a16z Podcast - a16z Podcast: What's in the Water at the George Church Lab?

Episode Date: February 26, 2019

with George Church (@geochurch) and Jorge Conde (@JorgeCondeBio) 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.

Hi and welcome to the A16Z podcast. I'm Hannah. Today's episode features a special conversation with renowned scientist George Church, known for his groundbreaking work and methods used for the first genome sequence and for his work in genome editing, writing, and recoding. Church's innovations have become an essential building block for most of the DNA sequencing methods and companies we see today. He is joined in this conversation with A16Z Bio-General partner Jorge Condé, who, among other things founded a company with Church out of the church lab. The two take us on a wild journey into the scientist's mind and work, starting with what the leading pioneer in this space makes of where we are today with CRISPR, especially given recent news about CRISPR babies in China, then moving on

to the broader implications of all that on a cultural level to finally what it takes to go from science fiction to lab to reality. 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 have come first? Oh, and questionally, a CRISPR baby. I mean, that was not a huge technical leap. They all involved societal and ethical questions, but that one probably had the clearest path because there was such divergence of opinion somebody was going to do it.

And would you have expected that it would have been? essentially a rogue effort versus a solo effort as it seems to have been the case in the China CRISPR. I wouldn't characterize a 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 they're 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. So let's talk a little bit about the way it's been sort of positioned, at least publicly. Can you describe a little bit what the experiment actually was? What did the scientists or scientists do in this particular case for the CRISPR baby? I've actually seen a lot of the data and the preprints, and this was a simple, in a certain sense, application of CRISPR to alleviate a potential for HIV infection.

You know, 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. This is CCR5. CCR5, which has already been approved for FDA clinical trials. for Sangamo, and for editing in adults that have AIDS. That's a different scenario, but vets many of the issues that come up as to whether this is a reasonable editing strategy. 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? Right. So what CRISPR does well is often described as editing. It really is damaging. That's 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, is you want to knock out the CCR-5 gene. And there's precedent for it, about up to 10% of certain parts of Europe have a double null. To double-null in this case, basically, two non-functional CCR-5. 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 resistant to all HIV viruses, but that's not the point. It's like a vaccine. It makes you resistant to whatever you're vaccinated against. And analogies were made in the consenting for this between this and vaccination. There is no good vaccine. There is no cure for HIV AIDS. And right now, if you get it, and there are 37 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. Sure. Well, 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. So I read that the double nulls for CCR5 have increased predisposition to West Nile. That is correct. So there is a risk for almost every preventative and therapy, and this is the 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. And I may be taking you a little bit out of context here, but I've heard you describe CRISPR as genetic vandalism. Yeah. So do you think that that's a good application for germline editing? Well, it's vandalism in the sense that it can add or delete

a small number of base pairs typically in the range of one to hundreds. is not going to do something really wacky, except it may be some incredibly low frequency. Again, no drug is without its side effects, and that's why there's all the fine print that accompanies all the approved 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 you would, want. 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? So first of all, in the approved clinical trials on 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 percent are properly edited, meaning double nulls. That's enough, though, because all the rest are wiped up by the virus, and then the ones that are edited dominate the T-cell population. So it's one way of thinking about it. So it's basically selection for the edited T-cells,

so you don't develop immunosuppression. Right. 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 Moseaicism. It's quite possible that what you see, in the pre-implantation embryo when you select a few cells out of that plasticist is not represented to the final and the final is less mosaic or maybe even non-mosaic.

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 or different or multiple different cell types. Correct. And the same thing I should note is true for adult gene therapies is that whether it's done ex-vivo or en vivo, it used 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. We need more data. Great. 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, it shouldn't have. I mean, it's an end of one. We shouldn't have all said, oh, IVF is perfect because we have one perfect baby. So you're referencing the test tube hysteria around the first. 1978, which subsided. It grew too much, and it subsided too quickly based on an end of one. And I think here we have an end of two, maybe an end of three. and there's going to be a lot of attention paid to the actual outcomes rather than how we got there, hopefully. If you had been in charge of the project, would you have done CCR5, or is there another different, obvious application that you'd have gone after first? I'm very pre-clinical. In other words, I create technologies that's been used by companies that I found.

They do the clinical trial. So I probably would not be doing clinical trial at all, just to put it in context. But in terms of choice of target, I have said publicly already that 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, salicemia, and sickle cell, cystic fibrosis, and so forth, ignoring the fact that if you're in an IVF PGD clinic anyway, you can select. To do your CRISPR editing of your Mendelian disease, you could just do selection for most of these things.

So I think it's kind of like they're rationalizing their choice, which, you know, in the same sense that they might feel is rationalizing to pick a more prominent disease. But also, I think in all these, 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. Right. And just something that the critics might think that's attractive, that Christopher 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 an example of a disease that is very common, and most of the gene therapies are rare, whether they're editing or not. 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 and something that 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 from an in vitro fertilization into the mother. And so, by some people's definition, that's still kind of a lab resource rather than a baby.

And those are typically used for Mendelian diseases, meaning that you can see in the parents, for example, both parents could be unaffected carriers. You can predict that 25% of their children will, or their embryos in vitro fertilization could be affected with a very serious disease. So now that the genie's out of the bottle, we have the first CRISPR babies born. First of all, what was the role of ethics or ethicists in the first project in the CCR5, Chinese CRISPR-5 project, and what do you see as the role of ethicists going forward? Well, so the National Academy of Sciences in the U.S. and with participation of China and other countries in February 2017 came out with a report where they 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 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 to be, these are all regulatory agencies around the world, would recommend for any therapeutic clinical trial. They should all be focused on safety and efficacy and ethics, and that's what these 10 items look like for germline as well. Do you suspect, or do you expect, I should say, 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, do you think there will be a pause? Well, there probably will be something that looks like a pause, but it will probably be an acceleration. So the same thing happened with a prominent 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 with almost every major ethical debate, is it attracts attention, attracts money, whatever is ethical at the time is accelerated. And then so 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 unconscious.

On the contrary, I'm very much pro-regulation. I think that regulation is what saves us from philidomide 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 down. They're actually agents of smoothing things out. Yeah, and I think it's pretty clear. 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. 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 that they're no longer compared to the placebo. They're compared to whatever they're in increment over or whatever therapy already work. and they often fail, but help brand new category, you know, monoclonal antibodies or cell therapies or gene therapies, those just blow past and create all sorts of new improvements, traumatic improvements in safety and efficacy.

So the FDA is, that's their mandate, is to cure people, not to stop people from practicing medicine. 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, the way we treat disease or managed disease or even diagnosed disease? Well, first of all, if we started diagnosing, that would be a really big thing. I mean, it's really we're as a population, even worldwide, we're underdiagnosed. 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 preventative medicine. So 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, is preventative is sort of in the 1 to 5% of the pie chart, but its payback is enormous. And so basically you're saying misaligned incentives in human behavior has sort of mitigated how much prevention we actually do. That's right. But that would be a huge breakthrough. 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're ready for medical practice, thousands of them. And those can be prevented. We often talk about gene therapy. Actually, that's 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, it's like most infectious ages have potentially billions of customers, then that bring the price down radically. But in addition to... gene therapy, either in an adult's, 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. So you're describing 23 and me meets 10-year? No, I am not, actually.

I'm describing a whole genome sequencing, which is not, there are a very small number of companies that provide whole genome sequencing because everything else, anything less of whole genome sequencing, is not medically powerful enough. Anything less than that misses, gives you false assurance. That combined with some sort of dating,

that is an odd combination, and possibly further combined with whoever's paying for the Mendelian cost right now, which are about a million dollars per person, It doesn't have to be gene therapy, which happens to be a million. It can be just caregiving. 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. And this actually works. So Doria Shorim has eliminated significant, I mean, the only disease like Tasey's, acts by practicing aversion 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, whether they're carriers or not, never know if anybody else's effect, but still avoid meeting.

I mean, the analog version of this was back in the day in certain communities, Jewish communities where there was disease, the rabbi would essentially place function. That's what Doria Shereem was. Exactly. It was started by an individual. who had five children in a row that were affected by the TASX, which is a terrible burden on the child in the family that typically die before they're four years old, very painful.

And so he correctly determined that you could do this very inexpensively and humanely. Via matchmaking. Via matchmaking, right. 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. Called gnome.

Thank you, called gnome. Not gnomy, called gnome. We used to have this constant back and forth that you thought it should be called no me. I would call it noam, yeah. I thought it should be called gnome. And this was the market test. More people listened to you than to me,

which is incredibly frustrating. Yeah, and now I listen to you. Thank you. I just said noam. Okay. My rejoiner on that always was, if you want to call it no me, then I want to call you Jorge Iglesias.

And you were never a big fan of that one. Oh, okay. I have no problem with that name. I think it's a better name. It's a nice name. It's going to increase the brand. It's just as more syllables, that's all. But it just rolls off the tongue.

It does, yes. 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 walking around that have had their whole genomes 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 had 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 happened yet if it's not cost? 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'm convinced that it would be valuable for the world, it cost effective, medicine, preventative. And I think the three reasons are, one is cost. The 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, 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 genome 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 seatbelts. So seatbelts 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, you know, the kind of ordinary

math, which is, hey, I've got a less than 1% chance of ever using a seatbelt, ever needing one, so I'm not going to bother. And then the thing that made the difference was technology to sense the buckling and turning off an annoying sound. Oh, the beep. 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. So I don't benefit from being sequenced, the collective? 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 at the other extreme, which is totally useless. It's this strange thing where one to four percent 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. you're one of the unlucky 4%. And 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 that data would be better than anecdotes, but you need both. And I think it's going to 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. So two questions for you on the three ones you've laid out. The first one is, in the early days of Nome, 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. That is even more true than it was back in 2007. Right, so you're collecting off this chair, off this table, and you've got me. Got it. So why is security and privacy? Is it even a meaningful thing to think about if it's an impossible thing to achieve? Well, the point is if it's preventing people from getting their own genome sequence, 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 willfully getting my genome and looking at it and somebody surreptitiously taking it, okay? So we can pass laws and punish people for surreptitiously taking the 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 could 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 companies 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. And 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, right?

Got it. And I think that's where we are today, finally. By the way, you may not remember this, but we were laying out the risk factors and all of the 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 in a way my favorite one that you contributed was the potential risk that someone could plant your DNA at a crime scene right yeah high risk or low risk so that was also in a personal genome project consent form which started around that same time as noam did is a high risk or low risk you know i'd say that we're getting more 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. The CODIS is just a few handful of simple sequence repeats that are used in criminal investigations like... Like forensics. Yeah, forensic and, you know, CSI type stuff.

Now you'd need the whole genome, because if somebody felt it was being hacked, they'd say, well, you know, let's check the old genome. A defense attorney could ask for the whole genome. Furthermore, you can ask for methylation to show that it's the right age. For example, like I had my DNA from 20 years ago, and you'd have to show, or you could check the immune status. So you could say, oh, you know, does the immune status coincide with what the, which should be an argument for you to be like constantly sequencing your immune, your blood DNA, so you can date whatever. It's like a temporal genome.

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 the, you know. you know, 2005. 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. The Personal Genome Project was one of the first recognitions about how identifiable both your genome is, and also 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 being their medical records

and 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 consent so they knew these risks, they accepted them. And you had to take a quiz, right? Exactly. Up to that point, many of the consent forms were long,

written in legalese, a lot of language, the institution rather than a 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 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 risks and all the benefits, and we had a record of that. So those were some of the key points

of the personal genital project but the other key point is we really wanted to share it not just what a lot of people call sharing even to this day, you know, 13 years later they call sharing medical data for research is really a silo that's hard to get into. Unfortunately it's not impossible to get into it's not really encrypted the way you want it 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 access to it legitimately. So we wanted something that was 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 high-level enthusiasm among the participants. So you were obviously participant

1-001 of the Personal Genome Project. You're an open book. If you go to your lab website, you have everything you're working on, 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? So I didn't expect to because I felt that I was likely to be on the 96% that would get a blank report. As it turned out, it did learn a couple of things. So one of 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. This is APOE4 status. APP, presenolin 1 and 2, 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 antitripsin 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 the 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're underdiagnosed.

Oh, wow. And I was having poor reactions of 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, strict vegan diet, was enough to bring me down from almost 300 to almost 200. So it's not generic advice. It's something that's 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, I asked me to be an institution review board. There's sort of an ethics and protocol reviews of human subjects research. They wanted me to participate as initially the only subject, or is at least part of the first ten. 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 on to me was ridiculously. painful. I remember that. In retrospect, it was crazy. It was like a six millimeter punch, 12 stitches, no anesthetic, or at least not in the right

place. And then we switched over to a cream anesthetic, which is instead of 12 injections in the wrong place, it was cream in the right place, and then a simple bandage rather than stitches, and a one millimeter punch. So that was an example for me being eyewitness or, you know, guinea pig one. I said, no, that's not an example. 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 all studies, but it certainly applied to the personal genome project.

So switching gears to the church lab. So if you go on your website, you have a list of sort of the active projects that you're working on. And I mean, it almost reads like screenwriters for like coming up with the next, you know, 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, I mean, this is like Willy Wonka's chocolate factory for science. So what do you look for in incoming students for the church lab? And then let's go from there. Yeah. So 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 are they 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 The genome from $3 billion down to now sub-thousand dollars 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, oh, 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 different ways of doing next-gen sequencing, several different ways of doing editing, then that's an attractant. 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 us 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've got plenty of geniuses. We're looking for people that are nice. And how does one demonstrate niceness?

Well, you know, I think at 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 you build up this momentum of knocking off things that look like science fiction, turning them into 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.

So if I go through the list of things that you're working on, it's a pretty, you know, broad array of things. So you are crispering dogs to keep them young. You are crispering pig organs or had been working on editing pig organs to make them useful for transplantation. And then you run the other end of the spectrum. You're re-engineering 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 Iglesias lab, formerly known as the church lab, Like, what's in the water that gets this lab to produce so many startups and spin-outs? What is that entrepreneurial energy that's sort of been fostered and created here? Right. So it may look like a diverse set of projects, but they're actually have common thread that is surprisingly focused, meaning most people wouldn't fit in this lab because we're sort of 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 the 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 psychologists. 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. What's an idea that was pitched to you that you said, wow, that's too crazy. Well, I'm usually one pitching the crazy ideas. I mean, not to say that we don't have a lot of creativity in the lab.

That'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. Personal Geno Project was one of those creative solutions.

Surveillance for synthetic biology is another one I suggested in 2004, biocontainment using recoding is a way that we can make any organism resistant to all viruses and horizontal transfer. Most of these things now work. And many of these things are now companies. That's correct. And their foundation was some sort of safety ethics component to the company. And part of the secret sauce is hidden in plain view.

Like you say, we're quite transplanting. 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's 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. And just a lot of things people reject too easily. They either don't think of it at all, or they think about it and reject it. And 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.

Do you recruit entrepreneurs that happen to be scientists, or are you turning scientists into entrepreneurs? 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've 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. So the church lab, you were pioneers in sequencing, so reading DNA. You were pioneers in CRISPR, so writing DNA. What comes next? Well, so there's three

dimensional structure of living organisms. So we'd really like to know every voxel, every volume element, every pixel in the body of a embryo or a larger section of tissue. We'd like to know every molecule here. And we now have tools for doing DNA RNA and 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 genome. So some people call it, we call this GP Wright or genome project right. But it could just be heavy editing. So we set the record of 62 edits. in the pigs and we now have evidence so we have 10,000 edits in a single cell that's unbelievable 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 is that triple criteria which is cool, basic science, philosophically interesting, technological factors of a million, and societal benefit. Last question. Ten years from now, or just looking forward to the future, do we get the Neanderthal baby or do we get the mammothal baby first?

Well, we never really said that we were going to a Neanderthal baby. It was a response to a journalist, whether it was technically a boss a lot, 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.

Great. Well, thank you, George. Thank you for making time. And it's a real pleasure. Yeah. Thank you.