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Health See other Health Articles Title: The True Revolution in Medicine Venter and Topol on the True Revolution in Medicine Eric J. Topol, MD: Hello. I'm Dr. Eric Topol, Editor-in-Chief of Medscape. I'm really thrilled to have with me Dr. Craig Venter [founder and CEO of the J. Craig Venter Institute and Synthetic Genomics Inc.]. We're going to be discussing genomics in medicine and all sorts of things. As you know, Craig is really a hero of mine, a friend of mine, but also the most accomplished scientist of our era. It's really a great privilege to have a chance to sit down with you today. J. Craig Venter, PhD: It's good to be with you. Genomics in Medicine: 13 Years Later Dr. Topol: You've been thinking a lot about genomics over many years. I still remember that White House meeting in 2000 with President Clinton and [current National Institutes of Health (NIH) director] Francis Collins. At that time, of course, it was said that genomics was going to have a big impact on medicine. Now we're here 13 years later. What do you think? Where are we going to go with genomics in medicine? What's holding us back? Dr. Venter: Well, lots of things. Everything from how we fund science to the rate of change in medicine. Fortunately, as you know, we've had a huge technology change in the past decade -- not a lot of genomic advances but a lot of technology changes. We had a giant building filled with 300 sequencing machines that sequenced the human genome in 9 months. We had another giant building with a computer that was 1.5 teraflops. Both of these were 4-story buildings. Today, as you know, each of those buildings can be replaced with small boxes, and that 9-month period can be replaced with merely a week or two. So things have changed dramatically. The Human Genome Project[1] ended up costing about [$3 billion] globally. Our team spent around a mere $100 million on the project, but those efforts are replicable in terms of affecting patients. Now, it probably costs less than $10,000 to sequence a genome if we're being realistic about it. That's starting to change the number of genomes that can be done. We're starting to get actionable data. If you have lung cancer, as you know, the most important thing is to sequence the cancer gene, which determines whether Pfizer's crizotinib [a personalized drug for non-small cell lung cancer] will work on your type of tumor. There's probably no more important information to have, but these are just dribs and drabs coming out. Cancer and Genomic Disease Dr. Topol: That's actually one of the questions about cancer or genomic disease. If somebody has cancer, it's now at the point where you get whole genome sequencing of the tumor, the germline, and find out what the driver mutations are and how to develop precision therapy based on those mutations. As you may know, 11 of the 12 drugs approved by the US Food and Drug Administration (FDA) for cancer over the past year cost over $100,000 each. So, what you're talking about in terms of sequencing costs plummeting, do you think that sequencing cancer tumors is a logical way to move the standard of care in the years ahead? Dr. Venter: It really depends on the pharmaceuticals. The Pfizer drug was discovered almost by accident in that the clinical trial failed. Then they found that if you had a certain point mutation you had a 60% chance of tumor regression with crizotinib. I think it needs to be part of drug testing and drug development in the future because these markers don't need to be causal, only coincidental. And that understanding needs to be part of how the clinical trials are done from the outset. If we use genomics and incorporate it into every part of medicine, we'll start to build the databases to make it so that these [personalized drugs] aren't rare events, but we need large numbers to do so. That's the problem. Having my genome, having Jim Watson's genome, and having a few other people's genomes doesn't change the course of medicine. We need tens of thousands of sequenced genomes. Dr. Topol: Maybe millions, right? Dr. Venter: Yes. Tearing the Walls Down Dr. Topol: Why don't we tear the walls down and have all of the sequencing that is being done pulled together? Wouldn't that be a way to accelerate sequencing in the same way that technology is accelerating? Dr. Venter: Well, there are problems. The sequencing technology today, even though it's faster and cheaper, is still not up to snuff. In fact, the most accurate genome sequence was my genome, which was sequenced in 2007. It was the first and only truly diploid genome for which we could separate half the types. So, although we've gotten faster and cheaper, the technology has gotten less accurate. It's going to be a real challenge for the FDA to get whole genome sequencing up to diagnostic-quality standard. Dr. Topol: That is such an important point you made about your diploid genome. In general, we don't do de novo assembly. We have a shaky human reference genome. What are your thoughts about that one? Dr. Venter: It's done in a way to avoid the [hefty] costs but it's also the real part of genomics that's needed. What you want to know about yourself is your complete diploid genome, which means, "here's the sequence of the chromosomes that you got from your mother; here's the one you got from your father." Because, in doing that, we can actually find what's called compound heterozygotes. As you know, that is totally different from simple sequencing. You have this single-nucleotide polymorphism (SNP) variation, and probably most genetic diseases, like most human traits, are a combination of what we get from both parents. Without the complete diploid genome, we won't know the true impact of the genetics associated with disease. World's First Carbon-Neutral Research Building Dr. Topol: So much of what's missing today is the rare or low-frequency variant alleles that we're hopefully going to find a lot more of in the future. But you're now building a new institute here in La Jolla, California, which I drive by all the time. It looks really fantastic. When is that going to be ready and what are you going to do in there? Dr. Venter: It's a unique model. We're going to be the first truly independent research institute on the University of California San Diego (UCSD) campus. It's part of, but also independent of, UCSD. It's going to be putting new things into action. It's going to be the world's first zero-carbon or carbon-neutral research building. It's not so hard to do with an office building, but it's very hard to do when you have computers and fume hoods and are following Occupational Safety and Health Administration (OSHA) regulations for air changes. It's really trying to put all of these things into action to show that you can build an environmentally interactive building and do high-level research. We're going to do all of the things we currently do. There is going to be a lot of synthetic genomics research and a lot of environmental genomics. We're going to continue our ocean sampling and similar techniques that we've used to start this new field -- the microbiome. The Microbiome's Role in Health and Disease Dr. Topol: I wanted to get into that because it is such a hot area. Again, you were ahead of the curve. Years ago, you were pushing on the microbiome. And now, particularly the gut microbiome seems to be linked with obesity, diabetes, even hypertension. Where are we going to go with the microbiome? Are we all going to start having gut microbiome sequencing? Dr. Venter: It's not just the gut. It's the oral cavity. It's the skin. It's the vagina. It's really important because, as you know, we have 20,000-plus human genes. We have about 10 million bacterial genes. So, the complexity of the bacterial metabolism affects what's circulated in our blood. We all have about 50 chemicals circulating through our brains right now from bacterial metabolites of human chemicals, as well as chemicals from our diet. Nobody has ever looked or even asked the question of what they do because we didn't know they were there. It's not surprising that it affects medicine. We are humans in a microbial environment. We're breathing microbes and viruses right now. They're part of our whole physiology. Again, we need large populations to understand that. But almost everywhere people look now, using our techniques with the microbiome, they're finding clear associations. There is going to be microbial replacement therapy, but hopefully, instead of the kind of antibiotic therapy we've been using, we can go to very targeted therapy. We're developing synthetic phage at my company, Synthetic Genomics, to target very specific bacterial populations. For example, if you want to get rid of H pylori, you don't wipe out your entire bacterial populations. You get rid of just the H pylori. Dr. Topol: Or for C difficile,maybe we can get past fecal transplants? Dr. Venter: Exactly. Dr. Topol: That would be nice. Dr. Venter: We can simply define those populations and do it with a simple pill or suppository in a very defined population. It will work for that individual, instead of just using average medicine practices for the average population. A Better Way of Making Influenza Vaccine Dr. Topol: [Let's continue with] synthetic biology, which is another area that you've been leading. When we were together at the WIRED for Health program in October, you were talking about making vaccines and about the way we now make flu vs the way we'll make them in the future. Can you give us a little snippet about that? Dr. Venter: Take H1N1; by the time there was a vaccine available even for healthcare workers, the pandemic peak had passed. We have a very slow response for making flu vaccine. If the H1N1 pandemic had been as bad as people had predicted, we would have been in very deep trouble in the world. It would have been much more like the movie Contagion than it ended up being. We're looking for new ways to make the vaccine quickly. We now have it down to less than 12 hours by simply making the virus synthetically using synthetic DNA. Biomedical Advanced Research and Development Authority (BARDA) at NIH sends us a flu virus test sequence in an email. After that, we have 12 hours to make it, and then we get that to Novartis to take to its cell culture facility for producing flu vaccine in North Carolina, which makes the current practice of using 9 billion chicken eggs each year to make flu vaccine seem really archaic. Dr. Topol: It's amazing, isn't it? It sounds like a much better solution. When could that get rolling? Dr. Venter: It's basically waiting for FDA approval. We're ready for a pandemic, and that's the good news. We're trying to get approval to use this method with the annual influenza vaccine. The way the flu vaccine is chosen each year is, again, a pretty archaic process. It doesn't use molecular information, doesn't use sequence information. We're part of a group that just published the 10,000th flu genome. We're part of a group that's tracking the emergence of the flu virus around the world. We're developing algorithms to actually predict the changes going forward based on what we've seen, but synthetically we can have on the shelf a vaccine against every imaginable flu strain that you just pull down and expand if needed. In fact, it's going to get even more exciting because we're building what we're calling a digital biological converter, being that digital information and DNA information are now interchangeable. So, as BARDA sends us an email of the pandemic sequence, we're trying to build devices that allow us to use electromagnetic waves to send a new vaccine around the world in less than a second. You just need one of these converters to download it. In the future, people will be able to download protein drugs. For example, if you have diabetes, you could download insulin from the Internet to your home. You'll also be able to download vaccines. Twitter and Other "Fun" Stuff Dr. Topol: Now we're really getting into the digital medical revolution. Let's get into some fun stuff, like Twitter. You're on that occasionally. What do you think of Twitter? Dr. Venter: I think it's a good way to get information out quickly. Like anything on the Internet, the joke is that if you had an infinite number of monkeys and an infinite number of typewriters, you'd get all the great works of literature reproduced. I would say that the Internet proves that that's totally false. We don't get better and better literature out of it; we get worse and worse. But Twitter is a very effective way of getting information out quickly and getting responses. Quite often I can find things on Twitter before any of the news outlets have it. It's a great way for communicating to the scientific community. People think of it as the short stretch, but you can attach an awful lot of information to it. Dr. Topol: No question. Dr. Venter: I'm finding it very useful. Dr. Topol: You're a biker; have you been on any trips lately? Dr. Venter: I haven't had time for any long ones, but I had a very nice trip yesterday afternoon in an antique BMW with a sidecar. Dr. Topol: Sounds pretty good. What about an electric car? Dr. Venter: I came here today in a Tesla. Dr. Topol: The roadster or the S? Dr. Venter: The new S car. Dr. Topol: What do you think of that? Dr. Venter: It's actually going to change transportation. I had a Roadster before. That was more like a fancy go-kart. Tall people like you have trouble getting in and out of those. With the S car, there are no knobs or buttons. It's all touchscreen. It's just fantastic. Once people try it, they won't want to go back to other kinds of transportation. In fact, we get software upgrades while the car is sitting in the garage because it's attached to the Internet all the time, even while you're driving. There was actually a problem with the car, so a technician in the Bay Area logged on to my car and repaired it while it was sitting in the garage overnight. As soon as we can do that with people we'll be all set. Funding Science: Spending It Badly? Dr. Topol: As you know, we're kind of in peril with research in this country, with things like sequestration and whatnot. Where do you see the funding going? The opportunities, perhaps you'd agree, are more exciting than ever. Then we have funding issues. Where are we going to go with that? Dr. Venter: We're not short on science funding in this country. We have incredible amounts of science funding. We just don't spend it very well. Peer-review funding is risk-averse. We have a few agencies, like Defense Advanced Research Projects Agency(DARPA), that go out on a limb and take risks. NIH is just the opposite. Nobel laureate Hamilton O. Smith, in 1994, submitted a grant to NIH with our new method to sequence the first genome in history. It was turned down with extreme prejudice, but as soon as we sequenced the first genome and published it, we could get all the funding in the world. So once it's proven and already established, you can get funding for it. You can't get funding for new ideas very easily. People like you were very successful and used last year's grant to fund the next thing because you're ahead of the game, but investigators with single grants can't do that. We need to find a way to become risk-liking. I just don't know whether the government can do that. They may have to contract independent parties, much as DARPA does. They bring in academicians for short periods of time to do the funding. We're not short on money; we just spend it really badly, and this has been a long-time problem. Dr. Topol: I know. Can we have a peer review of the peer-review system? How do we get this thing shaken up to be better? Dr. Venter: The academics might not like it, but peer review is like the prisoners running the prison. They're not going to vote for change. Universities like this system because it helps support the universities. We have to change it so that 25%, 30%, 40% of the money is set aside for true risk research with independent parties to do that. That's going to disrupt a lot of things. I argue that the American public should be outraged that there's not 10 times to 100 times more breakthroughs in medicine every year over what we're getting, particularly for the money that's being spent. San Diego: A Hub for Progress Dr. Topol: I couldn't agree with you more about that. Now, speaking of progress, San Diego is a hub partly because you're here. I know that you even got Bill Clinton to say some nice things about San Diego, but what are your thoughts about the future of digital-world genomics in this San Diego hub? You're obviously having a big impact here. Dr. Venter: One of the reasons we came back here after going to school here a very long time ago, in the early 1970s, is that the spirit of cooperation here is greater than anywhere else. In Washington, DC, there are a lot of great universities and institutions. But they don't talk to each other. I was at NIH for 9 years. People on one floor don't talk to people on the other floor. It's really isolated and it's a different kind of culture. Maybe it's the sunshine here and the ocean, and people get outside and interact; whatever it is, we can get a lot more done here because of cooperation and collaboration than you can in other environments in this country. Dr. Topol: We've got the life science industry here and IT wireless and so many academic institutions and institutes. It's really extraordinary, and it's great having you here to give it an extra jolt -- that's for sure. Dr. Venter: It's a great place. There's such a talent pool here. We don't have any trouble hiring top people all the time, and that makes a big difference. You can't do that in an isolated center. Life at the Speed of Light Dr. Topol: Well, you had a great book, A Life Decoded.[2] I learned a lot about you from that book. Are you going to do another book? Dr. Venter: I have one coming out in October. Dr. Topol: Tell us about that. Dr. Venter: It's called Life at the Speed of Light. It really talks about what we've done in synthetic biology, basically within my lifetime and starting 2 years before I was born in 1946. In 1944 was when Oswald Avery's experiment was done to prove that DNA was the genetic material.[3] Even the community was slow to accept that. People wanted proteins to be the genetic material. So, basically in a single lifetime we've gone from very screwed-up notions of what genetics was thought to be, to understanding with Watson and Crick in 1953 the structure of DNA,[4] to Marshall Nirenberg[5] working out the genetic code, and how we went on from this 4-letter code to making all the proteins, to understanding all of these structures. And now we can send things through the digital world -- the interconversion of the two. That's what we did by making the complete genome chemically from bacteria and transplanting it and getting a new species. We proved that, in fact, DNA contains all the information necessary for life. People think that epigenetics is some separate field from genetics, but epigenetics is still genetics. It still starts with that 4-letter code and creates everything in the cell. All of this happened within the past 70 years. That's pretty extraordinary. I think people lose sight of that. These aren't ancient findings. A hundred years ago people had no idea what genetic material was. We're just at the start of the true revolution in medicine now that we can read it. We can read it on individuals. We can understand it. We can relate it back to physiology if we can define a human phenotype on a broad scale. In the next few decades, all the questions that we've had about nature and nurture will be answerable for the first time in history. That has to change how we do diagnostics, how we do preventive medicine, and how we treat diseases -- knowing who can really benefit from what pharmaceutical. I think it's going to be the most exciting era if we do it intelligently. Dr. Topol: Undoubtedly you will have a profound impact, and in just a matter of time, right? Dr. Venter: That's just it. Things do take a lot of time to get accepted in the community. Post Comment Private Reply Ignore Thread
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