The Biggest Thing to Happen to Biomedicine in Decades?

Editor's Note: Over the course of his 30-plus-year career, George Church has pioneered not one, but several transformative fields in medicine, including genomic sequencing, synthetic biology, and, most recently, genome engineering. In this One-on-One, Medscape Editor-in-Chief Eric Topol talked with Dr Church about his many research interests, the promise and controversy of CRISPR gene editing, and how he never gets bored.

From Dropout to Harvard Scientist-Engineer

Eric J. Topol, MD: Hello. This is Medscape One-on-One. I'm Eric Topol, editor-in-chief of Medscape. I'm delighted to have with me George Church, one of the most noted scientists, engineers, and geneticists in the world, and certainly one of the most interesting people in all of biomedicine. George is a professor at Harvard, where he has done an immense amount of work.

People in the medical community may not be familiar with your background. You were at Duke and received combined degrees in 2 years in zoology and chemistry. And then something happened during your postdoctoral work, when someone told you, "Forget it."

George Church, PhD: I flunked out during my PhD and had to go to a lesser university, Harvard, for my PhD with Walter Gilbert.

Dr Topol: Then you were at University of California, San Francisco, for a stretch?

Dr Church: Yes, I worked with Gail Martin on embryonic stem cells and then returned to Harvard in 1986.

Dr Topol: You have expanded your reach. Can you tell us about the Wyss Institute [at Harvard]?

Dr Church: The Wyss Institute is about biologically inspired engineering. It's basically innovative and an incubator for translation into companies.

Dr Topol: Do you want to be known more as an engineer or a scientist?

Dr Church: I overlap from basic science to putting things into societal settings.

Dr Topol: You have done so many different things over the course of your career—everything from sequencing the genome and involvement in many companies related to that, to synthetic biology. You wrote one of the most extraordinary books, Regenesis. That book had a special feature, with its 70 billion copies.

Dr Church: This was an experiment that I did with my own hands. I used a computer program to translate the book into DNA. Then I made 70 billion copies of it, which was more than the sum of the top 100 books of all time. Then I read it out with next-generation sequencing. And this has now taken on a life of its own. It's becoming a real industry.

Dr Topol: Do you think that data storage in DNA will actually take off?

Dr Church: Yes. We have had funding from Technicolor, and we've been encoding some of their archival movie footage. It is a very special application—it's archiving information. It's very challenging to do that for long periods of time, with changing standards and degrading media. DNA has an amazing record of 700,000 years without particularly good technology. And there's no disk drive that's quite in that league yet. It's a million times smaller than any other media.

Dr Topol: There may be a future there, and even more likely so since you've gotten involved.

Bringing Back the Woolly Mammoth

Dr Topol: What about the de-extinction work that you have been doing, where you are trying to bring back extinct animals?

Dr Church: Increasingly it's being seen more as environmental ecological conservation of current ecosystems. As it turns out, there are keystone species that are sometimes missing. That's definitely true for the tundra, which is one of the biggest ecosystems in the world, in Siberia and Canada. At the same time, the Asian elephants are endangered. The idea is to extend their range back out to their nearest relative, which is the mammoth. We happen to have very high-quality DNA sequences for this extinct species. We are basically trying to make cold-resistant Asian elephants to save that species and save the carbon that's locked in the tundra.

Dr Topol: Is this possible?

Dr Church: We've experienced stranger things. They actually like the cold. They'll play in the snow. It's just getting them from zero to minus 40.

Dr Topol: Is that a side project?

Dr Church: That is a side project. It's adequately funded, but our main work is on finding therapies for human diseases.

Dr Topol: Yes, let's get into that. But you are involved in a bunch of projects—you do need a lot of stimulation! I can't imagine that you ever get bored.

Dr Church: No, definitely not.

Dr Topol: So how many people work in the Church lab?

Dr Church: We have about 100 right now.

CRISPR: Its Promise and Controversy

Dr Topol: This is not the only other area, but this is an area of significant effort right now—genome editing. The CRISPR revolution has taken us by surprise. You and I are close to the same age and we lived through the Asilomar Conference [on Recombinant DNA]. In the 1970s, what was the big controversy?

Dr Church: Back then the controversy was that we might accidentally cause a problem—for example, putting an Se40 cancer gene into an E coli vector, a gut bacteria, thereby accidentally causing colon cancer. None of those fears materialized, but they were combined with fears that had been around since in vitro fertilization began, at about the same time. Even if we didn't make a mistake, we might go off and start devaluing life or something, which also hasn't yet happened. Now that we have really powerful ways of engineering human cells, those issues have come up again.

Dr Topol: Let's fast-forward to the past few years, when genome editing has become center stage. You've been a principal in that. For those who are not fully initiated, can you describe why CRISPR is such a big deal?

Dr Church: Our group and others have pursued about 10 different ways of doing genome editing since I started my lab in 1986. This is the first technique that works well in every species. We have some that work well in E coli but don't work in humans. We have others that work in humans, but they were very hard to repurpose for a new gene. This one is the easiest. For $60 you can get a kit from a nonprofit, and along with a regular microbiology lab, you are up and running. Every organism has been tried and it works. It's mainly academic excitement. When you get to therapeutics, where you are going to be spending half a billion to a billion dollars on clinical testing, I don't think it's that significant. But then the second feature comes in, which is not just the ease of use but the efficiency of editing.

Dr Topol: That's pinpoint precision—when you want to take out an "A" and go right there. You don't want any off-target effects, because that could have harmful consequences. So how good are we at precision editing?

Dr Church: Straight out of the box, with a good computer program predicting where you should do the editing, you can get error rates down lower than the spontaneous mutation rate, meaning that the stuff just hitting you in the air is worse. There are about six new technologies for improving the editing error rate, and it's hard to say why if we're already below the spontaneous mutation rate. But those are another factor of 1000. If you do it from a clonal cell line, such as a stem cell line, and you characterize the clone, that's another factor of 1 million. So we were many orders of magnitude. That doesn't mean that something can't go wrong, but it's probably going to be a systems biology error rather than an off-target DNA. That would my prediction.

Dr Topol: So, you think that the chance of having a downstream untoward consequence years later, such as cancer, is quite unlikely?

Dr Church: As long as you use the best practices, you would have to hit a tumor suppressor gene, which means that you would have to have off-targets there. Because you can test all of this stuff in advance, it's unlikely that you are going to get off-target. But there are systems biology issues. When you change one thing by any mechanism, by drugs or gene therapy, you get a secondary effect that has nothing to do with DNA.

Dr Topol: It's complicated.

Dr. Church: That is what we need to remind ourselves of, and that's why we do the clinical trials.

Gene Editing of Embryos

Dr Topol: Speaking of clinical trials, there are now a number in genome editing for rare diseases, and some that are not so rare, such as hemophilia and sickle cell disease. Is it good to get these into clinical trials?

Dr Church: There are 2000 clinical trials for gene therapies in general. Only a tiny subset are in gene editing so far. But in 2017 we will start seeing the first CRISPR trials going on. And that will blow up to be at least as big as the rest of gene therapy. Some are even more common than hemophilia and sickle cell disease—there are infectious diseases, HIV, and cancer. There are already clinical trials on the universal CAR T cells for anticancer therapy.

Dr Topol: There was a baby who was saved by T-cell manipulation editing with TALENs [transcription activator–like effector nucleases]; that was the first time a person's life was saved through gene editing, even though it was ex vivo.

Now, there has been a lot of controversy with CRISPR. Instead of clinical trials that are going to begin in the next year or so, there is the controversy about editing the embryo.

Dr Church: I would presume that that would be a clinical trial too.

Dr Topol: Yes, but that is different from people who have a condition—this is the unborn. A lot of ethical issues have been raised. What are your thoughts about that?

Dr Church: There is a tendency to conflate the clinical trial, and the safety and efficacy testing that all new technologies have, with worries about using it in some way that is unlikely to be among the first set of things for which it is used. For example, if it is restricted to reversing very serious genetic diseases like Tay-Sachs to a normal DNA variant—for example, in the male sperm—you are not risking embryos. In fact, you could save embryos because the alternative is typically termination of pregnancy.

That scenario hasn't been discussed very much. Usually people jump to some scenario that may be 50 years away, in which we are creating super-genius babies. We need to get a grip on what is the likely medical pathway. It would be very hard to refuse parents the option of avoiding an abortion and having a non–Tay-Sachs family.

Dr Topol: In the UK, they are going forward with this, at least with research. Where does it stand in the United States? Has it been banned?

Dr Church: It's legal in China, the United States, the UK, and a number of places. It's just that you need private funding in some of these places.

Dr Topol: That's what I meant—it's not supported by the government, the National Institutes of Health (NIH), here in the United States.

Dr Church: That's different from a ban. For example, embryonic stem cell research was not supported by the government, but it exploded economically in California, Massachusetts, and a few other places, where $3 billion was committed to it. That's very far from no support. In fact, it could have the unintended opposite consequence that if the NIH doesn't support it, then it's going to be supported privately.

CRISPR Patent Dispute

Dr Topol: It might move more quickly and get even more funding. It is controversial, though, that it could be used in a way that is of concern to people. Another controversy has been this whole patent dispute, which is perhaps a distraction. But it has received a lot of media coverage. What are your views about that?

Dr Church: I don't think it's any more of a distraction than the race for sequencing the human genome. If that is what gets people's attention, then finally people are paying some attention to science, though not in the way I would have wanted. Fortunately, I'm not involved directly in the patent dispute because our patents on CRISPR are undisputed.

Dr Topol: Have you collaborated with Jennifer Doudna and the group at Berkeley?

Dr Church: I have worked with her. We haven't coauthored a paper. I have coauthored a lot of papers with Feng Zhang. I'm not taking sides. I like both sides.

Dr Topol: What did you think of Eric Lander's "The Heroes of CRISPR" in Cell^[1] a few weeks ago?

Dr Church: I offered to proofread it for him in advance, but he only gave me a few hours before it came out. It was a good idea to give credit but others saw some bias, and in the end, not much credit was given to the young people who actually did the work. That was one of my key critiques. If you are going to give credit, give it to Luhan Yang, Prashant Mali, Le Cong, and so on.

The Next Big Push

Dr Topol: Would you say that genome editing is the biggest thing that has happened in medicine in decades?

Dr Church: I don't need to say it because other people have said it. I say wait and see. We have three other technologies that don't make double-strand breaks. One of the problems with double-strand breaks is that it is a side reaction, called nonhomologous end-joining, that is not precise editing. It's very imprecise editing. Any method that is easily reprogrammed without double-strand breaks would be even better.

Dr Topol: Even with the technology that exists today, last year you published^[2] that you could edit 60 genes simultaneously, and you brought back the idea of xenotransplants.

Dr Church: Yes, that's true. I may be getting ahead of myself. We should celebrate where we are. But even with CRISPR, it seemed daunting to change more than one or two genes at a time. We took on the 62 endogenous retroviruses, which had basically set back—15 years ago—a billion-dollar investment in commitment to transplantation from pigs to humans, which was a very promising direction. With CRISPR we could do that in 14 days.

Dr Topol: The thought that, with genome editing, we could deal with the massive problem of donors and organs for transplant is really striking. Where do you go next? You've done so much. What will be your big push over the years ahead?

Dr Church: With CRISPR, we are going to engineer wild species, because a huge fraction of our health problems are caused by rodent and insect vectors—Lyme disease, Zika, malaria, and so forth. But the next thing has to do with the BRAIN [Brain Research through Advancing Innovative Neurotechnologies] initiative. We have wonderful Intelligence Advanced Research Projects Activity (IARPA) funding for connecting the brain activity map with the connectome at the synapse level of resolution, and turning that into visual machine-learning algorithms, which is the killer application in the Internet, where you have driverless cars, Google recognition of images, and so forth. That's far behind where it should be, due to a lack of understanding of how the mammalian visual cortex works.

Dr Topol: Your impact on the BRAIN initiative is going to be very significant. It's striking that you have all of these different bases covered, and you are making momentous contributions in each. It also gives the sense that there is so much more that can be achieved.

This has been fantastic. If there is an interesting person in all of biomedicine, it must be you.

I wish we had hours to chat so that the Medscape audience could hear more of your thoughts and what you think are going to be directions for the future. But thank you so much for joining us.

And thanks so much to all of you on Medscape. We'll continue to bring along some of the most interesting people in the world of medicine, and certainly that is fulfilled by George Church. Thank you.