Genomic Medicine Has Reached Clinical Practice

An Expert Interview with Eric J. Topol, MD

Jacquelyn K. Beals, PhD

March 22, 2011

March 22, 2011 — Editor's note: The Scripps Translational Science Institute has held a genomic medicine conference/course for 4 years, unique because of the equal participation of researchers and clinicians, and offering talks and panels of broad interest. The 2011 program presentations covered genomic diagnostics and sequencing, especially in cancer and diabetes, and a futuristic projection of where the field is heading.

In an interview with Medscape Medical News, course director Eric J. Topol, MD, director of the Scripps Translational Science Institute, chief academic officer for Scripps Health, and professor of translational genomics at The Scripps Research Institute in La Jolla, California, discusses highlights of the recent conference, The Future of Genomic Medicine IV, sponsored by Scripps Translational Science Institute.

Medscape: This is the fourth year of the Scripps conference on the future of genomic medicine. How do you feel it compared to previous years?

Dr. Topol: Without question, it was our most successful one yet. The reason is, it wasn't just hard-core genomic science that was being presented. We had a terrific blend of perspectives from journalists like Amy Harmon of The New York Times, and Thomas Goetz, the editor of Wired Magazine, and people coming at it from so many different perspectives.

One of the highlights was Howard Jacob from the Medical College of Wisconsin, Madison, who sequenced the first individual, a young boy, to save his life. There were so many things that were exciting. You could tell we'd made a quantum jump from prior years toward actualizing genomics in medicine.

These meetings attract a unique audience and participants, with 200 or so physicians and other healthcare professionals and almost the same number of scientists. It's a very interesting mix of half clinical and half science/research. What's great is that we finally achieved that kind of balance with the right kind of line-up for everyone, and each of the speakers keyed into that.

This year, we had an incredible futuristic talk by Juan Enriquez about where this is all headed — genomics and digital medicine. I think it was fully comprehensible, not over the heads of people, and that was a great thing. We also posted a syllabus online as a primer for physicians and healthcare professionals who were not up to speed on genomics, so they could spend some time on that. But that was less necessary [with our] excellent balance. It was fun! And we had this new venue, right on the ocean, which didn't hurt either!

Medscape: What did Enriquez talk about? And what were some other highlights of the meetings?

Dr. Topol: Each year we try to pick someone for the keynote lecture who has a unique insight into the field and its impact. What's great about Juan is he's not a genomicist and he's not a physician. He's a venture capitalist and he's a futurist — he's written books, for example, As the Future Catches You. He gave an exceptional presentation on where genomics is going to take us and how technology is going to change medicine. It really grabbed everyone. It was quite striking and people could identify with where he was pointing for the future of medicine.

Another major highlight — I mentioned the Howard Jacob presentation and what's going on at the Medical College of Wisconsin. They have a whole committee and a line-up of people with unknown disorders waiting to get sequenced, which is really far beyond where this was in December when it was first reported that they'd sequenced this boy and saved his life. Now they have another 30-plus children waiting in the queue to get sequenced, and they have a committee that decides who goes next. That was really fascinating — along with all the procedures they'd been through at the Medical College of Wisconsin — because that's been a pioneering effort to use sequencing to elucidate what's wrong with an individual with a serious illness.

The other biggie, of course, was Dan Van Hoff, who gave a presentation about cancer genomic medicine. He got a standing ovation — the only one of the program. He also got our annual Scripps Award in Genomic Medicine for his pioneering efforts in cancer. He clearly had an emotional, as well as a medical, impact on the group.

Medscape: What were some of the high points from your "Fireside Chat"?

Dr. Topol: I put together a presentation on the future of genomic medicine, and talked about why this field is taking off now, in spite of some uncertainties. I got into many different things that are catapulting the field forward. I'll do that each year now — just kind of a "future" talk.

We'll be able to do fetal DNA sequencing through maternal blood to preempt amniocentesis. We'll be able to do full carrier recessive-trait sequencing across all known recessive genes for couples planning to be parents. We're making major inroads in cancer in terms of therapies directed to the specific mutation, like in melanoma. I reviewed the cystic fibrosis breakthrough trial that was directed toward a very infrequent cystic fibrosis mutation — it's the first trial ever to show striking efficacy, and that's since the 1989 discovery of the gene for the cystic fibrosis mutation. So it took a while, but we're learning from these experiences about individualized medicine, where you only concentrate on a specific mutation of cystic fibrosis, rather than trying to cure the disease. The same with cancer, and the same with sequencing someone to save one's life, and the same with pharmacogenomics, which I zoomed in on a fair amount. I wound up where this field is going with the frank prevention of disease, an exciting opportunity that is looming and highly alluring. You can see it, it's going to happen. It's just a matter of when.

Medscape: What recent advances are moving us toward the prevention of disease?

Dr. Topol: I described projects that we're doing in heart attack, isolating cells and then getting the nucleic acid signature, so that ideally we can tell who's going to have a heart attack. We haven't done it yet, but we're moving in that direction. That would be sensed via an embedded nanosensor that would communicate with your cell phone! The same for cancer cell detection; in someone at high risk for cancer, as indicated by their genomic sequence before they ever had cancer, we would have continual surveillance of their blood and an embedded nanosensor that's talking to the person's cell phone. Basically, because of genomics, we're setting up opportunities like this to prevent the most common and important diseases of man. I have a book coming out called Digitizing Man, so I've put a lot of thought into this. I gave some previews of what's going to be in the book when it comes out at the end of this year.

Medscape: Last year's program focused on cancer, infectious disease, and applications. This year's emphasis was clearly on sequencing and diagnostics. Looking at the 4 meetings, what do they show about the direction the field is moving in?

Dr. Topol: Well, it's moving forward now. It's really got momentum, in spite of the consternation — that's putting it mildly — expressed by some. And that includes some journalists, as well as some in the field. Even the leader of the NHGRI [National Human Genome Research Institute in Bethesda, Maryland], Eric Green, had a relatively sobering piece in Nature [2011;470:204-213], when they had the 3 perspectives by Lander and Green and Mardis. Green talked about 15 to 20 years, and we're thinking about 15 to 20 weeks for steady progress, and I think we're starting to really see that!

Up until this year, there were fewer "exemplars" — we had the Plavix story that was a step in the right direction, but now we're seeing a lot more success stories like that. They span not just pharmaco and genetics any more, they're spanning these other areas. I talked about how, at some point, we should be able to get rid of the terms "idiopathic" and "cryptogenic" in medicine, which would be fantastic. I mean, who wants to walk around as an idiopathic individual, with whatever significant disease?

Another advance was the first reimbursement, ever, of whole-genome sequencing. That was presented at the conference. And I mentioned the first molecular autopsy, where someone had died but they're now sequencing that individual's DNA to find out why he died. It's actually a relative of Steve Quake, the genomics guy, engineer, up in Stanford. His young cousin died suddenly and now they're doing a molecular autopsy. It's happening in so many different areas now. In the past people thought, well, you can sequence a tumor or find a genotype related to drug interaction. Now it's more pervasive and it's gaining a lot of momentum.

Medscape: I was interested in the session on diabetes, obesity, and metabolic disorders. What's exciting in that area?

Dr. Topol: That area has lots of opportunity because we know type 1 diabetes is an immune-mediated disease, and we now know all the common variants in genes that are implicated. I think that is a really big opening, now that those genes have been identified, to zoom in with sequencing. Ideally, for type 1 diabetes, we should be able in the years ahead to get the insight to cure that disease, prevent that disease — it has to be prevented before the pancreatic islet cells are destroyed, so "curing it" means preventing it. Once the islet cells are destroyed, that's a different story, having to get islet cell transplants or stem cells, or you name it. I really believe that's going to be a big opportunity for genomics, from all the headway that's been made.

With respect to type 2, probably the imminent goal is the pharmacogenomics. There's been a big step forward with respect to understanding metformin (the number 1 drug in type 2) and the pharmacogenomics of that. There are 11 different classes of drugs for type 2 diabetes, and it's the most confusing area in all of medicine! Understanding, at the individual level, which drug is the right one to use and the right dose is essential. I think that's where we'll see, in the next few years, that type 2 will be ameliorated with management and better control of glucose, and hopefully with that better prevention of complications.

Medscape: I heard that 13 "new" genes had been identified as being associated with heart disease — 3 were previously linked to recognized risk factors but 10 seem to be a "black box."

Dr. Topol: I touched on that paper in my talk, and it was also presented by the last speaker, Muredach Reilly, from [the University of Pennsylvania Medical Center in Philadelphia] (he substituted for Dan Rader from the original program). There are 35 common gene variants now — genomic variants, a lot of them are not in genes but they're labeled by a gene nearby — and 13 are labeled as "new." The problem with these new ones is their very tiny impact, with odds ratios like 1.05, 1.08, or 1.10. You know, the first one to be unraveled was 9p21 [locus], which of course is not in a gene. We published a Nature paper in February to show part of how it works [2011;470:264-268]. But 9p21 is so important and so dominant! These new ones are of statistical interest, but we don't know yet whether they're of biologic significance. So they add to the list. Thirty-plus loci have been identified now for most common diseases; now you can add coronary disease to that group. But the new variants don't add to the heritability explanation. We still have less than 10% of the heritability explained by all the common variants.

Medscape: Could you talk more about the keynote talk? How was Juan Enriquez attracted to this area, and what's the source of his interest and expertise?

Dr. Topol: Well, he's a cofounder of Synthetic Genomics, Inc., of La Jolla, California, and the Life Sciences Project at Harvard Business School in Cambridge, Massachusetts, so he knows genomics at least from that standpoint. He's an exceptionally bright, informed guy. His book, As the Future Catches You, which came out several years ago and was very widely read and cited, has genomics in it. One example he used, and I remember it well — he has a bunch of zeros and ones for the word "love," and then a bunch of zeros and ones, minimally changed, that are digital for "hate." He points out how, in a digital world, you can make a few little changes and look at the difference! In genomics it's the same thing. He's been translating genomics unwittingly for the public for some time, because of his unique perspective of not being a genomicist. That helps a lot, because he's able to articulate it really well. He has a new book that's only available electronically, called Homo Evolutis, about how our species is further evolving through all these things. In the past, we've always had a genomics person [to give the keynote address]. But Juan and I were both speaking last September at a program, and I could tell he was perfect for this type of gathering because he can connect with anyone. He's a really fine speaker, and he had everyone hypnotized for 45 minutes.

Medscape: What other presentations or panel discussions dealt with hot topics or subjects of interest to your audience?

Dr. Topol: One of the panels I gave with Amy Harmon and Misha Angrist. Misha has a great view of the field. He has a background in genomics, and he has a book out, Here Is a Human Being: At the Dawn of Personal Genomics, that he wrote about getting his genome sequenced. He's at Duke and was one of the really great presenters. As was Thomas Goetz of Wired Magazine, the one that studied Sergey Brin and the whole Parkinson's disease genomics issue. Thomas wrote a feature article on that.

In the panel with Amy and Misha, just the 3 of us, we talked about how clinical trials might change. In her feature articles in The New York Times, Amy Harmon wrote about the clinical trials of the melanoma drug [PLX4032], the BRAF inhibitor. She wrote this incredible series of articles about a man and his cousin: One got the drug and it melted the tumor, and one got the placebo and died. Is it ethical to do those kinds of trials anymore? When you have such incredible scientific evidence of what your drug is directed at, how long can you keep doing placebo-controlled trials just to count up how many months of survival you get in people at such extraordinary risk? The panel talked about [whether] the current model of randomized clinical trials need to be rethought. I think a lot of people in the audience got stirred by that. We need to get rid of these trials of 10,000, or anything more than 1000, patients or we won't be able to continue to develop important therapeutics. It's too ridiculously expensive and time-consuming.

Medscape: Have you started thinking about where you want the meetings to head next year?

Dr. Topol: We haven't set up the program yet, but we're already discussing some of the folks we'd like to try to get here. We have the dates already: It's March 1 and 2, 2012. Same venue, right on the ocean — we've booked it for the next 3 years.

Dr. Topol has disclosed no relevant financial relationships.


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