An Interview With Dr Euan Ashley

A Tale of Medical Mysteries Unraveled by Genetic Detectives

; Euan A. Ashley, MRCP, DPhil


June 07, 2021

Robert A. Harrington, MD: My name is Bob Harrington from Stanford University. Welcome to our podcast on | Medscape Cardiology. Over the course of the many years that I've been doing this, I've had the privilege of getting to interview a series of friends and colleagues who double as both physicians and authors, and it's been really fun to talk with them about the book, or the essays, or the ongoing writing journey that they're on, as well as trying to understand how they put that in the context of being a physician. How does that add to the richness of their professional life, for example? It's really been fun, and I can tell you from the feedback we get on the podcast that they're some of the favorite interviews that I do.

So, today I'm really privileged to interview not just a physician-author but somebody who's a friend, a colleague here at Stanford University, and talk about his new book. The book is The Genome Odyssey: Medical Mysteries and the Incredible Quest to Solve Them. I had the privilege of reading this book over the past couple of days so that I was prepared to talk to my colleague today.

The author is my good friend and colleague, Dr Euan Ashley. Euan is a professor of medicine, genetics, and biomedical data science here at Stanford. He is an associate dean in our School of Medicine. He's a practicing cardiologist. He is an active cardiovascular researcher who runs a large laboratory — I suspect we'll get into some of the topics. He's the founding director of the Stanford Center for Inherited Cardiovascular Disease. He is a site leader, and a leader nationally, in the National Institutes of Health Undiagnosed Diseases Network. And he, like many other Stanford faculty members, is the founder and entrepreneur behind several local biotechnology companies. Euan, it's a privilege to have you here. Thanks for joining us on Medscape Cardiology, and I look forward to the conversation.

Euan A. Ashley, MRCP, DPhil: It's my pleasure to be here, Bob. Thank you so much for having me. I love the podcast, so it's my privilege to be on it.

Harrington: Well, now that I just reminded myself of your Scottish accent, I left out the most important part of your bio: that you have an ongoing research interest in single-malt Scotch whisky, so perhaps we'll come back to that.

Ashley: That may be the most important of my research interests.

Harrington: I was pleased to see that it made the jacket cover of the book.

Ashley: It's usually the thing that people remember the most.

Harrington: I had the privilege of reading your book this weekend, and I have to say, as a fellow nerd — and you described yourself in some ways as a nerd throughout the book — I loved the science. I loved the history of science, but I also really appreciated what a great story you told and the language that you used. Is there something in the Scottish personality that makes one a natural writer?

Ashley: That's very kind of you to say. I'm not sure about something in our background or heritage. I know that certainly the power of narrative is so strong, and I think it really pervades all of medicine. We're constantly telling each other stories about patients. Every morning report is a story; every time you talk to any other colleague or patient, it is a story. So I do see the natural narrative in medicine, and I think that's what people cling on to. I was hoping to write a book that included science, as you mentioned, but that was really framed around real people, real patient stories. And as I passed it around my various family members before it ever got to be read by anyone else, it was often those human stories they commented on and that they enjoyed the most.

Harrington: There are some great ones, and I'm going to pick out a few of my favorites and ask you about them because it is the power of narrative. Our mutual friend Abraham Verghese talks about this. He's been on this podcast and is one of this country's great writers who believes in the power of narrative as a way of teaching medicine, so I'm glad you made reference to that. Euan, let's not assume anything, so let's start with the basics of The Genome Odyssey. Some of our audience will be hardcore scientists who say, "Well, I can tell you about the genome," but not everybody will, so why don't you level the playing field and tell us what the genome is and why it fascinates you.

Ashley: The genome is the blueprint within almost every cell in our body — red blood cells don't have nuclei so they don't have the genome — but it is our own individual, completely unique code. People are probably aware that identical twins share basically a genetic code, but it's not actually even identical among identical twins. Everybody has their own unique code. It connects us at some level to every living organism on Earth; it connects us to the history of the human race. It's, in its essence, 6 billion letters, and each one of them is an A, T, C, or G.

You mentioned my nerd-like tendency, but a big part of what attracted me to the genome is that it is a computable thing. It is 6 billion bases of data. I was drawn in early on as the technology allowed us to start to sequence, when we spell out the letters of the genome, at a speed and a rate that we just couldn't do before that. I was watching technology advance in a speed beyond anything I'd witnessed in my history of science of medicine. It seemed so exciting. I wanted to jump on and see what I could contribute. It contains so much. There isn't a disease that doesn't have a genetic component; there isn't an aspect of your human body that doesn't have a genetic component. We also have to always balance that with the environment that we're in, but there's a genetic component to so much of what we are and what we do in medicine. It just drew me in and fascinated me for years.

Harrington: For the people who have not yet read the book but who are thinking of it, that to me was one of the things that captured me — your fascination with it comes across. I loved the dropping of the occasional fact, like if you were to unravel those 6 billion base pairs, it forms a length that would go to the moon and back multiple times. I think that captures the reader's attention, and again, as you say, for somebody like you interested in science from a young age, with parents who are in the field, that really does come across.

Ashley: I think that much of my interest in science was driven by reading popular science books. I had great teachers at school, but in reality it was actually outside of class that I really got a fascination with science. And my biology teacher — who, just to be clear, thought I was a total buffoon and would amount to nothing, and told my parents that — at one parents evening did me another favor: He gave me a copy of Richard Dawkins' The Selfish Gene, which was one of the most impactful books. It includes the origin of the word "meme," actually, for any of our younger listeners. Yes, the origin of that was in the last chapter of that book. It means something a little different now from what he coined. But what I got from his book early on was just his fascination with the natural world and his fascination with science, and his explanatory style drew me in. And I hoped that it might be possible to try to ape that a little bit and potentially write my own book one day.

Harrington: I was pleased that you told the story of your biology teacher who thought you might amount to very little. It's nice to see you've proven him wrong, which is a good lesson for many of our listeners out there — to continue to follow their love, follow their passion, because it usually does persevere, and that's a good lesson that's in the book. Before I go through the four sections of the book, which again I found really helpful, I'm amazed how each one of those sections could have been a book in and of itself.

Ashley: When I started writing, I honestly didn't know if I was writing a book. I knew I had a sense of stories that I wanted to tell and to spread the word, and I hoped that others who would read the patient stories would gain something from them. And I knew I could write scientific papers; I've written plenty of those over the years. But this is a whole different style of writing. I mean, I thought probably at some point I might try to write a book, but I had that pegged at some distant moment, in a sabbatical in 10 or 20 years or so — retirement or something like that. And it was actually this moment in time.

In fact, we were lucky enough to spend some time with the Office of Science and Technology Policy of the Obama administration, and I had taken a couple of my students to this event in Pittsburgh, at which Atul Gawande and the president were present. Atul Gawande was interviewing President Obama on stage, and Obama, I think we all realized toward the end of his presidency in particular, is also a nerd. He just loves science and technology, and this came across so much at this particular event. I think it was basically in the audience of that event that I felt — with these two very inspiring writers and humans talking to each other — at that moment that I shouldn't wait. I should try to write. So on the way home on the plane, I basically started writing. But I wrote with no sense of where it was going to go. As you mentioned, each of the individual sections could have turned into a book. It was great editing that managed to keep it in place and provide some structure to it, and I learned a huge amount from the editors.

Harrington: Let's talk about the process of writing, and then I'll get into some of my specific questions. You say you just started writing. And that usually is because somebody has a story that they want to tell, but it fits so nicely with the four sections. Did you come up with that or did your editor say, "Look, this really falls nicely into four discrete sections." What was that moment?

Ashley: It's a really good point and great observation because I had, as I mentioned, just started getting some stories down. I was hopeful that these were ones that a reader would find interesting. But a huge credit goes to my agent and to my editor at the publishing house who said, "We see a lot of potential here, but it's a little unformed, and if someone's going to read a book they want to feel that there's some sense of narrative arc from beginning to end." So in some ways, the beginning part was easy in the sense that the early genomes were going to come first because the rest of the book depends on that. And in fact, the first story, with my colleague Steve Quake, also contained elements around his heart disease, specifically. So that provided a nice entryway into explaining for the general reader what an ECG was, what an echocardiogram was, and concepts that would come to be revisited throughout the rest of the book.

That part I think I could have done almost by myself, but what really helped was having these experts and consummate professionals in the publishing world who really understood books and understood the reader's perspective, to say, "Well, obviously if we start with the early stuff, the last part should be facing toward the future." How do we now organize these stories in the middle, which were a little bit of a large grab-bag of things — how do we organize them in a way that will make sense for the reader? Eventually we divided them into disease detective stories, and then some specific inherited cardiovascular disease stories, all with the genome as a constant thread. But these different sections suggested themselves in the end.

A Fortuitous Encounter With Steve Quake

Harrington: Well, it comes together beautifully. Let's go to something that you already mentioned, which is the Steve Quake story. As you've pointed out, we've had the privilege to live through a lot of genomic history in a short period of time. Tell the Steve Quake story because it's fascinating, number one, that you wander into his office and he's looking at his genome. Number two, then you assemble what you called an all-star team to do this. I think people might be amazed at how many people and the man hours, the woman hours, it took to get this all done. So, tell the story because maybe it's the entryway into hearing about the book.

Ashley: Absolutely. It was a major turning point for me and I think a little bit for Steve as well. Steve is a colleague, and now friend, though at the time I did not know him. He was already a renowned bioengineer. He was here at the bioengineering department at Stanford, and we were planning a seminar in genetics because our new chair was coming, so I wandered over to his office. I remember it well because Stanford has a very gratuitously complicated numbering system, so finding anybody's office in that building is an achievement. I felt that I had achieved something when I got to his door and found him. I always have this crystallized picture of him in his office because it's one of those offices with all the journals from the past 10 years, which are all electronic now; but back then he had piles of journals all over the place.

Steve Quake (L) and Euan Ashley. Courtesy of Euan Ashley.

You could barely see him, and then in the corner of his office he was there pecking away at his keyboard. He's this world-famous scientist, and I came in to talk about this bland topic of a seminar we were planning. Instead, he had other ideas. He said, "Hey, come look at this," and he points at this screen, and it's basically his genome on the screen — A's, T's, G's, and C's. He's pointing at gene names, and he pointed at a gene I knew quite well. Out of 20,000 genes, he could have pointed at any one, but he points at the myosin binding protein C, which is one of the genes that causes hypertrophic cardiomyopathy. He says, "Hey, look, I've got a variant. What do you think about that."

And I was like, "Oh, could be nothing, could be something." I started just asking him about his family history, and suddenly he's telling me about quite a significant family history of heart disease, including his dad who has supraventricular tachycardia, quite a lot of coronary disease, strokes. Then I asked him this sort of key question in relation to inherited heart disease, which is, did anyone in your family ever die suddenly? And he said, "Well, it's funny you should say that, but my cousin's son died suddenly at age 19. He was a black belt in karate and just didn't wake up one morning."

Suddenly the whole thing changed. I was having this incredible moment in science where only the fifth person in the world to ever have his genome sequenced was sitting in front of me pecking at his keyboard. My jaw was on the floor looking at the genome, but all of a sudden I switched back into doctor mode because now I'm faced with someone with a very significant family history of heart disease, including early sudden death of a teenager, and he's literally showing me genes and variants that I know cause a disease that is associated with sudden death. So it switched in a moment, and I was suddenly inviting him into our clinic to become a patient. And he's saying, "Well, that's funny you should say that. My family's been telling me I should go see a cardiologist." And I'm like, "Well, you have one now." But then the dawning realization happened as I left that meeting and walked back to the cardiovascular building: that a patient was about to walk into a clinic with their whole genome essentially on a hard drive. He's only the fifth person in the world to ever have his genome sequenced, and the realization was he was walking into our clinic — we were that team. That was daunting and terrifying because, as you know well, we're used to looking at lipid panels with five numbers on them, or a CBC...

Harrington: Looking at the family history with little circles and squares and trying to identify relationships — yes, you had relationships, but you also had the source code.

Ashley: Just an incredible moment. For context, remember the Human Genome Project was 10 years between 1990 and about 2001. It was $3 billion of funding. It was 10 countries, 10 years to do one. And it wasn't even one as I described it, because it was half of one. But more on that another time. This was only 7 or 8 years after that, and suddenly we'd moved on; there were four or five more people who'd been sequenced. But it equally looked like the beginning of something really exciting, and I don't think I could have guessed what was going to happen in the following 10 years. But what seemed really clear was that genomes were going to become more available and more affordable; and given, as we talked about at the beginning, that every disease has a genetic component, it seemed inevitable. But we needed to be prepared for that world . If we're used to looking at five numbers and suddenly you have 6 billion letters, and you're trying to parse that in the context of a short clinical visit, how would you even do that?

So that was a question that I was facing. Of course, being in an amazing place like San Francisco — I was lucky to be here in this environment — I thought quite quickly of some colleagues who could help. I called them up and said, "I have this crazy thing. You know Steve." And they said, "Yeah, we've heard of him." And I explained that he has his genome, that there's a family history, and there's more than that. We need to do a workup — we've got that going — but we need help to parse the whole genome in the context of a single patient zero, which is what we called him at the time. And people just came. It was amazing. Another amazing thing: They didn't show up by themselves. Folks like Russ Altman brought not just themselves to the meeting but a team of 15 people. Suddenly there were 30 people crammed into this little conference room, all trying to work on a single genome of a single patient who was also in the room because he was part of the team.

Harrington: That was the amazing part of the story for me, as a researcher — that you said there's something here, and everybody just rolled up their sleeves, it sounded like, and devoted their expertise. Talk about doing unfunded research — this was the ultimate. You got a group of all-stars to give their time, their energy, their expertise. It's extraordinary.

But let me move on to some of the other topics. The Steve Quake story is a great intro. Then in part two, you start to get into what you call "the disease detectives." After you become a genome celebrity with the Steve Quake story, people start seeking you out. And you start learning all sorts of things when you would ask them questions about themselves, their family, their children. Does this happen any place other than Silicon Valley? What's the role that Silicon Valley played in this evolution over the next 10 years of the work that you were going to do?

Ashley: That's a great question. Certainly in those early days, Silicon Valley was awash with people who wanted to be on the cutting edge and had the resources to take them to the cutting edge. We were getting calls all the time from people who had realized that genome sequencing was going to be a thing. Maybe they had a family history; maybe they were just more interested in preventive care and wondering what was hiding in their genome. They would call us, and many times they were CEOs of large companies that many of us would have heard of. They were looking, in some cases, for the next big thing, clearly, and they just wanted to be part of that. And then in other cases there were very specific questions related to family history or very specific questions related to the future of preventive healthcare.

We heard some stories from New York at the time of some similarly high-level folks who were looking for that kind of interpretation. There were a handful of groups in the country at that point that were putting together pipelines that could potentially interpret a human genome in a way that would be helpful. But I think there was a certain uniqueness about the desire to change the world in a slightly unrealistic way that is part of Silicon Valley — the highly collaborative part and the willingness of people to sit there on the cutting edge and really look to see what does the world look like. I say at one point in the book that a futuristic tendency is a powerful driver of a creative ideation. That sounds like a lot of big words, but what I mean by that is if you're someone who can imagine a different future, then you're almost forced to imagine how to get from here to there. And of course, those are different skill sets in a way. Imagining the future is kind of fun, but how you get from here to there is a little bit more the nuts and bolts. But I do think there was a uniqueness about that time and place, and also unique interactions between Stanford and Silicon Valley.

Enduring Cardiac Tumors and Defibrillation: Ricky and Leilani

Harrington: That comes across. As you talk about, for example, the founding of one of your companies, Personalis, there are some great stories for the readers who are interested in how the biotechnology world emerges. Some good stories there. Let's get into section three because section three might have been my favorite section. And maybe I say that because, like you, I'm a clinician, but these stories are really the essence of narrative. The two stories I want you to think about are Ricky and Leilani. In full disclosure, I know Leilani through the American Heart Association (AHA), where she has been a powerful voice for patient advocacy.

Euan Ashley with Leilani Graham. Courtesy of Euan Ashley.

The stories are amazing for different reasons. One of the things I really enjoyed about the Leilani story was how you weave it into the whole history. As an AHA person, to hear about CPR and the beginnings of defibrillation, and this young woman who is an NYU student and is saved by defibrillation... Then that ties you into hypertrophic cardiomyopathy and Jim Spudich and biochemistry. How you weaved all of this in a way that we could read it... It's an extraordinary story.

Ashley: You're so kind, Bob. Telling these stories is my privilege, and when I think about what our patients go through — and in this case, these two remarkable young human beings and what they've lived through from such an early age — it is just awe-inspiring, honestly. Being able to tell those stories as you weave in the aspects that we find so fascinating, as doctors and scientists, that have led to the major advancements that have allowed us to bring lifesaving therapy to these individuals, was really too enticing to pass up, and I hope I managed to do it justice.

You're asking about Ricky, a very unusual individual in that he had a condition that would appear to be something called Carney complex. There are many, many aspects to that, but neuroendocrine tumors and myxomas cardiac tumors are a major part of it. He first came to the attention of one of our colleagues, Dan Burns in pediatrics, when Ricky was younger, just 5 or 6 years old. He had a very large tumor in his right ventricle that was bobbing in and out his tricuspid valve. Basically, a fill-in GP (general practitioner) — they'd gone to see a different GP because he was having some palpitations — and that individual did a clinical exam. He heard this plopping, bizarre murmur and said, "I don't know what that is, but you need to go see someone."

This was a locum GP that was filling in, so that's where his story began. He had an initial heart surgery. He had a testicular tumor that was removed. He had a pituitary tumor that was removed. He had another heart surgery. And another heart surgery. Then I met him. I start the story with we were waiting for our next clinic patient, and sometimes you're well informed and you've looked in advance, and sometimes you're just like "Who's coming next?" I swiveled around and looked at the screen, and this long-axis view of his left ventricle was there, and there were two massive golf balls bobbing around in his left ventricle. It's one of those things where you do a double take, and you're like, "That can't be real." And suddenly everybody in the room swiveled over, and both in the outflow tract of the left ventricle and in what looked like the subvalvular apparatus of his mitral valve were two large myxomas.

That's where our story with him began. He's just an incredible young man. The story goes through a number of twists and turns, including him being on the transplant list, including him deciding that he wanted to take himself off the transplant list, including at one point his close relative dying in an accident and looking to donate their heart to him, and a number of other remarkable things. But it leads up to a moment where we had to make a decision about whether he was going to be a heart transplant candidate or was there some kind of heroic surgery that could be done.

Harrington: That's the story. I don't want to go through the details. I'll let the reader have the pleasure of reading it, but I was impressed, and not surprised, by your powers of observation when you describe our mutual friend and colleague, Joe Wu. I could hear his voice the way you wrote it, which is... First off, Joe always wears a tie. And you noted that he had pulled on his tie, which Joe does before he says something. And in classic Joe fashion, he just says, "Let's get this done." I mean, how many times have you called Joe and you say, "Joe, I've got this difficult patient." And he says, "Well, let's get it done; send them over." That was a great story and about a great surgeon, but I won't spoil the story. You should go ahead and read it.

Ashley: I have another story that's about Joe. It's not in the book, but I loved it because it reflects exactly the same issue. It's the only time I've been on the helipad. I was on for the CCU (cardiac crucial care unit). We had this patient who had an anesthesiologist with them being transferred in the helicopter, and they'd had essentially a series of tension pneumothoraces in the helicopter. And this anesthesiologist had to basically put in cannulas two or three times to try to stabilize the patient. I was called up to the helipad and was like, "Why do they want me on the helipad? You probably need someone else." I mean, I am the CCU attending but... So it became clear as the helicopter landed in this tiny little space. That's how we met, and then I got the immediate story from the anesthesiologist. Clearly, this patient needs an operation, so we basically called Joe inside of a helicopter on the roof — it was still slowing down the rotors. And Joe is a man who gets things done. I basically described the story and he said, "Give me 2 minutes." That was a long two minutes. He called back, and all I heard at the end of the call was "OR eight." Done. We took the patient straight from the helipad back to the operating room and saved the patient in the end, due to Joe's team's amazing work. So I think that sometimes you need a surgeon to get it done, and he's often the guy to help.

The Olympic Skier Accused of Cheating

Harrington: What I also appreciated is that you're telling all of this elegant science, and then at the end of the day what you really need is the surgeon to just get this done. It's remarkable. As we get into the last section, Euan, in our last couple of minutes, I'm going to let you pick. Do you want to tell the story of elite athletes or do you want to tell the story of PCSK9?

Ashley: Well, I'm thinking that your listeners might have heard quite a lot about PCSK9, although I love that story too. But the elite athlete was such an unusual one. Shall we tell that one? This is a story that has just fascinated me, but it really is at the fundamentals — and I deal with it in the part of the book where we talk about how the genome was used for drug discovery, and that's part of the PCSK9 story. But this was an Olympic athlete who'd won more medals than anyone else in cross-country skiing. He came from Lapland, and he grew up doing cross-country skiing to get to school in the morning and then in the evening. Remarkable. He won all these medals, multiple gold medals. He was like 15 seconds ahead of the nearest competitor. But this cloud hung over him, suggesting that he might be blood doping because every time his blood was taken he had this really high hematocrit, and that's the only way you can tell. If people know what blood doping is, you remove blood from yourself, you store it, you give it back. And those red blood cells obviously carry more oxygen and are performance-enhancing, similar to the idea behind EPO supplementation or even altitude training.

Skier Eero Mäntyranta at the 1964 Winter Olympics

He had this really high hematocrit, just beyond anything that anyone could consider. So this whole cloud was that he was actually bad. But what it turned out to be was — when several other members of his family also were found to be these remarkable athletes — that he had a genetic mutation in his EPO receptor. He was actually kind of a genetic superhuman. What it meant was that his EPO system was basically like "pedal to the metal." The accelerator was down the whole time, and his bone marrow was just making red blood cells constantly. It turned out that he had this kind of superhuman mutation, and in the end, when this was laid out and his whole family tree was there — there was a paper in PNAS — essentially he was exonerated. Science proved what he had told them all along, that he'd never done any blood doping. Just a remarkable story. Eero Mäntyranta was his name.

Harrington: It's a great story. There are a lot of great stories: gene therapy, CRISPR... just great stories that people should go and read. But I did particularly like the inherited endurance, which is a great story to tell.

Well, you and I could talk about this all afternoon. It's a terrific book. My guest on Medscape Cardiology is Euan Ashley from Stanford University. The book is The Genome Odyssey. Euan, thank you for talking with me. I know you've been busy with this, but we appreciate it, and like I said, I can really endorse reading it. I had a wonderful time reading it this weekend, so congratulations.

Ashley: Thanks so much, and thanks for having me on.

Bob Harrington, MD, is chair of medicine at Stanford University and immediate past president of the American Heart Association. (The opinions expressed here are his and not those of the American Heart Association.) He cares deeply about the generation of evidence to guide clinical practice. He's also an over-the-top Boston Red Sox fan.

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