What’s in the Water at the Church Lab? A Conversation Between George Church and Jorge Conde

George Church and Jorge Conde

Editor’s note: This article is based on an episode of the a16z podcast, which you can listen to here.

Renowned scientist George Church is known for his groundbreaking work and methods used for the first genome sequence, and for his work in genome editing, writing & recoding — in fact, Church’s innovations have become an essential building block for most of the DNA sequencing methods and companies we see today. In this conversation, a16z bio general partner Jorge Conde — who also founded a company with Church out of the George Church Lab — take us on a wild journey into the scientist’s mind and work, starting with what the leading pioneer in the space makes of where we are today with CRISPR (especially given recent news about CRISPR babies in China), to the broader implications of all of this on a cultural level, and finally to what it really takes to go from science fiction, to lab, to reality.

Jorge: So let’s start at the beginning. If we were to bet 10 years ago whether we’d have a CRISPR baby, a mammoth baby, or a Neanderthal baby, which would you have bet would’ve come first?

George: Oh, unquestionably a CRISPR baby. Yeah, that’s not a huge technical leap. They all involved societal and ethical questions, but that one probably had the clearest path, you know, because there is such divergence of opinion. Somebody was going to do it.

Jorge: And would you have expected that it would’ve been essentially a rogue effort versus a solo effort as it seems to have been the case in the China CRISPR baby news?

George: I wouldn’t characterize it as solo effort. I’ve seen the author list. It’s quite long and I also find it unlikely that a government as technically astute and as engaged in observation would be unaware of such an important thing. If I were a technically astute government there are a very limited number of topics I would be paying attention to, and these would be things like, you know, nuclear, biological encryption, and CRISPR. It’s a short list, so I don’t think it’s solo.

“If I were a technically astute government there are a very limited number of topics I would be paying attention to, and these would be things like, you know, nuclear, biological encryption, and CRISPR.”

Jorge: So let’s talk a little bit about the way it’s been positioned at least publicly. Can you describe a little bit what the experiment actually was? What did the scientist or scientists do in this particular case for the CRISPR baby?

George: I’ve actually seen a lot of the data and the pre-prints. And this is a simple, in a certain sense, application of CRISPR to alleviate a potential for HIV infection. About 900,000 people die every year of HIV, and this was an approach to it. And they did it by knocking out the gene that encodes the HIV receptor on the surface of T-cells.

Jorge: This is CCR5.

George: CCR5, which has already been approved for FDA clinical trials for Sangamo for editing in adults that have AIDS. That’s a different scenario, but it vets many of the issues that come up as to what is a reasonable editing strategy.

Jorge: So first of all, people have described it as knocking out the gene. Other people have described it as editing the CCR5 gene. Having seen the data, what exactly was done to CCR5?

George: What CRISPR does well is often described as editing. It really is damaging, is what it is. It’s not really that good at precision editing; hopefully it will be a good way in the future. And so what it does is it knocks out genes, and in this case that’s exactly what you want. You want to knock out the CCR5 gene. And there’s precedent for it, about up to 10% of certain parts of Europe have a double null…

Jorge: In this case, basically two non-functional CCR5s.

George: And you need really both non-functional in order to be resistant to the virus. And it doesn’t make you resistant to all viruses. It doesn’t even make you resistant to all HIV viruses — but that’s not the point. It’s like a vaccine that makes resistant whatever you’re vaccinated against. And analogies were made in the consenting of this between this and vaccination. There is no good cure for HIV AIDS, and right now if you get it — and there’s a million people who have been affected — if you get it, you’re doomed to a lifetime of combined antiretroviral therapy, which is not the thing that you would wish to have if you had any choice. While vaccines, if there did exist one, would be quite a good choice. And so this is as close as you can get to a vaccine.

Jorge: So I read that the double nulls for CCR5 have increased predisposition to West Nile.

George: That is correct. So there is a risk for almost every preventative and therapy, and this is a risk in this case. In most populations that’s considered a smaller medical risk. It’s obviously case by case for populations and individuals, and there are undoubtedly other advantages and disadvantages.

Jorge: And I may be taking you a little bit out of context here, but I’ve heard you describe CRISPR as genetic vandalism. Do you think that’s a good application for germline editing?

George: Well, it’s vandalism in the sense that it can add or delete a small number of base spheres, typically in the range of one to hundreds. It’s not going to do something really wacky except maybe some incredibly low frequency. Again, no drug is without its side effects. That’s why there’s all the fine print that the accompanies all the proved drugs. So I think in this case it is what you want. It’s exactly what you want. You want to destroy the CCR5 gene without destroying any adjacent genes. And that’s every allele that I’ve seen in the literature for CCR5, whether done in adults or done in tissue culture, is what what you would want.

Jorge: So I’ve read in this case, in the Chinese CRISPR baby publication, that there is some mosaicism — that he might not have functionally knocked out all of the CCR5. So is there any worry that after the post-experiment that this particular child might still be at risk for HIV infection?

George: So first of all, in the approved clinical trials in adults that have HIV AIDS, there is a lot of mosaicism. It’s considered part of the clinical trial, and maybe as little as 20% are properly edited, meaning double nulls. That’s enough, though, because all the rest are wiped out by the virus, and then the ones that are edited dominate the T-cell population. So that’s one way of thinking about it.

Jorge: So it’s basically a selection for the edited T-cells — you don’t develop immunosuppression.

George: So as long as there’s a fair number of properly edited ones. Now on the other hand, looking at the data I don’t see that much evidence for mosaicism. It’s quite possible that what you see in the pre-implantation embryo, when you select a few cells out of that blastocyst, is not representative of the final. And the final is less mosaic, or maybe even non-mosaic.

Jorge: So when they talk about a baby having mosaicism, in the case of the CRISPR baby, essentially what they’re referring to is that there are some cells that will have edits and some cells that won’t. And so essentially that child may grow up to be a mosaic of two different or multiple different cell types.

George: And the same thing, I should note, is true for adult gene therapies. Whether they’re done ex vivo or in vivo, it usually results in a high level of mosaicism, because the delivery is inefficient. And it may even be the case that the germline has lower mosaicism. I mean, we need more data. So the amount of off-target and mosaicism so far for these two babies seems to be low, but time will tell. You know, it could be that we’re just lucky the same way that the first in vitro fertilization, Louise Brown, turned out just fine. And so that greatly influenced us. It shouldn’t have. I mean, it’s an n of 1. We shouldn’t have all said, “Oh, IVF is perfect, because we have one perfect baby.”

“It could be that we’re just lucky the same way that the first in vitro fertilization, Louise Brown, turned out just fine. And so that greatly influenced us. It shouldn’t have. I mean, it’s an n of 1. We shouldn’t have all said, ‘Oh, IVF is perfect, because we have one perfect baby.'”

Jorge: You’re referencing the test-tube hysteria around the first IVF…

George: …in 1978, which subsided. It grew too much and it subsided too quickly, based on n of 1. And I think here we have an n of 2, maybe an n of 3, and there’s going to be a lot of attention paid to the actual outcomes rather than how we got there.

Jorge: If you had been in charge of the project would you have done CCR5, or is there another different obvious application that you would have gone after first?

George: Well, I’m very pre-clinical. In other words, I create technologies that are used by companies that I’ve found, and they do the clinical trial. So I probably would not be doing clinical trial at all — let’s just put it in context. But in terms of choice of target, I have said publicly already that the targets that have been championed by the critics, to the extent they champion anything, or the ones that they present as possibilities or as higher priority — although with great reservations even for those — are things that are typical Mendelian diseases, that is to say diseases that are very severe and are predictably heritable. Which are things like hemoglobinopathy, thalassemia, and sickle cell, cystic fibrosis, and so forth. Ignoring the fact that if you’re in an IVF PGD clinic anyway to do your CRISPR editing of your Mendelian disease, you could just do a selection for most of these things. So I think that it’s kind of like they’re rationalizing their choice, in the same sense that they might feel is rationalizing to pick a more prominent disease.

Jorge: But also I think in all the examples you just cited you would actually need to edit the gene to create function as opposed to knocking out — as was the case with CCR5.

George: Right. And to some extent the critics might think that’s attractive, that CRISPR is inappropriate at this moment because it gives us more time to think about it. But in any case, yeah, I think that we want example of a disease that is very common, and we want something that’s very serious, and certainly HIV falls in that category. So it struck me as a plausibly justifiable choice, possibly more justifiable than something you can avoid with genetic counseling, or with PGD IVF, or both. So IVF PGD stands for in vitro fertilization with prenatal genetic diagnosis. So the diagnosis can essentially be done before you implant the embryo for an in vitro fertilization into the mother. And so to some people’s definition that’s still kind of a lab resource rather than a baby. And then those are typically used for Mendelian diseases, meaning that you can see them in the parents. For example, both parents could be unaffected carriers. You could predict that 25% of their children will, or embryos in in vitro fertilization, could be affected with a very serious disease.

Jorge: So now that the genie’s out of the bottle, we have the first CRISPR babies born. What was the role of ethicists in the first project, in the CCR5 Chinese CRISPR baby project, and what do you see as the role of ethicists going forward?

George: Well, so the National Academy of Sciences in the U.S., with participation from China and other countries, in February of 2017 came out with a report that listed 10 items that would be recommendations for prerequisites for doing germline editing in children. I mean, obviously you can do germline editing in animals, or you can do it in cells in culture, or even embryos in culture, but actually implanting it and having it in children. And a lot of these had ethical components. Many of them were very similar to what you would expect the FDA, or the CFDA, or the EMA — these are all regulatory agencies around the world — would recommend for any therapeutic clinical trial. They should all be focused on safety, efficacy, and ethics. And that’s what these 10 items looked like for germline as well.

Jorge: Do you expect that we’re going to see more and more of these experiments going forward? Or do you think that after this first one, going back to the IVF example, there will be a pause?

“Whatever is ethical at the time is accelerated, and then whenever we become comfortable with it all that acceleration clicks into place, and it’s as if there’s been a steady growth.”

George: Well, there probably will be something that looks like a pause, but it will probably be an acceleration. So the same thing happened with recombinant DNA. There was supposedly a moratorium, but during that time — I mean, I was a first-hand observer — my research went faster. Because people were building incredible facilities for containment, and they had just state-of-the-art equipment that helped everything go faster, in my opinion. And I think the same thing has gone on with almost every major ethical debate is it attracts attention, attracts money. Whatever is ethical at the time is accelerated, and then whenever we become comfortable with it all that acceleration clicks into place, and it’s as if there’s been a steady growth. That doesn’t mean we should be incautious. On the contrary, I’m very much pro regulation. I think that regulation saves us from Thalidomide, and Vioxx, and hormone replacement therapy, and so forth, long term. So I think we need to support our regulatory agencies around the world. They are not agents of slowing things doing, they’re actually agents of smoothing things out.

Jorge: Yeah, and I think what’s pretty clear is we’re seeing that today in the regulatory environment, certainly here in the U.S. I mean, we’ve got the first cell therapies, the first gene therapies, the first digital therapies. It’s a pretty remarkable moment from a regulatory standpoint for new therapy.

George: To some extent I think they like new technologies more than they like the old ones. The old ones tend to fail because they’re so incremental they’re no longer compared to the placebo, they’re compared to whatever they’re an increment over, or whatever therapy already works, and they often fail. But a brand new category — monoclonal antibodies, or cell therapies, or gene therapies — those just like blow past, and create all sorts of new improvements, dramatic improvements in safety and efficacy. So the FDA, that’s their mandate is to cure people, not to stop people from practicing medicine.

Jorge: So just to take that vein, if we look forward, what do you see as, sort of, the next non-incremental, sort of, step-function change in the way we treat disease, or manage disease, or even diagnose disease?

“First of all, if we started diagnosing that would be a really big thing. As a population, even worldwide, we’re under-diagnosed.”

George: Well, first of all, if we started diagnosing that would be a really big thing. As a population, even worldwide, we’re under-diagnosed. There’s a lot of very cost effective diagnoses that partly because they’re cost effective they’re undervalued and the care providers are not compensated as much as some less effective but expensive medicine. So that’s one thing, diagnosis would be terrific, and that’s part of preventive medicine. We talk a lot about precision medicine, but the preventative part gets kind of swept under the rug a bit. If you look at the pie charts for a number of government agencies, including the NCI, NIH in general, this preventative is, sort of, in the 1% to 5% of the pie chart but its payback is enormous.

Jorge: So basically you’re saying misaligned incentives in human behavior has, sort of, mitigated how much prevention we actually do?

George: That’s right. But that would be a huge breakthrough, if we could do more diagnosis and more prevention. Now the ultimate diagnosis for genetics is whole genome sequencing and environmental monitoring with sequencing as well for pathogens, allergens, and so forth. The therapeutic cognate of that is, you know, preventing serious Mendelian diseases that are very predictive and very often single gene, or have enough of a single-gene component that they are ready for medical practice, thousands of them. And those can be prevented. We often talk about gene therapy actually as a million-dollar drug. It is once and done, so you don’t have a lifetime of dosing, but it is expensive, we need to acknowledge that. Partly because a lot of them are rare. If you get a common gene therapy, like, let’s say, aging reversal, or some major infectious agent that everybody wants to be vaccinated against — most infectious agents have potentially billions of customers — then that will bring the price down radically. But in addition to gene therapy, either in adults, children, fetuses, or germline, there is the option of doing IVF PGD that we already mentioned, and even earlier in matchmaking. So if you never meet or fall in love with someone who is predisposed to create heavily diseased, genetically diseased children, that’s very both cost effective and humane.

Jorge: So you’re describing 23andMe meets Tinder.

George: No, I am not, actually. I’m describing whole genome sequencing, which there are a very small number of companies that provide whole genome sequencing, because anything less than whole genome sequencing is not medically powerful enough. Anything less than that misses and gives you false assurance. That combined with some sort of dating that is an odd combination, and possibly further combined with whoever is paying for the Mendelian costs right now, which are about $1 million per person. It doesn’t have to be gene therapy, which happens to be $1 million, it can be just care giving. It adds up, and somebody’s paying for that, typically insurers and employment benefits, and they could be saving this money if they could encourage their clients, patients to avoid falling in love, marrying, and having children when they have incompatibility.

Jorge: When they’re carriers of something.

George: Yeah. And this actually works. So Dor Yeshorim has eliminated significant Mendelian disease, like Tay-Sachs, by practicing a version of this that probably isn’t perfectly generalizable, but there are versions of this that could keep a great deal of privacy and allow people to just never know whether they’re affected or not, or whether they’re carriers or not, never know if anybody else is, but still avoid needing…

Jorge: I mean, the analogue version of this was back in the day in certain Jewish communities where there was disease, the rabbi would essentially…

George: That’s what Dor Yeshorim was. It was started by an individual who had five children in a row that were affected by Tay-Sachs, which is a terrible burden on the child and family. They typically die before they’re four years old, very painful. And so he correctly determined that you could do this very inexpensively and humanely.

Jorge: Via matchmaking.

George: Via matchmaking, right.

Jorge: So let’s take another blast back to the past. So about 10 years ago you and I started a company in whole genome sequencing.

George: Called Knome.

Jorge: Thank you, called Knome, not Kno-me. Called Knome. We used to have this constant back and forth that you thought it should be called Kno-me.

George: I would call it Kno-me, yeah.

Jorge: I thought it should be called Knome, and this was the market test. More people listened to you than to me, which was incredibly frustrating.

George: Yeah, but now I listen to you. Should’ve said Knome.

Jorge: Thank you. My rejoinder on that always was, “If you want call it Kno-me then I want to call you Jorge Iglesias.” And you were never a big fan of that one.

George: Okay, I have no problem with that name.

Jorge: I think it’s a better name.

George: It’s a nice name.

Jorge: It’s going to increase the brand.

George: It just has more syllables, that’s all.

Jorge: But it just it rolls off the tongue.

George: It does, yes.

Jorge: So 10 years ago we basically made the bet that whole genome sequencing was important, that interpretation of that data would be relevant, that it would be meaningful. Ten years hence there still are not many people that are walking around that have had their whole genome sequenced, despite the fact that the cost has now fallen arguably below $1,000, or at least we’re at that $1,000 threshold. So I have two questions for you. Number one is, is the $1,000 threshold for this to be useful for everyone to get sequenced too high a dollar number? In other words, does it need to be $100 or $10? And number two, to the extent that this hasn’t happened yet, why hasn’t it happened yet — if it’s not cost?

George: I would say there’s three reasons why it hasn’t happened yet, and I’ve been living this reality for most of my career. I am convinced that it would be valuable for the world; it’s cost effective medicine, preventative. And I think the three reasons are: One is cost. Cost should probably be $0. Secondly, it’s privacy. We should have a convincing mechanism of people getting benefit from their genome without necessarily knowing their genome, or anybody else knowing their genome. You can have something where it’s only an encrypted form and not available to anybody including insurance and government. That’s second. And the third is most people don’t understand the value proposition. It’s either misrepresented, but by both extremes. So some people say, “Oh, it’s so valuable that you’re going to whip out your cell phone and look at your genomes twice a day.” And at the other extreme they say, “I can’t imagine ever using it.” And the reality is somewhere in between, and I think the analogy is seat belts. So seat belts were essentially free. They were standard equipment. They were required by law that you buckle and there were a lot of ad campaigns to get you to do so, kind of like smoking. And none of those were effective because people did the kind of ordinary math which is, “Hey, I’ve got a less than 1% chance of ever needing one. So I’m not going to bother.” And then the thing that made the difference was the technology that sensed the buckling and turning off an annoying sound.

Jorge: Oh, the beep?

George: Yeah, so that’s what made the difference, and we need an equivalent thing. It’s a public health issue, it’s not an individual health issue.

Jorge: So I don’t benefit from being sequenced, the collective…

George: Yeah, most people, 95%, 96% will get a blank sheet. They should get a blank sheet in terms of really actionable, very serious Mendelian diseases. And that should be the expectation, not the two extremes that you’ll use it every day, or that everybody will use it every day, or the other extreme which is totally useless. It’s this strange thing where 1% to 4% of the population will have a very big impact on their life. And the bottom line for their care providers, millions of dollars, huge impact on the whole family, if you’re one of the unlucky 4%. We need to get that message out there, and I think that bringing the price down to $0 and showing that it’s protectable, encrypted so that nobody can get access to it except for things that benefit you, or your family, or society, that will get their attention. But it’s going to take a little bit more than that. It’s going to take some anecdotes. You would think the data would be better than anecdotes, but you need both. And I think it’s going happen very soon now because we finally have the $0 genome and the encryption, and we’re starting to get communication of this rare advantage where you’re not exempt. Even though the odds are that you’re exempt, you don’t know that you’re exempt until you get your genome sequenced.

“You would think the data would be better than anecdotes, but you need both.”

Jorge: So two questions for you on the three ones you’ve laid out. The first one is in the early days of Gnome, I remember when we would think about this question of security. You correctly pointed out that if you really wanted my genome you would just wait for me to leave the room and collect it from all of the genomes.

George: Exactly. That is even more true than it was back in 2007.

Jorge: Right, you’d collect it off this chair, off this table, and you’ve got me.

George: Got it.

Jorge: So why is security and privacy…is it even a meaningful thing to think about if it’s an impossible thing to achieve?

George: Well, the point is, if it’s preventing people from getting their own genome sequenced, if they think that them seeing their own genome puts them at risk for somebody, like, hacking or requesting it, or subpoenaing it — then yes, it’s a problem. Because there is a difference between me woefully getting my genome and looking at it, and somebody surreptitiously taking it. So we can pass laws that punish people for surreptitiously taking our DNA. We do have the Genetic Information Non-Discrimination Act of 2008 that is along those lines. It’s not perfect, but it shows the intention of the public, so that can kind of handle the abandoned DNA problem, and we can keep shoring that up, and building up those laws. But then there’s the question if I look at my genome, if I have my genome available in text format, unprotected, then anybody can come along and demand it, right? The insurance company can say, “I know you know it so I want to see it.” The government can say, “I want to see it so I can convict your brother.” If it’s encrypted so that even you can’t hack it, then you can just say, “Sorry, it’s out of my hands. I don’t have my genome. If you want my genome you’re going to have to steal it from me.” And I think that’s where we are today finally.

Jorge: By the way, you may not remember this but we were laying out the risk factors and all of the other things for the consent form on all the things that a potential recipient of their genome data would have to think about. By far and away my favorite one that you contributed was the potential risk that someone could plant your DNA at a crime scene.

George: Right, yup.

Jorge: High risk or low risk?

George: So that was also in the Personal Genome Project consent form, which started around that same time as Gnome did. Is it high risk or low risk? You know, I’d say that we’re getting more and more sophisticated at sequencing and methylation analysis. You’d have to have the whole genome now, rather than back then it might be just the CODIS parts. That is, the CODIS is just a few handful of simple sequence repeats that are used in criminal investigations.

Jorge: Like forensics?

George: Yeah, forensics, and, you know, CSI kind of stuff. Now you’d need the whole genome, because if somebody felt it was being hacked they’d say, “Well, let’s check the whole genome.” A defense attorney could ask for the whole genome. Furthermore, you could ask for methylation to show that it’s the right age. So for example, looking at my DNA from 20 years ago and you’d have to show… or you could check the immune status. So you could say, “Oh, does the immune status coincide with the…” Which it should be an argument for you to be constantly sequencing your immune, your blood DNA, so you can date whatever samples are taken.

Jorge: Take a sample genome.

George: Yeah. So for every hack there’s a counter-hack, so I think I’m glad that we’re not at that stage right at the moment, even though we predicted it back in 2005.

Jorge: So going back to 2005, can you describe briefly what the Personal Genome Project was? Because it was the first effort to really start to think through these issues.

George: The Personal Genome Project was one of the first recognitions about how identifiable both your genome is, even parts of it, and your medical records. And people were starting to want to share genomic data and medical records, ideally integrated so that you could see what an individual — what we would now call precision medicine record would look like — back in 2005. And I wrote an editorial saying that this was a risk; that the data could leak out, and once it leaked out the people could be re-identified and all of their diseases could be determined from either the medical record, or the genome, or both.  And this has played out. I mean, there’s many examples of millions of people, their medical records or their genome leaking out in various ways. And of course now since then Wikileaks has occurred, which is just an example of how they can be officially stored publicly after leaking. So I think that was what we were concerned about, and we started the Personal Genome Project so that we could get people properly consented so they knew these risks, they accepted them.

Jorge: And you had to take a quiz, right?

George: Exactly. Up to that point many of the consent forms were long, written in legalese, a lot of language protecting the institution rather than the person. And you would sign them often under course of circumstances where you were afraid you weren’t going to get the best medical care if you didn’t sign it. So we added to that a simple multi-choice exam where you, kind of, simultaneously got educated if you didn’t get a perfect score, until you got a perfect score. So it wasn’t like we wanted 90% comprehension, we wanted 100%: that you knew all of the risk and all of the benefits, and we had a record of that. So those were some of the key points the Personal Genome Project did. But the other key point is we really wanted to share it. What a lot of people call sharing even to this day, you know, 13 years later, call sharing medical data for research is really a silo that’s hard to get into. Now fortunately that’s not impossible to get into. That’s not really encrypted the way you would’ve wanted to be, and so there’s a lot of potential for leakage. But it’s hard enough for regular scientists of good intention to get in and to get access to it legitimately. So we wanted something that’s more like Wikipedia where you didn’t have to agree to be a co-author on a paper, you didn’t have to pay a lot of money. You literally could use it for whatever you wanted to use it for, commercial, private, teaching, whatever just by clicking on it. And that project still exists today in many countries now, with a high level of enthusiasm among the participants.

Jorge: So you were obviously participant 001 of the Personal Genome Project. You’re an open book. If you go to your lab website you have everything you’re working on and everything you’ve ever worked on. You’ve described your phenotype in detail, which I think is fascinating. Did you learn anything from having access to your own genome that you found particularly interesting or enlightening?

George: So I didn’t expect to because I felt that I was likely to be in the 96% that would get a blank report. As it turned out I did learn a couple of things. One of them my family was very concerned about because I had a family history of cognitive decline, was that I had no risk factors for Alzheimer’s.

Jorge: So this is APOE4 status?

George: Every known factor, so that was reassuring, although I try to tell people not to be reassured, that there’s always something new to learn. Secondly, I’m an alpha-1-antitrypsin compound heterozygote, which just means I have two different risk factors that result in a risk for lung disease. So I should probably avoid pollution, which is probably not a bad thing for everybody to avoid, and smoking. And those were the two main things that I learned. So it’s not that different from getting a blank sheet quite frankly, but probably more importantly was having my medical records publicly available meant that a hematologist gave me personal advice on my incorrect use of statins. So it turned out that I was not being properly diagnosed, going back to we were under-diagnosed, and I was having a poor reaction to statin as well as low efficacy. It wasn’t doing its job. And so we tried a little bit of nudging them around and finally gave up when I showed and determined that a vegan diet, a strict vegan diet, was enough to bring me down from almost 300 to almost 200. So that’s not generic advice, that’s something very personal, and precision, and empirical. So that was another advantage of having people look on. And then there was an advantage to the project of me being guinea pig number one. The IRB, Harvard Medical School IRB asked me to…

Jorge: IRB is?

George: The Institutional Review Board. It’s, sort of, an ethics and protocol reviews of human subject research. They wanted me to participate as initially the only subject, or as at least part of the first 10. And that was beneficial in that when we were developing the skin biopsy for induced pluripotent stem cells, the skin biopsy, the first one we tried out on me, was ridiculously painful.

Jorge: I remember that. It was like a punch.

George: In retrospect it was crazy. It was like a 6-millimeter punch, 12 stitches, no anesthetic, or at least not in the right place. And then we switched over to a cream anesthetic, which instead of 12 injections in the wrong place it was cream in the right place, and then a simple bandage instead of stitches, and a 1 millimeter punch. So that was an example for me being eyewitness or guinea pig. I said, “No, that’s not an acceptable protocol,” immediately, right? And I might not have said that if I were like, detached, and I just said to one of the staff physicians, “Oh, just go do it.” So that’s a summary of why sometimes it’s important for the top researcher to also be a guinea pig in the study. And I don’t think this applies to all studies but it certainly applied to the Personal Genome Project.

Jorge: So switching gears to the Church Lab. So if you go on your website you have a list of the active projects that you’re worked on, and I mean, it almost reads like screenwriters coming up for the next great movie. Talk to me about the Church Lab. How do you think about what you work on? And even one step before that, how does one get into the Church Lab? Because from an external standpoint, this is like Willy Wonka’s Chocolate Factory for science. So what do you look for in incoming students for the Church Lab?

“Actually many of the things we do look hard from the outside, but from the inside they look like they’re low-hanging fruit and they happen way ahead of schedule.”

George: A lot of it looks like science fiction and most people would run away from that, not run towards it — and they did when I was starting out. But now we have a track record. Same level of creativity and risk taking, but actually many of the things we do look hard from the outside, but from the inside they look like they’re low-hanging fruit and they happen way ahead of schedule. So for example, things that did look like science fiction were fluorescent next-generation sequencing and nanopore sequencing. Both of those were wacky when I started them in the 1980s. And the whole idea that you could bring down the price of a genome from $3 billion down to now sub-$1,000 also seemed science fiction. But now that we’ve done it, now it becomes a beacon for people to say, “Oh, whoever did that, we should go there.” And if the same lab also helped bring in multiple ways of doing genome editing, including CRISPR — if you just do one you could be lucky, but if you do several then several different ways of doing next-gen sequencing, several different ways of doing editing, then that’s a track record. To get in, self-selection is another major filter. We do such quirky stuff that people don’t even bother to apply unless they’re kind of already on our wavelength. So then the biggest filter for me, and I tell this in the first interview, the first conversation I have, is we’re looking for people that are nice. We’re not necessarily looking for geniuses. We got plenty of geniuses. We’re looking for people that are nice.

Jorge: And how does one demonstrate niceness?

George: Well, you know, I think to some extent just having that conversation. If they want to be cutthroat they’re not going to come back. If they’re kind of sitting on the fence, then they’re going to rise to the occasion. They’re going to be influenced by that conversation and by all the people that have already passed through that filter that are in the lab. And you create a culture where you try not to compete with other labs if you can avoid it. Sometimes it’s unavoidable, but you can avoid it by inviting them to work with them, leaving alone fields where there’s plenty of momentum and a lack of interest in collaboration. Making sure there’s a diverse enough set of ideas going on in the lab so that everybody gets to leave with a subset of those ideas as a parting gift, or continue to collaborate if they want to as long as they want to. So I think it’s you build up this momentum of knocking off things that look like science fiction, turning them to science fact, and create a culture of ability to fail and to jump back, and to be nice to your colleagues within and outside the lab.

Jorge: If I go through the list of things that you’re working on, it’s a pretty broad array of things. So you are CRISPRing dogs to keep them young. You are CRISPRing pig organs, or have been working on editing pig organs to make them useful for transplantation. And then you run the other end of the spectrum, you’re reengineering biology to create a mirror universe of things that would be essentially immune to all known viruses or microbes. How do you pick the projects? What is it about what’s in the water in the…well, in the Eglesius Lab, formerly known as the Church Lab? What’s in the water that gets this lab to produce so many startups and spinouts? What is that entrepreneurial energy that’s been fostered and created here?

George: It may look like a diverse set of projects, but they actually have a common thread that is surprisingly focused. Meaning most people wouldn’t fit in this lab because we’re into radical transformative technologies, not incremental. A lot of labs don’t even want to touch technology until it’s working in a company. We work years before that company and we create that company, and then the company has another few years before it’s sufficiently worked out that it can be adopted by a technology adoption lab — which is before most biologists. So anyway, that’s one thing that we’re a little bit on the edge and it’s an acquired taste, or maybe even a rare taste.

Jorge: What’s an idea that was pitched to you that you said, “Wow, that’s too crazy?”

George: Well, I’m usually the one pitching the crazy ideas. I mean, not to say that we don’t have a lot of creativity in the lab. It’s pretty rare. In fact, we’ve kind of banned the word impossible. We certainly try to behave ethically but I think that many things there’s a technological solution to some of the ethical components, not all of them. And we try to explore creative solutions to ethical problems. The Personal Genome Project was one of those creative solutions; surveillance for synthetic biology is another one that I suggested in 2004. Bio containment using recoding is a way that we can make any organism resistant to all viruses and horizontal transfer. Most of these things now work.

Jorge: And many of these things are now companies.

“Part of this secret sauce that’s hidden in plain view — like you say, we’re quite transparent — is we can keep other people’s secrets, but our own, we try to get people to adopt them.”

George: That’s correct, and their foundation was some sort of safety ethics component to the company. And part of this secret sauce that’s hidden in plain view — like you say, we’re quite transparent — is we can keep other people’s secrets, but our own, we try to get people to adopt them. Part of the thing that we do that is, instead of saying, “Failure is not an option,” which was one of the Apollo slogans, we say, “Fail fast. Just pick yourself up quickly, have a bunch of things going in parallel. Find the low-hanging fruit empirically as well as theoretically.” A lot of things people reject too easily. They either don’t think of it at all or they think about it and reject. So if we see something that looks a little hard we’ll put it up on the shelf or in plain view so we can keep reminding ourselves — whenever a new technology makes that possible, we pull it back off the shelf and we do it. And so we have that culture of constantly re-evaluating things that are on the edge of science fiction.

Jorge: Do you recruit entrepreneurs that happen to be scientists, or are you turning scientists into entrepreneurs?

George: I mainly recruit people who are multilingual, multidisciplinary. Because I found it’s hard to build a multidisciplinary team from disciplinarians. You have to have a lot of people who already have done two things, and even if you get two people who have done two things each they don’t have to overlap, but they’ve done enough translation that they can start talking to each other. And if you have enough of those multidisciplinary individuals, then you can sprinkle in a few disciplinarians, and you have an amazing team.

Jorge: So the Church Lab, you were pioneers in sequencing, so reading DNA. You were pioneers in CRISPR, so writing DNA. What comes next?

George: Well, so there’s a three-dimensional structure of living organisms. We’d really like to know every voxel, every volume element of every pixel in the body of an embryo or larger section of tissue. We’d like to know every molecule there. We now have tools for doing DNA, RNA protein in 3D at super resolution, finally. So that’s one thing. We would like to be able to do higher levels of multiplexing in the terms of editing synthesis of genomes. We call it GP Write, or Genome Project-Write. But it could just be heavy editing. So we’ve set the record of 62 edits in the pigs, and we now have evidence that we have 10,000 edits in a single cell.

Jorge: That’s unbelievable.

George: So it goes from 2 to 62 to 10,000. And we want uses for each of these things, so each of these projects we have a driving societal benefit for each, and we have a driving technology where we say, “We don’t just want a factor of 1.5, we want a factor of a million or 10 million.” And so that’s what pushes each of these projects — that triple criteria, which is cool, basic science, philosophically interesting, technological factors of a million, and societal benefit.

Jorge: Last question. 10 years from now, or just looking forward into the future, do we get the neanderthal baby, or do we get the mammoth calf first?

George: Well, we never really said we were going to do a neanderthal baby. I mean, it was a response to a journalist…whether it was technically possible or not, but nobody has articulated a reason to do it. But for the mammoth there are lots of reasons both for the environment and for enriching the diversity of a living, endangered species. So this is not about de-extinction, this is about making hybrids. And many of the species are already hybrids of multiple species, but now we can have the benefit of synthetic genes and ancient genes.

Jorge: Thank you, George. Thank you for making time and it was a real pleasure.

George: Thank you.

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