In this episode of The Future of Medicine, we welcome Stephen Quake, a bioengineer, physicist, and serial entrepreneur whose innovations have transformed how we measure biology and deliver care.

Dr. Quake shares how his early fascination with building and experimentation led him from physics into biology, where he helped pioneer microfluidics, enabling the automation of complex biological experiments. He reflects on founding multiple companies to bring these technologies into real-world use, reshaping research and diagnostics.

The conversation explores the development of noninvasive prenatal testing (NIPT), a breakthrough that allows doctors to detect chromosomal conditions using a simple blood draw instead of invasive procedures. Dr. Quake explains the key insight behind this advance: counting DNA molecules, and how it has since impacted millions of pregnancies worldwide.

They also discuss the early days of genome sequencing, including Dr. Quake’s decision to sequence his own genome and what it revealed about the future of personalized medicine. From there, the conversation expands into liquid biopsies, transplant monitoring, and early cancer detection, highlighting how blood-based diagnostics are transforming how we detect and manage disease.

Looking ahead, Dr. Quake shares his perspective on the next frontier: using advanced molecular tools and AI to detect disease earlier, understand human biology more deeply, and ultimately reshape the practice of medicine.

The Transcript

Euan Ashley: Steve Quake, welcome to the Future of Medicine.

Steve Quake: Thank you. It's terrific to be here. Yeah.

Euan Ashley: It's, it's, it's really great to have you, and thank you for, uh, speaking at Grand Rounds today. Um, hard to know where to start with you and your career and the impact that you've had, but we always love with our guests on, on the show to talk about their background and, you know, what, what first drew them into science and medicine. And I've talked to you about this before, so I know one or two of the stories that relate to that. But tell us for, for the, for the listening audience, how, you know, when, when did you first know you were gonna be a mad scientist, uh, and and how did you move on from there?

Steve Quake: Yeah. Well, you know, I think the first experiment I might have done Yeah. As a young boy was to try to make gunpowder.

Euan Ashley: Right. And what led you to, how old were you, first of all?

Steve Quake: Oh my gosh, I don't know. Somewhere in elementary school. Yeah. Right. Um, and, you know, my parents had given me this two volume set of books called The Way Things Work. Okay. And you could read through it and explain like all kinds of technological things and how this and that works. Yeah, yeah. Yeah. Um, and I like shooting off fireworks. Yeah. Um,

Euan Ashley: Who, who

Steve Quake: Doesn't exactly. Unfortunately, I still have all my fingers. Yeah, yeah, yeah. But, uh, I thought, oh, I should try to make my own. And I read in the book, you know, the formula for gunpowder and what goes in it. And so I went and tried to gather the ingredients and mix 'em up. Yeah. And, uh, you know, didn't quite appreciate the role of compression at all, but, uh, so it was a failed experiment. I see.

Euan Ashley: That's good that it was a failed experiment. You, you told your parents you were doing this? 

Steve Quake: Of course not.

Euan Ashley: No, of course not. It's not right. Yeah. In the backyard. Yeah,

Steve Quake: Exactly Right. Could have burned down the forest or something.

Euan Ashley: Yeah. Yeah. So building things, inventing things, cooking up new things was something says like it was, you know, almost in your DNA as it were from an early stage.

Steve Quake: Absolutely. And, you know, I grew up in the early days of the personal computer revolution, and so that was in the mix as well. I learned how to program the computer and use it to control things and, you know, uh, you know, learn a little bit electronics, and I sort of as

Euan Ashley: Well. Yeah, you used to get the magazine. I mean, I, I think I, I did the same. We sort of shared this. We would get a magazine through and it would have software code written on it. And you'd type it in and then hack it a little. Absolutely. That was also your Experience.

Steve Quake: For sure. Yeah, for sure. All those trade rags coming from this far off place called Silicon Valley.

Euan Ashley: Yeah. Yeah. For me, it was a very far off,

Steve Quake: It felt far off for me. I upstate New York, so it was far off for me too. Yeah, yeah. Yeah.

Euan Ashley: And that, you know, when did that transition then to an idea of, of a, of a specialty called science or, you know, a profession called science?

Steve Quake: You know, when I first went to college as an undergraduate, uh, I knew I was interested in physics. Um, yeah. But I was also interested in engineering computers. Yeah. And so I was sort of undifferentiated. I was probably gonna be one path or the other, but I had some very inspiring science, physics and math teachers.

Euan Ashley: Yeah. And where was your undergrad?

Steve Quake: Uh, here at Stanford. Yeah. Yeah. Yeah. And a couple of very inspiring teachers. Yeah. Um, and that sort of set me on the path of, of science, and, uh, I'm kind of stuck with it. Yeah.

Euan Ashley: It seems like it, it, it's gone, it's gone pretty well. But computer science and, and engineering, uh, obviously today, you know, very, very obvious, uh, the impact that they're having.

Steve Quake: Yeah. Maybe I took the wrong path. 

Euan Ashley: Yeah.

Steve Quake: I don't know.

Euan Ashley: But biology is, is obviously, uh, an area where you've had, you know, a huge impact. Biology and medicine will come to, to talk about that impact. Um, but, but you started on the engineering side, sort of making things work. Uh, how did you first start to pay more attention to biology? Or what was it drew you into that?

Steve Quake: Yeah, so as an undergraduate, I trained in physics and math and was very much in that, uh, mode when I got to graduate school. And I was trying to decide what to specialize in for my PhD. And I spent my whole first year kind of trying to survey all of physics about, you know, what would be the most interesting problems to work on. Yeah. And what I got to was, well, that interface between physics and biology would be the most interesting. Yeah. Because physics felt very mature as a field, and biology was expanding in all directions and just felt like there was more to discover in biology. Yeah. Um, using the sort of approaches and philosophies of physics. And so I was at that interface of biology and physics for a long time. Um, but then brought in this idea of measurement and developing new measurement apparatus is, and that's where the engineering started to fold into it. Right.

Euan Ashley: I remember also one of our prior conversations, you talked about the impact of reading Fey's work. Talk about that a little bit.

Steve Quake: Yeah. Oh, when I was in high school, I had his autobiography and stumbled across it and read it and, you know, um, just loved his fearlessness and his, his irreverence. Yeah. Um, and, you know, uh, uh, that was very inspiring to me. I mean, I, I reread it again last year. Oh yeah. It certainly is. Didn't age well. No, I was pretty sure. It didn't age so well, but, you know, for the moment of the time it was, yeah.

Euan Ashley: Six sixties. When would he have written that? He, he,

Steve Quake: I think he wrote it in the eighties.

Euan Ashley: Oh, I see. Okay.

Steve Quake: But, you know, it was definitely about things from World War II era and beyond.

Euan Ashley: Exactly. Yeah. Right, right. No, very interesting. And of course, you're on path to you know, geographically at least, uh, down, down to Southern California, of course. But you were at graduate school and graduate school was started here. Right. But you ended up...

Steve Quake: In Oxford? I did it, I did my doctorate in theoretical physics at Oxford. Yeah. Yeah. But I came part of it here visiting to do experiments.

Euan Ashley: I see. Yeah. And why Oxford?

Steve Quake: You know, for the adventure of it, basically. Uh, I had not had the opportunity to study abroad as an undergraduate. And so I thought, well, I'm either gonna travel abroad Yeah. Um, and, and work as a ski bum or something. Yeah. Or if I get a fellowship, maybe I'll go study abroad. I ended up getting a fellowship, and so that paid for my, my experience. Nice. 

Euan Ashley: So, that was a Marshall Scholarship. Yeah. Yeah. And you went to Oxford pretty prestigious thing. Uh, what, remind me what college you were at.

Steve Quake: Merton. 

Euan Ashley: Oh, Merton. Yeah. One of the older ones.

Steve Quake: The oldest. Yeah.

Euan Ashley: Okay.

Steve Quake: <laugh>.

Euan Ashley: So, but pretty amazing, but very different place from Stanford and New York.

Steve Quake: Oh, yeah. I struggled with that. Yeah. Yeah. I struggled with that. You know, there were formal dinners every night. Right. You had to wear a tie and a jacket and academic gown. 

Euan Ashley: Don't think I've ever seen you wearing a tie Yeah. Of that. I have seen you wearing a jacket. Yeah.

Steve Quake: So, you know, I did all kinds of experiments, Uhhuh <affirmative>, to understand what the true limits of the dress code were. I see. Okay. And, you know, you definitely needed to wear the tie uhhuh. You didn't have, you had to have a collar on your shirt, but like, I got through with a rugby shirt. Okay. Socks ended up being important. They didn't, like, I didn't wear socks one day, but the big discovery was that they could regulate the, um, the dress code, but they couldn't regulate taste. I see. So I had the most hideous polyester ties you could imagine. And those were fine. Yeah. Okay. Like, they didn't gimme a hard time about 'em that was

Euan Ashley: In color, any fabric. Yeah.

Steve Quake: I mean, day glow, it was wild.

Euan Ashley: Yeah, right. Physics professor for sure. Making Wow. Right. Um, and then you, you came back and then you were, uh, a Caltech.

Steve Quake: Yeah. I started my faculty career at Caltech. Spent almost a decade there. Yeah. Um, started as an assistant professor and moved up the ranks. And it was a wonderful, wonderful place and experience. I mean, you know, just the, the history, the focus on what it does. I mean, they really just do great science and, uh, kind of the, the community there. It was just terrific for me. Yeah. Um, 'cause I was able to really go across disciplinary boundaries. I sort of collaborated with a ton of people. Yeah. Knew almost everybody. And, um, it was just a great spirit of working together. Yeah.

Euan Ashley: Did you have a specific mentor down there that sort of led you in a, in a, in a direction of measurement and it sort of helped underline your interest in, in biology and intersection with physics? Or was it really around collaboration?

Steve Quake: You know, there were so many things that were going on in that period. I mean, I worked very closely with a fellow named Axel Cher. That's where we got the Microflex off the ground, sort of e lithography person. Double E background. Yeah. Just a lovely person. And we mentored several students and postdocs together and, uh, launched a whole bunch of the microfluidics worked there. Yeah. Uh, Francis Arnold was a mentor for me. Yeah. Um, and we worked together on using those micro tools for screening and m evolution. And, uh, uh, she's remained a good friend to this day. Yeah. And, and those are probably the two closest collaborators. But I worked with a bunch of the biologists. I mean, Henry Lester, Bruce Hay, Mel Simon. It just kinda went on and on. Yeah.

Euan Ashley: Well, I think, I mean, many people have been exposed to and been impacted by your inventions that came sort of in, in your Sanford time and beyond. Some, some of them, especially the, the doctors might not know that really your early career was around essentially inventing microfluidics. Principles were there, but really, in terms of making it practical and making applications, that's the first time I think, I don't, I'm not even sure if we met, but the first time I was in a talk that you gave was in Seattle at the Institute of Systems Biology. And, uh, it was all about microfluidics. So that's how we all knew you. And of course, flow down was a huge success and really has impacted, continues to impact the, the field. Maybe just for, for the, for the audience, just remind us what that is and, and I mean, there are valves that are, you don't call them these, but other people call them quake valves, <laugh>. They do. Tell us about, tell us about that.

Steve Quake: Yeah. So, you know, when I started at Caltech, I was interested in, uh, trying to do automation of biology. 'cause I knew I wanted to work on the interface of physics and biology. I knew the biologists tended to have labs with lots of people, and there's a lot of manual labor involved. And I, I, that's not what I wanted to mentor. And so I thought, all right, let's build tools that automate biology. And I had been following, you know, these ideas about trying to make the integrated circuit of biology. Yeah. Um, miniaturized plumbing with valves and pumps and pipes and all that. And it started to dabble in it a little bit when I was a postdoc, and really then leaned into it as an assistant professor. And, uh, we tried a bunch of different things. And eventually, uh, one of the things we landed on was these valves where we figured out how to bash, fabricate tens of thousands of valves on a single chip, sort of arbitrary plumbing complexity.

Steve Quake: Uh, and then, you know, went about trying to figure out what to use that for. Yeah. Um, and one of the first things we decided to use it for was protein crystallization. Yeah. Um, and I knew we were onto something when I sent my postdoc up to James Berger's or my student Yeah. Up to James Berger's lab for a week, and at Berkeley. And he did in a week, more than more experiments than James's best postdoc had done in a year. I see. So we were like, okay, this is, we're onto So angry. Yeah, exactly. And then it just went from there. Yeah.

Euan Ashley: Yeah. And then Fluid, was that your first company? Yeah. Yeah. Yeah. So what, tell us about that. Was it just a very obvious thing to do? Was it something you'd always wanted to do, or did it come out of, of somewhere else? 

Steve Quake: Well, um, it was a little bit maybe in the, in the family history. My dad was an early software entrepreneur, so I'd seen over his career him founding companies and getting 'em off the ground. Yeah. And it was also a bit that it was pretty clear that making these chips was complicated enough that no biologists would be able to do it. Yeah. It required a bunch of specialized knowledge. And so to see these tools have impact in biology would require somebody making them in some kind of commercial availability. And so, you know, I, I didn't wanna stop all the work just being published as a paper I wanted to see have very broad impact. And, uh, it seemed like starting a company was the way to do that. Yeah.

Euan Ashley: Did you find it easy? Or was, I mean, it's never easy.

Steve Quake: It's never easy.

Euan Ashley: Oh my gosh. Yeah. I mean, raising money is, is never, never easy. One of the things that I, that I think places like Caltech Stanley, Stanford stand out, is that there's quite a few people around who've done it. So you can sort of, you know, round the corner and find somebody who can give you advice. Was was, was that what you found at Caltech, or were you really trying to break out on, on your own and sort of learn, had to learn it by yourself?

Steve Quake: Much different environment at Caltech. Yeah. Um, and Caltech had a tech transfer office that was run by a fellow named Larry Gilbert in those days. And he was terrific. And he mentored me and many other faculty on how to be an entrepreneur. Mm-hmm. Um, I eventually found the CEO guise Worthington, who was up here in the Bay Area. Yeah. And we founded Fluidy, and he quit his day job, and he commenced two other guys to quit their day job, very confident they'd be able to raise money and launch this thing. And like almost a year later, it still haven't been able to raise money. <laugh>, they're living on ramen. I mean, you know, one guy was getting ready to sell his motorcycle. It was, it was, yeah. You know, much harder than any of us realized it was gonna be. And biotech was in kind of a down Right, uh, cycle then. And Larry, uh, introduced us to, one of the things he did was introduce faculty entrepreneurs to potential investors, and eventually introduced us to Fellowing Bruce Burrows, who became the first investor in the company. Yeah. Um, and, uh, Bruce wrote us our first check, and that got the whole thing going. And, uh, and then it was, you know, off and

Euan Ashley: Running. Yeah. Yeah. When was the fir what, do you remember how long it was between when you started the company and when the first kinda product really shipped to the first customer?

Steve Quake: Oh my gosh. I mean, that was, lemme think about that. Um, it, it must have been three or four years. Yeah, yeah. Yeah. Seriously. So we had to figure out how to do manufacturing. Yeah. I mean, and that in itself was a challenge.

Euan Ashley: You spoke about this during your, your grand rounds, but it's, universities are great at some things like Yeah. And they're great environments for collaboration and for pushing envelope, demonstrating, you know, the end of one. But then to scale that, you know, manufacturing or to even think about selling something is, is a whole different set. Absolutely. Set of skills. Oh, last time I checked, which was last night, but correct me if I'm wrong, you have started 12 companies.

Steve Quake: Yeah.

Euan Ashley: Give or take. So we'll definitely touch on one or two of them as, as we move forward. But, uh, there are probably, when I first contacted the Office of Technology and License Licensing here at Stanford, um, we were talking about a variety of different faculty who'd started companies also. And, and they, uh, I think re I think they refer to the Quake factory 'cause in the sense that if you were a factory of company, company information, but each of those has a very specific I idea, and is often based around a very specific technology that is new. It's a, it is an amazing adventure. Maybe we can come to talk more about that, uh, sort of duality as a, as a faculty member. But yeah, I really wanted to, to get to some of, you know, what I would say in terms of lives affected, millions of lives affected in this case, patients. And, and many of the, the listeners I think here, uh, will be familiar with non-invasive prenatal testing. And there're really, I think there are several people who contributed to early work. But, but I think from, from my perspective, there's really two, two big, big names in the world. And, and you both worked both together and, you know, maybe even a little competitively we're a while Dennis Lowe, of course, in Hong Kong. Um, and, and your work here at Stanford, that all started though, with something quite close to home.

Steve Quake: Yeah. I mean, so I never worked in anything clinical before. It was all very basic science oriented. And, uh, when I first became a father, we had to interact with doctors and have amnio and this sort of thing. It was just, you realize just this is not, was not a good state of affairs to have to take risks about your baby just to get a diagnostic measurement. And so that sensitized me to it, um, that there's, uh, an important problem to be solved there. And, um, it was in the back of my mind for a number of years. And then eventually I stumbled across his literature on cell-free DNA. Um, and of course, in the late nineties, Dennis and Jim Waco had been first to show that, uh, with molecular methods that some of the cell-free DNA and the blood is from the baby. Yeah.

Euan Ashley: And in their case, they were folks in the white, white,

Steve Quake: White folks in the white chromosome. Exactly.

Euan Ashley: And so, picking up, uh, in the context of a male baby, women, of course say female mother, and the y chromosomes must be coming from the

Steve Quake: Exactly the fetus. And that work had set off a decade long effort to try to build a practical diagnostic. And many things were tried and failed, and there's no biochemical difference between fetal and maternal DNA and such forth. No way to enrich.

Euan Ashley: And sorry to, but Dennis was in, in Oxford around that kind of time. Did you overlap with

Steve Quake: Them? We were. Have you ever seen the picture? No, I have not. I'll show you the picture sometime. Okay. Yeah. So it turns out we were in Oxford at exactly the same time you were. Wow. He was getting his medical training. I was doing my PhD. His wife was a physicist in my department, in the physics department. And we graduated at the same time. We never met Yeah. But at, at Oxford as students. But at, at the graduation, someone snapped a picture of him and her, and I'm in it. Wow. We were standing near each other. Really didn't realize it. And the first time I visited Dennis in Hong Kong. Yeah. He says, I'm gonna show you something. Oh. He goes, pulls out this picture, and it's three of us in the same picture wearing graduation roads in Oxford. I know that. Yeah. I have a copy of it somewhere. Okay. Amazing. Um, amazing. Yeah. But, uh, so anyways, there was this long effort to try to figure out how to, how to take advantage of this phenomenon. And I think the key discovery was this counting principle. Yeah. Um, if you can count the molecules right. And measure overrepresentation, that was the breakthrough that enabled all of NIPT. And that's sort of what we did here at Stanford. And, and

Euan Ashley: This is counting specific molecules of DNA that then mapped to specific chromosomes mm-hmm <affirmative>. So you could look for overrepresentation of chromosomes and therefore see

Steve Quake: Yeah, yeah. Yeah. The whole, it was a huge red herring to try to separate maternal from fetal DNA. You don't need to do that. Right. Um, all you need to do is look at the overrepresentation and it has this amazing property that it can be as sensitive and precise as you want. If you just count high enough, the higher you count, the better it works. It goes like one over squared event. Yeah. So it's a very unusual property for Yeah. Diagnostic tests. Yeah.

Euan Ashley: And how, what technology were you using?

Steve Quake: Um, so we started trying to do with digital PCR. Right. Um, and Christina,

Euan Ashley: And just remind us what that

Steve Quake: Yeah. Is. Okay. So digital PCR is a way to get around the non-linearities of PCR amplification, um, by trying to amplify single molecules in discrete wells. Yeah. And had been around for a long time as a concept. Yeah. It goes back to someone named Sykes and, uh, Bert Vogelstein and others had been trying to do with emulsions and have published some papers for cancer. For cancer. Right. And we'd seen that. And I had a rotation student in the lab who became my PhD student, Christina fan, and I said, for your rotation project, why don't you try to replicate this VGO steam paper? Yeah. Um, and let's try and make digital PCR happen mm-hmm <affirmative>. Um, and she couldn't do it. Yeah. Um, it's very fickle thing. The chemistry is challenging. The emulsions are all, are hard to work with. And, uh, so then flu dim had just then made their digital PCR chef, and they made the first commercial digital PCR product.

Steve Quake: So then we said, all right, let's use that. Um, and that worked right away. Yeah. Um, and so we were able to count molecules, we could do these kind of dummied up experiments and show that it, it, it would work in principle. And then we tried to do what the real clinical samples, and you couldn't count high enough on a single chip for those. And I said, I don't care. Use as many chips as you need. It'll spread the sample over them. It doesn't matter what it costs. Yeah. She, uh, she didn't listen to me. Um, she was very conscious of my budget, which I guess I appreciate it, appreciate that. But I wanted her to do this experiment. Yeah. And so eventually the first sequencers had just come out then. Yeah. Um, we had ours at Helicos, Illumina had theirs. And I said, alright, fine. If you're not gonna do it with digital PCR, let's do it with sequencing and try that. That's another way of counting. Yeah. Uh, and for some reason she agreed to do that. Okay. Um, and, uh, and that's how we ended up doing the counting. And that's mostly how it's done today. Yeah.

Euan Ashley: Yeah. Re remarkable. And then as, I mean, as a test, you've obviously talked about amniocentesis, which was the, the principle method for, for getting a sample of fetal DNA in the past about, or cells in order to, to do karyotyping. Um, but in terms of impact, in terms of the number millions of lives affected, I think you made this point well in your talk, if, if you're giving an individual a choice between a large needle that we'd be, uh, approached towards the head of their unborn child or a blood test, you know, most people are gonna choose the blood test. Absolutely. Um, and of course it's a, it's a different test, uh, in the sense is that it's, it's for screening, but it, uh, it, it essentially takes you to the same place, which is an answer to a question.

Steve Quake: You know, it's interesting this question of screening versus diagnostic. Yeah. Um, and, you know, <laugh> my perspective on that, when a diagnostic test doesn't work well, it gets used as a screen. Yeah. Yeah. If it works well as a diagnostic. Yeah. And in the NIPT world, there are some that don't work very well, um, because, you know, they're optimized for cost or something like that, or just weren't designed well. Yeah. And so, you know, they all market them as screens, but the best ones are as good as amnio. Yeah. In fact. Yeah. And so, uh, you know, I think it is just a matter of time and accumulation of data and experience before that actually becomes the gold standard. Yeah. I

Euan Ashley: Think the test characteristic is what matters, not what you label the test as. Uh, you also showed the paper I that I was, I remember when it came out the way you sequenced essentially an entire baby's genome from the, the blood of, uh, with some knowledge of the family, but otherwise from the blood of, of the mother and cell-free DNA, which is remarkable.

Steve Quake: Yeah. Yeah. Yeah. I mean, so this counting principle works not just for chromosomes, but for, you know, whatever, however you wanna bin the genome. You could do structural variation. Yeah. You made the bins so small, they're just a single base pair. Yeah. That's, you read out, um, essentially the whole genome. And in that paper you're talking about, we did it two ways. Um, so one way was to, uh, get haplotype information from the parents, and then you could reconstruct the fetal genome from that. The other was to do it completely, uh, uh, completely naive to the parents. And so you could just draw, um, uh, the blood sample without having worked out the genetics of the mom or the, or the dad and, and do a pull down to get the exomes and do the counting principle on the exomes. Um, and, and that worked as well. Yeah.

Euan Ashley: And I mean, its essentially, it, it has taken over for all the obvious reasons. I mean, the test characteristics, its have improved over time, more than just chromosome counting has happened over time. It certainly, routine sequencing of fetal genome isn't, isn't something that happens yet. But, but obviously the technology moves in that direction. Um, and it's become a, you know, an everyday routine clinical test that everyone, um, really expects to have. It's not always reimbursed. It seems to be reimbursed more often, thankfully, than it used to be. Things take a while mm-hmm <affirmative>. It turns out in, in diagnostics. Um, but, and then the company you started, uh, was taken over by Alumina mm-hmm <affirmative>. That case. And, uh, of course now this is just a routine medical test that happens in millions of times every year. Yeah. Um,

Steve Quake: It's been an amazing journey. It's incredible.

Euan Ashley: Yeah. Journey and

Steve Quake: Impact mark, a real transition in the diagnostic world. I think in that, from the business perspective, people used to look down on it, venture capitalists didn't like it 'cause it diagnostics read as antibody tests, 10, 20 bucks, something like that. Yeah. Um, and so hard to build a big business around it, but, you know, invasive biopsies have been expensive. Those are thousands of dollars of tests. Yeah. Yeah. So if you can replace that with something that's safer and better. Yeah. Um, you can charge less than what the invasive costs, but still enough that the business starts to look very, very attractive. And the numbers add up. And, um, yeah.

Euan Ashley: Well, when you think about the current state of non-invasive testing, or the prior state of non-invasive testing, it was based on, you know, one protein marker, you know, ultrasound of the neck of the baby. You know, it just, that speaks to a, a very, a world that now sounds like it's 200 years ago. Yeah. When we think about the, the molecular world, we Yeah, sure. Currently we live in. So, well, we talked about, uh, briefly the first time, I think I heard you talk, but the first time we really interacted, we were meeting in the Clark building, uh, planning, I think Mike Snyder, who's now the ex chair of genetics here at Stanford, but at the time was about to be the next chair of genetics. Uh, and I believe I remember well actually wondering into your office after I found it. And there you are, like pecking on your keyboard.

Euan Ashley: I still think you don't do full typing. Right. <laugh> of your many skills. That's not what, but anyway, I find you behind piles of journals. I still remember this. Um, and we were supposed to talk about the seminar that we were putting together for Steve, but instead you had up on your screen, your genome, which just, just mind blowing to me because there were only, I think, four people in the world who'd had their genome sequence. They were essentially mostly unknown other than Jim Watson. And, uh, you had sequenced your own genome with two people in your lab for, if I recall this, $50,000 or so on your, on the machine that you invented Helicos. And the one prior, I think was done on Illumina with a group of like 30 people over six months. And, you know, it just was a very different thing. It cost $250,000.

Euan Ashley: So you'd already made headlines for sequencing your genome, but nobody had really spent a lot of time yet thinking about what medicine might do with that genetic information. And that was the beginning of a, an adventure, I think, a little bit of an adventure for, for both of us, it sounded like, for, for me. And, and thinking about trying to build for ourselves first for you definitely as patient zero. And then for the world of like, what does it look like if you have an entire genome of, of, uh, of an individual. Um, and, and I tell that story a lot 'cause it had a big impact on, on the way up my career went. But I, but I wonder how, how you fit that into the overall picture of your career where you've invented multiple things.

Steve Quake: Yeah. I mean, well, there's a bunch of unpack there, I suppose. Yeah. Um, you know, when you go back to the early days of the Human Genome Project, when it was just getting underway, people appreciated the massive cost that it was gonna take with existing technologies and the need for newer technologies. And so many of us in the physics community were aware of that. Yeah. Um, and thought, oh, we're physicists. We can invent measurement machines. And so a bunch of us were involved in that. Uh, I was one, and we, uh, this is still at Caltech, we invented the first single molecule sequencing and kind of published a paper on that, um, that turned into a company called Helico. And they scaled it up massively. And, you know, it was, their product was the first sequencer capable of doing an entire human genome with Yeah.

Steve Quake: Just one machine in principle mm-hmm <affirmative>. But nobody was actually doing it. Yeah. So I'm like, all right, we're gonna try it out. Yeah. See if we can really make it happen. Yeah. Um, and, uh, so we did it, we sequenced my genome, um, and published it. Uh, the editor at Nature Biotech wrote a really nice piece about how is a genome altruist by giving my genome out there, because there were, at that point, every individual genome was revealing many new loci, hundreds of thousands of loci of human variation. And so it was really starting to fill out our view of, of, of what human variation looked like. Um, and, uh, and then we began to think about, you know, well, can we interpret it? Yeah. Um, and you came in and we put a whole team together here at Stanford to try to answer the question of what happens when a patient walks into his doctor's office with a <laugh> and says, help me.

Steve Quake: Right. Um, and, you know, that was, that was fun. And I love being part of it because, uh, you know, as you may recall, yeah. Uh, I, I was the one who had done the sequencing, so I knew that strengths and weaknesses, you know, potential errors and how much trust you should have on any given base call. Um, and so I was in the room while all the discussions were happening about what or what might not be in my genome, and the, the poor Janet counselor had her head in her hands. This was not the way it was supposed to happen in the textbooks, but, uh, it all turned out okay.

Euan Ashley: It, I think it did. But, uh, pretty interesting times, like you said, it was, we were challenging our colleagues, Janet customers, to suddenly deal with whole, whole genomes and to think about how this might happen. You as the inventor of the technology were also the patient, and you were in the room as we, as we discussed it, as you said. Um, and I think that, I mean, in the end, uh, pretty clear at that point, really no one had received medical advice on the basis of having their whole genome data. Um, but we discovered a bunch of things with that big team, and it really took a team. I mean, Ruland helped, of course, on the pharmacogenomic side, a to buts team, uh, really put together a, a whole, uh, you know, engine for a common variant.

Steve Quake: And it was like an early version of a polygenic risk score, what he did.

Euan Ashley: Right, right.

Steve Quake: Exactly. I mean, very much ahead of his time. Yeah.

Euan Ashley: Yeah. Pulling together, you know, built one of the first databases of genetic variation in relation to human disease, and then built polygenic risk scores. And then our team, we thought, thought about rare disease, and we tried to put all of that together. Um, and then also we had you in the, in the clinic, like you finally, your family had been on at you <laugh> to go see a cardiologist. There was one in front of you, so you ended up coming into our clinic and we tested you on a bike. I took very

Steve Quake: Good care of.

Euan Ashley: Oh, good. I'm glad. Yeah. Uh, check to your heart. Thankfully, we didn't find anything there, but, um, we did find a, a few things that were of relevance for your disease and, and for, for your risk of, of disease, really heart disease. And, uh, I ended up making some of, of the first kind of recommendations that were genomically informed, I think famously famous, at least in my mind. We had, we did an NPR interview together, kind of like this, as I recall, might have been the last time you and I were next to each other in a microphone. And they, they asked if you had actually taken the advice that we'd given you. And I think at the time, your answer was, no,

Steve Quake: <laugh>, you got me over the hump eventually. Yeah. Yeah. You got me over the hump eventually.

Euan Ashley: Right. So, uh, glad to hear that you bought into the genomic, uh, medical, uh, revolution that you helped ignite. Um, you know, and now sequencing genos for medicine is, is routine. Yeah. I mean, it literally is something that, that we do every day, and it happens around the world. So it's exciting, I think, to see that. I still think we're far short of the, realizing the full potential of genomic information for, for medicine, but, uh, especially for rare disease, I think we've seen a lot of lives impacted and hopefully, you know, I think that in addition to the work you did with cell-free DNA, that's, that's a whole other area where I hope you would, you would gain some sense of pride and fulfillment from, from being there at the beginning. Oh,

Steve Quake: It was a ton of fun. Yeah. It was a ton of fun. And maybe to get back to your earlier question, you know, once we did my genome Yeah. Uh, I felt like I had to make a decision. Did I want to get full in into the human genomics Yeah. Field Yeah. Or do something else. And it was clear that the bigwigs in the field were just raising enormous amounts of money. And it was like, for them all about scale and resources and Yeah. How many could you do? And that didn't seem intellectually interesting to me. Yeah. And so, you know, I kind of made a very conscious decision, all right, we did my genome, we did one tumor genome Yeah. And I'm not gonna find something else to do. Yeah. And it was because of that decision and creating kind of the open space Yeah. That I turned into liquid biopsies. Yeah. Right. Yeah. And that sort of, you know, um, ended up being a very good decision. Yeah. Yeah. Well,

Euan Ashley: And I remember at the time talking to you as, as we were thinking, you know, what, we, we've done one patient, we've done 10, and the next we have to do a hundred or a thousand there. And ly think about how this is gonna impact medicine more broadly. But at the time, it was around then that you had another conversation at Pete's Coffee, I think, with one of my forensic colleagues, Hannah Valentine. Just, just tell us, tell us about

Steve Quake: That. Yeah. So we had published the first NIPT paper. Yeah. And, uh, uh, Hannah called me up and said, Hey, is this gonna work for heart transplant? Because we have a similar problem. We have to do invasive biopsies, and we've gone through all this trouble to give these patients a new heart. Right. Then what do we do? We go start pulling pieces of it out every couple of months to see if it's rejecting or not. Yeah. And wouldn't it be so much better if there was a blood test? Yeah. Um, and so we put our heads together and figured out that we could monitor the specific cell-free DNA from that transplanted heart, because the donor's genome was different Yeah. Than the recipients. And the amount of donor DNA in the blood by actually sequencing and looking at polymorphisms, uh, would reflect how much rejection is happening, or it's not

Euan Ashley: Genome transplant.

Steve Quake: Yeah, exactly. We called it a genome transplant. Yeah.

Euan Ashley: Well, and even more than that, I mean, I've done the cardiac biopsies not for many years now, but I'm glad, thankfully we're all doing many fewer of them. But the catheter that's used actually called a Stanford catheter, but that doesn't mean it's great <laugh> in this case, you're passing it through one of the valves that tri customer develop in the heart, and then just sort of poking it towards the middle of the heart, which first of all isn't necessarily the right place to go, but it's the place you can access. And then you just kind of grab and and pull. It's it, you think of a biopsy, you hope that there's millimeter precision. This is not one of those things. It's rather a barbaric procedure actually. So, you know, the same way that amniocentesis is something that you would never invent if there was an alternative. I think that you could say the same for cardiac biopsy. Yeah. So, but this was another story that, you know, and you alluded to this earlier. It, it didn't immediately work like the, you there were challenges with signal, but eventually it worked very successfully. Yeah,

Steve Quake: Yeah. Yeah. That's right. I mean, it, uh, the first pilot experiment worked very well, and then when the first time we tried to scale it up to a larger study Yeah. It stopped working. And, uh, you know, it took off a long time to get to the bottom of it. And you know, it, one of the interesting things about the project is it's a precision measurement. We're trying to measure things at the 1% level and Yeah. You know, small sources of noise and error throughout the whole thing can really mess that up.

Euan Ashley: And this is not like within IPT you're counting chromosomes and doesn't matter, as you mentioned, whether you'd separate the mother and the fetus Here, you really have to, the part, the point is separating

Steve Quake: Here. The point is to separate and in fact, so we would genotype the donor and the recipient Yeah. And some of the errors in the genotyping arrays were propagating their way through the whole thing. I see. Yeah. And we had to figure those out. Yeah. Compensate for them. And then it all started working. Yeah. But it took a while to get there. Yeah.

Euan Ashley: Yeah. None of these things happen overnight, but then a pivotal clinical trial and then a company, uh, and now thankfully there are many, many fewer cardiac biopsies. Oh, yeah. It's not just the heart, I guess. No,

Steve Quake: Me as well. Kidney. Lung, yeah. Yeah. It's a principle that works on any solid organ, which is

Euan Ashley: Yeah.

Steve Quake: Super powerful and flexible. Yeah.

Euan Ashley: Amazing. And of course, there's a whole revolution also happening. You talked a little bit about it today, within the, within the cancer world, uh, thinking about both early detection and potentially non-cancer, early detection. And I think what is more, uh, I think, sort of embedded now clearly in, in mainstream medicine is the idea of minimal residual disease testing for cancer recurrence, let's say after surgery, which is very powerful. So let's move towards molecular tests rather than relying on imaging. You know, why wait till a cancer is big enough that you can image it if you can pick up small numbers of molecules in the circulation. So, um, it's really, I think, been extraordinarily impactful across, across all of of medicine, um, mostly in DNA, but, you know, RN a's out there too. Mm-hmm <affirmative>. And, uh, you have at least one company now that's focused on RNA and, and a lots of really interesting science. Uh, just tell us a little

Steve Quake: About that. Yeah, I mean, so cell-free, RNA ends up being a very powerful way to measure phenotype. Not everything is genetic, and you don't always have a different genome in your body. Right. And so, uh, the RNA ends up being a very good compliment to DNA and, uh, we initially went back to, um, uh, maternal health Yeah. To try to solve the problem of preterm birth mm-hmm <affirmative>. Uh, which the genetic component contributor is very small, but there's clearly a phenotype thing. So we thought maybe RNA would provide Yeah. A signal for that. And it does.

Euan Ashley: And the RNA from, is it specific cell types that it's reading out, or what, what is the signal actually coming from?

Steve Quake: Some of it comes from the placenta, some comes from mom's immune system. Those are the two main contributors for I see. Preeclampsia anyways. And for preterm birth, you can also measure fetal transcripts, which is very interesting. Yeah. I think bio sort of scientifically. Yeah. Um, but we haven't seen the clinical application of that yet. Yeah. Um, and so that now led to another adventure. Meir V launched the Encompass test 9,001 prospective clinical trial. Yeah. And so last year that's now kind of out there and it's been sort of amazing to see. Yeah. Um, and you know, for preterm birth, which is almost 10% of pregnancy is affected by it, um, with no meaningful diagnostic. Yeah. Um, before this, um, we think that's gonna be just, um, another major, major impact. Yeah. Um, on helping save lives.

Euan Ashley: I mean, any of us who've worked at the bench understand that DNA is fairly robust. RNA falls apart just by looking at it. Uh, it's, it's pretty stable circulating,

Steve Quake: You know, it's that sort of counterintuitive thing. Yeah. That, um, you know, the su free RNA that survives in your blood, uh, has been either trapped in exosomes or wrapped on protein particles, so it's got some kind of protection Yeah. Um, that has kept it intact and it's remarkably stable, much more stable than completely purified RNH you get on the bench top. Yeah. Right. Um, which is very labile. Yeah. Um, and we've got amazing luck going back into, you know, bank plasma really and serum from years ago really. And lots of cell-free RNA um, yeah. Because of, you know, it's not completely purified.

Euan Ashley: It stabilized. Yeah. Stabilized or, yeah. I, I mean, I think I, I remember one of the early insights I think from you or Dennis, was just how short the half-life of DNA was in a pregnant

Steve Quake: Dennis did beautiful work on that. Absolutely. You know, looking at why chromosome after delivery of a male baby and right. It goes down and turnover time is half an hour. Yeah. Right. It's really short.

Euan Ashley: But the RNA is stable enough that, that, that even in bank samples, you can find it. Yeah. Yeah. That's, that's remarkable. Um, you've invented so many things in the last few years. You've, uh, spent quite a lot of your time not, uh, taking grant money and inventing things with it, but rather giving out money, uh, with a big vision as part of the roles. You've played multiple roles within the Chan Zuckerberg Initiative. Uh, how did, how did that first come about and tell us about your time there.

Steve Quake: Yeah. You know, that was an amazing adventure. Yeah. Um, you know, when Mark and Priscilla decided to launch their science philanthropy, they reached out to the leaders of Stanford and UCSF and asked for advice and universities put together committees to help propose ways to design an institute and what to work on. I was part of that. Yeah. Um, and then eventually got asked, uh, along with Joe DeRisi to be the founding leader of the institute, the first biohub. And so we brought Berkeley into the fold. So we had all three major Bay Area institutions to take on a couple of big problems mm-hmm <affirmative>. Um, one an infectious disease, which was Joe's interest area, and another in building cell atlases, which is what Yeah. I wanted to do. Um, and you know, it, uh, we were talking about this earlier that the, you know, powerful and as much as we know about the genome, you still can't predict the cell types of organism from the genome. That's an unsolved problem. And we had developed single cell techniques to do that to characterize, uh, geo expression of, of single cells, and thereby in principle, create an atlas of all the cell types in the human body. Right. And we set out to do that Yeah. Um, at the biohub and succeeded. Yeah. Um, you know, it was, uh, just great team science. There's like 150 authors on each paper, involved dozens of groups from all three institutions and figure how to coordinate. That was a new thing for me.

Euan Ashley: Um, you were getting every human tissue and then sending it out to labs and then getting Yeah. A lot

Steve Quake: Of work

Euan Ashley: Trail level. Right, right. And then that is available to the world.

Steve Quake: We just gave the data away Absolutely. Even before we published it. Yeah. So we had a very strong commitment, uh, to open science. And, uh, we were probably the first organization to require the use of preprints. Yeah. So everyone we funded, we said, you've gotta put a preprint of your workup when you submit it to peer review journal. Yeah. Um, and for our big projects, we not only put the preprint up, we put the data out there. Yeah. Um, and we gave people access to the data before the papers were published and in the name of trying to accelerate science and lift boats everywhere. Yeah.

Euan Ashley: I mean, I, I think there isn't an institute or initiative with a more bold aim, <laugh>. This is obviously something that people focused on, uh, managing or curing all disease within. I think initially a, a 10 year period and maybe a little bit longer.

Steve Quake: A hundred year period.

Euan Ashley: A hundred year. A hundred

Steve Quake: Year period. Okay. Yes. Okay.

Euan Ashley: Um, and I think that the word manage is, is key, but we live in an amazing moment for discovery science. Yeah. And it's translation to medicine. And I think, you know, this was your initial work in the context of Biohub the last few years. You were also helping build other biohub. There's mult multiple of them now.

Steve Quake: Yes, exactly. Well, I moved on to manage all of Mark and Priscilla Science Philanthropy as the head of science, and part of that was creating a bio network, which we established in Chicago and New York, as well as in collaboration with the Allen Institute now post in Seattle. Yeah. Um, and more generally funding science globally. I mean, we funded grants in something like 30 different countries. Yeah. And, um, that was a lot of fun to be part of that, um, and to really try to get that launched. And, um, uh, and we, part of what I got to do is lead the pivot towards ai. Yeah. Right. I mean, that was, you know, not the obvious thing to do at the time. Yeah. But, um, it was, you know, sort of, there was enough early kind of examples that it felt like the perfect thing for CZI to be investing in. Yeah. Still risky, wasn't clear it was gonna work out. Um, but a good thing for philanthropy to do. Yeah.

Euan Ashley: What struck me with that was just how, how elegant the foundational work for the cell atlas is <laugh> for the, the pivot towards ai. Oh, yeah. The idea of AI and biology. I mean, it, it's, and it couldn't have been predetermined. 'cause so much of what we understand about the power of the new AI in this third revolution is only been two or three years as old. Uh, so in a sense, uh, you, you might have had other reasons for originally initiating the, the cell atlas work, but of course it was just good for the world. And then it's, it's perfectly poised thinking about now a sort of silico immune system or some of these other ideas that are coming out as potential priorities for the, for the Biohub Group Bio Network, uh, going forward, um, I think Priscilla's actually coming on our podcast into our grand rounds. Terrific. In two. So we'll be able to, to follow up and ask her,

Steve Quake: Is she gonna give grand rounds herself?

Euan Ashley: I think she might, we may do it in this format, though. All we may talk

Steve Quake: About it. Uh, is she being a physician? She's certainly qualified to, uh,

Euan Ashley: No, we are very excited that to, they have such a big vision mm-hmm <affirmative>. That goes all the way from very basic discovery all the way through to disease. Um, and obviously we're really excited about the impact of AI at multiple levels, molecular levels, cellular levels, all the way up to patient in interaction levels. So, um, we have missed out a whole bunch of stuff Yeah. That you've invented over the years an IM impact that you've had. But I wonder just to spend the last few minutes sort of thinking about more generally, uh, you know, in, in your, in, in anyone's early career, physicians, scientists, physician scientists, they're, they're trying to build, hoping for maybe one, one big hit, uh, something that has impact maybe all the way through to a patient and maybe starting a company that has some impact. You, you've done this tenfold more than more than most people. Uh, and I wonder, uh, what, what lessons do you take or, or what do you just do, do you ascribe that sort of disproportionate success?

Steve Quake: Uh, you know, it's hard to know 'cause I don't get to replay the tape. Yeah. <laugh>. Yeah. Yeah. Um, you know, part of it is being willing to jump into the unknown Uhhuh <affirmative>, um, and work on emerging areas rather than mature ones. Yeah. Um, and that enriches your chances I think of Yeah. Of doing something like that. And so, and then, you know, so I've transitioned in my career from one area to another. Yeah. And as I know, I sort of, when things get mature, I get bored. You're right. Right. You know, I look for sort of what's the next emerging thing to work on? Where's the gunfighter? Yeah, exactly. Yeah. Uh, but I mean, also it's just working with terrific people. I mean, I've been so fortunate to have great students and postdocs and collaborators over the years, and that's driven so many things as well. Yeah. Um, yeah. We've

Euan Ashley: Talked a little about in the past about the sort of secret sauce of, of Stanford and the ready collaboration, but also just the fact we're all here in one place. Is that, do you think a a an important part of

Steve Quake: A hundred percent. Yeah. Like when I moved from Caltech to Stanford Yeah. Um, I, I knew that there were a bunch of cell biologists and such forth that I wanted to collaborate with the stem cell folks and that, and that all came to pass. Yeah. I had no idea how much fun I'd have with the doctors Yeah. And physicians. Right. That opened up a whole new world to me. And yeah. We've done things as we talked about in the grant round, that was, that's the whole story of that. Yeah. Yeah. Um, over the last 20 years, um, that I, I never thought that was gonna happen, and yeah. It would've been hard to do it anywhere else.

Euan Ashley: Right. It is a great, great environment for that. Last question then really is, I mean, this podcast is called The Future of Medicine <laugh>. Right? There are a few people better positioned. We've certainly had a lot of guests on who've given us a view. Eric Topo was on recently, and, uh, he's very well positioned as well. Um, but you're someone who invents the future. So what did, what, what are you most excited about, you know, in the next few years? Either for yourself or, or just more generally?

Steve Quake: Yeah. I mean, so I am on a sort of liquid biopsy world. Yeah. Very bullish about, um, the early cancer detection work, multi cancer detection. Yeah. I feel like there's been a bunch of early attempts, a bunch of marketing and things. Yeah. It hasn't quite come together yet. Right. But it's poised to do it now. Yeah. I think we know enough, um, collectively. Yeah. That's gonna really, uh,

Euan Ashley: Do you think that will be DNA methylation plus RNA? Do you, do you, you know, do you have a sense of what the re you know, what the measurement will be

Steve Quake: Of I'm most optimistic about hydroxy methylation. Oh, okay. That's like your best compromise between methylation and RNA. It's right in between. Right. It's the genes that are being turned on. But it's the DNA measurement. Um, it's remarkably predictive. Um, you know, the NCI is doing this vanguard trial of early cancer detection, only two, uh, companies in it and one's methylation. The other's hydroxy methylation. Right, okay. Uh, but the other one I'm super enthusiastic about is dementia and neurodegeneration. I think, you know, there's gonna be tests for that. That whole field is ripe for disruption. Yeah. There's been a lot of orthodoxy and receive wisdom and Yeah. You know, I think there's gonna be some amazing things happening there.

Euan Ashley: We certainly, we certainly need it. Well, Steve, we could talk for much longer and you've certainly done many more things, but I'm glad to have a chance to, to talk about your entire life so far. Many more things still to happen. Uh, thank you for joining us in the future of medicine.

Steve Quake: Thank you. You, it's been great to.