Podcast Rewind: It's Personalized – The Future of Data-Driven Health

Dr. Robert Rountree:

This is the Thorne Podcast, the show that navigates the complex world of wellness and explores the latest science behind diet, supplements and lifestyle approaches to good health.

I'm Dr. Robert Roundtree, Chief Medical Advisor at Thorne and functional medicine doctor. As a reminder, the recommendations made in this podcast are the recommendations of the individuals who express them and not the recommendations of Thorne. Statements in this podcast have not been evaluated by the Food and Drug Administration. Any products mentioned are not intended to diagnose, treat, cure, or prevent any disease.

Hi everyone, and welcome back to the Thorne Podcast. I am greatly honored to have with me this week Dr. Lee Hood MD, PhD, who is a pioneer in the fields of human genomics, cancer research, Alzheimer's research, and also the co-founder of the Institute of Systems Biology in Seattle, among many other things. Dr. Hood has published more than 1000 peer reviewed articles, and his work has enabled the completion of the Human Genome Project. Before we get started, Dr. Hood, how about you tell us how your career got started?

Dr. Lee Hood:

Well, it's a pleasure to be here and to talk about my favorite of all topics, that is data driven health. Really, my career in many ways got started when I was six years old in Montana, and my younger brother was born with Down syndrome. I was struck by the fact that the doctor had no idea what caused it, yet it created this really profound change, and it became more evident to my brother Glenn grew up. I started asking myself, "Gee, what is this that makes some of us healthy and some of us not healthy?" And with that kind of a start, I went to Caltech as an undergraduate and got a terrific education in math and computer science, physics, well, not computer science at that time, math, physics and chemistry, and biology of microorganisms and viruses. And since I'd really gotten interested in human biology, I went to medical school, Johns Hopkins, for three years and graduated early, because I wanted to go into a research career and not a physician career.

I actually went back to Caltech and I studied molecular immunology and it gave me a wonderful window into the enormous complexity of humans and the deficiency and tools we had for really assessing that complexity. And after my graduate degree at Caltech, I was at NIH for three years and learned how to be a real scientist and run my own lab. And then went back to Caltech where in a sense my real academic career began in 1970.

And when you sit down at the beginning of such a career and ask yourself, "I can go any place in the world, what do I really want to do?" And it turned out that there were two things that were obviously of interest. One was continue in my efforts in molecular immunology, and that was a real driving part of my career for the first 20 to 30 years. But the other was this idea of human biology, and in thinking deeply about it being kind of staggered with complexity of human beings. And it was very much like the parable of the elephant and the six blind men, each blind man feeling a different part of the elephant and declaring it was a spear or a fan or a tree trunk or whatever.

What is interesting about the parable was at that time, medicine did very much the same thing. It made very few measurements. It mostly looked at the outside of a patient and tried to deduce what it was. And it was obvious to me that there were a number of things that were going to have to occur if we were to deal with complexity. So one was the idea that we really needed to be able to generate lots of data on human beings, so-called big data. And we didn't at that time have tools for doing it.

A second, was this really interesting idea that blood is a window into health and disease, because it [inaudible 00:05:02] all of your organs and the organs release molecules that if you can read them, will give you insights into the health of the corresponding organs. So the blood lets you review the entire internal part of the body in a way medicine previously couldn't touch. And then finally there was this kind of conceptual deficit of, "Look, we have all this data and all this information. What are we going to do with it? How do we put it together in a meaningful sense?" And that was the beginnings of my thinking about systems biology, which we'll talk about at later time. But that was integrating together different types of data from a human so you could get a coherent picture of the health.

Dr. Robert Rountree:

It really strikes me that you've been writing multiple waves of a complete transformation in the world of biology and biochemistry, physiology. I mean, this is not your grandmother's biology, this is not your father's biology. And certainly having studied biology in college, I majored in it, I don't even see much resemblance between what happens now and what happens then. And the point that illustrates that the most is I'm imagining when you experienced that with your brother, they didn't even know what chromosomes were back then. Right? We've gone from not knowing what they were to sequencing them.

Dr. Lee Hood:

That's right. That was 1944. And it wasn't until 1959 that we realized that Down syndrome came from, in some cases, from the replication of a small chromosome. So you actually had an extra chromosome and it still constitutes a major technical challenge of how to deal with it. I'll tell you that it's not a single gene defect.

Dr. Robert Rountree:

Yeah. Now, I heard Caltech mentioned in there, wasn't there a guy named Linus Pauling that was involved with that institution and did you get a chance to interact with him at all?

Dr. Lee Hood:

Well, I'll tell you, my freshman year, two of my teachers were Linus Pauling on occasional lectures in chemistry. And he was brilliant. And he was a showman all the way. And he really taught me a lot about how to teach science to students in a way that engaged and compelled them. But the second freshman teacher I had was Richard Feynman-

Dr. Robert Rountree:

Oh.

Dr. Lee Hood:

... very famous physicist. And when I was there, he was just writing his three volume series that he put out for undergraduate physics. And we were the test class for beginning to look at various of those chapters. And what was utterly amazing about Feynman is he could take the most complicated concepts and make them dirt simple for you. So you were utterly convinced you understood everything, until you went back to the dorm and tried to work the problems he had given you to solve. And you realized you hadn't absorbed everything that he'd put out for you. But those two people really, and they really taught me a lot about how to give lectures to other scientists too, and what's important.

Getting buried in the details of data and how you got it and things like that, that's not what science is about. Science is about poising questions and then using all this fancy technology to solve them and come to conclusions about mechanisms and biomarkers and drug targets and fundamental mechanisms of disease, all the things we can use systems approaches now to do so beautifully.

Dr. Robert Rountree:

Maybe you could talk a little bit more about what systems biology was or is. I don't think we had that phrase when I was in training. What does that mean exactly? And how does systems biology apply to day to day practice of medicine common diseases that we see like Alzheimer's or metabolic syndrome?

Dr. Lee Hood:

Well, I think the idea of systems biology is that one has to take a holistic, global and comprehensive view of the biological system you're interested in. And that means these things I described earlier in the elephant analogy. One key to understanding a systems approach to wellness or disease, either one, is you have to generate a lot of data at different states. So you can see how changes in wellness or changes progression and disease actually makes differences. A second absolutely central concept for systems biology is the idea that the circuitry of the body that mediates physiology, and indirectly wellness and disease, is made up of biological systems or biological networks. And what systems biology attempts to do is relate its data to biological networks and then to be able to look dynamically at wellness or dynamically at disease and see how these systems change in the context of disease progression or the loss of wellness. And those provide insights into how you can deal with unwanted changes.

A final point of view that has come to the fore very much more recently, is the idea that humans are still terribly complicated. And if you look at them one system at a time, that's still really insufficient. So from a computational point of view, we have to integrate together many new computational tools like knowledge graphs, like digital twins and like hyper scale AI. What they collectively will allow us to think about doing in the future, we can't do it now, is to essentially be able to take an enormous amount of data from an individual, and feed it into a digital twin that has the sum total of human medical knowledge, that it compares the individual against, and allows an analysis of individuals at a level that gets down to a microscopic windows we can't even imagine today.

Dr. Robert Rountree:

So it seems to me we're talking about a disease like Alzheimer's that the digital twin is particularly applicable. And I say that because there's been so much focus by the pharmaceutical industry on amyloid as being quote, "the cause of Alzheimer's." And their thinking is, "Well amyloids the problem, we need to get rid of it and we'll solve the problem." Whereas from a systems biology perspective, Alzheimer's seems like a much more complex disease.

Dr. Lee Hood:

That is absolutely correct. And look, pharma has already proven that amyloid is not the answer, because it's had more than 500 clinical trials in the last 14 years. All have failed. Almost all of those trials have been directed against amyloid or [inaudible 00:13:06] other classic proteins that people have argued cause Alzheimer's. And getting rid of those proteins doesn't change the features of Alzheimer's at all. And indeed, there are people that have Alzheimer's that have no amyloid whatsoever in their brain that's been deposited. So Nathan Price and I here at the Institute for Systems Biology have pioneered a beautiful digital twin system for Alzheimer's that has accumulated at the top level, physiologic data and fundamental mechanisms we know about how the normal brain operates, and at the biochemical level, all of the different types of data we have both for normal and in Alzheimer's patients. And we can use this conglomerated data then to begin looking at the data from individual patients and making predictions.

Dr. Robert Rountree:

Do you have any sense or theories, pet theories about what combination of susceptibility factors and lifestyle factors are really the things that drive Alzheimer's forward?

Dr. Lee Hood:

Well, just to make it simple, at a very high level, it's really clear that Alzheimer's is a metabolic disease and a major metabolic deficiency in the brain that is a fundamental component of that. It's also clear that the factors that can really impact brain metabolism include proper diet. They include exercise. They include proper sleep and things like ... It's living a healthy life. But the digital twins also lead to specific drugs that may be useful at various stages.

Dr. Robert Rountree:

So the way you would use the digital twin would be to predict for an individual what markers might be particularly useful, for example, like a inflammatory marker, like C reactive protein, you might predict that?

Dr. Lee Hood:

Exactly. Yeah, you could predict what known things are useful. And in the future when we gather all of the literature of modern medicine into the system, then we can go into areas that we haven't even thought about too. Because when you talk about things like diet, exercise, you're [inaudible 00:15:43] many, many metabolic things and making general statements. But with the data that we're going to accumulate in the future, we'll be able to be more and more specific, and unambiguously say you're at a stage where here's what we should do for you.

Dr. Robert Rountree:

So I understand that you're using this approach with predicting cancer as well. And I think a number of years ago I heard you talking about prostate cancer specifically. And what struck me is that in mainstream medicine we have one major screening tool, which is the prostate specific antigen. We do a PSA and then maybe a digital rectal exam, and that's about it. But in your talk, you were mentioning how we can measure mixes of proteins in the bloodstream. As you said earlier, the blood is kind of the window into the health of the body. So it seems like that kind of approach called proteomics has got a huge potential.

Dr. Lee Hood:

You know it does. And I think we can be much more expressive about how we can avoid chronic diseases now. One of the precision population experiments we did was a company called Arivale that brought scientific wellness to consumers. The strategy was to do a genome and longitudinal phenome analysis of these patients. And we did so over a period of four years. And during that time, we were able to demonstrate beautifully that more than almost 200 patients had transitioned from wellness to disease as diagnosed clinically. And since we had blood draws prior to the disease, up to four or five years before, we could go back and look and see in the blood if there were signals of this disease transition. And we looked at 10 transitions to various kinds of cancer. And for each case, we're able to show anywhere between a year and three or four years prior to the clinical diagnosis, there were major protein changes in the blood that signaled that transition that occurred at that point in time.

And the really key point is, having these early transition markers years before the actual disease manifests, means that we can use them to figure out how to reverse the disease at that very early stage when the disease is simple, and its reversal should be correspondingly simple. And we're actually playing with that idea with Alzheimer's now. And once we can initiate a data driven analysis of every individual and track them with regard to when these transitions come at early points, we could hope to keep people from ever moving into a disease state, once we'd figured out how to do that early reversal. This is one of two major ways that we can approach through prevention, chronic diseases, and have real hope in the future that we can diminish their impact on healthcare today. And just to give you an idea of how big their impact is, chronic diseases require about 86% of the healthcare dollars today to manage. And suppose we could essentially eliminate that?

Dr. Robert Rountree:

I have to ask you, what do you think is the near and ultimate future of DNA sequencing for disease susceptibility? Do you think that the day will come when every doctor has got a sequencer in their office and the patient can come in for an evaluation, you get a drop of blood and 30 minutes later you've either sequenced their entire genome or you've at least got certain genetic variance reported? Is that something that's feasible?

Dr. Lee Hood:

No, I think actually what's going to happen is every individual in the future will have their genome sequenced at birth. And since the genome sequence doesn't change, apart from cancer, that means you'll know all of the proclivities that individual has from the very earliest stage of their life, and you'll be able to prepare them for future possibilities of diseases that could be onset. So I think these will be large factories. I think the genome will be done for less than $10 to genome. It'll make it much simpler than virtually all medical tests today. And it'll be utterly a routine kind of procedure done on everyone. And I think we will read the DNA. That is, the DNA is the source code for how you develop, how you age and so forth. And we'll be able to understand better and better where the defects are and how we can ameliorate them.

And what's going to be very important in that is following with regular cycles, say every six months, a phenome analysis. And of course the phenome is the conjunction of your genome, your lifestyle, and your environmental exposure. But we can assess the phenotype, again, by looking at blood analytics, the gut microbiome, a lot of digital health devices that make various measurements. And we can do this not just for the body, but we can do that digital analysis of the brain that can analyze your 25 major cognitive features, and tell you when you're deficient and actually reconstitute those deficiencies. The key point about the brain and brain health is it's totally flexible, and even 80 year olds can have reconstituted lost cognitive functions. Really remarkable findings of a remarkable scientist called Professor Michael Merzenich at UCSF, and a company called Posit, that makes it now possible to do the kind of analyses on the brain that I've talked about here.

Dr. Robert Rountree:

So it's never too late. You're never too old to change things around.

Dr. Lee Hood:

But you're much better off to do things as you age, so you maintain all cognitive function, rather than lose them seriously and then have to struggle to reconstitute them when you're 80.

Dr. Robert Rountree:

Well, I think we need to take a break right now, and when we come back, we'll answer some questions from our listeners.

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And we're back. So now it's time to answer some questions that have come in from the community. Our first question this week comes from a listener who asks, what changes to the everyday person's life came out of the Human Genome Project? And I want to clarify this question by saying, well, Dr. Hood was really instrumental in the Human Genome Project and getting our DNA sequence, which is a major accomplishment. So I think that makes him pretty well qualified to tell us what has changed as a result of that information.

Dr. Lee Hood:

Right. Well, one thing I will say to begin with is, the human genome sequence was finished almost 20 years ago, and it's just today that we're beginning to see some of the effects with regard to health, that the genome can contribute. They fall into a series of interesting categories. So first, the American Society of Human Genetics has identified 76 variants in the human genome that lead to actionable possibilities for preventing or ameliorating disease. So if you have one of those, you can actually carry out actions that will avoid the consequence of that kind of gene. I'll give you an example of one that's really horrifying. It's a gene that encodes a disease called malignant hypothermia, and it's a defect that if the individual with that defective gene takes certain types of anesthetics, that triggers a hypothermic reaction that is irreversible and it kills you.

Dr. Robert Rountree:

Wow.

Dr. Lee Hood:

And of course, the simple actionable possibility, knowing that you have that chain is, we know which anesthetics you have to avoid, and you never need to worry about that. And that is a really dramatic example of what defects can do for an individual. So the human genome is just beginning to make its impact on health, and there are a handful of programs around the world that are doing this, but they're going to grow exponentially.

Dr. Robert Rountree:

So it seems like the key word here is it's allowed for personalized medicine, is it allows us to look at somebody's genome and say, "You shouldn't take this drug. Or maybe you shouldn't eat this particular food. Or maybe you're going to benefit more from certain kinds of exercise than other people." So it's really, it's predictive and it's personalized.

Dr. Lee Hood:

It is predictive and personalized, but it is also complicated as to whether you need physicians to be involved in dispensing these actionable possibilities. One of the reasons that this company called Arivale that was a data driven health company failed, is because it identified many actionable possibilities relating to disease, but it couldn't give them to the patients directly. It could only say, "Take this data to your doctor and let him make the diagnosis." And part of the problem with that is, an awful lot of doctors couldn't make the diagnosis, so there was a real conundrum. And I think as we educate patients and as we educate the healthcare system, we'll have more latitude on the wellness side of things, and we won't have to have doctors prescribing everything. But it is a tricky area today.

Dr. Robert Rountree:

So the next question, "Is cancer becoming more common, or are we just living longer and getting better at detecting it?" I assume what's behind that is saying, "Well, if you live longer that's the risk, that eventually you're going to have a very high chance of getting cancer." And cancer is thought of as a disease of DNA, which I think is still kind of the predominant hypothesis. So what do you think?

Dr. Lee Hood:

So what I would say is all of the above are true. It is true that if you live longer, you have a longer period of time that you're at risk for cancer. It is true that, excuse me, our diagnostic techniques are becoming better and better, and we can diagnose cancer early, and hopefully we can reverse cancers before they become irreversible. And of course, the general driving force in cancer is seen as mutation in your genes. And in fact, most cancer cells have many, many different mutations in your genome. But it's just a few of those mutations that drive the whole process of cancer itself.

And in fact, cancer is one of the most exemplified examples of precision medicine today, because one can actually sequence the tumor of an individual, identify variants and then identify drugs that could block the reactions of variants that have been demonstrated to be drivers of certain kinds of cancer. The limitation with this approach is one, those drugs and the drugs are generally antibodies, monoclonal antibodies, are terribly expensive. And number two, they typically last for nine months to a year. And then you become totally resistant, the patient does, to that drug, and maybe worse off than you were before. So it gives you another year of life, it costs you a lot of money, but it doesn't cure you. And that's something that is not really made clear when many physicians talk about the wonders of precision cancer medicine.

Dr. Robert Rountree:

Which again, makes the case for what you were talking about earlier in your discoveries from Arivale, that you could detect changes in the overall system, not necessarily like an increase in a tumor marker, but you could tell that something was off that was heading down the cancer pathway. And if you could do that, then maybe you can suggest some kind of lifestyle change that will head it off at the pass. That seems like the ideal.

Dr. Lee Hood:

That's absolutely correct. The idea then is for cancer, because mutations keep on going, in most cases you're not going to beat the cancer with drugs or therapies. I will say one remarkable new area in cancer therapy is immunotherapy where we're learning to harness in a number of different ways the body's own immune system to attack the cancer. And I think the effectiveness of that approach, we're just beginning to optimize and everything. And that'll be another direction we can take. But overall, I would say the ideal way to deal with cancer is to detect it really early and reverse it really early. And then you're done. And we can only do that if we have a data driven program where patients are tested routinely every six months to a year to look for these transitions, so we can identify them and do the reversal.

Dr. Robert Rountree:

So the next question asks about a technique, which maybe you can explain to our audience a little bit. It's called the CRISPR technique, or I think it's also called CRISPR/Cas, or CasPER. Could this CRISPR technique be used to extend the human lifespan? And I think that even leads to a bigger question. How much of our genes can we actually modify? And if we can do these modifications, what are the implications? Does it mean we could potentially live forever because we just keep changing our genes? Is the sky the limit? Or are there certain blocks to what we can actually accomplish?

Dr. Lee Hood:

Well, I think the first question you have to ask is, what is genome engineering? And this technique, CasPER CRISPR/Cas9, that won the Nobel Prize, what four or five years ago, has given us the ability to go into a genome and snip out defective pieces, and replace them with normal pieces. That's called genome editing. And it opens up the possibility of really exciting things. But a really critical question is, if you're born with a defect and the defect is identified as a teenager, an adult, or so forth, you have to remember that all the cells in your body have that defect. And the question is, can you engineer the change in the key cells that count with regard to that defect?

So one place we've succeeded in doing that is in stem cells for the bone marrow. For example, there are people that have defective hemoglobinopathies, and it's been demonstrated that you can actually get a bone marrow stem cell from the patient, re-engineer it, make it normal, give it back to the patient, and then use those stem cells to regenerate a population of normal cells that will replace the function lost by the defective gene.

And again, it's easiest now to think about doing that in terms of single gene effects. Though in principle, you ought to be able to go to stem cells and change 20 or 50, or even a hundred genes, if you knew which genes to change. And for most complex diseases, we don't today know which genes to change. So most of the focus of genome engineering is in areas where you can use stem cells to change the relevant cells and grow them out in the individual, and is focused on just single gene defects, where you can assay very carefully the effects. I will say that this genome engineering has enormous technical challenges. Not all of them have yet been solved. We have to be incredibly cautious about using genome engineering on human beings until we're assured every step of the way prevents any one of a host of complications that might arise and lead to complexity.

There was a very famous case in China of someone who attempted to cure gene defects in twins at an early stage. And it was a reprehensible act, because at that stage we weren't even remotely near being confident that we could do that without damage to the patient. We have to be cautious about figuring out all of the tricky aspects of this technique, but we will. And in time gene engineering will be a routine aspect of what we can do. If we did our complete genomes at birth, we'd be able to look at all of the gene defects we might have, and if there were defects we could manage by gene engineering, one could think about using that information to do appropriate gene engineering. So it's a technique that's very gradually going to come into use as we solve the technical problems for making it safe with human beings. We are nowhere near thinking about redesigning a human to make them more efficient, except possibly in very, very simple single gene [inaudible 00:36:35].

Dr. Robert Rountree:

I think some people would be reassured to hear that we're not quite at the place of cloning human beings or creating human beings in a test tube, because it's fraught with challenges.

Dr. Lee Hood:

And we don't know how. I mean, how would you go about designing a better human? You haven't the faintest idea, how do we do that?

Dr. Robert Rountree:

All right, folks, that's all the time we have for this week. Dr. Hood, thank you so much for coming on the podcast. If our listeners want to follow more of your work, what's the best way to find out what you're up to and what the latest is?

Dr. Lee Hood:

Well, I'll tell you, we've actually collaborated with Scientific American to create an issue-

Dr. Robert Rountree:

Oh-

Dr. Lee Hood:

... an 80 page issue on human wellness. And there are a whole series of articles by leaders in the field there, discussing this dramatic new approach to health. And I think this is going to be coming out in the next six months. And I would encourage you to look at that article. The second possibility ism my colleague Nathan Price and I have written a book called The Quest for Human Wellness: Prediction, Data Driven Prevention, And in Your Hands, that will be coming out from Harvard University Press next May. And this book discusses from the beginning to the end, what you need to do to have a transformation in healthcare, from a disease oriented approach to a wellness and prevention oriented approach.

Dr. Robert Rountree:

Terrific. Well, I'm really excited to see that. Can't wait to get my hands on a copy, so thank you. That was all. That was an excellent discussion. Until next time, thanks for listening to the Thorne Podcast. Make sure to never miss an episode by subscribing to the show on your podcast app of choice. If you've got a health or wellness question you'd like answered, simply follow our Instagram and shoot a message to @ThorneResearch. You can also learn more about the topics we discussed by visiting Thorne.com and checking out the latest news videos and stories on Thorne's Take Five daily blog. Once again, thanks for tuning in, and don't forget to join us next time for another episode of the Thorne Podcast.