All the interns had the amazing opportunity to talk with the co-founder of ISB, Dr. Leroy (Lee) Hood, MD, PhD this summer. Below is the transcript:
Could you elaborate on your involvement in the founding of several biotechnology companies? What was the process by which they were founded? Can you go into detail about the ones that are the most significant to you?
I’ve been involved in starting about seventeen different biotech companies and the first two I started were among the most successful of the companies. So, I went to Caltech in 1970 and started developing technologies, instruments, and things like that. By 1979, we had developed one instrument, with two more well along and a fourth in mind. I went to the president of Caltech (a professor at this time) and said ‘Look I’ve developed a series of instruments and I’d like to commercialize them.’ And the president said ‘Well the role of Caltech is not commercialization, it’s scholarship and education.’ I said ‘My view was that any scholar had a responsibility to transfer useful knowledge to society and I felt transferring these instruments to society would be useful for other scientists.’ He said that Caltech was not interested in that, and if you want to do it ‘you’re on your own.’ So, I went to nineteen different instrument companies in the next year and a half trying to sell these instruments, and only one was even remotely interested. It was quite a depressing experience. And then a venture capitalist, who became a good friend- Bill Bowes- in San Francisco, offered several million for us to develop these instruments. I went back to the president, and said that there’s a possibility for us to create a venture company to do this. He responded that Caltech did not want to have anything to do with venture companies. At that time, there was a lot of controversy surrounding whether academics should really start companies or not. After six months, it was clear that was the only offer on the table. What was interesting was, at that time, I gave a lecture to the Caltech trustees about these instruments and how they were going to transform biology. And the chairman of the trustees of Caltech was Arnold Beckman who ran Beckman Instruments company and I had gone to them three different times and the third time his manager said ‘We know what you are selling and we aren’t interested don’t come back.’ After my lecture Arnold Beckman came up to me and said ‘This is exactly what Beckman Instruments needs. I think we should talk with them about this.’ I said, ‘Well I’d gone three different times and they didn’t seem very interested.’ He responded with ‘I find that really hard to believe.’ So he flew up the next morning to San Francisco where this division of Beckman was and he asked them about this possibility. And they actually lied and said I’d misrepresented what I had wanted to sell because I’d wanted to start a company and make a lot of money. And so Arnold Beckman was understandably angry about that. So I wrote up a long history of how I’d done the negotiation and who I’d spoken with about everything. I gave it to the president and said ‘Why don’t you fix that’ and the president, I don’t think had the courage to give it to Arnold. What happened, to make a long story short, is in the end, we started a venture capital company called Applied Biosystems and it was in the black the first year it was underway because the first of the instruments that we did- the automated protein sequencer- was so well designed, they essentially used our design. It was a really successful company, and it was a bit of a stressful company to generate because of the controversy with Arnold Beckmen- which later got settled and everything was fine. And so Applied Biosystems did manufacture all four instruments, and it probably became the most successful instrumentation company for biology in the world. The second company that I helped start was Amgen, which is a pharmaceutical company in Thousand Oaks, California. And this was again back in 1980, right at the beginning of the explosion of the initial biotech companies and everything. And at Amgen, there were four or five scientific co founders of the company plus business people. And we decided a really interesting product for Amgen would be erythropoietin- a human hormone that induces the production of red blood cells- and there were a lot of people with chronic kidney disease that had enormous troubles with anemia. And we saw this as a natural drug for those individuals. And it turned out later to be a really effective drug for cancer patients that lost a lot of their red blood cells as well. Erythropoietin was expressed at very low levels, and a strategy we worked out with the instruments we developed was to take proteins available at vanishing low quantities and this automated protein sequencer we developed was two hundred times more sensitive than any previous instrument. So we were able to microsequence a very small amount of erythropoietin. And then that was what Amgen used to finally clone the gene and produce the drug. And erythropoietin turned out to be the first billion dollar drug the new biotech industry had ever made. And of course Amgen now is a major pharmaceutical company with a market gap of probably around 200 billion dollars. That was a pretty successful company. In all of these companies, you’re very involved for the first two or three or even four years to help them get started. But then the people want to become independent so you let them take the company forward. I did that both for Applied Biosystems and Amgen. I started other companies that I think, in the long run, will turn out to be more significant, but you know, it’s going to take a while for the vision that promoted them to get accepted into the healthcare system.
Do you think any of these companies will take a systems biology approach to developing drugs and/or instruments?
I think pharmacy companies will start to begin doing that, they are taking baby steps to do so. But, you know, anything new takes ten or twenty years to get accepted and systems biology we really started pushing it in 2000 when I co-founded the Institute for Systems Biology. So, one of the things about paradigm changes, and systems biology was a real paradigm change, is it just takes a long time for a practicing scientist to accept them. Because they are really used to what they learned, and new ideas they accept with some difficulty. And that’s even more true of companies. It’s very hard for new companies to start breathing new things.
What did you see in the world, your own life, and the scientific community in general that motivated you to co-found the Institute of Systems Biology as the first ever institute dedicated to systems biology? Why did you think an institute like ISB was important to develop?
When I went to Caltech in 1970, I was really interested in human biology. And I figured that the first major problem with human biology was the enormous complexity of humans. And in fact, a really good analogy that I thought of at the time was The Elephant and Six Blind Men- each blind man felt a different part of the elephant and declared it was a spear or a rug or a fan, depending on which part they felt. And what it meant was they didn’t have a coherent view of the elephant, and that got me thinking about things. One, that if you really wanted to understand human complexity you had to be able to generate a lot of data on humans. And that’s external data and internal data. And the instruments that I developed were a means for doing that. Number two, in thinking about how you can get internal information easily it became obvious to me that the blood is really a window that lets you look at all of the organs and everything because blood is a part of all organs and the molecules of the organ are secreted into the blood. If you can identify these molecules, you can assess how healthy the organ is. The third idea that was really important was the beginnings of thinking about systems biology- how do you put all these different types of data together to get a coherent picture of what the human was? That kind of thinking led me to get involved in seven different paradigm changes. I’ll name each of them briefly. First, bringing engineering to biology: developing the instruments and making it possible to generate lots of data on humans. One of the instruments, the automated DNA sequencer, got me involved at the beginning of The Human Genome Project. I played a major role in that project. And that enabled me to do, once we had a human genome, was to look at variability and correlate with either wellness or disease phenotypes. I realized in developing the instruments my lab got very large. And Caltech really disliked large labs and put pressure on me to get smaller. So what I came up with was to do the technology development, you need a lot of skills in physics, chemistry, biology, mathematics, engineering, and so forth. And so I decided what we could do is start a new applied department of biology that was cross-disciplinary and the faculty represented all the different kinds of skills. Caltech vetoed that idea so Bill Gates let me move to Washington and start it at the University of Washington in 1992. When I came to Washington to start that department, what I wanted to do was build on top of it a systems biology effort. And it turned out over the first eight years, that at a big state university like University of Washington, it was difficult to introduce a new kind of science which systems biology was- and that’s for a whole bunch of different reasons. In 2000, I decided if I was ever really going to push systems biology forward, I would have to resign and start a new institute. And we did it with The Institute for Systems Biology. First, solving some interesting problems in biology and turning to focus on medicine. And so, that’s why I started it. And it has been, as you can tell, superbly successful and is still one of the leading institutions driving systems biology forward, and much more recently, a systems approach to medicine. I ended up being in seven paradigm changes and systems biology was the result of those.
Could you please talk about the work you did relating to the development of the sequencer/synthesizer instruments that helped to pave discoveries in the Human Genome Project?
Well, to develop the instruments that we did, and they were all automating chemistry processes, we had to bring together good chemistry and an understanding of the sequencing reactions for proteins and DNA, or the synthesis reactions of peptides and DNA. The DNA and protein sequencers and synthesizers were the first four of six instruments that my lab developed. And those were the instruments that Applied Biosystems started with. But the hardest instrument by far to develop was the automated DNA sequencer because the chemistry for carrying out the sequencing reactions required the development of a whole series of new chemical compounds and the ability to attest those chemical compounds to DNA. So, we had to synthesize the size of four different types. And then we had to figure out how to be able to couple them to a different die to each of the four different bases, and that’s a part of the sangers sequencing process. And then we had to be able to figure out the engineering of the instruments and how you move fluids around, mix things, and get the sequencing reaction done. And then we had to develop a capillary gel separation system that separated the DNA fragments that represented the different nucleotides. Then, an instrumental baser instrument that would be able to read off the different color fluorescent dyes. Afterwards, the computational tools to convert color space into sequence space. We needed chemistry, biology, engineering, and computer science to do that and being able to mix those together with experts from all different areas made it possible to build this sequencer in about- well the prototype was built in about three and a half years. We then started Applied Biosystems and we worked together with them to actually make the instrument very robust so that any biologist could use it. Then we worked with them to scale up the rate at which you could do DNA sequencing. And that’s the instrument that made The Human Genome Project possible. For each of the other instruments, we had to do similar things, although none of the rests were quite as challenging.
What inspired you to carry out studies in Alzheimer’s Disease (AD), cancer, and wellness? Would you please talk more about your research in these areas?
So, at Caltech there was no human biology, no access to patients, no real ability to study the pathology of humans. And so, when I moved to the University of Washington, I immediately started to take up studies in those areas that you talked about. And cancer was a real area to begin with because it was a very easy one, to get models for cancer in animals like mice and study them experimentally in ways that you could never study them in humans. And two, you could then transfer the knowledge you gained from mice to understanding human tumors, and then carry out studies in the focused and constrained ways you have to do in studying humans. So, cancer was an area that we are just now beginning to really apply systems thinking. And something that’s called precision medicine. And precision medicine today is almost entirely about cancer research, therapies, and things like that. And, I have to say, current cancer treatments are for the most part, incredibly disappointing still, because with most of the therapies, they only delay the continuation of the cancer, they don’t cure it. And it means you have a miserable life at the end when you finally go through the dissolution that leads to death. So a hope for cancer in the future though, is a new strategy that has emerged over the last ten years called immunotherapy, and that’s a strategy that can use the precision of the immune response to attack cancer cells very specifically rather than as we do chemotherapy or radiation, kind of kill all rapidly dividing cells. But, the immune system is complicated, there are still real complications in using it. However, I would guess in the next ten years we’ll have these worked out and have really targeted immune therapies that will let us deal with many different kinds of cancer. A second area I got interested in is Alzheimers because my wife, in 2005, was diagnosed with AD. And I looked into it very deeply then, and it was clear there were no effective drugs whatsoever. In fact, what we can say is- over the last fourteen years or so- there have been five hundred clinical trials for AD drugs, not one of them has worked until very recently the FDA approved a drug, which is quite inappropriate and I can almost guarantee they are going to reverse that approval. It’s under investigation now by the NIH. It gave the FDA a black eye, and many of their scientists resigned in protest to that decision. But, what has turned out to be really interesting is that I had a student in my lab at Caltech called Dale Bredesen who went on to become a neurobiologist and became very interested in AD. He actually- about eight years ago- did a thought experiment in systems biology and said ‘how can you optimize nervous and synaptic communication?’ that begins to get lost early in AD. And what he came up with was a regimen of thirty six different things that included lifestyle, exercise, diet, supplements, drug, sleep, and it was called a multimodal therapy. And what you actually did was a biochemical analysis of the blood to see what a given AD patient was missing in those thirty six elements. And then you would attempt to correct what they were inefficient in. And this actually worked really well with very early AD patients. He showed that you could actually convert them from normal, if they underwent this change in lifestyle, diet, etc. He could convert them from early AD to normal. But what was interesting is that if they gave up this changed lifestyle, they almost immediately reverted back to AD. And then they could come back again. Then, there was a finished trial that looked at elements of lifestyle and validated this. There was a clinical trial that was very interesting. So, what I’m very interested in is set up at ISB- a collaboration with a company that is using an AI technology called digital twins. To describe it in a simple way, what we’ve done is to basically create a whole series of differential equations that mimic three major networks that operate in the human brain that seem to be involved in very central ways in AD. And then what we can do- and we’ve fed in enormous amounts of information to this model about what’s normal and abnormal- in an operational sense, is take the biochemistry of the AD patient, or even patients at high risk for AD, and we can put it into this digital twin apparatus and it can give us this diagnosis on therapy approach. So it’s all in the very early stages but we are thinking about making a major company in AD. In fact, I spent all of this past weekend together with a really famous computer scientist and two big investors that are thinking seriously about funding, in a major way, this AD program. It will actually be very cross-disciplinary, use many different approaches, and really, for the first time, try to deal with a disease that costs the American health care system 600 billion dollars a year, for just 6.2 million patients with AD. And half the money is the loss of income for the productivity of the AD patients’ caretakers, and the other half is what they attempt to treat the patients with (like being in homes to be taken care of). So, we feel within a five-ten year period with this company, we will be able to reduce the rate of AD by 50%, and in principle that could save 300 billion dollars to the healthcare system. It shows you the kind of effect you could have on society as well as the effect you could have on the individuals that have this kind of disease.
What motivated you to affiliate ISB with Providence in 2016 and become Providence’s Senior Vice President and Chief Science Officer? How does your previous scientific work and ISB’s affiliation with Providence help transform the current American healthcare system towards scientific wellness and P4 medicine?
Well, I’ll tell you, it is in the process of doing that, it has not succeeded yet. After I started ISB, I really took a systems view of healthcare, and that’s when I formulated this idea of P4 medicine- that it should be predictive, preventive, personalized, and participatory. The question was how to do that. Thinking further about healthcare, it really has two major domains: wellness and disease. In the early 2000s, healthcare was all disease, no wellness at all. So, I decided then I would really go after wellness. After a period of roughly ten years or so, we had developed enough technologies that we could take on the study of wellness. What we did first in 2014 was to recruit a hundred of my friends, and we analyzed about five hundred blood analytes. We did this three times in the first nine months of the study. We analyzed their gut microbiome that determines the ratio of different bacterial species in the bacteria that lived in the gut. And then we did some digital measurements with a Fitbit and other things. Collectively, what we showed is that you can integrate this data together, and for each individual, they would point to unique lists of actionable possibilities, that if the individuals carried them out, it would either make them well or avoid disease. We identified about two hundred of these with the first study. We got so excited that we started a company called Arivale, where we were going to bring this thing we called ‘scientific wellness’ to consumers. Over a period of four years, we gathered 5,000 consumers that were carrying out these tests twice a year now. We had, by this time, five or six hundred different actionable possibilities and unique lists. With this longitudinal data that we gathered over the four years showed one, scientific wellness really did work well and two, we were able to- because we had people from 21 to 93- develop an algorithm that told you your biological age, the age your body says you are as opposed to the age your birthday says you are. And the younger you are in biological age, relative to your birthday, the better you’re aging. And what this metric, this algorithm, also did was not only tell you what your biological age is, but it gave you clues as to how you could age better. So we actually started a company to do this, and you can get your biological age done if you want to. The other thing we showed is that for individuals that were sick, for example we had 250 type two diabetics in the Arivale population, we showed their average biological age was six years older than that of their chronological age. We looked at a couple of patients with severe COVID, and their biological age was almost twenty years older. You can see it’s a really good metric for wellness, and it can detect disease or healthy aging. A third thing we did which was really cool is that in these 5,000 people we saw, there were about 170 examples of transitions from a well state to a disease state, for all the major chronic diseases. We took ten that transitioned to various kinds of cancer, and we looked at the bloods prior to the clinical diagnosis, to show for each of them, there were blood analytes that were way off scale years before the clinical diagnosis. This means we can do early detection of disease transitions, and what we are doing now is setting up partnerships with pharma and academics to look at how to reverse those very early disease transitions. The idea, in the future, will be that you never have to get sick if you have these regular blood analytes done. We will detect all your chronic disease transition years before they occur so you can be well all of your life up to the very end. The object of scientific wellness is that you’ll move into your 80s and 90s, even 100s, mentally alert and physically capable as well as being enthusiastic and passionate as you are now. That’s the objective of scientific wellness. So that was one paradigm change that I call ‘The Science of Wellness,’ we know a lot about it now. I have just given you three examples and I can give you ten. That was the sixth paradigm change. The last paradigm change is when the CEO of Providence St. Josephs, a big health care system with 51 hospitals all up and down the west coast with 10 million patients, came and asked for me to become their Chief Science Officer and bring to Providence scientific wellness and systems biology, as well as have ISB affiliate with Providence. We did all of this, and then I decided for the seventh paradigm change, which is what I call ‘Beyond The Human Genome Project,’ is to propose, over the next ten year period, bring scientific wellness to a million people, and twice a year we will do their phenome analysis. The phenome is everything you can measure about a human except their genome: like blood analytes, gut microbiome, brain waves, everything! We are planning on proposing to the government that we would like to get money, just as we did for the first Human Genome Project, that will let us carry out this very visionary idea. The essence of it is we’ll be able to follow each of your individual health trajectory and optimize it so you don’t get sick. I would argue that is the most profound paradigm change in medicine since its inception and its start in using science seriously a hundred years ago. That is the final paradigm change and that’s what will keep me busy for the next 10-15 years. And hopefully it will bring you a whole new dimension to your wellness. You are old enough now that you will move right into an appropriate time and be able to get into such programs and it will change your expectations on what you would like to do with your life. The really interesting question is ‘suppose you have 20 or 30 extra years of functional life, what should you do with that?’ And you ought to think of something creative and productive that will really make you as excited as science is doing right now. So you want to think about where you’re going to be in your 70s because you will still be functional and capable of doing exciting new things that are going to change the world.
In the next decade, what critical breakthrough in systems biology do you see occurring that would have a profound impact on major diseases?
I could name a whole lot, but I will tell you one that I think is going to be very profound, and that’s the use of the most powerful modern AI (Artificial Intelligence) techniques. To be able to take all of the data we’ll gather from this million people, and sort through it in a way for relevancies that humans could never do. Because we are talking literally about cross-comparing billions upon billions of data points. It will give us insights in a general way that we can then attack with domain expertise and medicine to really translate them into how we’re going to change the quality of your healthcare. So I think AI with big data is absolutely going to give us things that we can’t get any other way. And in fact one other point I’d make is that I think the routine computational methods for comparing things, even with the biggest computers we can imagine today, aren’t going to be sufficient to begin to handle this problem. What’s really cool is that there’s a completely new type of computing called quantum computing that over the next ten years will arise just in time for analyzing these massive data sets that we will be accumulating and then translate it to things we can understand. How’s that for a cool idea? I think the other thing that’s going to happen in the next ten years is that we will begin to accept scientific wellness and its use will drive the cost of generating the information we generate now down by orders of magnitude. It’s just like the first Human Genome Project which drove the cost of sequencing down over about a fifteen year period by a million fold. We’ll do exactly the same with the human phenome measurements. In fact, probably most of them will be made by digital devices you have at home and you’ll send it in and let a big AI system come back and tell you what your actionable possibilities are.
What are ways you maintain a work/home life balance?
One, I think your interactions with your colleagues are really important, and to exhibit passion, enthusiasm, support, and excitement over what they’re doing as well as what you’re thinking about is really what makes life worth living. Having terrific students and post-doctoral fellows that are excited as you are about their sciences I think is very important. Secondly, a thing I always felt important for me in terms of health is exercise. So I exercise for maybe 45 minutes in the morning and then I try to get out for long runs late in the afternoon after I’m done with my work. I find that just gives a sense of well being and alertness. I think exercise is one of the major factors. So my biological age is 15 years younger than my chronological age which I think comes from a reasonable diet, good exercise, and things like that.
The third thing that I always try to do is have one new thought a day, one really interesting new thought. Now, I don’t always succeed, but I’m always thinking about new ways to approach what I’m doing to think about it and tie it together to other ideas.Lee Hood, MD, PhD
When you come up with these things, you can really get excited. For example, I find when I’m writing something- like the book I wrote during COVID on what twenty first century wellness should be- I often go to bed wondering about how I’m going to express this idea in the context of whatever chapter I’m writing. I would often wake up at about 5 o’clock and in twenty minutes have a solution to that problem. This idea of letting it percolate overnight and then getting excited about it in the morning has always worked well for me. I think what’s really interesting about each of us is that the things that motivate and excite us are probably going to be slightly different. We just have to discover what they are and try to use them. You can absolutely model yourself after people and just see if it works for you. One of the interesting things I almost always tell students is if you think about career trajectories where the x-axis is time and the y-axis is peak of your career, most people’s career is kind of a bell-shaped curve and it goes up to a maximum and you fade away as you get older. The interesting idea is if you go up towards that maximum, and then change fields, and start thinking about something new and feel insecure about having to learn about new things, you can actually start a new curve upward. And if you do that every 10-15 years, you’ll find most of your careers in upward ascent, learning about new and exciting things. I encourage you not to get stuck in a rut, but to take advantage, and there will be many opportunities that will come along where you can step outside of what you’re doing and begin a new thing that is equally and more exciting. Don’t just do the same thing, but change every 10-15 years and explore new territory.
What would be one new found piece of advice that you would advise anyone wishing to pursue STEM, medicine, systems biology, etc. to follow that you’ve found to be helpful over the past few unpredictable years, especially with COVID-19?
Wherever you go, you should try and interact with really outstanding colleagues, because they stimulate you way beyond what you might do by yourself. So, be excited about it and work with people who are themselves really exciting and can get you really excited. So many times in my life I have had a casual conversation after a meeting or a class where someone said something simple, and all of a sudden it changed how I thought about things. And those are the kind of people that are exciting to be around so when you go to college you want to go to schools where there will be students and teachers that will challenge you. Later in life, you want to put yourself in job positions where you still can get that same level of excitement and so forth. You can seek those things out and make them happen yourselves. Always have a good time. Always be changing your thinking around. These are really the keys to being the successful, passionate, and enthusiastic scientists.
Link to ISB Profile: Leroy Hood, MD, PhD · Institute for Systems Biology (isbscience.org)
Link to Hood-Price Lab: Hood-Price Lab | The Hood-Price Lab (isbscience.org)