it has to be just enhancement is a line that people are, I hope, not crossing, that it really is about disease and being able to make people healthier as we're doing this. Um, but to the extent that there are certain medical industries that are, you know, that are not covered by insurance, that people that are not regulated, there are certain parts of the world that do things differently, where people can go and seek certain things. Um, I do hope that there is a consensus scientifically about places we don't go, because otherwise there will be ways to, that people will find to do things.

    11. PAPeter Attia2:26:57

        I, I mean, is it worth just explaining the story of, of kind of the initial blow-up around CRISPR and, and what took place in China and how, um, how that brought the scientific community in some ways closer around this consensus?

    12. WCWendy Chung2:27:13

        Sure. So the circumstance in China was, um, something I have to admit was, I thought, was a little unusual. So it was a circumstance, uh, in which the CCR5 gene was manipulated to try and prevent, um, children from getting infected with HIV, um, by manipulating that gene. It's not as if that was curing a disease, to your point. It's not as if it was, uh, preventing a disease that was a foregone conclusion. It was preventing transmission of infectious agent that those children were at increased risk for, but it was not a foregone conclusion that they would have been HIV or HIV positive.

    13. PAPeter Attia2:27:52

        Wasn't it also the case that there was very little chance they were going to be because this was an IVF, uh, these were, these were children born of IVF, and the sperm are washed in that situation, and therefore-- 'cause in this case, I believe the father was HIV positive-

    14. WCWendy Chung2:28:07

        Right

    15. PAPeter Attia2:28:07

        ... the mother HIV negative. Um, but it was a situation where it was v- almost entirely possible to prevent the transmission of HIV to the offspring. Is that correct?

    16. WCWendy Chung2:28:19

        Right. So that, that was my point in terms of I don't think heroic measures needed to be made to be able to go. Um, there were perfectly, I think, reasonable ways that, uh, are very effective, not just reasonable, but very effective. So it was an odd sort of selection of a use case, I guess-

    17. PAPeter Attia2:28:35

        Hmm

    18. WCWendy Chung2:28:35

        ... is the point that I'm making scientifically. If I were gonna, uh, anyway, if I were gonna do something, I would have done it for this use case. But, um, regardless of that, the scientific community also, um, you know, just I think rallied around that, uh, a line had been crossed, right? That this was essentially a form of enhancement. It wasn't something that was saving a life, saving a high probability of something for which there were no other treatments, anything else. And, um, but, but I think, you know, the other point that I made is true, which is that this is-- the world is global and, you know, scientists are in all sorts of places and, um, it only takes one person, right, to be able to do something that's crossing a line. And, uh, there are people that, you know, there is tourism, medical tourism in places, and people I've seen go to, you know, where they feel that there's, um, something that they think is important that they'll seek. And so I think it is important for hopefully people to uphold certain s- ethical standards and for us to, you know, have those guiding principles so that people know where those lines are.

    19. PAPeter Attia2:29:37

        Do you think it would have been different if the first use of CRISPR in humans was to do something that we could all agree on would be a great use case? Um, in other words, would be, would, would, would the field be in a different place today? So what, what year was this that, that, uh, and I'm blanking on the name of the scientist who did this, but I know he's been basically, if not put in jail, certainly put out of science.

    20. WCWendy Chung2:30:01

        Right. Um, I can't recall the year either. Um, but I'm trying to think of what would have been that perfect use case. What were you thinking?

    21. PAPeter Attia2:30:11

        Uh, sickle cell.

    22. WCWendy Chung2:30:12

        Ah. Um-

    23. PAPeter Attia2:30:13

        Let's say you took a kid or, or Tay-Sachs, for that matter. You, you-

    24. WCWendy Chung2:30:16

        Uh-huh

    25. PAPeter Attia2:30:16

        ... took a, you took a kid who had a disease that was going to significantly impair the quality of their life. You used gene editing to fix the gene-

    26. WCWendy Chung2:30:26

        Uh-huh

    27. PAPeter Attia2:30:26

        ... and produce a phenotype that could have a normal life expectancy. Um, so again, same technology, but far better application.

    28. WCWendy Chung2:30:37

        So I think what, um, most people in the field, and this is usually possible, is that rather than trying to diddle the genes, if you're at the stage of an embryo with in vitro fertilization, you can simply do selection of an embryo that doesn't have that genetic risk, and therefore you're not-

    29. PAPeter Attia2:30:57

        Yep

    30. WCWendy Chung2:30:57

        ... increasing the risk of something off target, and you're still accomplishing what it is that you were set out to achieve. Um, I have seen some ethicists make the, excuse me, make the argument that if there were a very limited number of embryos and that were not possible to do, would that be, you know, a circumstance in which, like you said, for the purposes of direct therapy for a very bad disease in which that couple had no other alternative in terms of having a biological child, would that be possible, knowing that that would potent-- well, would affect the germline? So as opposed to what we were talking about before would be something. And that is what I would say is gets us close to the edge in terms of thinking about that, um, sort of the use case that you were talking about, but not as a matter of routine and not a routine goal in terms of the, at least, you know, intention to do in a universal way.
22. 2:31:55 – 2:35:33

    The future of clinical genetics

    1. PAPeter Attia2:31:55

       ball, you know, and you could look into the future in twenty forty, you know, probably you're coming to the end of your career, you're thinking about retiring, um, but you're looking back at a forty-plus year career in a space that has probably seen more transformation than most fields in all of medicine. What would you not be surprised to see happening in twenty forty in this field?

    2. WCWendy Chung2:32:33

       So I would not be surprised that diagnosis is trivial. Um, I do hope we're getting to that point. I think there are not just with the cost of sequencing decreasing, but with machine learning, artificial intelligence, the ability to ingest huge amounts of information, genomic information, clinical information, other information, um- You know, the, the, the diagnostic ability in medicine in general, and I won't say this is limited just to genetics and genomics, but is especially true in this field, diagnostics will be hopefully trivialized, and I hope, although I can't, I can't guarantee it's gonna happen, I hope from an equity point of view will be more accessible to more people around the world just because that, uh, cost barrier will decrease. What I'm not sure of is on the therapeutic point of view to what we've been talking about, how much of that we will have realized within twenty years. While I'm optimistic we will have gotten a lot of that done, I'm not sure how, how much it will penetrate, um, either parts of society in the United States or globally in terms of what we'll be able to do. Um, and this is just, uh, I think it's very hard for me to predict timing. Um, and I think Bill Gates is, has a quote similar to this. You know, I do think within some point in the next hundred years we'll get to this point, whether it's the next twenty years or not, and exactly how, what percentage of individuals we will have been able to serve, I'm not sure. Um, because there are gonna be, as I s- alluded to, these kind of step functions, these transformative things that, uh, it's just very hard for me to predict given that I feel like we got stuck, um, for the last twenty years, but I do feel like we're gaining momentum. But there's-- it doesn't take much in society and in science to get us stuck. Um, so I think that's just a word of caution. I, I would not have predicted, I, I hate to make things about COVID, but I would not have predicted in society what's happened in the last ten years or some of the trajectories we've had. So I will, uh, not use my crystal ball and, and I'll say we'll be far, much farther ahead, but, but I don't know. Big confidence interval on where we're gonna be in twenty years.

    3. PAPeter Attia2:34:44

       Well, Wendy, congratulations on your, um, your new role at, um, Boston Children's Hospital. Obviously, for folks not aware, that's certainly probably one of the three most preeminent children's hospitals in North America. Um, and maybe you would argue the single most. Uh, but, but anyway, that sounds like a wonderful opportunity. I assume you'll be able to stay involved in SPARK and GUARDIAN, uh, as a PI, uh, as those, uh, tend to expand. So, uh, especially wanna thank you for making time on the day that you're literally moving to Boston to make time to sit down for so long. So congratulations, and thank you again very much for your input.

    4. WCWendy Chung2:35:21

       Thanks. It's been a lot of fun. [outro music]

Episode duration: 2:35:33