Personal Profile: Interview with George Church

Editor's note: The interview series in Rejuvenation Research is a unique and, I believe, highly valuable feature of the journal, giving readers insights into the thinking and motivation of some of the most influential movers and shakers in the many disciplines—not only biomedical ^{1 –7} but also political, sociological, ethical, and more ^8,9 —that impinge on the crusade to defeat aging. Dissemination of the views and insights of such people is essential to the process of communication between the field of biomedical gerontology and the many constituencies that will be affected by progress against aging—a dialogue that, as I ^{10 –20} and others ^{21 –32} have noted recently, is essential if we are to develop effective interventions against aging with all possible speed.

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George Church

George Church is Professor of Genetics at Harvard Medical School and Director of PersonalGenomes.org, providing the world's only open-access information on human Genomic, Environmental & Trait data (GET). His 1984 Harvard PhD included the first methods for direct genome sequencing, molecular multiplexing, and barcoding. These led to the first commercial genome sequence (pathogen, Helicobacter pylori) in 1994. His innovations in “next-generation” genome sequencing and synthesis and cell/tissue engineering resulted in 12 companies spanning fields including medical genomics (Knome, Alacris, AbVitro, GoodStart, Pathogenica) and synthetic biology (LS9, Joule, Gen9, Warp Drive) as well as new privacy, biosafety, and biosecurity policies. He is director of the National Institutes of Health (NIH) Center for Excellence in Genomic Science. His honors include election to the National Academy of Sciences (NAS) and the National Academy of Engineering (NAE) and Franklin Bower Laureate for Achievement in Science.

Dr. Church, you are widely lauded as a particularly creative and innovative pioneer in an unusually wide variety of areas of biology and biotechnology. What factors most influence your choices of what areas to explore?

G.C.: They may seem like an “unusually wide variety,” but they all center on exponentially improving technology for reading and writing DNA. Everything else flows out from that. Reading led to the Personal Genome Project and ethics. Writing led to stems cells and gene therapy. Etc.

Your latest high-profile breakthrough was the development of a “programmable” method for gene targeting. In your view, how much, and how soon, will this technology enhance our medical prowess.

G.C.: There are already phase two clinical trials on human genome engineering (with zinc finger nucleases). Our new RNA-guided nucleases (also know as CRISPR, Cas9) seem to be more efficient and much easier to “program”—and with very low toxicity. It will be interesting to see more specificity and optimization data that will be flooding in soon, because of the ease of this CRISPR system.

Do you view the postponement of age-related ill health as a likely major theme of near-term biomedical research? I refer here specifically to what we might call “preventative geriatrics”–treating people who are still essentially healthy, rather than treating the specific diseases of old age like any other disease.

G.C.: I see an opportunity for an increased focus on rare protective DNA variants, like those in CCR5, FUT2, APP, PCSK9, and possibly many more to come from sequencing super-centenarian genomes. Another opportunity is rapid prototyping of preventative therapies (for senescence and cancer) via reversal of those traits in tissue/organ culture via genome and epigenome engineering.

A number of commentators, including this journal's editor, Aubrey de Grey, have opined that biomedical gerontology suffers from a dearth of communication between basic and applied researchers, with those whose expertise lies in exploiting knowledge for biomedical ends being insufficiently tapped into the community generating that knowledge to be able to move forward as fast as they might. What is your view?

G.C.: I would frame it differently. Yes, basic researchers need not worry about medical end users. “Applied researchers” focused on “biomedical ends” are typically not “disruptive.” So the missing ingredients are interdisciplinary technologists who not only bridge basic and applied, but moreover, completely transform what those two groups consider feasible. It is not sufficient to have academic dreamers and commercial “producers.” We also need experienced and adventurous engineers in academia that don't care if a company will be inconvenienced by a novel, disruptive tool.

Despite its obvious biological absurdity, and despite the energetic efforts of leading biogerontologists in the media and elsewhere, policy-makers and the public seem largely incapable of letting go of the idea that aging is somehow totally independent of disease, to the extent that they believe aging is a “good thing” even though the diseases of old age are not. The tragic result is that enthusiasm for research to postpone aging remains slight, as does funding for it. In your opinion, what underlies such intense determination to ignore expert thought in this area?

G.C.: Typically such “tragic results” are the fault of the expert—inadequate communication of progress and connecting the dots adequately on plans. Progress curves, like those in electronics and DNA reading/writing, provide context for carefully stated caveats about extrapolation. We need more outreach to clarify the difference between hype (typically about the present) and thoughtful plans (about the future).

In addition to the public's confused attitude toward aging, preventative geriatrics faces the challenge that it is a subset of preventative medicine, which always faces the challenge that people's intuitive assessment of risk/benefit tells them to avoid any remotely novel or experimental medical intervention until they are already sick. Do you see this scenario changing any time soon?

G.C.: The recent extremely personalized cystic fibrosis drug Kalydeco received FDA approval in only 3 months from the New Drug Application. The quite novel ingestible sensor from Proteus was also FDA approved recently. I don't see public (or even FDA) acceptance of novelty as the issue. The issue is encouraging radical innovation in the academic and corporate R&D labs. Historically, pharma company funding has flowed toward minor nudges to existing drugs to extend patent lifetime, and academic funding flows toward imitating pharma with small-molecule screens. Methods like stem cells initially got strong cutbacks on embryo cells rather than expanding forward to adult (iPSCs, induced pluripotential stem cells) stem cells. Similarly gene therapy was cut back for a decade due to unfortunate retroviral insertion sites rather than expanding forward toward non-insertional vectors, gene targeting, etc.