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Radical Technology Meets Radical Application: an Interview with George Church

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Radical Technology Meets Radical Application: an Interview with George Church The CRISPR Journal Volume 2, Number 6, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/crispr.2019.29074.gch INTERVIEW Radical Technology Meets Radical Application: An Interview with George Church Kevin Davies and George M. Church George Church has been a towering figure in genomics for more than three decades, dating back to the early days of DNA sequencing and the inception of the Human Genome Project. Since then, his interests and influence have spread to systems and synthetic biology, next-gen sequencing technology, and personal and consumer ge- nomics. Church has also had an important role in the launch of CRISPR technology, including a landmark paper in 2013 that marked one of the first demonstrations of CRISPR genome editing in human cells. His group re- mains among the most creative of research labs, pushing CRISPR to the boundaries of areas including multiplexing technology, de-extinction, xenotransplantation, and gene drives. Church sat down with Kevin Davies in his office at Harvard Medical School. Davies: George Church, thanks for the invitation to to make them more human-compatible and eliminate your office. You’re a member of The CRISPR Journal their viruses. But we could also make organs from hu- editorial board, let me remind you. mans. And these are surprising me, how quickly all this is going, and in particular, how you can get definite Church: That’s right—one of my many conflicts of interest. insights, even diagnostically important insights into very late-onset diseases, such as Alzheimer’s, schizo- Davies: What are some of the key things that are going phrenia, and bipolar, in about two to four weeks, even on in the Church Lab at the moment? though the onset should take 20–70 years. We’re mak- ing mostly brain organoids, but we have vascularized Church: I think the theme is technology development— ones, so we are keen on getting good blood flow so radical, enabling, transformative technologies, if we can. we can make bigger organoids. Downloaded by Harvard University FRANCIS A COUNTWAY from www.liebertpub.com at 12/22/19. For personal use only. Most of them are paired with some really cool applica- We’re doing aging reversal. And gene drives, which tions, a little out of reach with current technologies. We allow us to cure diseases by dealing with carriers, the an- pair radical technology and radical application. imal vectors. We’re also looking at other approaches to For example, GP-write is something we’ve been work- Lyme disease, including vaccines and people who are ex- ing on for a long time, before it was even named that. The ceptionally resistant, analogous to what we’ve done with idea is to recode genomes, and the application is to make human immunodeficiency virus. any organism resistant to all viruses, even viruses we’ve Encoding data into DNA. The most recent break- never seen before. That is recoding, which we’re doing through there is that we encoded a terabyte of develop- from bacteria to mammals, humans, and plants. mental data into mice. So, every mouse in the colony Another is organoids. We make organs in pigs by mak- encodes a fresh terabyte of data, and it only takes a bil- ing dozens, maybe 80 different changes in their genome, lionth of its body. Kevin Davies, Executive Editor, The CRISPR Journal, New Rochelle, New York, E-mail: [email protected]; and George M. Church, Department of Genetics, Harvard Medical School, Boston, Massachusetts, E-mail: [email protected] 346 INTERVIEW WITH GEORGE CHURCH 347 Davies: That’s in addition to your book, Regenesis, tation to use 293 cells, which are quite abnormal, just like is it? HeLa cells or K562. These are all bizarre aneuploid— they are even variable in what their genome looks like. Church: That’s right. My book was the first encoded in We felt those were completely unacceptable surrogates DNA, in 2012. That was half a megabyte. Since then, for clinical applications. we’ve gone from half a megabyte to a terabyte. Davies: Did the system that Doudna and Charpentier Davies: You first got into genome editing before you described in 2012 with the single guide RNA influence got into CRISPR, correct? your thinking? Church: Oh, way, way before. I got into recombinant Church: That was extremely fundamental. I’ve said this DNA in the 1970s—our editing is an honorary member in the past. CRISPR had been on our list, but Jennifer’s of the recombinant DNA family. I was one of the first em- work bumped Sp-Cas9 way up on our list at that point. ployees at Biogen, which used recombinant DNA. As We ended up using a different guide from the one she soon as I established my lab in 1986, we had two things: used . Feng showed in his Science (2013) paper,1 one was reading the genomes, the other was writing ge- side-by-side with ours, that her guide did not work in nomes. We did homologous recombination, which was his hands. precise editing. We didn’t make a claim that it didn’t work. We just Since then, we’ve gotten grade inflation and distortion said, ‘‘Here is one that does work,’’ and that was the of the word ‘‘editing.’’ But back in the 1980s, when we one that we published. It ended up sweeping through. started working on editing, it meant doing exactly what Everybody ended up using that, at least for the Strepto- you wanted—making exact changes, whether they’re coccus pyogenes work. big or small. Now, it’s like, if you can mangle a gene—I call it genome vandalism—that counts as edit- Davies: In the fall of 2012, you e-mailed Jennifer to ing! Most people who are actually editing would be ap- say, ‘‘Congratulations on a spectacular paper. By palled by that definition. the way, we’ve got this working in human cells.’’ Davies: Before the big CRISPR papers in 2012 and Church: Right. If I know that I’m converging on some- 2013, Feng Zhang spent a period in your lab as a re- body’s work, I try to check with them. Even though we search fellow, working initially on TALENs, right? considered Jennifer a focused biochemist, there was a nonzero probability that she might get interested in Church: Yes, he was a Harvard Junior Fellow. We pub- human clinical applications. I thought it was courtesy lished six papers together. to let her know. I didn’t know all the other people who might be working on it. Davies: Did your interest in CRISPR begin with Kevin Keith Joung was part of a NHGRI CEGS grant with Esvelt? me, so I knew he’d be interested. We started the grant, promising to do zinc fingers with Keith, and then we Church: Probably Prashant Mali. Prashant, Feng, and switched to TALENs with Feng, and then CRISPR. We Downloaded by Harvard University FRANCIS A COUNTWAY from www.liebertpub.com at 12/22/19. For personal use only. Kevin all worked together in a little corner in my lab in went far beyond what we had promised in the grant. the Wyss Institute. They were all postdocs, very friendly and very sharing. CRISPR was just on our list of nucle- Davies: You published in January 2013, in the same ases. There were a bunch of nucleases—Argonaut was issue of Science as Feng’s paper. A couple of years another nuclease on our list. But we were always looking later, you wrote to The Scientist to correct the narra- for precise editing. And we wanted to do it in normal tive that they’d put out in a story because it hadn’t human cells. mentioned your work and accomplishments in the We tried to limit because there are so many things we same context as Feng. Was that a fleeting bit of dis- already do. We wanted to make it harder on ourselves. gruntlement? So, precise editing in human cells was our initial goal, and we did it. The very first paper in January 2013 was Church: It was just a technical correction. I make such precise editing in human cells. And nobody else did nor- corrections rarely. It just said ‘‘three discoverers of the mal human cells for quite a while. There’s a great temp- CRISPR-Cas9 system’s utility in gene editing.’’ 348 INTERVIEW WITH GEORGE CHURCH But the point is that the first two had not shown editing, trials victorious. Gene therapies hit a major speed bump and the third one was side by side with ours, and we were in 1999–2000. But now we’re seeing the field blossom. the only lab to show editing in normal human cells. I did And it’s not just CRISPR, which is mainly subtractive, not want anybody to be left out, but that was it . It was but also adding a gene that is missing or too low, the latter not me. It was all the postdocs. And not just from my as we are doing in our aging reversal studies: adding back group. I felt that Martin Jinek had been left out of the genes that drop during aging. story, and Prashant Mali and Luhan Yang and Le Cong. My hopes are to lower the expense greatly. I don’t want Le Cong was actually a shared student between my lab my legacy to be the most expensive drugs in history. We’ve and Feng Zhang’s. He was first author of Feng’s 2013 brought down the price of reading human genomes from $3 paper.
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