AI transcript
0:00:03 Hi, and welcome to the A16Z podcast. I’m Hannah.
0:00:07 Today’s episode features a special conversation with renowned scientist George Church,
0:00:11 known for his groundbreaking work and methods used for the first genome sequence
0:00:14 and for his work in genome editing, writing, and recoding.
0:00:17 Church’s innovations have become an essential building block
0:00:21 for most of the DNA sequencing methods and companies we see today.
0:00:25 He has joined in this conversation with A16Z bio-general partner Jorge Conde,
0:00:29 who, among other things, founded a company with Church out of the church lab.
0:00:32 The two take us on a wild journey into the scientist’s mind and work,
0:00:37 starting with what the leading pioneer in this space makes of where we are today with CRISPR,
0:00:39 especially given recent news about CRISPR babies in China,
0:00:43 then moving on to the broader implications of all that on a cultural level
0:00:48 to finally what it takes to go from science fiction to lab to reality.
0:00:49 So, let’s start at the beginning.
0:00:55 If we were to bet 10 years ago whether we’d have a CRISPR baby, a mammoth baby,
0:01:00 or a Neanderthal baby, which would you have bet would have come first?
0:01:05 Oh, and questionably, a CRISPR baby, you know, I mean, it was not a huge technical leap.
0:01:10 They all involved societal and ethical questions,
0:01:14 but that one probably had the clearest path, you know,
0:01:19 because there was such divergence of opinion, somebody was going to do it.
0:01:24 And would you have expected that it would have been essentially a rogue effort
0:01:28 versus a solo effort, as it seems to have been the case in the China CRISPR baby news?
0:01:30 I wouldn’t characterize it as a solo effort.
0:01:32 I’ve seen the author list, it’s quite long.
0:01:38 And I also find it unlikely that a government as technically astute
0:01:44 and as engaged in observation would be unaware of such an important thing.
0:01:48 If I were a technically astute government,
0:01:51 there are very limited number of topics I would be paying attention to.
0:01:58 And these would be things like, you know, nuclear, biological, encryption, and CRISPR.
0:02:01 It’s a short list, so I don’t think it’s solo.
0:02:05 So let’s talk a little bit about the way it’s been sort of positioned, at least publicly.
0:02:11 Can you describe a little bit what the experiment actually was?
0:02:15 What did the scientists or scientists do in this particular case for the CRISPR baby?
0:02:19 I’ve actually seen a lot of the data and the preprints.
0:02:25 And this was a simple, in a certain sense, application of CRISPR
0:02:31 to alleviate a potential for HIV infection.
0:02:37 You know, 900,000 people die every year of HIV, and this was an approach to it.
0:02:44 And they did it by knocking out the gene that encodes the HIV receptor on the surface of T cells.
0:02:45 This is CCR5.
0:02:52 This is CCR5, which has already been approved for FDA clinical trials for Sangamo
0:02:56 and for editing in adults that have AIDS.
0:03:00 That’s a different scenario, but vets many of the issues that come up
0:03:04 as to whether this is a reasonable editing strategy.
0:03:08 So first of all, people have described it as knocking out the gene.
0:03:11 Other people have described it as editing the CCR5 gene.
0:03:15 Having seen the data, what exactly was done to CCR5?
0:03:21 Right, so what CRISPR does well is often described as editing, it really is damaging.
0:03:24 It’s not really that good at precision editing.
0:03:28 Hopefully there will be a good way in the future.
0:03:30 And so what it does is it knocks out genes.
0:03:34 And in this case, that’s exactly what you want, is you want to knock out the CCR5 gene.
0:03:35 And there’s precedent for it.
0:03:40 About up to 10% of certain parts of Europe have a double null.
0:03:43 To double null in this case, basically, two non-functional CCR5s.
0:03:48 And you need really both non-functional in order to be resistant to the virus.
0:03:50 And it doesn’t make you resistant to all viruses.
0:03:55 It doesn’t even make you resistant to all HIV viruses, but that’s not the point.
0:03:58 It’s like a vaccine, it makes you resistant to whatever you’re vaccinated against.
0:04:03 And analogies were made in the consenting for this between this and vaccination.
0:04:08 There is no good vaccine, there’s no cure for HIV/AIDS.
0:04:14 And right now, if you get it, and there are 37 million people who have been affected,
0:04:19 if you get it, you’re doomed to a lifetime of combined antiretroviral therapy,
0:04:24 which is not the thing that you would wish to have if you had any choice.
0:04:24 Sure.
0:04:28 Well, vaccines, if there did exist one, would be quite a good choice.
0:04:32 And so this is as close as you can get to a vaccine.
0:04:37 So I read that the double nulls for CCR5 have increased predisposition to West Nile.
0:04:38 That is correct.
0:04:42 So there’s a risk for almost every preventative antiretroviral therapy.
0:04:43 And this is the risk in this case.
0:04:47 In most populations, that’s considered a smaller medical risk.
0:04:51 It’s obviously a case by case for populations and individuals.
0:04:54 And there are undoubtedly other advantages and disadvantages.
0:04:58 And I may be taking you a little bit out of context here, but I’ve heard you describe
0:05:02 CRISPR as genetic vandalism.
0:05:06 So do you think that that’s a good application for germline editing?
0:05:10 Well, it’s vandalism in the sense that it can add or delete a small number of base
0:05:16 pairs, typically, in the range of 1 to hundreds.
0:05:22 It’s not going to do something really wacky, except it may be some incredibly low frequency.
0:05:24 Again, no drug is without its side effects.
0:05:28 And that’s why there’s all the fine print that accompanies all the approved drugs.
0:05:31 So I think in this case, it is what you want.
0:05:32 It’s exactly what you want.
0:05:36 You want to destroy the CCR5 gene without destroying any adjacent genes.
0:05:41 And that’s every allele that I’ve seen in the literature for CCR5, whether it’s done
0:05:46 in adults or done in tissue culture, is what you would want.
0:05:50 So I’ve read in this case in the Chinese CRISPR baby publication that there is some
0:05:55 mosaicism that he might not have functionally knocked out all of the CCR5.
0:06:00 So is there any worry that after the post-experiment that this particular child might still be
0:06:02 at risk for HIV infection?
0:06:08 So first of all, in the approved clinical trials on adults that have HIV/AIDS, there
0:06:11 is a lot of mosaicism.
0:06:13 It’s considered part of the clinical trial.
0:06:20 And maybe as little as 20% are properly edited, meaning double nulls.
0:06:24 That’s enough, though, because all the rest are wiped up by the virus, and then the ones
0:06:28 that are edited dominate the T-cell population.
0:06:29 So it’s one way of thinking about it.
0:06:34 So it’s basically selection for the edited T-cells so you don’t develop immunosuppression.
0:06:35 Right.
0:06:37 So as long as there’s a fair number of properly edited ones.
0:06:43 Now on the other hand, looking at the data, I don’t see that much evidence for mosaicism.
0:06:49 It’s quite possible that what you see in the pre-implantation embryo when you select a
0:06:57 few cells out of that blastocyst is not representative of the final, and the final is less mosaic,
0:06:59 or maybe even non-mosaic.
0:07:04 So when they talk about a baby having mosaicism in the case of the CRISPR baby, essentially
0:07:08 what they’re referring to is that there are some cells that will have edits, and some
0:07:10 cells that won’t.
0:07:16 And so essentially that child may grow up to be a mosaic of two different or multiple
0:07:17 different cell types.
0:07:18 Correct.
0:07:22 And the same thing I should note is true for adult gene therapies is that whether they’re
0:07:27 done ex vivo or in vivo, it usually results in a high level of mosaicism because the delivery
0:07:29 is inefficient.
0:07:33 And it may even be the case that the germline has lower mosaicism.
0:07:34 We need more data.
0:07:35 Great.
0:07:42 So the amount of off-target and mosaicism so far for these two babies seems to be low,
0:07:43 but time will tell.
0:07:49 You know, it could be that we’re just lucky the same way that the first in vitro fertilization,
0:07:51 Louise Brown, turned out just fine.
0:07:55 And so that greatly influenced, it shouldn’t have, I mean, it’s an N of one.
0:07:59 We shouldn’t have all said, “Oh, IVF is perfect because we have one perfect baby.”
0:08:03 To your referencing the test tube hysteria around the first IVF.
0:08:11 1978, which subsided, it grew too much and it subsided too quickly based on N of one.
0:08:15 And I think here we have an N of two, maybe an N of three, and there’s going to be a lot
0:08:20 of attention paid to the actual outcomes rather than how we got there, hopefully.
0:08:25 If you had been in charge of the project, would you have done CCR five or is there another
0:08:28 different obvious application that you’d have gone after first?
0:08:29 Very preclinical.
0:08:33 In other words, I create technologies that’s been used by companies that I found, and they
0:08:34 do the clinical trial.
0:08:39 So I probably would not be doing a clinical trial at all, just to put it in context.
0:08:44 But in terms of choice of target, I have said publicly already that targets that have been
0:08:49 championed by the critics to the extent they champion anything, or the ones that they present
0:08:56 as possibilities or as higher priority, although with great reservations, even for those, are
0:09:03 things that are typical Mendelian diseases, that is to say diseases that are very severe
0:09:11 and are predictably heritable, which are things like hemoglobinopathy, salicylium, sickle
0:09:18 cell, cystic fibrosis, and so forth, ignoring the fact that if you’re in an IVF-PGD clinic
0:09:25 anyway, to do your CRISPR editing of your Mendelian disease, you could just do selection
0:09:26 for most of these things.
0:09:33 So I think it’s kind of like they’re rationalizing their choice, which in the same sense that
0:09:37 they might feel is rationalizing to pick a more prominent disease.
0:09:40 But also, I think in all the examples you just cited, you would actually need to edit the
0:09:45 gene to create function as opposed to knocking out, as was the case with CCR five.
0:09:49 And in some sense, the critics might think that that’s attractive, that CRISPR is inappropriate
0:09:53 at this moment because it gives us more time to think about it.
0:09:58 But in any case, yeah, I think that we want an example of a disease that is very common,
0:10:04 and most of the gene therapies are rare, whether editing or not, and we want something that’s
0:10:09 very serious, and certainly HIV falls in that category.
0:10:15 So it struck me as a plausibly justifiable choice, possibly more justifiable and something
0:10:21 that you can avoid with genetic counseling or with PGD IVF or both.
0:10:27 So IVF-PGD stands for In vitro fertilization with prenatal genetic diagnosis.
0:10:32 So the diagnosis can essentially be done before you implant the embryo from an in vitro fertilization
0:10:33 into the mother.
0:10:39 And so by some people’s definition, that’s still kind of a lab resource rather than a
0:10:40 baby.
0:10:45 And those are typically used for Mendelian diseases, meaning that you can see in the
0:10:49 parents, for example, both parents could be unaffected carriers.
0:10:55 You can predict that 25% of their children will or their embryos in vitro fertilization
0:10:58 could be affected with a very serious disease.
0:11:03 So now that the gene is out of the bottle, we have the first CRISPR babies born.
0:11:09 First of all, what was the role of ethicists in the first project in the CCR-5 Chinese
0:11:11 CRISPR baby project?
0:11:14 And what do you see as the role of ethicists going forward?
0:11:19 Well so the National Academy of Sciences in the US and with participation from China and
0:11:24 other countries in February 2017 came out with a report where they listed 10 items that
0:11:31 would be recommendations for prerequisites for doing germline editing in children.
0:11:38 I mean obviously you can do germline editing in animals or you can do it in cells in culture
0:11:42 or even embryos in culture but actually in planting and having children.
0:11:44 And a lot of these had ethical components.
0:11:50 Many of them were very similar to what you would expect the FDA or the CFDA or the EMA
0:11:56 to be, these are all regulatory agencies around the world, would recommend for any therapeutic
0:11:57 clinical trial.
0:12:03 We should all be focused on safety and efficacy and ethics and that’s what these 10 items
0:12:06 look like for germline as well.
0:12:10 Do you suspect or do you expect, I should say, that we’re going to see more and more
0:12:15 of these experiments going forward or do you think that after this first one, going back
0:12:18 to the IVF example, do you think there will be a pause?
0:12:23 Well there probably will be something that looks like a pause but it will probably be
0:12:25 an acceleration.
0:12:29 So the same thing happened with the prominent DNA, there was supposedly a moratorium but
0:12:34 during that time, I mean I was a first-hand observer, my research went faster because
0:12:39 people were building incredible facilities for containment and they had just state-of-the-art
0:12:42 equipment that helped everything go faster in my opinion.
0:12:47 And I think the same thing has gone with almost every major ethical debate is it attracts
0:12:54 attention, attracts money, whatever is ethical at the time is accelerated and then so whenever
0:13:00 we become comfortable with it, all that acceleration clicks into place and it’s as if there’s been
0:13:02 a steady growth.
0:13:07 That doesn’t mean we should be incautious, on the contrary, I’m very much pro-regulation.
0:13:14 I think that regulation is what saves us from phalidomide and Vioxx and hormone replacement
0:13:17 therapy and so forth, long-term.
0:13:21 So I think we need to support our regulatory agencies around the world.
0:13:25 They are not agents of slowing things down, they’re actually agents of smoothing things
0:13:26 out.
0:13:28 Yeah, and I think it’s pretty clear we’re seeing that today in the regulatory environment,
0:13:29 certainly here in the US.
0:13:34 I mean, we’ve got the first cell therapies, the first gene therapies, the first digital
0:13:35 therapies.
0:13:38 It’s a pretty remarkable moment from a regulatory standpoint for a new therapy.
0:13:41 To some extent, I think they like new technologies more than like the old ones.
0:13:47 The old ones tend to fail because they’re so incremental that they’re no longer compared
0:13:50 to the placebo, they’re compared to whatever they’re an increment over or whatever therapy
0:13:57 already works and they often fail, but brand new category, monoclonal antibodies or cell
0:14:04 therapies or gene therapies, those just like blow past and create all sorts of new improvements,
0:14:06 traumatic improvements in safety and efficacy.
0:14:11 So the FDA is, that’s their mandate, is to cure people, not to stop people from practicing
0:14:12 medicine.
0:14:18 So just to take that vein, if we look forward, what do you see as sort of the next non-incremental
0:14:23 sort of step function change in the way we treat disease or manage disease or even diagnose
0:14:24 disease?
0:14:28 Well, first of all, if we started diagnosing, that would be a really big thing.
0:14:33 It’s really, we’re as a population, even worldwide, we’re under-diagnosed.
0:14:38 There’s a lot of very cost-effective diagnoses that partly because they’re cost-effective,
0:14:45 they’re undervalued and the care providers are not compensated as much as some less effective
0:14:47 but expensive medicine.
0:14:51 So that’s one thing, diagnosis would be terrific and that’s part of preventative medicine.
0:14:56 So we talk a lot about precision medicine, but the preventative part gets kind of swept
0:14:57 under the rug a bit.
0:15:01 If you look at the pie charts for a number of government agencies, including the NCI,
0:15:09 NIH in general, is preventative is sort of in the 1 to 5% of the pie chart, but its payback
0:15:10 is enormous.
0:15:14 And so basically you’re saying misaligned incentives and human behavior has sort of
0:15:17 mitigated how much prevention we actually do.
0:15:21 That’s right, but that would be a huge breakthrough so we could do more diagnosis and more prevention.
0:15:26 Now the ultimate diagnosis for genetics is whole genome sequencing and environmental
0:15:30 monitoring with sequencing as well for pathogens, allergens and so forth.
0:15:39 The therapeutic cognate of that is preventing serious Mendelian diseases that are very predictive
0:15:44 and very often single gene or have enough of a single gene component that they’re ready
0:15:47 for medical practice, thousands of them.
0:15:48 And those can be prevented.
0:15:52 We often talk about gene therapy, actually that’s a million dollar drug.
0:15:57 It is once and done so you don’t have a lifetime of dosing, but it is expensive, we need to
0:15:58 acknowledge that.
0:16:00 Partly because a lot of them are rare.
0:16:06 If you get a common gene therapy, like let’s say aging reversal or some major infectious
0:16:11 agent that everybody wants to be vaccinated against, it’s like most infectious ages have
0:16:16 potentially billions of customers, then that will bring the price down radically.
0:16:22 But in addition to gene therapy, either in adults, children, fetuses or germ line, there
0:16:28 is the option of doing IVFPGD that we already mentioned and even earlier in matchmaking.
0:16:36 So if you never meet or fall in love with someone who is predisposed to create heavily
0:16:43 disease, genetically diseased children, that’s very both cost effective and humane.
0:16:45 So you’re describing 23andMe meets 10andMe.
0:16:47 No, I am not actually.
0:16:52 I’m describing a whole genome sequencing, which is not, there are a very small number
0:16:56 of companies that provide whole genome sequencing because everything else, anything less than
0:17:00 whole genome sequencing is not medically powerful enough.
0:17:04 Anything less than that misses because you false assurance.
0:17:09 That combined with some sort of dating that is an odd combination and possibly further
0:17:14 combined with whoever is paying for the Mendelian costs right now, which are about a million
0:17:18 dollars per person, doesn’t have to be gene therapy, which happens to be a million.
0:17:21 It can be just caregiving.
0:17:27 It adds up and somebody is paying for that, typically insurers and employment benefits
0:17:34 and they could be saving this money if they could encourage their clients, patients to
0:17:38 avoid falling in love, marrying and having children when they have incompatibility.
0:17:39 Their carriers of something.
0:17:40 And this actually works.
0:17:48 So Dorya Sharim has eliminated significant menial disease like Tasex by practicing a
0:17:53 version of this that probably isn’t perfectly generalizable, but there are versions that
0:17:59 could keep a great deal of privacy and allow people to just never know whether they’re
0:18:02 affected or not, or whether they’re carriers or not, never know if anybody else is affected,
0:18:05 but still avoid meeting.
0:18:09 I mean, the analog version of this was back in the day in certain communities, Jewish
0:18:12 communities where there was disease, the rabbi would essentially replace function.
0:18:13 That’s what Dorya Sharim was.
0:18:14 Exactly.
0:18:20 It was started by an individual who had five children in a row that were affected by Tasex,
0:18:25 which is a terrible burden on the child and the family that typically died before they’re
0:18:27 four years old and very painful.
0:18:34 And so he correctly determined that you could do this very inexpensively and mainly.
0:18:35 Via matchmaking.
0:18:36 Via matchmaking.
0:18:37 Right.
0:18:39 So let’s take another blast back to the past.
0:18:44 So about 10 years ago, you and I started a company in whole genome sequencing.
0:18:45 Called Nome.
0:18:46 Thank you.
0:18:47 Called Nome.
0:18:48 Not Nome.
0:18:49 Called Nome.
0:18:52 We used to have this constant back and forth that you thought it should be called Nome.
0:18:53 I would call it Nome.
0:18:54 Yeah.
0:18:55 I thought it should be called Nome.
0:18:56 Yeah.
0:18:57 And this was the market test.
0:18:59 It was the youth into me, which is incredibly frustrating.
0:19:00 Yeah.
0:19:01 And now I listen to you.
0:19:02 Thank you.
0:19:03 Like I said, no.
0:19:04 Okay.
0:19:08 My rejoiner on that always was, if you want to call it know me, then I want to call you
0:19:12 Jorge Iglesias and you are never a big fan of that one.
0:19:13 Okay.
0:19:14 I don’t have no problem with that name.
0:19:15 I think it’s a better name.
0:19:16 It’s a nice name.
0:19:17 It’s going to increase the brand.
0:19:20 It just has more syllables, that’s all.
0:19:22 But it just, it rolls off the tongue.
0:19:23 Does.
0:19:24 Yes.
0:19:28 It basically made the bet that whole genome sequencing was important.
0:19:32 That interpretation of that data would be relevant, that it would be meaningful.
0:19:36 Ten years hence, there still are not many people walking around that have had their
0:19:41 whole genomes sequenced despite the fact that the cost has now fallen arguably below $1,000
0:19:44 or at least we’re at that $1,000 threshold.
0:19:46 So I had two questions for you.
0:19:52 Number one is, is the $1,000 threshold for this to be useful for everyone to get sequenced
0:19:53 too high a dollar number?
0:19:57 In other words, does it need to be $100 or $10?
0:20:02 And number two, to the extent that this hasn’t happened yet, why hasn’t it happened yet if
0:20:03 it’s not cost?
0:20:06 I would say there’s three reasons why it hasn’t happened yet.
0:20:10 And I’ve been living this reality for most of my career.
0:20:15 I’m convinced that it would be valuable for the world, it costs effective medicine, preventative.
0:20:18 And I think the three reasons are one is cost.
0:20:20 The cost should probably be $0.
0:20:22 And secondly, it’s privacy.
0:20:27 We should have a convincing mechanism of people getting benefit from their genome without
0:20:29 necessarily knowing their genome or anybody else knowing their genome.
0:20:34 You can have something where it’s only an encrypted form, not available to anybody, including
0:20:36 insurance and government.
0:20:37 That’s second.
0:20:41 And the third is most people don’t understand the value proposition.
0:20:44 It’s either misrepresented, but by both extremes.
0:20:48 So some people say, oh, it’s so valuable that you’re going to whip out your cell phone and
0:20:50 look at your genome twice a day.
0:20:54 And at the other extreme, they say, I can’t imagine ever using it.
0:20:58 And the reality is somewhere in between, and I think the analogy is seatbelts.
0:21:00 So seatbelts were essentially free.
0:21:01 They were standard equipment.
0:21:04 They were required by law that you buckle.
0:21:09 And there were a lot of ad campaigns to get you to do so, kind of like smoking.
0:21:15 And none of those were effective because people did, you know, the kind of ordinary math,
0:21:19 which is, hey, I’ve got a less than 1% chance of ever using a seatbelt, ever needing one.
0:21:21 So I’m not going to bother.
0:21:26 And then the thing that made the difference was technology to sense the buckling and turning
0:21:28 off an annoying sound.
0:21:29 So that’s what made the difference.
0:21:30 And we need an equivalent thing.
0:21:32 It’s a public health issue.
0:21:35 It’s not an individual health issue.
0:21:37 So I don’t benefit from being sequenced, the collective.
0:21:43 These people, 95, 96% will get a blank sheet.
0:21:50 They should get a blank sheet in terms of really actionable, very serious Mendelian diseases.
0:21:51 And that should be the expectation.
0:21:56 Not the two extremes that you’ll use it every day, or that everybody will use it every day,
0:21:57 or the other extreme, which is totally useless.
0:22:04 It’s this strange thing where 1% to 4% of the population will have a very big impact
0:22:05 on their life.
0:22:12 And the bottom line for their care providers, millions of dollars, huge impact on the whole
0:22:17 family, if you’re one of the unlucky 4%.
0:22:19 And we need to get that message out there.
0:22:24 And I think that bringing the price down to $0 and showing that it’s protectable, encrypted
0:22:29 and so that nobody can get access to it except for things that benefit you or your family
0:22:33 or society, that will get their attention.
0:22:36 But it’s going to take a little bit more than that’s going to take some anecdotes.
0:22:40 You would think that data would be better than anecdotes, but you need both.
0:22:43 And I think it’s going to happen very soon now, because we finally have the $0 genome
0:22:50 and the encryption, and we’re starting to get communication of this rare advantage where
0:22:54 you’re not exempt, even though the odds are that you’re exempt, you don’t know that you’re
0:22:57 exempt until you get your genome sequenced.
0:22:59 So two questions for you on the three ones you’ve laid out.
0:23:04 The first one is, in the early days of Nome, I remember when we would think about this
0:23:10 question of security, you correctly pointed out that if you really wanted my genome,
0:23:13 you would just wait for me to leave the room and collect it from all of the genome.
0:23:14 Exactly.
0:23:15 That is even more true than it was back in 2007.
0:23:16 Right.
0:23:18 So you collect all of this chair off this table, and you’ve got me.
0:23:19 Got it.
0:23:24 So why is security and privacy, is it even a meaningful thing to think about if it’s
0:23:25 an impossible thing to achieve?
0:23:30 Well, the point is, if it’s preventing people from getting their own genome sequenced, if
0:23:36 they think that them seeing their own genome puts them at risk for somebody like hacking
0:23:41 or requesting it or subpoenaing it, then yes, it’s a problem, because there is a difference
0:23:46 between me woefully getting my genome and looking at it and somebody surreptitiously
0:23:47 taking it.
0:23:48 Okay?
0:23:51 So we can pass laws that punish people for surreptitiously taking my DNA.
0:23:56 We do have the Genetic Information Non-Discrimination Act of 2008 that is along those lines.
0:24:00 It’s not perfect, but it shows the intention of the public.
0:24:05 So that can kind of handle the abandoned DNA problem, and we could keep shoring that
0:24:07 up and building up those laws.
0:24:11 But then there’s the question, if I look at my genome, if I have my genome available
0:24:16 in text format, unprotected, then anybody can come along and demand it, right?
0:24:20 Insurance companies say, “I know you know it, so I want to see it.”
0:24:24 And they can say, “I want to see it, so I can convict your brother.”
0:24:29 And if it’s encrypted so that even you can’t hack it, then you can just say, “Sorry, it’s
0:24:30 out of my hands.
0:24:31 I don’t have my genome.
0:24:33 If you want my genome, you’re going to have to steal it from me.”
0:24:34 Right?
0:24:35 Got it.
0:24:36 And I think that’s where we are today, finally.
0:24:39 By the way, you may not remember this, but we were laying out the risk factors and all
0:24:46 of the other things for the consent form on all the things that a potential recipient
0:24:48 of their genome data would have to think about.
0:24:53 By far and away, my favorite one that you contributed was the potential risk that someone
0:24:55 could plant your DNA at a crime scene.
0:24:56 Right.
0:24:57 Yep.
0:24:58 High risk or low risk?
0:25:03 So that was also in a personal genome project consent form, which started around that same
0:25:04 time as Noam did.
0:25:06 Is it high risk or low risk?
0:25:14 I’d say that we’re getting more and more sophisticated at sequencing and methylation analysis.
0:25:17 You’d have to have the whole genome now rather than back then, it might be just the CODIS
0:25:18 parts.
0:25:26 CODIS is just a few handful of simple sequence repeats that are used in criminal investigations
0:25:27 like —
0:25:28 Take forensics.
0:25:31 Yeah, forensics and CSI type stuff.
0:25:35 Now you’d need the whole genome because if somebody felt it was being hacked, they’d
0:25:37 say, “Well, let’s check the whole genome.”
0:25:39 A defense attorney could ask for the whole genome.
0:25:42 Further, you could ask for methylation to show that it’s the right age.
0:25:47 For example, I can have my DNA from 20 years ago, and you’d have to show — or you could
0:25:48 check the immune status.
0:25:53 So you could say, “Oh, does the immune status coincide with what the –” which that should
0:25:59 be an argument for you to be constantly sequencing your immune, your blood DNA, so you can date
0:26:01 whatever samples you’re taking.
0:26:03 For every hack, there is a counter hack.
0:26:08 So I think I’m glad that we’re not at that stage right at the moment, even though we
0:26:11 predicted it back in 2005.
0:26:16 So going back to 2005, can you describe briefly what the Personal Genome Project was?
0:26:19 Because it was the first effort to really start to think through these issues.
0:26:25 The Personal Genome Project was one of the first recognitions about how identifiable
0:26:31 both your genome is and also even parts of it and your medical records.
0:26:37 And people were starting to want to share genomic data and medical records, ideally integrated,
0:26:43 so that you could see what an individual, what we would now call precision medicine,
0:26:46 record would look like, right, back in 2005.
0:26:51 And I wrote an editorial saying that this was a risk, that the data could leak out,
0:26:55 and once it leaked out, the people could be re-identified, and all of their diseases could
0:26:59 be determined from either the medical record or the genome or both.
0:27:00 And this is played out.
0:27:05 I mean, there’s many examples of millions of people being their medical records and/or
0:27:08 their genome leaking out in various ways.
0:27:12 And of course, now, since then, WikiLeaks has occurred, which is just an example of
0:27:17 how they can be officially stored publicly after leaking.
0:27:20 So I think that was what we were concerned about, and we started the Personal Genome
0:27:25 Project so that we could get people properly consented so they knew these risks, they accepted
0:27:26 them.
0:27:27 And you had to take a quiz, right?
0:27:28 Exactly.
0:27:34 Up to that point, many of the consent forms were long, written in legalese, a lot of
0:27:39 language protected the institution rather than the person, and you would sign them often
0:27:43 under course of circumstances where you were afraid you weren’t going to get the best medical
0:27:45 care if you didn’t sign it.
0:27:50 So we added to that a simple multi-choice exam where you kind of simultaneously got
0:27:55 educated if you didn’t get a perfect score until you got a perfect score.
0:28:00 So it wasn’t like we wanted 90% comprehension, we wanted 100% that you knew all of the risks
0:28:03 and all the benefits, and we had a record of that.
0:28:06 So those were some of the key points of the Personal Genome Project, but the other key
0:28:08 point is we really wanted to share it.
0:28:13 Not just what a lot of people call sharing, even to this day, 13 years later, they call
0:28:19 sharing medical data for research is really a silo that’s hard to get into.
0:28:22 Now, unfortunately, it’s not impossible to get into, it’s not really encrypted the way
0:28:27 you would want it to be, and so there’s a lot of potential for leakage, but it’s hard
0:28:33 enough for regular scientists of good intention to get access to it legitimately.
0:28:37 So we wanted something that was more like Wikipedia where you didn’t have to agree to
0:28:42 be a co-author on a paper, you didn’t have to pay a lot of money, you literally could
0:28:47 use it for whatever you wanted to use it for, commercial, private, teaching, whatever, just
0:28:53 by clicking on it, and that project still exists today in many countries now with high-level
0:28:56 enthusiasm among the participants.
0:29:01 So you were obviously participant one, 001 of the Personal Genome Project.
0:29:02 You’re an open book.
0:29:06 If you go to your lab website, you have everything you’re working on, everything you’ve ever
0:29:11 worked on, you’ve described your phenotype in detail, which I think is fascinating.
0:29:15 Did you learn anything from having access to your own genome that you found particularly
0:29:17 interesting or enlightening?
0:29:21 So I didn’t expect to because I felt that I was likely to be in the 96% that would get
0:29:23 a blank report.
0:29:27 As it turned out, it did learn a couple of things.
0:29:31 So one of them my family was very concerned about because I had a family history of cognitive
0:29:36 decline was that I had no risk factors for Alzheimer’s.
0:29:38 To this ApoE4 status.
0:29:39 APP.
0:29:40 Precinalin 1 and 2.
0:29:41 Every known factor.
0:29:46 So that was reassuring, although I try to tell people not to be reassured that there’s always
0:29:48 something new to learn.
0:29:54 Secondly, I’m an alpha 1 antitrypsin compound heterozygote, which just means I have two
0:29:59 different risk factors that result in a risk for lung disease.
0:30:02 So I should probably avoid pollution, which is probably not a bad thing for everybody
0:30:04 to avoid and smoking.
0:30:08 And those were the two main things that I learned.
0:30:13 So it’s not that different from getting a blank sheet, quite frankly, but probably more
0:30:18 importantly was having my medical records publicly available meant the hematologist
0:30:22 gave me personal advice on my incorrect use of statin.
0:30:26 So it turned out that I was not being properly diagnosed.
0:30:31 Going back to where we’re under diagnosed, and I was having poor reactions of statin
0:30:32 as well as low efficacy.
0:30:34 It wasn’t doing its job.
0:30:38 And so we tried a little bit of nudging them around and finally gave up when I showed and
0:30:43 determined that a vegan diet, strict vegan diet, was enough to bring me down from almost
0:30:46 300 to almost 200.
0:30:52 So it’s not generic advice, it’s something that’s very personal and precision and empirical.
0:30:55 So that was another advantage of having people look on.
0:30:59 And then there was an advantage to the project of me being guinea pig number one.
0:31:04 The IRB, Harvard Medical School IRB, asked me to be an institution review board.
0:31:10 There’s sort of an ethics and protocol reviews of human subjects research.
0:31:16 They wanted me to participate as initially the only subject, or at least part of the
0:31:18 first 10.
0:31:24 And that was beneficial in that when we were developing the skin biopsy for induced pleuripotent
0:31:29 stem cells, the skin biopsy, first one we tried out in me, was ridiculously painful.
0:31:30 I remember that.
0:31:32 And in retrospect, it was crazy.
0:31:39 It was like a six millimeter punch, 12 stitches, no anesthetic, or at least not in the right
0:31:40 place.
0:31:45 And then we switched over to a cream anesthetic, which is instead of 12 injections in the wrong
0:31:48 place, it was cream in the right place.
0:31:51 And then a simple bandage rather than stitches, and a one millimeter punch.
0:31:57 So that was an example for me being eyewitness or guinea pig.
0:32:01 I said, no, that’s not an acceptable protocol immediately.
0:32:06 And I might not have said that if I were detached and I just said to one of the staff physicians,
0:32:08 oh, just go do it.
0:32:14 So that’s a summary of why sometimes it’s important for the top researcher to also
0:32:16 be a guinea pig in the study.
0:32:21 And I don’t think it supplies all studies, but it certainly applied to the Personal Genome
0:32:22 Project.
0:32:24 So switching gears to the church lab.
0:32:28 So if you go on your website, you have a list of sort of the active projects that you’re
0:32:29 working on.
0:32:32 And I mean, it almost reads like screenwriters for like coming up with the next, you know,
0:32:34 great movie.
0:32:35 Talk to me about the church lab.
0:32:37 How do you think about what you work on?
0:32:41 And even one step before that, how does one get into the church lab?
0:32:44 Because from an external standpoint, I mean, this is like Willy Wonka’s chocolate factory
0:32:45 for science.
0:32:49 So what do you look for in incoming students for the church lab?
0:32:50 And then let’s go from there.
0:32:51 Yeah.
0:32:55 So a lot of it looks like science fiction and most people would run away from that, not
0:32:56 run towards it.
0:33:01 And they did when I was starting out, but now we have a track record, same level of creativity
0:33:03 and risk taking.
0:33:08 But actually many of the things we do are they look hard from the outside, but from
0:33:12 the inside, they look like they’re low hanging fruit and they happen way ahead of schedule.
0:33:18 So for example, things that did look like science fiction were fluorescent next generation
0:33:20 sequencing and Nanopore sequencing.
0:33:24 Both of those were wacky when I started them in the 1980s.
0:33:27 And the whole idea that you could bring down the price of the genome from three billion
0:33:33 down to now sub thousand dollars also seemed science fiction.
0:33:36 But now that we’ve done it, now it becomes a beacon for people to say, Oh, whoever did
0:33:38 that, we should go there.
0:33:43 And if, oh, if at the same lab also helped bring in multiple ways of doing genome editing,
0:33:48 including CRISPR, if you just do one, you could be lucky, but if you do several different
0:33:52 ways of doing next-gen sequencing, several different ways of doing editing, then that’s
0:33:55 an attractant to get in.
0:33:56 Self selection is another major filter.
0:34:00 We do such quirky stuff that people don’t even bother to apply unless they’re kind of
0:34:02 already on our wavelength.
0:34:06 So then the biggest filter for me, and I tell us in the first interview, the first conversation
0:34:09 I have is we’re looking for people that are nice.
0:34:11 We’re not necessarily looking for geniuses.
0:34:13 We got plenty of geniuses.
0:34:15 We’re looking for people that are nice.
0:34:16 And how does one demonstrate niceness?
0:34:19 Well, you know, I think, to some extent, just having that conversation, if they want to
0:34:21 be cutthroat, they’re not going to come back.
0:34:26 If they’re kind of sitting on the fence, then they’re going to rise to the occasion.
0:34:31 They’re going to be influenced by that conversation and by all the people that have already passed
0:34:33 through that filter that are in the lab.
0:34:39 And you create a culture where you try not to compete with other labs if you can avoid
0:34:40 it.
0:34:44 Sometimes it’s unavoidable, but you can avoid it by inviting them to work with them, leaving
0:34:49 alone fields where there’s plenty of momentum and a lack of interest in collaboration, making
0:34:53 sure there’s a diverse enough set of ideas going on the lab so that everybody gets to
0:34:59 leave with a subset of those ideas as a parting gift or continue to collaborate if they want
0:35:01 to as long as they want to.
0:35:06 So I think you build up this momentum of knocking off things that look like science fiction,
0:35:12 turning them into science fact and create a culture of ability to fail and to jump back
0:35:15 and to be nice to your colleagues within and outside the lab.
0:35:19 So if I go through the list of things that you’re working on, it’s a pretty broad array
0:35:20 of things.
0:35:25 So you are crispering dogs to keep them young, you are crispering pig organs or had been
0:35:30 working on editing pig organs to make them useful for transplantation.
0:35:34 And then you run the other end of the spectrum, you’re re-engineering biology to create a
0:35:39 mirror universe of things that would be essentially immune to all known viruses or microbes.
0:35:41 How do you pick the projects?
0:35:44 What is it about what’s in the water in the, well, in the Iglesias lab, formerly known
0:35:45 as the church lab?
0:35:52 Like, what’s in the water that gets this lab to produce so many startups and spinouts?
0:35:56 What is that entrepreneurial energy that’s sort of been fostered and created here?
0:35:57 Right.
0:36:02 It may look like an averse set of projects, but they’re actually have common thread that
0:36:08 is surprisingly focused, meaning most people wouldn’t fit in this lab because we’re sort
0:36:12 of into radical transformative technologies, not incremental.
0:36:17 A lot of labs don’t even want to touch technology until it’s working in a company.
0:36:23 We work years before that company and we create the company and then the company has another
0:36:29 few years before it’s sufficiently worked out that it can be adopted by a technology
0:36:32 adoption lab, which is before most biologists.
0:36:37 So anyway, that’s one thing that we’re a little bit on the edge and it’s an acquired taste
0:36:39 or maybe even a rare taste.
0:36:41 What’s an idea that was pitched to you that you said, “Wow, that’s too crazy?”
0:36:43 Well, I’m usually the one pitching the crazy ideas.
0:36:47 I mean, not to say that we don’t have a lot of creativity in the lab.
0:36:48 That’s pretty rare.
0:36:51 In fact, we’ve sort of banned the word impossible.
0:36:55 We certainly try to behave ethically, but I think that many things, there’s a technological
0:36:59 solution to some of the ethical components, not all of them.
0:37:03 And we try to explore creative solutions to ethical problems.
0:37:06 Personal Genome Project was one of those creative solutions.
0:37:10 Surveillance for synthetic biology is another one that I suggested in 2004.
0:37:16 Biocontainment using recoding is a way that we can make any organism resistant to all
0:37:19 viruses and horizontal transfer.
0:37:20 Most of these things now work.
0:37:21 And many of these things are now companies.
0:37:22 That’s correct.
0:37:27 And their foundation was some sort of safety ethics component to the company.
0:37:30 And part of the secret sauce is hidden in plain view.
0:37:31 Like you say, we’re quite transparent.
0:37:35 We can keep other people’s secrets, but our own, we try to get people to adopt them.
0:37:39 Part of the thing that we do that is, instead of saying failure is not an option, which
0:37:42 was one of the Apollo slogans, we say, “Fail fast.
0:37:44 Just pick yourself up quickly.
0:37:46 Have a bunch of things going in parallel.
0:37:50 Find the low-hanging fruit empirically as well as theoretically.”
0:37:54 And just a lot of things people reject too easily.
0:37:57 They either don’t think of it at all, or they think about and reject it.
0:38:02 And so if we see something that looks a little hard, we’ll put it up on the shelf or in plain
0:38:06 view so we can keep reminding ourselves whenever a new technology makes that possible, we pull
0:38:08 it back off the shelf and we do it.
0:38:12 And so we have that culture of constantly reevaluating things that are on the edge of
0:38:14 science fiction.
0:38:18 Do you recruit entrepreneurs that happen to be scientists, or are you turning scientists
0:38:19 into entrepreneurs?
0:38:26 I mainly recruit people who are multilingual, multidisciplinary, because I found it’s hard
0:38:31 to build a multidisciplinary team from disciplinarians.
0:38:36 You have to have a lot of people who already have done two things, and even if you get two
0:38:39 people who have done two things each, they don’t have to overlap, but they’ve done enough
0:38:42 translation that they can start talking to each other.
0:38:46 And if you have enough of those multidisciplinary individuals, then you can sprinkle in a few
0:38:49 disciplinarians and you have an amazing team.
0:38:53 So the church lab, you were pioneers in sequencing, so reading DNA.
0:38:58 You were pioneers in CRISPR, so writing DNA.
0:38:59 What comes next?
0:39:02 Well, so there’s three-dimensional structure of living organisms, so we’d really like
0:39:08 to know every voxel, every volume, element of every pixel in the body of an embryo or
0:39:09 a larger section of tissue.
0:39:13 We’d like to know every molecule here, and we now have tools for doing DNA, RNA, and
0:39:17 protein in 3D at super resolution, finally.
0:39:18 So that’s one thing.
0:39:22 We would like to be able to do higher levels of multiplexing in the terms of editing synthesis
0:39:23 of genomes.
0:39:27 So some people call it, we call this GP Right, or Genome Project Right, but it could just
0:39:28 be heavy editing.
0:39:34 So we’ve set the record of 62 edits in the pigs, and we now have, we have 10,000 edits
0:39:35 in a single cell.
0:39:36 That’s unbelievable.
0:39:38 So it goes from two to 62 to 10,000.
0:39:39 And we want uses for each of these things.
0:39:45 So each of these projects, we have a driving societal benefit for each, and we have a driving
0:39:50 technology where we say, we don’t just want a factor of 1.5, we want a factor of a million
0:39:51 or 10 million.
0:39:58 And so that’s what pushes each of these projects is that triple criteria, which is cool, basic
0:40:04 science, philosophically interesting, technological factors of a million, and societal benefit.
0:40:08 Last question, 10 years from now, or just looking forward into the future.
0:40:11 Do we get the Neanderthal baby, or do we get the mammoth calf first?
0:40:16 Well, we never really said that we were going to a Neanderthal baby.
0:40:20 I mean, there’s a response to a journalist, whether it was technically possible, but nobody
0:40:21 has articulated a reason to do it.
0:40:26 But for the mammoth, there are lots of reasons, both for the environment and for enriching
0:40:29 the diversity of a living endangered species.
0:40:34 So this is not about de-extinction, this is about making hybrids, and many of the species
0:40:40 are already hybrids of multiple species, but now we can have the benefit of synthetic genes
0:40:41 and ancient genes.
0:40:42 Great.
0:40:43 Well, thank you, George.
0:40:44 Thank you for making time.
0:40:45 It was a real pleasure.
0:00:07 Today’s episode features a special conversation with renowned scientist George Church,
0:00:11 known for his groundbreaking work and methods used for the first genome sequence
0:00:14 and for his work in genome editing, writing, and recoding.
0:00:17 Church’s innovations have become an essential building block
0:00:21 for most of the DNA sequencing methods and companies we see today.
0:00:25 He has joined in this conversation with A16Z bio-general partner Jorge Conde,
0:00:29 who, among other things, founded a company with Church out of the church lab.
0:00:32 The two take us on a wild journey into the scientist’s mind and work,
0:00:37 starting with what the leading pioneer in this space makes of where we are today with CRISPR,
0:00:39 especially given recent news about CRISPR babies in China,
0:00:43 then moving on to the broader implications of all that on a cultural level
0:00:48 to finally what it takes to go from science fiction to lab to reality.
0:00:49 So, let’s start at the beginning.
0:00:55 If we were to bet 10 years ago whether we’d have a CRISPR baby, a mammoth baby,
0:01:00 or a Neanderthal baby, which would you have bet would have come first?
0:01:05 Oh, and questionably, a CRISPR baby, you know, I mean, it was not a huge technical leap.
0:01:10 They all involved societal and ethical questions,
0:01:14 but that one probably had the clearest path, you know,
0:01:19 because there was such divergence of opinion, somebody was going to do it.
0:01:24 And would you have expected that it would have been essentially a rogue effort
0:01:28 versus a solo effort, as it seems to have been the case in the China CRISPR baby news?
0:01:30 I wouldn’t characterize it as a solo effort.
0:01:32 I’ve seen the author list, it’s quite long.
0:01:38 And I also find it unlikely that a government as technically astute
0:01:44 and as engaged in observation would be unaware of such an important thing.
0:01:48 If I were a technically astute government,
0:01:51 there are very limited number of topics I would be paying attention to.
0:01:58 And these would be things like, you know, nuclear, biological, encryption, and CRISPR.
0:02:01 It’s a short list, so I don’t think it’s solo.
0:02:05 So let’s talk a little bit about the way it’s been sort of positioned, at least publicly.
0:02:11 Can you describe a little bit what the experiment actually was?
0:02:15 What did the scientists or scientists do in this particular case for the CRISPR baby?
0:02:19 I’ve actually seen a lot of the data and the preprints.
0:02:25 And this was a simple, in a certain sense, application of CRISPR
0:02:31 to alleviate a potential for HIV infection.
0:02:37 You know, 900,000 people die every year of HIV, and this was an approach to it.
0:02:44 And they did it by knocking out the gene that encodes the HIV receptor on the surface of T cells.
0:02:45 This is CCR5.
0:02:52 This is CCR5, which has already been approved for FDA clinical trials for Sangamo
0:02:56 and for editing in adults that have AIDS.
0:03:00 That’s a different scenario, but vets many of the issues that come up
0:03:04 as to whether this is a reasonable editing strategy.
0:03:08 So first of all, people have described it as knocking out the gene.
0:03:11 Other people have described it as editing the CCR5 gene.
0:03:15 Having seen the data, what exactly was done to CCR5?
0:03:21 Right, so what CRISPR does well is often described as editing, it really is damaging.
0:03:24 It’s not really that good at precision editing.
0:03:28 Hopefully there will be a good way in the future.
0:03:30 And so what it does is it knocks out genes.
0:03:34 And in this case, that’s exactly what you want, is you want to knock out the CCR5 gene.
0:03:35 And there’s precedent for it.
0:03:40 About up to 10% of certain parts of Europe have a double null.
0:03:43 To double null in this case, basically, two non-functional CCR5s.
0:03:48 And you need really both non-functional in order to be resistant to the virus.
0:03:50 And it doesn’t make you resistant to all viruses.
0:03:55 It doesn’t even make you resistant to all HIV viruses, but that’s not the point.
0:03:58 It’s like a vaccine, it makes you resistant to whatever you’re vaccinated against.
0:04:03 And analogies were made in the consenting for this between this and vaccination.
0:04:08 There is no good vaccine, there’s no cure for HIV/AIDS.
0:04:14 And right now, if you get it, and there are 37 million people who have been affected,
0:04:19 if you get it, you’re doomed to a lifetime of combined antiretroviral therapy,
0:04:24 which is not the thing that you would wish to have if you had any choice.
0:04:24 Sure.
0:04:28 Well, vaccines, if there did exist one, would be quite a good choice.
0:04:32 And so this is as close as you can get to a vaccine.
0:04:37 So I read that the double nulls for CCR5 have increased predisposition to West Nile.
0:04:38 That is correct.
0:04:42 So there’s a risk for almost every preventative antiretroviral therapy.
0:04:43 And this is the risk in this case.
0:04:47 In most populations, that’s considered a smaller medical risk.
0:04:51 It’s obviously a case by case for populations and individuals.
0:04:54 And there are undoubtedly other advantages and disadvantages.
0:04:58 And I may be taking you a little bit out of context here, but I’ve heard you describe
0:05:02 CRISPR as genetic vandalism.
0:05:06 So do you think that that’s a good application for germline editing?
0:05:10 Well, it’s vandalism in the sense that it can add or delete a small number of base
0:05:16 pairs, typically, in the range of 1 to hundreds.
0:05:22 It’s not going to do something really wacky, except it may be some incredibly low frequency.
0:05:24 Again, no drug is without its side effects.
0:05:28 And that’s why there’s all the fine print that accompanies all the approved drugs.
0:05:31 So I think in this case, it is what you want.
0:05:32 It’s exactly what you want.
0:05:36 You want to destroy the CCR5 gene without destroying any adjacent genes.
0:05:41 And that’s every allele that I’ve seen in the literature for CCR5, whether it’s done
0:05:46 in adults or done in tissue culture, is what you would want.
0:05:50 So I’ve read in this case in the Chinese CRISPR baby publication that there is some
0:05:55 mosaicism that he might not have functionally knocked out all of the CCR5.
0:06:00 So is there any worry that after the post-experiment that this particular child might still be
0:06:02 at risk for HIV infection?
0:06:08 So first of all, in the approved clinical trials on adults that have HIV/AIDS, there
0:06:11 is a lot of mosaicism.
0:06:13 It’s considered part of the clinical trial.
0:06:20 And maybe as little as 20% are properly edited, meaning double nulls.
0:06:24 That’s enough, though, because all the rest are wiped up by the virus, and then the ones
0:06:28 that are edited dominate the T-cell population.
0:06:29 So it’s one way of thinking about it.
0:06:34 So it’s basically selection for the edited T-cells so you don’t develop immunosuppression.
0:06:35 Right.
0:06:37 So as long as there’s a fair number of properly edited ones.
0:06:43 Now on the other hand, looking at the data, I don’t see that much evidence for mosaicism.
0:06:49 It’s quite possible that what you see in the pre-implantation embryo when you select a
0:06:57 few cells out of that blastocyst is not representative of the final, and the final is less mosaic,
0:06:59 or maybe even non-mosaic.
0:07:04 So when they talk about a baby having mosaicism in the case of the CRISPR baby, essentially
0:07:08 what they’re referring to is that there are some cells that will have edits, and some
0:07:10 cells that won’t.
0:07:16 And so essentially that child may grow up to be a mosaic of two different or multiple
0:07:17 different cell types.
0:07:18 Correct.
0:07:22 And the same thing I should note is true for adult gene therapies is that whether they’re
0:07:27 done ex vivo or in vivo, it usually results in a high level of mosaicism because the delivery
0:07:29 is inefficient.
0:07:33 And it may even be the case that the germline has lower mosaicism.
0:07:34 We need more data.
0:07:35 Great.
0:07:42 So the amount of off-target and mosaicism so far for these two babies seems to be low,
0:07:43 but time will tell.
0:07:49 You know, it could be that we’re just lucky the same way that the first in vitro fertilization,
0:07:51 Louise Brown, turned out just fine.
0:07:55 And so that greatly influenced, it shouldn’t have, I mean, it’s an N of one.
0:07:59 We shouldn’t have all said, “Oh, IVF is perfect because we have one perfect baby.”
0:08:03 To your referencing the test tube hysteria around the first IVF.
0:08:11 1978, which subsided, it grew too much and it subsided too quickly based on N of one.
0:08:15 And I think here we have an N of two, maybe an N of three, and there’s going to be a lot
0:08:20 of attention paid to the actual outcomes rather than how we got there, hopefully.
0:08:25 If you had been in charge of the project, would you have done CCR five or is there another
0:08:28 different obvious application that you’d have gone after first?
0:08:29 Very preclinical.
0:08:33 In other words, I create technologies that’s been used by companies that I found, and they
0:08:34 do the clinical trial.
0:08:39 So I probably would not be doing a clinical trial at all, just to put it in context.
0:08:44 But in terms of choice of target, I have said publicly already that targets that have been
0:08:49 championed by the critics to the extent they champion anything, or the ones that they present
0:08:56 as possibilities or as higher priority, although with great reservations, even for those, are
0:09:03 things that are typical Mendelian diseases, that is to say diseases that are very severe
0:09:11 and are predictably heritable, which are things like hemoglobinopathy, salicylium, sickle
0:09:18 cell, cystic fibrosis, and so forth, ignoring the fact that if you’re in an IVF-PGD clinic
0:09:25 anyway, to do your CRISPR editing of your Mendelian disease, you could just do selection
0:09:26 for most of these things.
0:09:33 So I think it’s kind of like they’re rationalizing their choice, which in the same sense that
0:09:37 they might feel is rationalizing to pick a more prominent disease.
0:09:40 But also, I think in all the examples you just cited, you would actually need to edit the
0:09:45 gene to create function as opposed to knocking out, as was the case with CCR five.
0:09:49 And in some sense, the critics might think that that’s attractive, that CRISPR is inappropriate
0:09:53 at this moment because it gives us more time to think about it.
0:09:58 But in any case, yeah, I think that we want an example of a disease that is very common,
0:10:04 and most of the gene therapies are rare, whether editing or not, and we want something that’s
0:10:09 very serious, and certainly HIV falls in that category.
0:10:15 So it struck me as a plausibly justifiable choice, possibly more justifiable and something
0:10:21 that you can avoid with genetic counseling or with PGD IVF or both.
0:10:27 So IVF-PGD stands for In vitro fertilization with prenatal genetic diagnosis.
0:10:32 So the diagnosis can essentially be done before you implant the embryo from an in vitro fertilization
0:10:33 into the mother.
0:10:39 And so by some people’s definition, that’s still kind of a lab resource rather than a
0:10:40 baby.
0:10:45 And those are typically used for Mendelian diseases, meaning that you can see in the
0:10:49 parents, for example, both parents could be unaffected carriers.
0:10:55 You can predict that 25% of their children will or their embryos in vitro fertilization
0:10:58 could be affected with a very serious disease.
0:11:03 So now that the gene is out of the bottle, we have the first CRISPR babies born.
0:11:09 First of all, what was the role of ethicists in the first project in the CCR-5 Chinese
0:11:11 CRISPR baby project?
0:11:14 And what do you see as the role of ethicists going forward?
0:11:19 Well so the National Academy of Sciences in the US and with participation from China and
0:11:24 other countries in February 2017 came out with a report where they listed 10 items that
0:11:31 would be recommendations for prerequisites for doing germline editing in children.
0:11:38 I mean obviously you can do germline editing in animals or you can do it in cells in culture
0:11:42 or even embryos in culture but actually in planting and having children.
0:11:44 And a lot of these had ethical components.
0:11:50 Many of them were very similar to what you would expect the FDA or the CFDA or the EMA
0:11:56 to be, these are all regulatory agencies around the world, would recommend for any therapeutic
0:11:57 clinical trial.
0:12:03 We should all be focused on safety and efficacy and ethics and that’s what these 10 items
0:12:06 look like for germline as well.
0:12:10 Do you suspect or do you expect, I should say, that we’re going to see more and more
0:12:15 of these experiments going forward or do you think that after this first one, going back
0:12:18 to the IVF example, do you think there will be a pause?
0:12:23 Well there probably will be something that looks like a pause but it will probably be
0:12:25 an acceleration.
0:12:29 So the same thing happened with the prominent DNA, there was supposedly a moratorium but
0:12:34 during that time, I mean I was a first-hand observer, my research went faster because
0:12:39 people were building incredible facilities for containment and they had just state-of-the-art
0:12:42 equipment that helped everything go faster in my opinion.
0:12:47 And I think the same thing has gone with almost every major ethical debate is it attracts
0:12:54 attention, attracts money, whatever is ethical at the time is accelerated and then so whenever
0:13:00 we become comfortable with it, all that acceleration clicks into place and it’s as if there’s been
0:13:02 a steady growth.
0:13:07 That doesn’t mean we should be incautious, on the contrary, I’m very much pro-regulation.
0:13:14 I think that regulation is what saves us from phalidomide and Vioxx and hormone replacement
0:13:17 therapy and so forth, long-term.
0:13:21 So I think we need to support our regulatory agencies around the world.
0:13:25 They are not agents of slowing things down, they’re actually agents of smoothing things
0:13:26 out.
0:13:28 Yeah, and I think it’s pretty clear we’re seeing that today in the regulatory environment,
0:13:29 certainly here in the US.
0:13:34 I mean, we’ve got the first cell therapies, the first gene therapies, the first digital
0:13:35 therapies.
0:13:38 It’s a pretty remarkable moment from a regulatory standpoint for a new therapy.
0:13:41 To some extent, I think they like new technologies more than like the old ones.
0:13:47 The old ones tend to fail because they’re so incremental that they’re no longer compared
0:13:50 to the placebo, they’re compared to whatever they’re an increment over or whatever therapy
0:13:57 already works and they often fail, but brand new category, monoclonal antibodies or cell
0:14:04 therapies or gene therapies, those just like blow past and create all sorts of new improvements,
0:14:06 traumatic improvements in safety and efficacy.
0:14:11 So the FDA is, that’s their mandate, is to cure people, not to stop people from practicing
0:14:12 medicine.
0:14:18 So just to take that vein, if we look forward, what do you see as sort of the next non-incremental
0:14:23 sort of step function change in the way we treat disease or manage disease or even diagnose
0:14:24 disease?
0:14:28 Well, first of all, if we started diagnosing, that would be a really big thing.
0:14:33 It’s really, we’re as a population, even worldwide, we’re under-diagnosed.
0:14:38 There’s a lot of very cost-effective diagnoses that partly because they’re cost-effective,
0:14:45 they’re undervalued and the care providers are not compensated as much as some less effective
0:14:47 but expensive medicine.
0:14:51 So that’s one thing, diagnosis would be terrific and that’s part of preventative medicine.
0:14:56 So we talk a lot about precision medicine, but the preventative part gets kind of swept
0:14:57 under the rug a bit.
0:15:01 If you look at the pie charts for a number of government agencies, including the NCI,
0:15:09 NIH in general, is preventative is sort of in the 1 to 5% of the pie chart, but its payback
0:15:10 is enormous.
0:15:14 And so basically you’re saying misaligned incentives and human behavior has sort of
0:15:17 mitigated how much prevention we actually do.
0:15:21 That’s right, but that would be a huge breakthrough so we could do more diagnosis and more prevention.
0:15:26 Now the ultimate diagnosis for genetics is whole genome sequencing and environmental
0:15:30 monitoring with sequencing as well for pathogens, allergens and so forth.
0:15:39 The therapeutic cognate of that is preventing serious Mendelian diseases that are very predictive
0:15:44 and very often single gene or have enough of a single gene component that they’re ready
0:15:47 for medical practice, thousands of them.
0:15:48 And those can be prevented.
0:15:52 We often talk about gene therapy, actually that’s a million dollar drug.
0:15:57 It is once and done so you don’t have a lifetime of dosing, but it is expensive, we need to
0:15:58 acknowledge that.
0:16:00 Partly because a lot of them are rare.
0:16:06 If you get a common gene therapy, like let’s say aging reversal or some major infectious
0:16:11 agent that everybody wants to be vaccinated against, it’s like most infectious ages have
0:16:16 potentially billions of customers, then that will bring the price down radically.
0:16:22 But in addition to gene therapy, either in adults, children, fetuses or germ line, there
0:16:28 is the option of doing IVFPGD that we already mentioned and even earlier in matchmaking.
0:16:36 So if you never meet or fall in love with someone who is predisposed to create heavily
0:16:43 disease, genetically diseased children, that’s very both cost effective and humane.
0:16:45 So you’re describing 23andMe meets 10andMe.
0:16:47 No, I am not actually.
0:16:52 I’m describing a whole genome sequencing, which is not, there are a very small number
0:16:56 of companies that provide whole genome sequencing because everything else, anything less than
0:17:00 whole genome sequencing is not medically powerful enough.
0:17:04 Anything less than that misses because you false assurance.
0:17:09 That combined with some sort of dating that is an odd combination and possibly further
0:17:14 combined with whoever is paying for the Mendelian costs right now, which are about a million
0:17:18 dollars per person, doesn’t have to be gene therapy, which happens to be a million.
0:17:21 It can be just caregiving.
0:17:27 It adds up and somebody is paying for that, typically insurers and employment benefits
0:17:34 and they could be saving this money if they could encourage their clients, patients to
0:17:38 avoid falling in love, marrying and having children when they have incompatibility.
0:17:39 Their carriers of something.
0:17:40 And this actually works.
0:17:48 So Dorya Sharim has eliminated significant menial disease like Tasex by practicing a
0:17:53 version of this that probably isn’t perfectly generalizable, but there are versions that
0:17:59 could keep a great deal of privacy and allow people to just never know whether they’re
0:18:02 affected or not, or whether they’re carriers or not, never know if anybody else is affected,
0:18:05 but still avoid meeting.
0:18:09 I mean, the analog version of this was back in the day in certain communities, Jewish
0:18:12 communities where there was disease, the rabbi would essentially replace function.
0:18:13 That’s what Dorya Sharim was.
0:18:14 Exactly.
0:18:20 It was started by an individual who had five children in a row that were affected by Tasex,
0:18:25 which is a terrible burden on the child and the family that typically died before they’re
0:18:27 four years old and very painful.
0:18:34 And so he correctly determined that you could do this very inexpensively and mainly.
0:18:35 Via matchmaking.
0:18:36 Via matchmaking.
0:18:37 Right.
0:18:39 So let’s take another blast back to the past.
0:18:44 So about 10 years ago, you and I started a company in whole genome sequencing.
0:18:45 Called Nome.
0:18:46 Thank you.
0:18:47 Called Nome.
0:18:48 Not Nome.
0:18:49 Called Nome.
0:18:52 We used to have this constant back and forth that you thought it should be called Nome.
0:18:53 I would call it Nome.
0:18:54 Yeah.
0:18:55 I thought it should be called Nome.
0:18:56 Yeah.
0:18:57 And this was the market test.
0:18:59 It was the youth into me, which is incredibly frustrating.
0:19:00 Yeah.
0:19:01 And now I listen to you.
0:19:02 Thank you.
0:19:03 Like I said, no.
0:19:04 Okay.
0:19:08 My rejoiner on that always was, if you want to call it know me, then I want to call you
0:19:12 Jorge Iglesias and you are never a big fan of that one.
0:19:13 Okay.
0:19:14 I don’t have no problem with that name.
0:19:15 I think it’s a better name.
0:19:16 It’s a nice name.
0:19:17 It’s going to increase the brand.
0:19:20 It just has more syllables, that’s all.
0:19:22 But it just, it rolls off the tongue.
0:19:23 Does.
0:19:24 Yes.
0:19:28 It basically made the bet that whole genome sequencing was important.
0:19:32 That interpretation of that data would be relevant, that it would be meaningful.
0:19:36 Ten years hence, there still are not many people walking around that have had their
0:19:41 whole genomes sequenced despite the fact that the cost has now fallen arguably below $1,000
0:19:44 or at least we’re at that $1,000 threshold.
0:19:46 So I had two questions for you.
0:19:52 Number one is, is the $1,000 threshold for this to be useful for everyone to get sequenced
0:19:53 too high a dollar number?
0:19:57 In other words, does it need to be $100 or $10?
0:20:02 And number two, to the extent that this hasn’t happened yet, why hasn’t it happened yet if
0:20:03 it’s not cost?
0:20:06 I would say there’s three reasons why it hasn’t happened yet.
0:20:10 And I’ve been living this reality for most of my career.
0:20:15 I’m convinced that it would be valuable for the world, it costs effective medicine, preventative.
0:20:18 And I think the three reasons are one is cost.
0:20:20 The cost should probably be $0.
0:20:22 And secondly, it’s privacy.
0:20:27 We should have a convincing mechanism of people getting benefit from their genome without
0:20:29 necessarily knowing their genome or anybody else knowing their genome.
0:20:34 You can have something where it’s only an encrypted form, not available to anybody, including
0:20:36 insurance and government.
0:20:37 That’s second.
0:20:41 And the third is most people don’t understand the value proposition.
0:20:44 It’s either misrepresented, but by both extremes.
0:20:48 So some people say, oh, it’s so valuable that you’re going to whip out your cell phone and
0:20:50 look at your genome twice a day.
0:20:54 And at the other extreme, they say, I can’t imagine ever using it.
0:20:58 And the reality is somewhere in between, and I think the analogy is seatbelts.
0:21:00 So seatbelts were essentially free.
0:21:01 They were standard equipment.
0:21:04 They were required by law that you buckle.
0:21:09 And there were a lot of ad campaigns to get you to do so, kind of like smoking.
0:21:15 And none of those were effective because people did, you know, the kind of ordinary math,
0:21:19 which is, hey, I’ve got a less than 1% chance of ever using a seatbelt, ever needing one.
0:21:21 So I’m not going to bother.
0:21:26 And then the thing that made the difference was technology to sense the buckling and turning
0:21:28 off an annoying sound.
0:21:29 So that’s what made the difference.
0:21:30 And we need an equivalent thing.
0:21:32 It’s a public health issue.
0:21:35 It’s not an individual health issue.
0:21:37 So I don’t benefit from being sequenced, the collective.
0:21:43 These people, 95, 96% will get a blank sheet.
0:21:50 They should get a blank sheet in terms of really actionable, very serious Mendelian diseases.
0:21:51 And that should be the expectation.
0:21:56 Not the two extremes that you’ll use it every day, or that everybody will use it every day,
0:21:57 or the other extreme, which is totally useless.
0:22:04 It’s this strange thing where 1% to 4% of the population will have a very big impact
0:22:05 on their life.
0:22:12 And the bottom line for their care providers, millions of dollars, huge impact on the whole
0:22:17 family, if you’re one of the unlucky 4%.
0:22:19 And we need to get that message out there.
0:22:24 And I think that bringing the price down to $0 and showing that it’s protectable, encrypted
0:22:29 and so that nobody can get access to it except for things that benefit you or your family
0:22:33 or society, that will get their attention.
0:22:36 But it’s going to take a little bit more than that’s going to take some anecdotes.
0:22:40 You would think that data would be better than anecdotes, but you need both.
0:22:43 And I think it’s going to happen very soon now, because we finally have the $0 genome
0:22:50 and the encryption, and we’re starting to get communication of this rare advantage where
0:22:54 you’re not exempt, even though the odds are that you’re exempt, you don’t know that you’re
0:22:57 exempt until you get your genome sequenced.
0:22:59 So two questions for you on the three ones you’ve laid out.
0:23:04 The first one is, in the early days of Nome, I remember when we would think about this
0:23:10 question of security, you correctly pointed out that if you really wanted my genome,
0:23:13 you would just wait for me to leave the room and collect it from all of the genome.
0:23:14 Exactly.
0:23:15 That is even more true than it was back in 2007.
0:23:16 Right.
0:23:18 So you collect all of this chair off this table, and you’ve got me.
0:23:19 Got it.
0:23:24 So why is security and privacy, is it even a meaningful thing to think about if it’s
0:23:25 an impossible thing to achieve?
0:23:30 Well, the point is, if it’s preventing people from getting their own genome sequenced, if
0:23:36 they think that them seeing their own genome puts them at risk for somebody like hacking
0:23:41 or requesting it or subpoenaing it, then yes, it’s a problem, because there is a difference
0:23:46 between me woefully getting my genome and looking at it and somebody surreptitiously
0:23:47 taking it.
0:23:48 Okay?
0:23:51 So we can pass laws that punish people for surreptitiously taking my DNA.
0:23:56 We do have the Genetic Information Non-Discrimination Act of 2008 that is along those lines.
0:24:00 It’s not perfect, but it shows the intention of the public.
0:24:05 So that can kind of handle the abandoned DNA problem, and we could keep shoring that
0:24:07 up and building up those laws.
0:24:11 But then there’s the question, if I look at my genome, if I have my genome available
0:24:16 in text format, unprotected, then anybody can come along and demand it, right?
0:24:20 Insurance companies say, “I know you know it, so I want to see it.”
0:24:24 And they can say, “I want to see it, so I can convict your brother.”
0:24:29 And if it’s encrypted so that even you can’t hack it, then you can just say, “Sorry, it’s
0:24:30 out of my hands.
0:24:31 I don’t have my genome.
0:24:33 If you want my genome, you’re going to have to steal it from me.”
0:24:34 Right?
0:24:35 Got it.
0:24:36 And I think that’s where we are today, finally.
0:24:39 By the way, you may not remember this, but we were laying out the risk factors and all
0:24:46 of the other things for the consent form on all the things that a potential recipient
0:24:48 of their genome data would have to think about.
0:24:53 By far and away, my favorite one that you contributed was the potential risk that someone
0:24:55 could plant your DNA at a crime scene.
0:24:56 Right.
0:24:57 Yep.
0:24:58 High risk or low risk?
0:25:03 So that was also in a personal genome project consent form, which started around that same
0:25:04 time as Noam did.
0:25:06 Is it high risk or low risk?
0:25:14 I’d say that we’re getting more and more sophisticated at sequencing and methylation analysis.
0:25:17 You’d have to have the whole genome now rather than back then, it might be just the CODIS
0:25:18 parts.
0:25:26 CODIS is just a few handful of simple sequence repeats that are used in criminal investigations
0:25:27 like —
0:25:28 Take forensics.
0:25:31 Yeah, forensics and CSI type stuff.
0:25:35 Now you’d need the whole genome because if somebody felt it was being hacked, they’d
0:25:37 say, “Well, let’s check the whole genome.”
0:25:39 A defense attorney could ask for the whole genome.
0:25:42 Further, you could ask for methylation to show that it’s the right age.
0:25:47 For example, I can have my DNA from 20 years ago, and you’d have to show — or you could
0:25:48 check the immune status.
0:25:53 So you could say, “Oh, does the immune status coincide with what the –” which that should
0:25:59 be an argument for you to be constantly sequencing your immune, your blood DNA, so you can date
0:26:01 whatever samples you’re taking.
0:26:03 For every hack, there is a counter hack.
0:26:08 So I think I’m glad that we’re not at that stage right at the moment, even though we
0:26:11 predicted it back in 2005.
0:26:16 So going back to 2005, can you describe briefly what the Personal Genome Project was?
0:26:19 Because it was the first effort to really start to think through these issues.
0:26:25 The Personal Genome Project was one of the first recognitions about how identifiable
0:26:31 both your genome is and also even parts of it and your medical records.
0:26:37 And people were starting to want to share genomic data and medical records, ideally integrated,
0:26:43 so that you could see what an individual, what we would now call precision medicine,
0:26:46 record would look like, right, back in 2005.
0:26:51 And I wrote an editorial saying that this was a risk, that the data could leak out,
0:26:55 and once it leaked out, the people could be re-identified, and all of their diseases could
0:26:59 be determined from either the medical record or the genome or both.
0:27:00 And this is played out.
0:27:05 I mean, there’s many examples of millions of people being their medical records and/or
0:27:08 their genome leaking out in various ways.
0:27:12 And of course, now, since then, WikiLeaks has occurred, which is just an example of
0:27:17 how they can be officially stored publicly after leaking.
0:27:20 So I think that was what we were concerned about, and we started the Personal Genome
0:27:25 Project so that we could get people properly consented so they knew these risks, they accepted
0:27:26 them.
0:27:27 And you had to take a quiz, right?
0:27:28 Exactly.
0:27:34 Up to that point, many of the consent forms were long, written in legalese, a lot of
0:27:39 language protected the institution rather than the person, and you would sign them often
0:27:43 under course of circumstances where you were afraid you weren’t going to get the best medical
0:27:45 care if you didn’t sign it.
0:27:50 So we added to that a simple multi-choice exam where you kind of simultaneously got
0:27:55 educated if you didn’t get a perfect score until you got a perfect score.
0:28:00 So it wasn’t like we wanted 90% comprehension, we wanted 100% that you knew all of the risks
0:28:03 and all the benefits, and we had a record of that.
0:28:06 So those were some of the key points of the Personal Genome Project, but the other key
0:28:08 point is we really wanted to share it.
0:28:13 Not just what a lot of people call sharing, even to this day, 13 years later, they call
0:28:19 sharing medical data for research is really a silo that’s hard to get into.
0:28:22 Now, unfortunately, it’s not impossible to get into, it’s not really encrypted the way
0:28:27 you would want it to be, and so there’s a lot of potential for leakage, but it’s hard
0:28:33 enough for regular scientists of good intention to get access to it legitimately.
0:28:37 So we wanted something that was more like Wikipedia where you didn’t have to agree to
0:28:42 be a co-author on a paper, you didn’t have to pay a lot of money, you literally could
0:28:47 use it for whatever you wanted to use it for, commercial, private, teaching, whatever, just
0:28:53 by clicking on it, and that project still exists today in many countries now with high-level
0:28:56 enthusiasm among the participants.
0:29:01 So you were obviously participant one, 001 of the Personal Genome Project.
0:29:02 You’re an open book.
0:29:06 If you go to your lab website, you have everything you’re working on, everything you’ve ever
0:29:11 worked on, you’ve described your phenotype in detail, which I think is fascinating.
0:29:15 Did you learn anything from having access to your own genome that you found particularly
0:29:17 interesting or enlightening?
0:29:21 So I didn’t expect to because I felt that I was likely to be in the 96% that would get
0:29:23 a blank report.
0:29:27 As it turned out, it did learn a couple of things.
0:29:31 So one of them my family was very concerned about because I had a family history of cognitive
0:29:36 decline was that I had no risk factors for Alzheimer’s.
0:29:38 To this ApoE4 status.
0:29:39 APP.
0:29:40 Precinalin 1 and 2.
0:29:41 Every known factor.
0:29:46 So that was reassuring, although I try to tell people not to be reassured that there’s always
0:29:48 something new to learn.
0:29:54 Secondly, I’m an alpha 1 antitrypsin compound heterozygote, which just means I have two
0:29:59 different risk factors that result in a risk for lung disease.
0:30:02 So I should probably avoid pollution, which is probably not a bad thing for everybody
0:30:04 to avoid and smoking.
0:30:08 And those were the two main things that I learned.
0:30:13 So it’s not that different from getting a blank sheet, quite frankly, but probably more
0:30:18 importantly was having my medical records publicly available meant the hematologist
0:30:22 gave me personal advice on my incorrect use of statin.
0:30:26 So it turned out that I was not being properly diagnosed.
0:30:31 Going back to where we’re under diagnosed, and I was having poor reactions of statin
0:30:32 as well as low efficacy.
0:30:34 It wasn’t doing its job.
0:30:38 And so we tried a little bit of nudging them around and finally gave up when I showed and
0:30:43 determined that a vegan diet, strict vegan diet, was enough to bring me down from almost
0:30:46 300 to almost 200.
0:30:52 So it’s not generic advice, it’s something that’s very personal and precision and empirical.
0:30:55 So that was another advantage of having people look on.
0:30:59 And then there was an advantage to the project of me being guinea pig number one.
0:31:04 The IRB, Harvard Medical School IRB, asked me to be an institution review board.
0:31:10 There’s sort of an ethics and protocol reviews of human subjects research.
0:31:16 They wanted me to participate as initially the only subject, or at least part of the
0:31:18 first 10.
0:31:24 And that was beneficial in that when we were developing the skin biopsy for induced pleuripotent
0:31:29 stem cells, the skin biopsy, first one we tried out in me, was ridiculously painful.
0:31:30 I remember that.
0:31:32 And in retrospect, it was crazy.
0:31:39 It was like a six millimeter punch, 12 stitches, no anesthetic, or at least not in the right
0:31:40 place.
0:31:45 And then we switched over to a cream anesthetic, which is instead of 12 injections in the wrong
0:31:48 place, it was cream in the right place.
0:31:51 And then a simple bandage rather than stitches, and a one millimeter punch.
0:31:57 So that was an example for me being eyewitness or guinea pig.
0:32:01 I said, no, that’s not an acceptable protocol immediately.
0:32:06 And I might not have said that if I were detached and I just said to one of the staff physicians,
0:32:08 oh, just go do it.
0:32:14 So that’s a summary of why sometimes it’s important for the top researcher to also
0:32:16 be a guinea pig in the study.
0:32:21 And I don’t think it supplies all studies, but it certainly applied to the Personal Genome
0:32:22 Project.
0:32:24 So switching gears to the church lab.
0:32:28 So if you go on your website, you have a list of sort of the active projects that you’re
0:32:29 working on.
0:32:32 And I mean, it almost reads like screenwriters for like coming up with the next, you know,
0:32:34 great movie.
0:32:35 Talk to me about the church lab.
0:32:37 How do you think about what you work on?
0:32:41 And even one step before that, how does one get into the church lab?
0:32:44 Because from an external standpoint, I mean, this is like Willy Wonka’s chocolate factory
0:32:45 for science.
0:32:49 So what do you look for in incoming students for the church lab?
0:32:50 And then let’s go from there.
0:32:51 Yeah.
0:32:55 So a lot of it looks like science fiction and most people would run away from that, not
0:32:56 run towards it.
0:33:01 And they did when I was starting out, but now we have a track record, same level of creativity
0:33:03 and risk taking.
0:33:08 But actually many of the things we do are they look hard from the outside, but from
0:33:12 the inside, they look like they’re low hanging fruit and they happen way ahead of schedule.
0:33:18 So for example, things that did look like science fiction were fluorescent next generation
0:33:20 sequencing and Nanopore sequencing.
0:33:24 Both of those were wacky when I started them in the 1980s.
0:33:27 And the whole idea that you could bring down the price of the genome from three billion
0:33:33 down to now sub thousand dollars also seemed science fiction.
0:33:36 But now that we’ve done it, now it becomes a beacon for people to say, Oh, whoever did
0:33:38 that, we should go there.
0:33:43 And if, oh, if at the same lab also helped bring in multiple ways of doing genome editing,
0:33:48 including CRISPR, if you just do one, you could be lucky, but if you do several different
0:33:52 ways of doing next-gen sequencing, several different ways of doing editing, then that’s
0:33:55 an attractant to get in.
0:33:56 Self selection is another major filter.
0:34:00 We do such quirky stuff that people don’t even bother to apply unless they’re kind of
0:34:02 already on our wavelength.
0:34:06 So then the biggest filter for me, and I tell us in the first interview, the first conversation
0:34:09 I have is we’re looking for people that are nice.
0:34:11 We’re not necessarily looking for geniuses.
0:34:13 We got plenty of geniuses.
0:34:15 We’re looking for people that are nice.
0:34:16 And how does one demonstrate niceness?
0:34:19 Well, you know, I think, to some extent, just having that conversation, if they want to
0:34:21 be cutthroat, they’re not going to come back.
0:34:26 If they’re kind of sitting on the fence, then they’re going to rise to the occasion.
0:34:31 They’re going to be influenced by that conversation and by all the people that have already passed
0:34:33 through that filter that are in the lab.
0:34:39 And you create a culture where you try not to compete with other labs if you can avoid
0:34:40 it.
0:34:44 Sometimes it’s unavoidable, but you can avoid it by inviting them to work with them, leaving
0:34:49 alone fields where there’s plenty of momentum and a lack of interest in collaboration, making
0:34:53 sure there’s a diverse enough set of ideas going on the lab so that everybody gets to
0:34:59 leave with a subset of those ideas as a parting gift or continue to collaborate if they want
0:35:01 to as long as they want to.
0:35:06 So I think you build up this momentum of knocking off things that look like science fiction,
0:35:12 turning them into science fact and create a culture of ability to fail and to jump back
0:35:15 and to be nice to your colleagues within and outside the lab.
0:35:19 So if I go through the list of things that you’re working on, it’s a pretty broad array
0:35:20 of things.
0:35:25 So you are crispering dogs to keep them young, you are crispering pig organs or had been
0:35:30 working on editing pig organs to make them useful for transplantation.
0:35:34 And then you run the other end of the spectrum, you’re re-engineering biology to create a
0:35:39 mirror universe of things that would be essentially immune to all known viruses or microbes.
0:35:41 How do you pick the projects?
0:35:44 What is it about what’s in the water in the, well, in the Iglesias lab, formerly known
0:35:45 as the church lab?
0:35:52 Like, what’s in the water that gets this lab to produce so many startups and spinouts?
0:35:56 What is that entrepreneurial energy that’s sort of been fostered and created here?
0:35:57 Right.
0:36:02 It may look like an averse set of projects, but they’re actually have common thread that
0:36:08 is surprisingly focused, meaning most people wouldn’t fit in this lab because we’re sort
0:36:12 of into radical transformative technologies, not incremental.
0:36:17 A lot of labs don’t even want to touch technology until it’s working in a company.
0:36:23 We work years before that company and we create the company and then the company has another
0:36:29 few years before it’s sufficiently worked out that it can be adopted by a technology
0:36:32 adoption lab, which is before most biologists.
0:36:37 So anyway, that’s one thing that we’re a little bit on the edge and it’s an acquired taste
0:36:39 or maybe even a rare taste.
0:36:41 What’s an idea that was pitched to you that you said, “Wow, that’s too crazy?”
0:36:43 Well, I’m usually the one pitching the crazy ideas.
0:36:47 I mean, not to say that we don’t have a lot of creativity in the lab.
0:36:48 That’s pretty rare.
0:36:51 In fact, we’ve sort of banned the word impossible.
0:36:55 We certainly try to behave ethically, but I think that many things, there’s a technological
0:36:59 solution to some of the ethical components, not all of them.
0:37:03 And we try to explore creative solutions to ethical problems.
0:37:06 Personal Genome Project was one of those creative solutions.
0:37:10 Surveillance for synthetic biology is another one that I suggested in 2004.
0:37:16 Biocontainment using recoding is a way that we can make any organism resistant to all
0:37:19 viruses and horizontal transfer.
0:37:20 Most of these things now work.
0:37:21 And many of these things are now companies.
0:37:22 That’s correct.
0:37:27 And their foundation was some sort of safety ethics component to the company.
0:37:30 And part of the secret sauce is hidden in plain view.
0:37:31 Like you say, we’re quite transparent.
0:37:35 We can keep other people’s secrets, but our own, we try to get people to adopt them.
0:37:39 Part of the thing that we do that is, instead of saying failure is not an option, which
0:37:42 was one of the Apollo slogans, we say, “Fail fast.
0:37:44 Just pick yourself up quickly.
0:37:46 Have a bunch of things going in parallel.
0:37:50 Find the low-hanging fruit empirically as well as theoretically.”
0:37:54 And just a lot of things people reject too easily.
0:37:57 They either don’t think of it at all, or they think about and reject it.
0:38:02 And so if we see something that looks a little hard, we’ll put it up on the shelf or in plain
0:38:06 view so we can keep reminding ourselves whenever a new technology makes that possible, we pull
0:38:08 it back off the shelf and we do it.
0:38:12 And so we have that culture of constantly reevaluating things that are on the edge of
0:38:14 science fiction.
0:38:18 Do you recruit entrepreneurs that happen to be scientists, or are you turning scientists
0:38:19 into entrepreneurs?
0:38:26 I mainly recruit people who are multilingual, multidisciplinary, because I found it’s hard
0:38:31 to build a multidisciplinary team from disciplinarians.
0:38:36 You have to have a lot of people who already have done two things, and even if you get two
0:38:39 people who have done two things each, they don’t have to overlap, but they’ve done enough
0:38:42 translation that they can start talking to each other.
0:38:46 And if you have enough of those multidisciplinary individuals, then you can sprinkle in a few
0:38:49 disciplinarians and you have an amazing team.
0:38:53 So the church lab, you were pioneers in sequencing, so reading DNA.
0:38:58 You were pioneers in CRISPR, so writing DNA.
0:38:59 What comes next?
0:39:02 Well, so there’s three-dimensional structure of living organisms, so we’d really like
0:39:08 to know every voxel, every volume, element of every pixel in the body of an embryo or
0:39:09 a larger section of tissue.
0:39:13 We’d like to know every molecule here, and we now have tools for doing DNA, RNA, and
0:39:17 protein in 3D at super resolution, finally.
0:39:18 So that’s one thing.
0:39:22 We would like to be able to do higher levels of multiplexing in the terms of editing synthesis
0:39:23 of genomes.
0:39:27 So some people call it, we call this GP Right, or Genome Project Right, but it could just
0:39:28 be heavy editing.
0:39:34 So we’ve set the record of 62 edits in the pigs, and we now have, we have 10,000 edits
0:39:35 in a single cell.
0:39:36 That’s unbelievable.
0:39:38 So it goes from two to 62 to 10,000.
0:39:39 And we want uses for each of these things.
0:39:45 So each of these projects, we have a driving societal benefit for each, and we have a driving
0:39:50 technology where we say, we don’t just want a factor of 1.5, we want a factor of a million
0:39:51 or 10 million.
0:39:58 And so that’s what pushes each of these projects is that triple criteria, which is cool, basic
0:40:04 science, philosophically interesting, technological factors of a million, and societal benefit.
0:40:08 Last question, 10 years from now, or just looking forward into the future.
0:40:11 Do we get the Neanderthal baby, or do we get the mammoth calf first?
0:40:16 Well, we never really said that we were going to a Neanderthal baby.
0:40:20 I mean, there’s a response to a journalist, whether it was technically possible, but nobody
0:40:21 has articulated a reason to do it.
0:40:26 But for the mammoth, there are lots of reasons, both for the environment and for enriching
0:40:29 the diversity of a living endangered species.
0:40:34 So this is not about de-extinction, this is about making hybrids, and many of the species
0:40:40 are already hybrids of multiple species, but now we can have the benefit of synthetic genes
0:40:41 and ancient genes.
0:40:42 Great.
0:40:43 Well, thank you, George.
0:40:44 Thank you for making time.
0:40:45 It was a real pleasure.
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.