A Gutsy Plan to End Human Disease as We Know It

; Stephen Quake, PhD


March 11, 2022

This transcript has been edited for clarity.

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape. We're having a one-on-one with Professor Stephen Quake, who's a friend of mine over many years. He has been lighting it up where the fields of physics, math, and biology all come together, for many years. He heads up the Chan Zuckerberg Biohub. We've got a lot to talk about today. Welcome, Steve.

Stephen Quake, PhD: Thanks, Eric. It's great to be here.

Topol: You've had a unique career path. People talk about transdisciplinary teams, and I think of your background. You've been involved in single molecules and microfluidics from the beginning. So can you tell us a bit about how you got into that?

Quake: I trained as a physicist and was interested in the interface between physics and biology. It seemed to me that biology was expanding in all directions. Physics have become fairly mature. And some connection between the two seemed like where I wanted to make my career.

I was very influenced by my freshman physics professor, Steve Chu, who did many great things in science, but one of which was to help invent optical tweezers that he used to pull on molecules. He roped me into helping him do that as part of my undergraduate research thesis, and he became a mentor. That led me into experimental biophysics and single-molecule biophysics, where I worked for a number of years.

As I started my independent career, I was interested in biological automation and metrology. And that led me to microfluidics and into genomics. For a while I was building instruments and trying to use the instruments to do science. That's brought me to where I am now and got me into everything from the cell atlases to noninvasive diagnostics.

Topol: Speaking of noninvasive diagnostics, you've made a big impact in the ability to diagnose the major fetal chromosomal abnormalities. Could you tell us about that and your latest work on being able to anticipate pre-eclampsia?

Quake: That's been a long journey. So much of science is personal. I suppose medicine is the same way — you get interested in things through your lived experience. When I became a parent, we went through the whole invasive amniocentesis thing with our first child. It was horrifying. I was left with this question: Why are we risking the life of our unborn baby to ask a diagnostic question? That didn't seem right. And that was rattling around in my head for quite some time.

I eventually stumbled across this literature on cell-free DNA. Every tissue in your body, when it dies, contributes DNA in your blood. And it turns out, when you're pregnant, some of the DNA comes from the baby. That had been known since the late '90s, and people have been trying for a long time to use it as a way to learn something about fetal genetics, without success.

I realized, coming into it from a different direction, that there was a very straightforward way to solve the problem. It was very much inspired by the work we had done in single-molecule biophysics, where a lot of those measurements are about counting molecules. So I had this notion that counting molecules is the way you think about things.

To make a long story short, we realized we could use next-generation sequencers to count molecules. And there was a very simple, elegant physics approach to identify the genetics of the baby without having to purify the baby's DNA separately from the mom's.

Topol: That set off a revolution in prenatal diagnosis. And it seems like you're about to do that again, being able to anticipate eclampsia. You had a paper in Nature in recent weeks.

Quake: That was a long time coming. That was almost a whole decade of effort once we finished with the genetics part because pre-eclampsia and preterm birth are about phenotype, not about genetics, necessarily. So we switched from DNA to RNA. Circulating cell-free RNA had also been discovered a long time ago, but it had not been investigated as carefully as DNA.

So we wanted to use that as a measure of phenotype of mom and baby and ask, what's the signal, the message about how things are going? There were false starts along the way, but we finally got it done and we are feeling really good about it. It's going to be a very general approach to monitor maternal-fetal health.

Topol: There's another thing that I found really intriguing, and I wonder what your thoughts are. When you started with the prenatal diagnosis and the samples were coming back from mothers at 12 weeks or so and picking up cancer, this was unanticipated. Now there are these various companies that are trying to get into the whole idea of being able to diagnose cancer at the earliest possible time through a tube of blood. Where do you think that's going?

Quake: I'm optimistic about that. You look at the current state-of-the-art tests that are used: PSA screening for men, mammograms for women. The performance is really not that great. And so there's plenty of room to improve on that. And I do accept the argument that the earlier you detect cancer, the better the outcomes are because you can treat it surgically. So I think there's a fundamental logic there that's sound. As with anything, there's a bit of a PR curve and fluff and things like that in the air. You can't believe everything you read in the marketing material from these companies. But fundamentally, I think the field is going in the right direction. It's going to provide something useful for human health over time.

Topol: You're into so many of these things. You were very successful in the program at Stanford. And then Chan Zuckerberg said, we're going to start this Biohub and we want you and Joe DeRisi at UCSF to head that up — 5 or 6 years ago? So you've been splitting your time in these two worlds?

Quake: I have. It's been a wonderful opportunity to give back to the scientific community. Coming up in my career, I had senior mentors who looked out for me and did really nice things along the way with no benefit to themselves. You want to have a chance to give back and keep the cycle going.

Mark and Priscilla decided that they wanted to make a big effort in science philanthropy and to start an institute in the Bay area, which we called the Biohub. We managed to pull together Stanford, UCSF, and Berkeley and tried to do something bigger than any one of us alone and bigger than would be done in any university in terms of the projects we were taking on.

We managed to pull it together. We've supported 100 faculty to work on the riskiest, most exciting ideas. We just announced the second cohort of another 80, so we're pushing 200 now. It has really done amazing things for the scientific and intellectual ecosystem in the Bay area. It's been just a joy to be a part of it — a heavy lift, but an awesome experience.

Topol: Is the reason why it's successful, besides being a funding source, because it's not like the NIH, where you basically have to have done some low-risk project and have the data done already? What is the secret sauce here?

Quake: It's very complementary. Philanthropy and public funding work together hand in hand. There's nothing that replaces the NIH at all; the NIH is so essential and important and has such a huge footprint on science. But given that they are using public money, people are appropriately cautious with how it's spent. It's hard to do really risky things, many of which might fail. That's where philanthropy tends to step in. Even though the dollars are smaller, you can fund those risky things.

Philanthropists often — self-made ones — have taken on huge risks, so they have comfort with that and it carries through with how they approach other activities in their lives. We had a mandate to go out and do really risky stuff, and a lot of the things we've done have gone on to receive federal funding and get into the system. That the symbiotic relationship between philanthropy and public funding. So faculty at Berkeley, UCSF, and Stanford can apply for funding and it gets reviewed by a science panel.

Topol: Now, do they have to actually have some pilot data about their hot idea?

Quake: Not at all. It's sort of a fund-the-person process. We want your most exciting idea. We want to know that you have a good, strong track record in science, and that's how you're graded.

Topol: And it's hundreds of millions of dollars, right?

Quake: The first 5 years was roughly $100 million. And we have another $100 million in the second 5 years.

Topol: You're also branching out to fund more hubs outside of the Bay Area. Is that right?

Quake: That's right. Last October, we celebrated the fifth anniversary of the Biohub. We took a few moments of reflection and organized a seminar. We had a lot of really fun speakers, both from outside the Biohub and from our internal groups. Mark and Priscilla also viewed that as a big anniversary, and they were thinking about science philanthropy.

By December, they had announced a reupping of their commitment to science philanthropy across the board. They extended the Biohub. They announced a new imaging institute. They announced the Kempner Institute at Harvard. And they announced that they were going to set up a network of Biohubs and asked me to help grow the organization from a regional one to a national one.

Topol: That's pretty striking. So you envision several of these Biohubs in the years ahead?

Quake: Yes. We'll grow the network to four or five new ones, I think.

Topol: Wow. Now, this is an outgrowth of Mark and Priscilla wanting to eradicate diseases of mankind, which is a fairly aggressive, ambitious goal. Of course, they have the resources to help in that regard. How do you see it? You're into tools. You've had a remarkable science and entrepreneurial track record of developing new tools that are really getting granular into understanding biology, diseases, and health. Is that the ticket to our path for disease eradication?

Quake: They are taking a very long view. The key to this that makes it not ridiculous — it sounds a little ridiculous to say it; I couldn't say it with a straight face for a while, but now I sort of can — is the long time scale. They see this happening over 100 years. If you look at how mortality in the United States has changed over the past 100 years, it went down by a factor of two. So you can have pretty substantial changes over that time scale. It's not so ridiculous.

When you have the long view, you can say, I'm going to invest in basic science and new technologies that are going to take decades to get into the clinic and are going to be incredibly transformative when they do. Once you've decided that is your time scale, you can say, I'm going to look at really fundamental things that will be transformative, both scientifically and technologically. And that's an awful lot of fun to think about.

Topol: It really is. Now, what we've seen over the years from these efforts is multilayered data — data from genome, microbiome, epigenome, proteome, environment, social determinants of health, and what's in electronic records. So we can potentially understand things at the individual level, which is unprecedented, and it just keeps getting richer as we get multiple sensors with continuous data output. But we don't have a way to analyze that data, at least not yet. What are your thoughts about the importance of data science as to part of the way that we're going to get progress?

Quake: It's a key part of the equation. The advances in AI have been just astounding over the past decade — not just on the clinical side but also on the basic-science side. AlphaFold is an amazing achievement. It's pointing toward new ways to think about how those computational tools interact — not just the human health or clinical side but also in basic science. We're just barely getting our heads around it as a scientific community.

Topol: I think you really nailed it there — the fact that there's a way that you can take an amino acid sequence and predict the tertiary structure of any protein. We're headed there because of AlphaFold. And that is just a precursor of many things we'll see throughout life science and medicine.

It's actually pretty remarkable what you've been able to accomplish in your still young career. Something else people will be interested in, because you've intersected these different fields of physics and brought it to life science in many respects, is medicine being able to build new startup companies.

Most of the Medscape audience are health professionals. How do they try to do this kind of stuff? What is the way forward? Many of them would like to be active, and they have great ideas. But they really don't have a path forward. Do you have any sense of what you could advise them?

Quake: Staying engaged in the scientific literature is super-helpful because you're following the thread there. Doctors are in a unique position to change the course of science because they're on the front lines, seeing what's happening in their patients and in their practices. That doesn't always filter back so straightforwardly.

There's always been kind of this priesthood of biologists who said, these are the important problems in biology because we're looking at medicine. And we think this is it. But those translations, I think, have never been perfect fidelity. And they've been selective in some ways.

I fell into the whole noninvasive prenatal testing field through an interaction with a clinician, and we made all that happen. That was not on the radar. Cell-free DNA was an obscure little corner of research at that point, and now it's become something very large. So those clinical insights can be super-valuable and they can change the course of science and research. So being alert for that is a privileged position for physicians.

I also think there are structured ways to get involved. At Stanford, we have a program called Biodesign, which has been super-popular. Many physicians are learning how to translate their ideas and technologies and in the companies. Many such programs have been set up. And those are quite helpful.

Topol: There are two things to emphasize that I think are important from what I've seen with your efforts. One is that you don't have any hesitation to work with clinicians. You understand that that's the complementary role. The second thing that I'm so impressed with is your remarkable perseverance. You don't give up easily.

We had the opportunity to work together in a company called Molecular Stethoscope using cell-free RNA. At first, the idea that maybe it could be like a liquid brain biopsy, because you could get cell-free RNA, came from your classic paper in PNAS — that it could give us insights about neurodegenerative disease.

But it's been many years since that idea came forward. I was ready to give up. I said, it's just not going to work. But you don't do that. Your middle name is perseverance. Is that tenacity, is that resilience, is that part of the story?

Quake: For sure. I'm stubborn. It's true. It's a miracle that I'm still married. It's a big part of science. Sometimes it takes a really long time to get stuff figured out. And you've got to follow the vision. I love that old vaudeville joke that it takes 20 years to become an overnight success. It's so true. There are so many examples of that in science.

Look at Jim Allison, with immunotherapies and PD-L1; he was slaving away on that for a decade. And it was not appreciated. It was a funny little corner. When it finally came to fruition, it was like everybody jumps on the bandwagon without appreciating all the effort that had gone into it, without any attention or any glamour. It was the same thing with CAR-T. Carl June will tell you the same story.

These things that all of a sudden appear out of nowhere — they don't appear out of nowhere. Somebody was persisting for a really long time when other folks didn't believe.

Topol: That is a point that just doesn't get enough emphasis. People think that somehow the mRNA vaccines came out of the sky in 10 months. But it was 30 years of work with Katalin Karikó and Drew Weissman and so many others along the way. You cannot just be brilliant and come up with great ideas. You have to be exceptionally patient. It often takes decades for these brilliant ideas to transform medicine.

Well, Steve, it's wonderful to have the chance to have a conversation with you. You're an inspiration. You have been one for me ever since that first time when your genome was presented at one of our Future of Genomic Medicine conferences. You were the first person I knew who had their genome sequenced and published in The Lancet, no less. You efforts help so many others to realize what can be done with really great ideas.

It's nice that the CZ Biohub is getting behind a lot of other young people to harness their potential to be able to affect the future of medicine. I don't know if we'll eradicate all the common diseases. We probably won't be around when that happens. But it takes a lot of big ideas, a lot of patience, a lot of transdisciplinary cooperation to get this stuff done.

Quake: Indeed. If we don't try, it's definitely not going to happen. So we're going to try.

Topol: Keep up the great work. I know a lot of people will be inspired by this discussion and what you've been doing to shake up medicine over many years. Thank you, Steve.

Quake: Thank you, Eric. It's been great to chat.

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