I want to become a genetic counselor. Looking for ways to engage with the field and booster resume for grad school applications then you should check out Sarah Lawrence is why genetic counseling Wednesday summer series. Every Wednesday, this june sarah Lawrence is hosting the series where you can interact through zoom with genetic counselors from different specialties. For an hour and a half, it kicks off on june 2nd. You can sign up at slc dot e D u slash DNA. Today again visit slc dot e D u slash DNA today to register to level up your resume for applications in the how is it? We find ourselves surrounded by such complexity. Vienna were hello, hello, you're listening or watching DNA Today. We are a genetics podcast and radio show. I'm your host, Killer Dean. I'm also a certified genetic counselor practicing in the prenatal space on this show. If you've listened or watched before, you know, we explore genetics impact on our health through conversation with leaders in genetics like genetic counselors, Researchers, doctors and patient advocates.

And I'm excited to show that this episode Marks 150th episode. So huge thank you to all our loyal listeners for getting us to this point. This is certainly a landmark and we really appreciate all of your support since the beginning in 2012. So next year's 10 years. Um and thank you again to our sponsors for supporting the show I'm really keeping us running. So today we are going to be celebrating the show by talking to dr you and Ashley a medical geneticist and cardiologist and dr Stephen quake, a physics professor, bioengineer and pioneer in micro fluid IX. So I want to start out by saying I read the book doctor actually that you wrote called the genome odyssey and it was such a fantastic read. Dr quake and I were just talking about how great of a writer you are before we hopped on the call here and that it really reads like a story. So I just wanted to thank you for writing such an engaging book that really goes through just the history that we're going to talk about between you two and your really special project, but also just really cool cases that you've brought up and really honoring like the patient perspective and patient advocacy.

So just fantastic job with the book. I'm excited to get into part of it today. Well thanks so much Karen, really it's very kind of you to say. And you know, I really inspired by the kinds of scientific stories that steve leads day in day out and also by just the lives and the journeys of our patients and so I hope to try and tell those and to leave them as they connect. And I'm excited to yeah, chat a little bit more about them with you today. So a little background for those that maybe haven't read the book yet back in 2010 Doctor actually you led the team that carried out the first clinical interpretation of a human genome or at least one of the first um and that genome was dr quakes, how did that come to be? How did you end up coming together? What was it about? Doctor Quakes genome that you're like well I think that this would be a good one to explore and dive into. Well what wasn't planned actually. I mean basically we were meeting one day about something else. We didn't know each other that well to be honest at the time and I was you know, just, just meeting, trying to plan a little seminar I think it was and I wind my way around stanford to try to get myself to steve's office and then found him in there surrounded by journals as as we see them today actually uh watching can fly just right there.

And I sat myself on one of those tears in the back and we started talking about the seminar but before we really got to that he's like here come over, look at look at this on the screen and on the screen I saw one of these old html tables, you know, like an early website and a bunch of AIDS TB letters. I recognize it is cheese and sees and a bunch of gene names and I'm like okay that's genetic data and he's and I'm like well what is that? And he's like well that's my genome and you know, at some level I was aware that he had been, I think the fifth person in the world to have his genome sequence. And he had done it because I'm sure he'll tell us in a few minutes, you know, with sequencing technology of his own invention. I I knew that, but but here it was right in front of me. And as a practicing cardiovascular geneticist, essentially I would I would be sending genetic tests at the time for 34 genes. They take three months to come back $5,000. The idea that there'd be a whole genome in front of me was just kind of a little bit mind blowing. So it was really after we started to look at some of those genes specific ones together and I realized that maybe we should be asking a little about his cardiovascular history and he started to share that, that the whole conversation moved.

It went from, you know, we're having a scientific collaborator meeting to maybe more of a doctor patient kind of thing. And I remember him saying at the time, you know, it's funny you should you should talk about this because my family has been trying to get me to go see a cardiologist. It was really I think in that moment that we realized that as a result of the family history and I'm sure he'll share uh he should come and and be be seen in the clinic. Um and then it was a kind of secondary thought, wait a minute, Someone is about to come into our clinic who has their whole genome and that was just a mind point thing. And the cheetah was like right there in front of us on the screen. And so that's kind of how it came about really by happenstance in many ways. But in other ways you know maybe it was meant to be And Dr. Quick, what led you to say I'm going to sequence my genome? I mean this was 2009. This was unheard of back then, which like 10 years is ancient history. I feel like an in genetics in terms of where we are today. Um what were you thinking about when you're like I want to sequence my genome. Well part of my research program has been to try to develop novel sequencing technologies and we had developed the first single molecule DNA sequencer.

And um it had left my lab, we've done a proof of principle experiment in the lab and he left the lab and gone into a company and they turned it big very talented team of people and turn that into a real commercial instrument which was at the time, the world's fastest cheapest sequencer. Um And there was a lot of debate about whether you could use it to sequence the human genome or not because of arguments about technical limitations, read length and error rates and things like that. And it wasn't at all obvious that even though it could sequence a lot of D. N. A. And do it really fast and inexpensively that it could do it on something the scale of the human genome and you know rather than kind of argue with people about it I just decide we're going to do it um and we'll just do the experiment um and decided to do my genome um in part because you know I didn't feel right asking someone else has put it that way. There were a lot of unknowns about um about what that would mean. And you know who's really in a position to give informed consent given that we don't know what the implications will be for people's health care and whatnot.

And I'm like all right this is when I'll do myself and see what's there. And you had met with a genetic counselor before. Dr Ashley was assembling a team to actually analyze and take it to the next level in terms of looking at your genome. I mean how is that process? Because you're probably more educated than the average patient seeing a genetic counselor. So did that feel different kind of being in the patient role? Well she was appalled because I wasn't just the patient role. I was in the scientist analyst role as well as the group was trying to um decide, you know what the conclusions were in the clinical annotation, some of that hinged on what one knew about genes and some of it hinged on what our confidence was and calling polymorphisms in the genome. And I was like the expert in the room who knew about the confidence uh in the genome and how much emphasis believed to put on it. And that's certainly not the way she was used to doing things. There were moments when her head was in her hands because it wasn't a textbook example of genetic counseling hospital that way. Yeah. Certainly have heard just thinking of like what could come up as we were saying, you're the fifth person in the world that had their genome sequence.

So most things we did not know what to anticipate. Was there anything before launching into the project that you were hesitant to learn about? Is there anything that you said? This is something I may not want to know about my genome? Or were you more on the sense of we're being a pioneer here and we're just going to find out what we're gonna find out? Yeah, No. I mean, for me, I was happy to learn anything that would tell me. I was very curious about the contents good or bad. And so, you know, there was no hesitation there. And the moments of pause, the hesitation were around. You know, does this mean I might lose my health insurance because it's something we discover and you might have to deal with that? It was sort of more practical consequences of the way we do things in society. But as far as the information and what would tell me about my health and potential future. I was very very curious about that and I want to know everything good or bad. And going back to that first time doctor actually when you were in the office and you're looking at this crazy spreadsheet with all these at GCS, what jean stuck out to you in terms of maybe having information that could be really useful in terms of dr quakes health and just coming from that cardiologist perspective.

Yeah. Well I remember it specifically because I saw the gene mice and binding protein C. And that is a gene that causes a condition known as hypertrophic cardiomyopathy and hypertrophic cardiomyopathy can be associated with a bad heart rhythms. Beatty was one example particular tachycardia and even sudden death. And so you know, I saw this variant and I know we all have variants but I recognized the genes. So that's when I started to take a bit deeper into his family history of cardiovascular disease. And he said, well my dad has, you know, nobody ever remembers their heart, their family history. You know, you know, this is a case. But at the beginning he's like, yeah, I don't think there's any history. And they said, well my dad has this rhythm ventricular or something and then, you know, ventricular tachycardia like yeah, that's it. And then, you know, I asked if anyone had ever died suddenly in his family because that's the most important question when we're taking a history for these conditions. And he said, Well, yeah, my cousin's son died suddenly a 19 year old with no prior family history of anything prior medical history. And that just kind of stopped us in our tracks. And and really the whole thing changed at that point.

And so a lot of our early focus on analyzing his genome was looking at mice and by improving seat specifically, fortunately that variant turned out not to be a positive for hypertrophic cardiomyopathy. And we brought him to the clinic and also screened him. Uh we pulled in a few favors to get, we put him on a another trend on the bike. We we exercised him, you know, doctors are foreign friends to have, we exercised him pretty hard. But he came through very well, I'm happy to say. Um, so in those, those genes, we were okay. But we did find some pretty important cardiovascular gene findings related mostly to cholesterol and coronary artery disease risk actually, rather than the dandelion condition hypertrophic cardiomyopathy. So we dug into those in a bit more detail over the course of the following few months. And so with that new information, was there anything you learned from his genome that then changed medical management or anything that led directly to that, that you would not have known or done not having that genome sequenced. Yeah, I think this is one of the key things for us and that we find his his uh this is all public.

He's shared this for many years. So I figured at this point it's in the book now we're talking about on the show publicly. So I think dr craig's consented at this point. Right. Exactly. But his LP literally one of the lipoproteins, it's like a bad cholesterol particle was particularly high and the genetic basis for that have been shown by some folks at Oxford a few years before. And so we met that we also met some other cholesterol and coronary artery disease risk genes. And then looked at the pharmacogenomics variance for the medicine that you would take to treat that, which is a cholesterol medicine called a staff. And so then we actually went to the regular old, how would we do this if we didn't have a genome. And and we we worked through his age, his cholesterol all that through this tree. And at the end it had this really useful um you know, endpoint which was used clinical judgment. I mean, he was basically in the middle, it didn't give any advice at all. And what it was basically saying to us was, well, do you have any other information to help this site like as the patient really risk of our so they're really eager to reduce their cholesterol or do you have any other information?

We were like, well maybe a genome perhaps. And so you know, so we basically looked into the genome and really came together with the clinical team to say here's the extra information we have and using that we were pretty clear that his risk was such and his benefit would be such that he should take cholesterol lowering medication and then dr quake did this lead to any of your other family members to be tested or provide them extra information that because you sequence your genome, it didn't just help you. But other family members as other medical aspects came up for them. Well it's pretty interesting. My wife very much in the genetic privacy and she said well since you had your genome not only sequence but published, I'm not doing anything with mine. So at least half of our Children's genome, it seems like a good rule to live by. It was her take on it. The more serious one was was the case that you mentioned that my my cousin's son had died as a teenager suddenly at night healthy and every other respect sudden death and they were obviously very traumatized by that and you know wanted to understand the cause if they could want to understand if their daughter was at risk of anything and you know there's something they should be doing proactively.

Um So I introduced him to you and and he took that on as a second study which is also discussed in the book. How do you keep research articles organized? I've struggled with this as a student for years and now as a genetic counselor, I have so many papers saved on my Mac but it's often hard to find one and even harder to sight when I'm writing. I finally found a solution though it's simple and easy. It's called paper pile. The goal of paper pile is to radically simplify the workflow of collecting, managing and writing papers. This app allows you to highlight an antarctic papers, manage, references, share and collaborate and get this even site directly in google docs. I wish I had discovered this when I was doing my thesis would have saved me hours of time and frustrations at every step. Paper pile aims to provide a just works solution that eliminates any unnecessary complexity. Especially the paper piles, new mobile apps, you can sink your library to all your devices so you can read an an OT on your ipad, iphone or android devices. So if you're a student researcher writer really anyone who's downloading and reading papers, you gotta check out paper pile for a streamlined approach. You can start your 30 day trial at paper pile dot com with code DNA.

Today Paper pile costs only $36 per year but with Codina today you save 20%. Again that's paper pile dot com for all your papers in one place. Nice and Heidi And so with all of this information. I mean looking at the genome When this was 10 years ago, there are a lot of spelling differences or variants as we call them. That maybe we're not as well understood at that point as they are today. Um when you were going through the genome, how were you able to figure out if a genetic change was just human diversity and doesn't affect human body versus being a problem like a pathogenic variant. How is it to actually go through and categorize all of these spelling changes? I don't know. I imagine you both had a role in this. Yeah. Yeah. It was really a different world from the one we live in now where we have access to hundreds of thousands of population samples to say. And even increasingly diverse population samples, not as far as we need to go there. But it's increasingly the case that we can look to very large numbers of samples to see what the population frequency Of this particular variant the spelling change.

So that we know if it was a common variant, it's unlikely to be a major cause of of a rare disease. But at the time you're right, we didn't have any of that. In fact, I remember while we were doing this, I think maybe there were 10 genomes released by someone else, you know, further down the line, You know, the next 10 from the first after the first five. And that was a major advance to get to 10. So we're nowhere near the hundreds of thousands and eventually millions that we're heading towards. So we had to build algorithms based on you know, fundamental knowledge of the genome. This causes a stop code on this. We mess up splicing and this was a new information but it hadn't really been applied at this scale before we had to try to say well how do we take those algorithms that understanding of basic machinery of the cell and and apply it at the level of a data set that that's the size of a whole genome. And so yeah that was very much a collaboration with steve's group and then the algorithms group on our side. And so I think at one point I don't know if it was a doctor quakes genome or another patient. Um but there was a change in the variant and you were trying to figure out well is this change pathogenic?

Even though we're seeing in those other genomes that were serving as the reference genome. And you're going on this odyssey of trying to figure out like okay, just because it's in the reference you know, doesn't mean it's normal. I imagine we're experiencing less of that now that we have so many but I mean how is that process? Like who who was thinking of oh maybe it's it is a pathogenic variant in that reference genome. How did that process all kind of unfold? Yeah. I mean initially it folded around unfolded around a family that we we dealt with after steve the West family had was one of the first to sequence their genomes on the aluminum platform. Part of the initial 10 genomes on that platform. And the only thing we knew about john West's genome at the time was that he'd been previously tested for factor five Leiden and he was trying to have that variant in hetero sagas form. And so we first went looking through, we had a whole family of genomes. Now we first went looking for that one change and we found that it wasn't there or rather you know, different variant was there. And so we were really confused. And that led us down a big rabbit hole that I talked about in the book that took us to buffalo in new york and the beginning of the human genome program and where the reference sequence really came from and how some part of it links to a a dutch scientist who was making the reference to, you know, and the Leyden of course from from Netherlands and where this this variant was first described as particularly common in that population.

And we found that of course because it came from real people, the human reference actually had some pathogenic variation in it. And that was something we had to start to account for going forward. So Yeah, it was really about thinking back as you said, it's like it's only 10 years ago, but it's a completely different world from the one we live in today. Yeah. And another aspect that's changed so much. It's just the cost of sequencing and how long it takes to do a sequence um doctor quake, how long did it take you to sequence your genome and do mind sharing like how much that ended up costing and how did that compare to other people that were doing the first four, I guess genome sequences. Yeah, so we did it over the course of roughly a month and you know, each run was was about a week and I think we did four runs total if I recall correctly. And then it was costing $50,000 which was 10 times cheaper than any of the genome have been done up to that point in terms of just the re Agent cost. Never mind the number of people involved. We only had uh three authors on the paper. Um one of them did the sequencing, one of them did the computation.

And there was me um whereas before it had been like you know, dozens of authors on the paper and the amount of men and women power that went into doing these things. We just enormous. And so we'd really our work marked the first time that this transition from giant factory level stuff to something a single investigator in the lab could do on their own essentially. Uh And that was very important for the field because it was a real I think democratizing point for the technology and meant that anybody who's interested in questions about genome could start playing in a sandbox. Whereas prior to that it had been the province of very small number of huge centers funded centers and big hierarchical thing. Yeah. I got to the point where you're showing that it could be a small team that's achieving this and like really that first step towards anybody having their genome sequenced. And that's kind of at the point where we are today. I don't know, maybe maybe I'm overstepping a little bit. Maybe not everybody getting their genome sequence but there is that ability there. And dr Ashley, I I love your analogy with the Ferrari. Would you mind sharing that in terms of looking at the cost of genome sequencing and how that's fallen over the years?

Yeah, of course, yeah. And this came about because I used to drive home from stanford Hospital, past the Ferrari garage garage in uh in Atherton, which is where the Silicon Valley billionaires live. So they need a Ferrari garage nearby. And I would sit at the stoplight and look at these cars that I, you know, had thought about since I was a little kid. of course there were a few $100,000. And like many scientists, I do mental math in my head while I'm driving home and at idle moments. And you know, all of us steven me and many, many others have been showing this graph of the decrease in cost of sequencing and he just described how his was, you know, 10 fold cheaper than the one before. Um and people were a little bit, I don't know, somehow they become immune to the, to what that really meant to steep down downhill curve on a graph. And so I think prior to one talk, I thought maybe I could put this in more tangible format instead of Ferrari dollars. And thinking of the human genome program being a few billion dollars down to where we are today. Or at least at that time I realized that if a Ferrari had dropped in cost as much as human genome sequencing and dropped it cost it would have dropped to around 40 cents.

Just, you know, my mind blowing, you know, change really unprecedented in technology and you know, I've revised that number all the way down. I think when I even wrote the book it was like 20 cents and now depending on which number you take, it's almost one cent depending on where you start. So just you know, a really spectacular change that has really now fueled magnificent change in how we approach genomic data for patients. I think that's such an easy way to understand the magnitude of how much it has dropped because you can look at the chart and try to appreciate it that way. And I think people that are very bath focus can appreciate it that way. And then the rest of the population can be like wow you're talking about a couple cents for a Ferrari. Like that is a huge difference. And in terms of like where we are today um you know you have this great quote in the book that says I realized he meeting dr quake was about to become the first patient in the world to walk into a doctor's office for a checkup with his genome. And now this is the case where people do come in to their doctor and either they've had genetic testing or they've had their full genome sequenced or maybe they're ex um um in different levels of that.

Where are we today in terms of like how many patients are doing this and how do you see that changing in the next few years? Or do you see a point where this is going to become almost like the new newborn screening where everybody's gonna have their genome sequenced? Yeah. I think you know, our initial thought was that this is going to be everywhere. The ones it gets cheap enough. Everyone's gonna have their genome sequence then of course didn't quite work out exactly like that. And I think maybe a year or two after we did this. If you'd asked me what progress we've made. I think you might have I'd have probably told you I was a bit disappointed in how fast and how far we've come because everyone wants it to happen now. But then if you take a 10 year view and look back on how far we've come in 10 years and it's mind blowing that we moved from the point where it was just unheard of to have a gino. This was like you know, five people in the world. And we've moved to the point now we're ordering it at least in in clinical setting is basically routine in most countries in the world. I mean it's not as available as it should be. There's still challenges with pears in certain places. But the value of the genome for genetic disease is really just not in question anymore.

And and it's it's available and we are certainly on a daily basis dealing with patients who have their full genome data. Either as you say, through exam or or full genome sequencing. In fact through our undiagnosed diseases network Program that I also talk about in the book. You know, we we sequenced not just an individual but as they come in the door, we also sequenced their family. So we sequenced 2-3 maybe even four individuals in a family to help make the diagnosis as they come in. So that's a sea change. That was just beyond our wildest dreams. I think when we first started. Yeah, I think that's a great perspective to have in terms of just the last 10 years. I can't imagine what the next 10 years you're gonna bring. Um and Doctor Quick, have you revisited your genome in terms of you know, we've talked a couple times now about just understanding more and more variants as time has gone on. Have you gone back on a regular basis just to check in if there are variants that have now, as we say, reclassified of understanding that maybe the impact on our health is a little bit different than we thought years ago. That's a really good suggestion. And I think I should visit my cardiologist that maybe we can get you on the doctor actually.

Schedule. Huh? Well, let me see if I have time in my schedule. It might be a long wait. We'll see. I don't know. Maybe he can move you up on the schedule. Can we get the old band back together? Do we have? It seems like you might want to, I don't know. Yeah, you got to write a sequel. Right. So there's gotta be something Right. Right. This is this is a good point. Yeah. Well, thank you so much everybody for tuning in. I highly recommend checking out the genome odyssey to dive deeper into the conversation we're having today. There is just so much more in the book and it is such an easy read. I think sometimes genetic books can be tough to get through and I have to say this one I really, really enjoyed and I was a little sad and it was over because there's just so many great captivating stories in there and it's in that format, so it's such an easy read. Um and I especially recommend it if you're intrigued by the heart because dr actually is quite the nerd when it comes to how the how it works and just so captivated by it that I was like I need to start learning more about cardiology. I think it's such an interesting field. And you really you really highlighted that and bringing the enthusiasm and I'm excited to say that we're gonna be doing a book giveaway.

So head over to our social media on twitter instagram Youtube facebook to connect with us and you can enter the giveaway on there. Um Any questions for the three of us, you can send into info at DNA podcast dot com. All of our episodes are available at DNA podcast dot com. And I just want to thank both of you so much for coming on and sharing all of your insight and really pioneering genome sequencing and how we're actually using that in the clinic. It's just It's fantastic to, you know, there's 150th episode but really to be able to look back on the last 10 years of genomic sequencing. So thank you so much for coming on the show and just sharing all this knowledge with the world. Thank you. Thank you. Thanks for having us If you're applying to genetic counseling grad schools in the near future. I highly recommend checking out Sarah Lawrence is why genetic counseling Wednesday summer series. This is the second year Sarah Lawrence will be hosting the series where you can interact through zoom with genetic counselors from different specialties for an hour and a half. This takes place every Wednesday in june at 12 p.m. Eastern. As many of you know, I graduated from Sarah Lawrence program last year and this series was a fun way to interact with perspective counseling students.

It was so cool to meet so many of you in the prenatal installment earlier in the month, myself and other prenatal genetic counselors shared about our roles and answered your very thought provoking questions live, There are still a few sessions left though. Not only will you hear from genetic counselors and a variety of specialties, you also have the opportunity to discuss ethical and social implications of genomic medicine, engage with current students and learn about the exciting present and projected future of the profession, anyone who attends all five will earn a certificate of completion and receive an application fee waiver register. Now before we are fully booked because we had really, really booked sessions earlier go to slc dot E D U slash DNA Today. Again that's slc dot e D U slash DNA today to be part of this interactive genetic counseling experience. Thanks for listening everybody join us next time to learn, discover new advances in the world.