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Genome Giants – Leroy Hood, Co-founder and Professor, Institute for Systems Biology

Leroy Hood is a pioneer of systems biology and Professor and Co-founder of the Institute for Systems Biology, Seattle. He is also the founding CEO of Phenome Health, and serves as Emeritus Science Advisor for Providence. Throughout his career, Lee has developed groundbreaking instruments that have enabled major advances in the biological and medical fields. His most recent venture is the formation of Phenome Health and its Beyond the Human Genome Project.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello, everyone and welcome to the latest Genome Giants interview. Today, we are going to be talking to legendary scientist, Leroy Hood, who will be taking us through his career and also his motivations as well. So, before we get stuck in, Lee, if you could just introduce yourself and tell everyone a little about what you do as well.

Lee: I’m Lee Hood. I’m at the Institute for Systems Biology. I am just starting a new non-profit called Phenome Health, which is all about precision population health. I suspect we’ll talk about that later. I think my main passion in life is science, reading and exercise. So, with that, I think we can get started.

FLG: You were born in Montana in 1938. What are some of your fondest memories growing up?

Lee: Growing up in Montana was absolutely wonderful. I had parents that gave me enormous freedom to do what I wanted to do. So, I was running around the mountains of southwestern Montana, when I was five and six years old. I had some of the best teachers I’ve ever had in my life during high school, they were enormously formative for me as a person and for the career path that I eventually ended up choosing. But I think Montana is an exceptional place. It has a small population. There’s a lot of freedom. There’s a lot of sense of independence, and you can go out and do what you want to do. I think those were all very important characteristics that were installed before I ever started my educational trajectory or my career trajectory.

FLG: You’re actually one of four children and your brother was born with Down syndrome. What was it like at the time for him growing up? How much did you understand at the time as well?

Lee: The Down syndrome birth of my brother, who was six years younger than myself, was really an interesting experience. I remember asking the doctor, ‘What causes this?’ and he said, ‘I have no idea whatsoever’. And of course, we didn’t discover chromosomes and chromosomal abnormalities until much later. It evoked an enormous debate in my family, my mother wanted to keep Glen as her own child and raise him. And my father said that it would be much better for him to go to the state institution where they have professional people that know how to deal with Down syndrome. And, as usual, my father won in these arguments. And I have to say, in retrospect, I think he was correct, because my brother Glen did go to state school, it was a great experience for him. By the time he was finished, he had three jobs, he owned a small house, he was subletting to other Down syndrome colleagues. I think he lived a wonderful full life that would have been very impossible to live in Missoula, Montana, or Shelby, Montana. So, in retrospect, I’m sure he was an exceptional Down’s patients and everything. But that really was the first time I asked the why question. And it clearly pointed towards science, although I can’t say I had any deep insights or anything.

FLG: What were you like as a child? When did you first start to show an interest in science?

Lee: I think I was a little bundle of energy. I’d love to hike and climb and run around. And I was curious, and I did a lot of reading. I think the first transformative experience for me in science was in the sixth grade when Mr. Graham, my math teacher, who I adored, he was a terrific math teacher, approached me and said, ‘I understand you want to be a pilot?’ And I said, ‘That’s right’. And he said, ‘Lee, I flew B-52’s during World War II in Indonesia, and I can honestly tell you, flying a plane is like driving a truck. Do you want to spend your life driving a truck?’ And that turned me around. And he went on to say, ‘Look, you should go into science’. It didn’t propel me immediately. But instantaneously, I was no longer wanting to be a pilot and I was thinking in a broader context.

FLG: You did your undergraduate education at Caltech. What did you study? What was your experience like at Caltech as well?

Lee: Before we get to Caltech, let me tell you about one of my superb teachers, Mr. Cliff Olsen, who was a World War II navigator who went to Caltech to learn navigational skills. He decided that he would take and persuade any good students he had to go to Caltech because he thought so much of what he saw there. So, in my junior year, Cliff Olson approached me, he was my chemistry teacher, and he said, ‘Look, next year, would you help me teach biology to the sophomores?’ And I said, ‘I’ll do it if I can use Scientific American to teach from’, and he said, ‘Okay’. So, I went and ended up giving a series of lectures, probably 10 in the course on various topics in Scientific American. But the one that absolutely transformed me, and this was 1956, I taught a lecture on the structure of DNA just three years after it was discovered. I remember thinking, this is an incredible molecule and if it’s the centre of biology, that’s where I’d like to go. At that same time, Cliff came to me, and he said, ‘Well, if that’s what you want to do, you should go to Caltech’. And I said, ‘What’s Caltech?’ And he said, ‘It’s a very famous technical school where you can learn deeply about science’. I went and looked up the requirements for Caltech and I said, ‘Gee, you have to take the advanced math test to get into Caltech and it’s all about calculus and I haven’t had calculus’. And he said, ‘Ah, don’t worry about it. Just take the test, you’ll do fine’. Today, you’d go out and you’d read a book and you’d learn calculus in a month or two and all of that kind of thing. That wasn’t how it was in those days.

So, anyway, where I really wanted to go was Carleton in Northfield, Minnesota, because it was a small liberal arts school and I’d love everything I’d read about it. I took the advanced math test. I’m quite confident I got one of the lowest scores of anybody that ever gotten into math. And in fact, I had one of my teachers in later years tell me that my math score led them to predict that I would be at the bottom of the class. But anyway, I got in and ended up going to Caltech rather than to Carleton. It was wonderful because it gave me all the basic tools I needed for a science, lots of math and lots of chemistry and lots of physics. And besides, I had two of the most inspirational teachers I’ve ever had there. So, one was Linus Pauling. He wasn’t then at Caltech, but he came back and gave freshman chemistry lectures. The other was Richard Feynman. I was in his freshman class as he was writing this classic trilogy of physics books. So, he experimented with us in all sorts of ways. And both of them were enormously charismatic. They believed that you teach in simple, easily understandable ways. And they were kind of infinitely aspirational. They set the standards for how I thought teaching should be and that’s what I aspired to. I can’t claim I came close to any of that. They were wonderful models for thinking about how to communicate to people. It was even broader than just teaching courses.

But at Caltech, I got to play football. I played football in high school as a quarterback. Our team had been undefeated during my last three and a half years, and we won state championships. My high school football team would have destroyed Caltech’s football team. There was no question. But it was a chance to get out and get exercise and do something besides study all the time. I sang in the chorus. I was class president. I did a lot of different things. Caltech was just a terrific experience. For me, I took a lot of humanities, because I always felt having a grounding in culture and history was really important context for communication and thinking about teaching too.

So anyway, Caltech was all good, except for one thing. I had decided, partly, as a result of my brother and a whole series of things, I was really interested in human biology. But we had almost no higher organism biology at Caltech. I learned about microbes, cell lines and all sorts of different things. But I didn’t learn about people. I decided, since I really was interested in studying human biology, and later human disease, that I had to go to medical school. And so, I talked with all of the faculty about where I should apply. I only applied to two places, Harvard and Johns Hopkins. Then, there was a big debate and different faculty members had very different motivations and arguments. But what really convinced me to go to Hopkins was, if you wanted to do something that was non-traditional medicine, and I never wanted to practice, I wanted to get the background so I could go back and get a PhD and learn how to do research and then I was going to do human biology research. They had an accelerated programme, where if you went in the summers, you could get it done in a little less than three years. So, I chose Hopkins and I got it done in three years. But Caltech was just a wonderful first step into science.

FLG: You returned to Caltech after Johns Hopkins, and you did your PhD there as well. Why did you decide to go back and what did your PhD focus on?

Lee: I’d looked at three or four places seriously. I looked at Stanford very seriously. I did look at Harvard Medical School. And I looked at the University of Colorado. They all had really attractive features. But what really convinced me about Caltech was, it had a real technology bent. I was convinced even then, before I’d started doing all this technology, that a part of the solution to human biology was going to be able to make measurements, faster, better, cheaper. Caltech seemed to have the grounding in excellent engineering and chemistry for doing just that. In fact, I remember going to the chairman of biology, Bob Sinsheimer, he was really a great scientist. And I said, ‘Look, Bob, Stanford has offered me $20,000 and you have only offered me $15,000 a year. Do you think we could make any modifications?’ And Bob Sinsheimer said, ‘No Lee, I think you’re just going to have to make a decision’. So anyway, that decision was Caltech. And I started at $15,000 a year and it was an absolutely wonderful place again for me to grow up in science for lots of reasons.

I will say before that, at Hopkins, I again, had a wonderful experience. And frankly, I got interested in almost all things – cancer, immunology, the immune system, biochemistry, and then maybe the very beginnings of molecular biology there. Those were the things that carried me through into the future. But again, I had one absolutely outstanding teacher, Barry Wood Jr., he was Harvard’s last all American football player, he played quarterback, and that resonated with me, and we talked about football. But he started as a young clinician, being the youngest Chairman of the Department of Medicine at Washington University in St. Louis. He built a spectacular department there. Then, he decided he wanted to go into basic science. So, he came to Hopkins and was Chair of Microbiology. One interesting side experience is, Barry came to me my senior year, and he said, ‘I’ve decided to offer you an assistant professorship in my department of microbiology, it will accelerate your career enormously and get you into the heart of science’. And it was one of the hardest things I ever had to turn down. I said, ‘No’. I was convinced I needed to go back and get a PhD, and really learn how to do science. I felt I’d really be set up. I ended up looking at Harvard, Stanford, Caltech and going back to Caltech.

FLG: After your PhD, what was your early career like and what were some of the challenges that you faced during that period?

Lee: I had a spectacular career as a graduate student because I chose to go into molecular immunology. When I was at Johns Hopkins, I started reading papers about this NIH investigator that was studying plasma cell tumours in mice, where you could obtain homogeneous antibodies to characterise them. I was very interested in how the body could generate this diversity of antibodies to protect us. I thought these myeloma tumour proteins would be an ideal way to study that. Ironically, when I went to Caltech, as a first-year graduate student, Bill Dreyer came as a new faculty member. So, I immediately went to him and said, ‘Look, I’m really interested in this’. His main project then was completely different. So, he said, ‘That’s terrific Lee. This is a good Saturday afternoon project where you can work on it and you can do it at your own leisure, and you don’t have to worry about competition’. So, I was really excited, and I learned how to make these plasma cell tumours in mice, and I learned how to purify the antibodies and I learned how to do manual protein sequencing. My first year, I had some absolutely spectacular results. And in my sophomore year, I was giving lectures at Berkeley and UCSD. So, I was in the fast track as a graduate student and really stayed there the whole time. It was just the most wonderful start to my career.

My mentor was not a hands-on person. But he was a great theoretical person. We used to have really fascinating conversations. And over those years that I was with him, he really taught me two things that guided my career. He said, ‘Look, if you want to do biology, be at the leading edge. Don’t be a librarian, just doing what people have already done before in more detail’. He said, ‘Go out and carve out your frontier and set the pace’. And so, I did that in molecular immunology, and it was really an exciting 20-25 years of my career. I followed all the way through from characterising proteins, getting into molecular biology and isolating the genes for all the immune receptor families, discovering all sorts of things. It was great back at NIH and then back as a faculty member at Caltech.

But the second thing he said to me really had a big impact on me too. And that was, ‘If you really want to change the field, invent a relevant technology that can give you a new window into its biology’. And Bill Dryer did that in several instances. He was one of the first that saw the power of fluorescent antibodies. He was one of the first that pushed the then classic method for doing quantitative analysis of amino acids and everything. He was a mentor that wasn’t interested in hands on, but he was really interested in theory, and he was terrific for me.

FLG: You have been involved in the development of ground-breaking instruments that have been instrumental in advancing biological and medical sciences. These include a DNA synthesiser, a peptide synthesiser, the first automated DNA sequencer, ink-jet oligonucleotide technology and nanostring technology.

Lee: I got one more! You forgot an automated protein sequencer, which is the first instrument I worked on actually.

FLG: What was the journey like? How did the skills you learned throughout your career prepare you for such developments?

Lee: Well, I’ll tell you, when I went back to Caltech, again, I had a firm handle on molecular immunology and that’s what I was going to do. I had really gotten into protein chemistry very deeply and I wanted to be able to actually make it hundreds of times more sensitive than it was at that time. Because there are a lot of really interesting proteins that are available in small amounts. And I saw that if we could increase the sensitivity of sequencing 200- or 300-fold, we could transform fields. But I also thought that once you add the amino acid sequence, in principle, you could synthesise DNA probes easily, you could make probes to clone a gene, characterise it, and sequence the gene. That thinking and that speculation about a microchemical facility, got me thinking about the first four instruments that I was really interested in. So immediately, at Caltech, I set off on a trajectory of what I call paradigm changes. They were all focused on dealing with human complexity. But they really revealed what I wanted to do with human biology and how I felt we should study human disease.

The first of these paradigm changes was basically bringing engineering to biology. That was not a popular thing to do at Caltech. I was three years into my tenure at Caltech and Bob Sinsheimer, my chairman, came to me and he said, ‘Lee, I advise you in the strongest possible terms to give up all of this technology development and focus on your biology’. And I said, ‘Bob, I’m doing just fine with my biology and this technology is really going to change the world’. And I wouldn’t give it up. I found 20 years later that the reason he came to me is the senior faculty at Caltech felt two things. One, they felt engineering and biology was inappropriate and they wanted to move me to the engineering department. And Bob said, ‘At least I didn’t ask you to do that’. I agreed with them. But the second thing is, I had to make my lab very large because I needed expertise in chemistry and physics and computer science and engineering. And so, I had a lot of people in my lab. Caltech was a traditional small science lab where your lab shouldn’t get bigger than 10 people. And one time doing both molecular immunology and then I got into neurobiology, and doing all this technology development, I had a lab with more than 65 people. That just didn’t sit well at Caltech. I think they never forgave me for it.

But anyway, it’s part of a later story. But I went to the Department of Biology and said, ‘Look, I have a solution for this. Why don’t I start an applied biology department where we have faculty members that consist of all the cross disciplinary talents I need, and I can keep my lab focussed on biology and the chemistry and engineering I’m doing?’ They absolutely rejected that idea. I’m sure they were worried it would be very competitive with biology, which it absolutely would have, no question. I will say everyone else at Caltech, the engineers, the chemists, the physicists, were utterly indifferent, they thought it was a great idea. We can come back to that later.

This technology really drove this first paradigm change. It was important in really two ways for me. One, we can really generate a lot of data on individuals and generating data and being able to analyse it was the first step in dealing with human complexity. The second thing that happened that really transformed my life is in the spring of 1985, I got invited to Santa Cruz with 11 other scientists to consider whether the Human Genome Project was a good or a bad thing. I got invited because I was developing automated DNA sequencing and that was essential for this project. We came to two interesting conclusions. One was that it was technically feasible, although at that time really hard. The second was, we were split six to six on whether it was a good idea. Those against it argued against it because it was big science and big science would swoop in and swallow up all small science. Biology at that time was all small science. So, people were really terrified of a big project like this.

And indeed, in the last five years of the 80s, when I went out into the biology community advocating for the Human Genome Project, I think, initially 80% or more of the people were absolutely opposed. NIH was utterly opposed. They argued, ‘We don’t need it because we’re putting $300 million into genetics each year and genetics is better than genomics’. And of course, they’re apples and oranges. They’re not related, you can’t make comparisons like that. And you can’t do with genetics, what you can do with genomics, and you can’t do with genomics….well, that’s not quite true, there are ways you can do a lot of genetics with genomics. But anyway, it was an enormous controversy for four years until a national academy committee, which I was on, had opponents and proponents that ended up universally endorsing it and saying, ‘This is a unique opportunity, we have to do it’. Then, NIH turned around in microseconds and they played an important role in the development of the Human Genome Project.

But the real hero in the early days was the Department of Energy, because it pioneered in those late 80s, when NIH was against it, and gave it a legitimacy that allowed us to go to congress and raise a little more than $3 billion over a 10-year period to do it. Without DoE behind it, that would never have happened.

FLG: What was it like for you watching this journey of the Human Genome Project play out?

Lee: Genome was one big step. And we can talk later about the final step that I’m taking now, which I think will be a real common culmination. What really excited me about the genome, there were a lot of things. It transformed virtually every field of biology, because you could get the genomes of all these organisms, and you could do science in different ways. And it transformed molecular evolution in a major way. But what I loved was it gave you access to human genetic variability and correlated with wellness and disease phenotypes. Those are very powerful tools.

FLG: How do you think the sequencing field has evolved? What do you see happening in the future as well?

Lee: Well, look, the automated DNA sequencing field has had three giant steps. The first giant step was Sanger inventing how you do di-deoxy sequencing, and that really enabled its automation. An interesting story is we started out trying to automate the alternative Maxam-Gilbert sequencing and really failed for reasons that are totally obvious now. But when we switched to di-deoxy, it went beautifully, and we were able in three years to develop a prototype instrument. I think what really excited me about the Genome Project is that you could do big science, you could put together a large amount of money, and you could push the technology, you could push the computational tools and you could push the sequencing technologies. And of course, what the Genome Project did, was to catalyse the initiation of seven orders of magnitude decrease in cost and increase in throughput of DNA sequencing. The first automated DNA sequencer was the one we invented, that did classic Sanger sequencing.

The second stage of DNA sequencing was something that George Church pioneered, when he essentially paralysed sequencing so you could do a million sequences at once, although they had to be very short reads. So that is second generation highly parallel short-read sequencing, and that’s what dominates today. Then, 10 years ago, the third field started to emerge, which is single molecule sequencing. And there are instruments out there that can do it beautifully. But in the future, the advantage of single molecule sequencing is you can get very, very long sequencing reads. So, as we do each human genome, you will have all the information you need to assemble that genome independently of any other imperfect comparisons. So, I think that the third and final generation is going to be this single molecule sequencing.

I can see the cost of sequencing coming down to $10 to $20 for a whole genome sequence. I can see the throughput, increasing to whatever you want to increase it to. So, you’ll be able to automatically go from the data to a fully assembled sequence that’s quite accurate for each individual. So anyway, that’s how I see sequencing evolving. But, in technology, nothing has been more impressive than the 106-107 decrease in cost of sequencing and increase in throughput and so forth. It’s really been spectacular. In fact, what we need to do is really push the same kind of transformational technologies with protein analysis and metabolite analysis and lipid analysis and all of the other molecules that are really important to analyse in the future.

FLG: As you alluded to earlier, in 1992, you founded the first cross-disciplinary biology department at the University of Washington. How did you manage to convince them to set up this department?

Lee: Well, it was really an interesting story. Increasingly, my colleagues at Caltech, the faculty members in biology, were unhappy about two things that I was doing. One was all this technology, and the second was the Genome Project. They were really quite negative on it. So, I thought to myself, science is really about having fun and enjoying your colleagues, and not being harped at and criticised all the time. I said, ‘Gee, Caltech is just not a good place for me anymore’. It was a wonderful place to grow up. It’s a terrific institution. But, in a sense, as David Baltimore said, ‘I just outgrew Caltech’ and I wanted to do bigger things than they were comfortable with. So, I started going around, and I went to Berkeley, and I got a job offer there. But the Berkeley biology faculty took a vote of confidence and one third of them were against my coming. I thought, ‘Ugh, I don’t want to get back into this again’. One of my former students, Roger Perlmutter, who was just a spectacular student, and he went up to the University of Washington after he did his postdoc with me and immediately got a faculty position and later was chairman of immunology there. He said, ‘Why don’t you come up and look at the University of Washington and we’ll see if we can get Bill Gates interested’. So, they invited me to come up and give three lectures in the series called The Dance Lectures about the future of biotechnology, which I did. Bill went to all three of these lectures and we had a dinner atop the Columbia towers at the end of my lecture and we talked for two or three hours. It was an absolutely fascinating conversation. Bill is obviously one of the brightest people I’ve ever met, and he loves biology and he’s interested in all the detail. Finally, he said, ‘Well, look, I’ll help you come up here. Why don’t you think about coming up and doing some of these kinds of things?’ So, he offered to put 12 million, which in 1992 was a fair sum of money, into an adjournment to get me to come up. He talked with the dean.

That was an interesting story. On my first visit to Seattle, I thought it was successful. I gave a lecture, I talked to a lot of the faculty and my final conversation with the dean, he said, ‘I don’t think we’re a good fit for you, because this is way too fancy for us. Medical schools aren’t so technologically oriented’. That was really a downer, because I convinced Bill’. But I thought, ‘Well, okay, that’s life’. I went back on a Friday, and the dean called me on a Monday and said, ‘Look, I’ve really made a big mistake. I’d like to come down and spend a day with you and convince you that I understand the mistake I made, and I want you to come, and this is a good place’. So, he came down, and we spent the day and we agreed I would do what I wanted to do. He was such a wonderful dean. I was excited about working under him. Because he was a real scientist and he understood biology and he understood science, in a way, the next dean never understood it.

So, anyway, I came up and he was a terrific chair and I got to do all these things. My department was enormously successful in developing all sorts of different technologies. But toward the end of this eight-year tenor in this department, the dean was a big trekker, and he went on a trekking hike with his wife in Sherpas in the Himalayas and got caught in a storm and an avalanche and he died there. Then, we had a new dean come up, who was a more classic outcomes clinician, and he saw the world very differently than I saw the world. I could see the handwriting on the wall. So, in 2000, I decided that I wanted to build systems biology on top of this cross disciplinary department. And I decided for lots of reasons that was going to really be hard at the university. So, I resigned and started the Institute of Systems Biology.

FLG: You’re actually credited with introducing the term systems biology. How did this come about? What was that journey like to setting up the Institute for Systems Biology?

Lee: I was thinking in the late 80s about how you integrate all these data together into systems. They weren’t very coherent thoughts at that time but at least I was beginning to probe it. I even wrote a couple of grants to NSF, which never got funded. I didn’t quite understand how to do systems biology at that time. I don’t think any of the reviewers even understood what I was talking about. But in the 90s, I thought moving to Seattle would be the chance to really build upon this new thing. And with all the technology that we had developed, it was becoming obvious that one approach that was very powerful to systems biology was to generate a lot of information on an organism, and then be able to convert that information into biological networks that were then just beginning to emerge mostly through protein-protein interactions. That was really the mantra that we started with in systems biology, and it worked absolutely beautifully. And so, we did a lot of classic biology and we looked at the galactose system in yeast and were able to do the dynamics of how the system changed. Once you initiated its ability to metabolise yeast, we could look at all the systems and see how they changed. We had a classic paper in Science on that approach, and one thing after another led to success, and now everybody’s doing systems biology. They each have their own different brands, but it is making people think in global, holistic and integrative ways. That’s good in biology because if you don’t do that, it’s so complicated. It’s going to be hard to get anywhere.

FLG: Since its inception, how has the field of systems biology has evolved? How do you think it will change going forward?

Lee: I think it’s evolved by bringing in all sorts of new technologies. What we really stressed in the beginning, and people are just now becoming realise, is that what you need to learn systems is to study the dynamics and see how the system changes. That’s the only way you get close to it. And what I’ve seen is that has been adopted, and new technologies that are revolutionary have been adapted. Imaging technologies that can let you see the brain down at the molecular level, and how it’s changing, or a small organism like the zebrafish, looking at different organs and seeing what’s going on with regard to metabolism. So, we’ve gained the tools, we’ve gained the insights of dynamics, and we’ve developed very powerful computational tools for analysis, integration, visualisation, and for creating computational models that you can hone to approach reality that then can make very powerful predictions. One example of this is a technology called digital twin that’s being used for human diseases in very striking ways e.g., cancer and Alzheimer’s.

The field has evolved spectacularly well. It’s like molecular biology was 25 years ago. Molecular biology was an enormous leap up from simple biochemistry. And systems biology, uses all the tools of molecular biology, but it brings the integrative and dynamic view that makes it a reality of translating complexity.

FLG: One of the things that you’re currently working on which you mentioned earlier, is the phenome project. What exactly is this project? How did this project come about as well?

Lee: Well, in the mid-teens, about 2014, I decided that we and others had developed enough technologies, that we could begin to look at human populations and for each individual give a lot of data and make predictions about wellness and disease. I started a pilot project on this in 2014, where I persuaded 108 of my friends to submit (over a year) three different analyses where we looked at 1,200 blood analytes – proteins, metabolites, clinical chemistries. We did the gut microbiome. We used a Fitbit for digital self and blood pressure measurements and other kinds of things like that. We got the whole genome sequence of each of them. We developed the tools then to begin integrating these data together. From these data analysis and integration, came a whole series of what we call actionable possibilities. These were possibilities that an individual could do and if they did them, they would either improve wellness, or avoid disease. And we, over a period of a year, generated probably 50-60 of these and each individual was different on what they needed and what they had to do. But it really validated what we call quantitative or scientific wellness, as opposed to just diet, sleep and exercise. Those are important and they were a part of what we did, but it was more bringing an appropriate equilibrium to the blood because it assessed all your organs so you could fine tune many different things from the blood. And looking at your gut microbiome because it has an enormous influence on the brain, and many other things that we’re just beginning to understand.

So, this programme was successful, and we started a company called Arivale that over a four-year period gathered together 5,000 clients to bring them scientific wellness. And we created during that time, these longitudinal data clouds. So, we did their genome again and then we did what we call the phenome analysis, which is all the other measurements beside the genome. The Arivale programme pushed us up to more than 200 actionable possibilities for wellness and people loved it. It wasn’t financially stable, and we really needed to bring in doctors. So those were the two major changes that had us shut it down in 2019. But from those data, we validated scientific ageing and we learned how to make a metric for wellness. For example, the younger you are in your biological age, the better you’re ageing. So, now we have a metric we can use to assess people and how well scientific wellness is doing.

When Arivale failed, I got asked in 2017 to become the Chief Science Officer at Providence, St. Joseph’s, where I’ve been for the past five years. I started this big project, which we’ve called Beyond the Human Genome Project. The idea is to increase over Arivale’s 5,000 individuals by 200-fold and do the same thing for a million people over a period of 10 years. And again, we would bring in scientific wellness, we would bring in healthy ageing. We’ve been able to demonstrate that you can calculate genetic risk for almost 100 different diseases and knowing that if you’re at high risk for particular diseases, we can follow you and catch the earliest transitions and reverse them. But most interestingly, we were able to show that over the four-year period of these 5,000 people in Arivale, we saw 167 transitions from wellness to disease and it included all the chronic diseases. So, we took 10 of the transitions to cancer and we looked at bloods drawn prior to the clinical diagnosis and showed that we could up to five years prior to the clinical diagnosis have markers that indicate that people had transitioned to a particular disease. So, the aim is to use those to reverse the disease at the early stage and prevent them from ever getting the disease.

So, Beyond the Human Genome Project is all about the science of wellness and the science of prevention. It is a classic example of P4 medicine – predictive, preventive and personalised. And that’s the science, we know how to do this science. But the fourth P is participatory, and getting people to do what’s good for themselves, getting physicians to accept this new kind of medicine and having healthcare leaders buy into it. That all requires a type of participation that we’re just learning how to do. That’s going to be the biggest challenge in this programme. But just as with the first Human Genome Project, I’m approaching the US government for federal funding to support this project. I believe at the end of this project, we’ll really have honed in on how we can follow and optimise the health trajectory for every individual, and essentially help you from ever transitioning into clinical disease. We will reverse these things before you get to diseases. So that’s the essence of the project, and it’ll keep me busy for the next 10 years or more!

FLG: You’ve had such a big career. How have you maintained a passion for science?

Lee: My biological age is 50 years younger than my chronological age. I really attribute that to the fact that I do a lot of exercise. I think exercise is a really important element of biological age. I do reasonable dieting and I try and manage my sleep. I love to travel. I’m really excited, actually, I’ll be coming to London in less than a month to visit some people and see some plays over there. I love to read. I have followed my mentor’s advice, I’m always at the leading edge. I’m always excited both of the opportunities and especially the challenges. And let me tell you, there are a lot of challenges in a project. If I thought the Genome Project had challenges, this really has challenges. But they’re just exactly what you need to get your blood flowing. I think this project will keep me going well into my 90s. So, it’s going to be an exciting time.

FLG: Definitely! Were there any major missteps throughout your career that you learned from?

Lee: I don’t know if it’s a misstep. I left Caltech because I couldn’t persuade people that what I was doing was good. And I asked myself, ‘Could I have spent more time persuading them? Could I have been more persuasive with them?’ I don’t know. It’s hard to say. And again, when I left the University of Washington, it was very impetuous, because I had several clashes with this dean and I just decided life was too short to go through these things, both for him and me, it would have been better if I left. And so, I did leave. Again, I wondered whether that could have been managed better.

But I’ll tell you, the most regenerative part of your career is when you have the courage to do something new in a different environment, because it turns on everything in solving hundreds of problems you never ever even imagined existed and it gets you into different levels of science that I’ve progressed through. So, I think the challenges are every bit as important as the opportunities. If I had to give advice to people, I’d say, every 10 or 15 years change your career in a major direction. All of a sudden, you’ll find yourself insecure, learning a tonne of new stuff, using all your past experience to think about the future in new and interesting ways. Those are the times when you really grow.

FLG: Outside of your career, you mentioned that you like exercise. What else do you like to do that’s not science?

Lee: For a long time, I did mountaineering. I was a really good rock climber. I climbed El Capitan to give you an idea. I had an outdoor life that was very active. I’ve hiked every single subsidiary of a major part of the Grand Canyon. And that’s really mountaineering, because a lot of them don’t have trails, and you have to figure out how to get down cliffs that are very dangerous, because they’re shale and crumbly, and things like that. I like challenges there too. I do that less now. But I love hiking and walking and things like that still. My wife made me give up technical climbing 15 years ago, she said, ‘Look, you’re really in good shape. But you can’t do the things you did when you were younger’. Absolutely true!

FLG: If you could turn your career into a film or a book, what would you call the title?

Lee: Determined optimism.

FLG: Why would you call it that?

Lee: Because in every new paradigm change you take, you run into enormous scepticism and criticism, and even hostility. I remember giving a lecture at Woods Hole, one of their Friday night lectures, these are big classic lectures given to the lay public and it must have been about 1987 or so. I came in and gave this lecture on the Genome Project. And it was incredible. The first question I got asked was, ‘You say automate this and automate that. Now, I ask you, where is the humanity in your science?’ It went downhill from there, and we had a vigorous argument. I think almost everyone was against me. To show you how bad it was, I came with my suitcase and my host had brought me to the lecture and everything. My host went home. When I was finished with the last questions, I had to go to a janitor, and say, ‘Do you know where speakers usually stay?’ Then, I had to wheel my thing up to the hotel, which was three blocks away. That was the level of animosity, but it didn’t deter me in the slightest, because I could see a future that they couldn’t see, and a few can see it now, but they can’t see it very clearly yet. In the Beyond the Human Genome Project, the ‘beyond’ is the longitudinal phenome. That’s the next big step that’s going to transform healthcare.

FLG: Thank you so much for talking to me today, Lee. You have had such an amazing career and you’ve got some amazing stories. So, thank you so much for sharing that with me today. It’s been great.

Lee: Good luck!