George: It wasn't that long ago. It was a dream to be able to get high quality genome know sequenced by any method for any amount of money. And now it's something that's affordable to regular people to do. Not just one embryo, but all of the embryos.

Noor: Welcome to the podcast. We have George Church. Today's a professor of genetics at Harvard who needs no introduction.

He is one of the very few academics who's making sci-fi real for, for all of us. So yeah, we're gonna have a pretty wide ranging conversation today, but welcome to to the podcast. Awesome to have you.

George: Great to be here. Thank you.

Noor: Yeah. So, uh, I wanted to start by just talking about you. Either been a co-founder or advisor or investor to so many different companies.

What do you think is, are some of the like, obvious things that put companies on the right path, and what are some of the things that, maybe, some patterns you've seen in, hey, these are failure modes where if you're trying to make, translate something from the academic or the research world to the real world, these are some mishap of things that go wrong.

George: Yeah, so I, I've been co-founder of about 48 companies, an advisor to a similar number. And I think the MA one, one of the main things that can go wrong is if the CEO is a mismatch with the technology or the team with, for example, one, one of my CEOs had never had a company less than 600 employees, and so had the mindset of having a big sales force and was selling things before they were really cost effective to be sold.

And so. The irony is the better the sales force, the faster you run out of your capital. And of course you have a lot of very happy customers because you underpriced. But that's one way. Another way is even earlier than that, when an academic is thinking about, often has an inflated view of their, of the potential of their baby project.

Or they had trouble getting a grant and they say, well, this is an alternative to getting a grant when in fact really anything that's too speculative for a grant is probably way too speculative for a startup. Another aspect of this though is what is failure to a venture capitalists? They expect 75% of them to fail in the sense of not returning on the investment or breaking even or worse.

But that isn't necessarily a failure in a global sense or in an academic sense, where you just want the idea to take roots in the world. We already got to

Noor: the na, the nature, the very nature of success itself. Okay, cool. What about the ones that either were commercial successes or in your mind basically a philosophical success of, hey, this was a idea that took better root in the world.

Is there any similarities or what would you say you, you've gleaned from the ones that you think?

George: Yeah, some of them are just, I think the best ones are really unpredictable and it depends, again, it depends on where. In the success pipeline you're talking about. 'cause some people don't consider it a success until a million people, uh, are happy customers.

Other people consider it a success when, you know, they get a liquidity event at the earliest moment. But anyway, some of 'em are surprising to me. For example, Eric Kelsick was, I was on his student committee and then he was a postdoc in my lab and he was a regular talented scientist. He became CEO of Dino Therapeutics and within just a few months of starting, he had $4 billion of commitments from big pharma.

And it just, as far as I know, he didn't go to business school. Another one was the Elephant projects, our endangered species and extinct, uh, species company called Colossal, but before it was colossal, uh, a stranger. Basically walked into my office and just was curious what we were doing, Ben Lamb. And he locked into this mammoth idea and he says, oh, I'm gonna go out and raise you $3 million.

I said, well, that'd be a whole lot more than we got now. And, and he went out and got a quarter of a million, so a quarter of a billion dollars instead of 3 million. Another example is the four CRISPR companies all within a few blocks of each other. Uh, I was involved in three of the four. And, and people were worrying that, oh, aren't they gonna sue each other and aren't they three of 'em go belly up?

And I said, no, probably it's, there's not, nearly four is not nearly enough. So I think a lot of it has a lot of success is predicted by the vision and persistence. But the founder, especially the founder, that that joins the company.

Noor: What do you think makes you personally different than other academics?

Why do you think you're more of an anomaly in terms of being so prolific on the commercial? Obviously academic front as well, but commercial front being more unique.

George: I think some academics stay away from it, not uh, because they, they think it's like playing the lottery. They think that it's unlikely that anything will come of it and it will consume a lot of time, and I think that's a fair critique.

A fairly large number of them felt that it was somehow tainting their research in one way or another. And there's still some other reasons are that they, that a lot of 'em would like to, but their licensing, office, licensing patenting office tells 'em that it's not patentable or that it's, or the patent office tells 'em that it's not patentable if they get it past their own office.

In principle, you can start a company without any ip, without any patents, but in practice it's enough to discourage either the inventor or the investors.

Noor: So those are some reasons not to. So I guess why despite, oh yes. Giving all of those objections. So credibility, why do you still do it? Right?

George: So what hap So what happened to me?

I dropped on my head as a kid or something.

Noor: Yeah, exactly.

George: It was, I think part of it was I was fairly addicted to technology development, which is again, a rarity among academic biologists. I think, uh, maybe it's increasing lately, but it, it's rare to have that as an entire focus. You might get lucky and somebody says, Hey, that's a drug, and then you go to your technology office and they get it patented and licensed.

But mine was very intentional. And not only that, but I would, I was addicted to things that. Technologies that were, that looked nearly impossible or useless so they, they would be particularly off-put for people. So that was just a predisposition and had nothing to do with money.

Noor: Cool. I guess switching gears a little bit, obviously we're super honored to have you as an investor at Orchid.

What excites you about whole genome sequencing of embryos?

George: Well, first of all, it's technological miracle. You're taking three cells out of 120 in an embryo. And getting very high quality genome sequence, hold genome sequence out of it. It wasn't that long ago, it was a dream to be able to get high quality genome sequence by any method for any amount of money.

Let's say $3 billion to pick a random number, and now it's something that's affordable to regular people to do. Not just one embryo, but lots of all of the embryos. So that's one thing. So that's the technological awe. That

Noor: must be so exciting for you because you were part of that very first.

George: Oh yeah. I was

Noor: announcing it go all the way till just a few cells must be, I don't know, maybe you thought that it was gonna happen back then, but that's like such a incredible arc, historical arc.

Just have seen it through.

George: Yeah, no, it's very, it's really very gratifying and, and if anything it encourages my. Horses need to be even more mistaking in the future. But in terms of the technology, obviously not in terms of human life, but yeah, it's, so, it's a affirmation that technology development can have, uh, impact on patients.

And on the, on the humane side, I know a fair number of people that were born by the IVF process. And, and some of them, uh, the average number of cycles it takes to get a baby is I think on the order of five. And one of them, one of my friends was six. And, and that requires quite a bit of persistence. It's not an easy thing, especially for the mother to have the hormone treatments at all, much less the failures.

So anything we can do to improve that, um, by, by saying implanting this embryo will delay the arrival of. Because it's, it's not going to, not likely to work. That's a kind of a humane component to it. Then there's the prospects for the future. All of these technologies I've been involved in have plummeted in price.

I mean sequencing been 20 million, full reduction, and I think that will almost certainly include all the things having to do with reproductive technologies. To the point where really this could be equitably distributed throughout the world and there's trillions of dollars are at stake and not to mention all kinds of pain and suffering, not just of the individual, but to the whole family.

So that, that would be incredible. And, and as genetics goes, these very severe diseases and withhold genome sequence, you can even get into slightly less severe. But they're very predictable, uh, the, the most severe ones.

Noor: Yeah. That, that's the thing that I, I found really interesting is that there's these neurodevelopmental disorders panel, there's baby seek, there's a lot of sequencing that's happening of infants in the pediatric setting and in the adult setting, all for monogenic causes of disease.

And I'm just curious, why do you think that's not further adopted? Why do you think that is?

George: I, I think it, it has to do with people being unconcerned about 1% risk. In general, that is to say smoking, wearing your seat belts, uh, taking vaccines. These are all things where you have roughly a 1% or less chance of dying and you feel like 99% chance of success.

That's really great odds at Las Vegas. Why isn't it great odds for these other three things? And, and it's just a. It's a strange relationship we have to public health, the things that are obvious to people that work at the School of Public Health, like I do occasionally. It's obvious that we should be implementing these things, uh, preventative medicine and so forth.

But another thing that's that's not fully under appreciated, I think even by some of the specialists, is that the risk of a false positive, usually in in medicine. Any kind of false positive is just stay away from that. For example, if you get a, if you're a, let's say 30 something year old woman who gets a diagnosis of BRCA one or two, that probably means they're, you're talking about bilateral mastectomy and ectomy and the possibility of not having kids, a false positive.

There is this horrible medicine. It's very, and fortunately it's rare, but. But if you put that into an IVF clinic or into premarital preconception, all of those have a much lower impact of a false positive 'cause. You're focusing on the positives and you're not ablating any part of any body part unnecessarily.

That's

Noor: a really good point. Specifically in the IVF setting because. You have multiple embryos. Currently, you're choosing by something like embryo grade, which we've already documented that there's intra intra and intra operator variability. Different embryologists give embryos different grades in different settings.

Versus for the genetics, yes, there's obviously the chance of false positive with with genetics you have Sanger sequencing and other nice orthogonal methods to try to reduce that as much as possible. But yeah, at the end of the day you have multiple embryos and you're prioritizing rather than what the unfortunate situation is with ongoing pres pregnancies with NIPT, is that okay if you get a positive result, you only have one mitigation option, which is termination, which is much worse than identify an embryo that hopefully is free of an anomaly.

And then. Have a healthy baby in a healthy pregnancy. So that's it. It's really a nuanced point.

George: There are all these contributors and a lot of it has to do with inertia. Uh, that concern that something sounds too good. It's amazing. Mm-hmm. How often that prevents technology adapt. Adoption is, oh, it can't be real.

It has to be hype and smoke and mirrors if it's, if it sounds so good. So there's all these reasons that. There's re reimbursement reasons, even though there, I think there's a tenfold return on investment for genetic counseling related things. In general, the insurance companies won't do it until they see it proven at their level, which means that one of 'em has to break ranks and try it out and, and yeah, completely try it out.

You can't just do actuarial tables and prove it on paper. And so anyway, there are all these things that, that, that cause resistance, but I think we're getting close to the year that we will point to and say. That was the year that it went viral.

Noor: No, totally. I think that's, yeah, a really good point. One thing that I think is exciting about genetic testing of embryos is that I think people sometimes care about their kids more than they care about themselves.

So I think that maybe that the orientation is, oh, I don't wanna find out maybe negative information about me, about my predispositions, but if I can prevent my child from having something that runs in my family or that has affected another sibling, that maybe that will be more of a motivation for folks.

George: I, I think you hit the nail on the head, and that would be my prediction, is that I've been looking for what is the tipping point? What is the going to be? The thing I, for a while I thought it was Angelina Jolie appearing on the cover of time saying, just volunteering her personal story about, uh, breast cancer, uh, prediction that was not, that didn't move the needle a bit.

I think this business about caring about your kids once you see that it working in IVF. Then people will start saying, okay, we can do it on adult, on on the adult members of our family as well. But who knows? There will be a tipping point. I just don't know what Yeah, that's the thing that don't know what it'll be.

Noor: Yeah. Because in our consenting process, you, you get the whole genome of the embryos and then you could have incidental findings about the parents. Right. The parents don't necessarily meant need to have had been sequenced. Right. And you could find out actually that the parent status. Through the embryos, which is, and there's often

George: something that the parents can do about it.

There's, yeah, at least for 70 adult onset genes, there's a lot you can do about it.

Noor: Yeah, exactly. Yeah. So basically there's been around 5 million IDF babies born. When it was initially introduced, there was wide skepticism and this, this fear of, of, you know what, why are we playing God? Similarly, when birth control was introduced, there was huge protests.

So like the reproductive field specifically is usually under attack. So when it comes to embryo screening specifically, do you feel like you draw a distinction between reporting to parents, the monogenic variance versus the polygenic side?

George: I, I think the main opinion is it should be up to the parents, but that's, but that requires that the parents are up to speed and so I think it, in an ideal world, they would be quite comfortable.

With the science and would have an unambiguous opinion and a general agreement in the family. But anyway, if they're comfortable with it as a family, then you can, there's no limit. There's no, I know everything about the genomes of everybody in my family and, and, and studies have been done, uh, that people don't tend to overreact to this genomic information, but it still is a good idea to make sure they have truly informed consent.

Noor: I really agree. I think that some people want the maximum amount of information, and some people just want a little bit, and I think that it feels very paternalistic when there's this outside party that's saying, this is in, in my opinion, this is the amount of information that you should or shouldn't have about your own embryos.

Your own kids are gonna go into your own body. But yeah, I think that there's, on the monogenic side, it's black and white versus on the polygenic side where you're predicting a propensity for an adult onset. Sometimes there's a dis distinction in how. People feel about it. Is there like a dis you know, big distinction in your mind?

George: I think some people would be justified in not staying away from things that are not actionable at all, and mm-hmm. Another set would be justified in staying away from things that are below a certain threshold. There, there's no magic number where you say, oh, you know, 75% predict predictability is threshold.

And I think it will vary from person to person, but in general, if you're just prioritizing, then you should take the one that that satisfies medical criteria for the best one. And like I said before, it's uh, the cost of, at the risk of false positives is not significant in some of these procedures that are done early in the conception process.

Noor: Yeah, that is a, i I would say like a very unique but not often noted feature of it. So I guess zooming out to, okay, let's say we're super lucky to get lots of adoption and this became the default way people had kids. What do you think the world would look like? Do you think that would be a crazy outcome?

Do you think it should be limited to people who are, are infertile, they're already going through IVF, it's a, a prioritization for them, or there's. Everyone else who's having kids, there's unfortunately, what is it like? I think. Something like 30 million Americans that have a rare disease, hopefully in the future, gene therapies will become much cheaper and personalized for all those very specific anomalies they have.

But yeah, this is a very, this is something that's been talked about in sci-fi for a long time. This idea of divorcing sex from reproduction. What if you, what if the default or the majority of people ended up having kids through IVF and through identifying the embryo that was free of whatever anomaly that they were concerned about?

George: It probably will be more widespread, and that might be a good thing. For example, uh, miscarriages are extremely psychologically prob, uh, problematic for many families. Uh, if you could reduce the number of miscarriages, that would be great. Again, like getting your genome analyzed, you don't know. Whether you're at risk until you look.

So, even though you, the risk may be low, so it might be that you don't know whether you're at risk for a miscarriage, so that it would, it could be, say, late in the process. So that, that, that's one consideration. The gene therapy angle, uh, as much as I have contributed to and proud of gene therapy, I am not seeing the prices come down quickly.

In fact, I see them creeping up. Million and a half to 2 million to three and a half million is the most recent gene therapy. And for good reasons. It's, it, there's a kind of a high fixed cost of research and development and clinical trials and a low denominator, which is the number of people that benefit from each of those clinical trials, um, while IVF is essentially already approved and it's just gonna get better and better, more and more cost effective.

So I actually see this shifting from. Emphasis on gene therapy. Gene therapy is very important if you're already born, but I, I emphasis the medical, public health, and medical profession shifting over towards earlier stages where genetic counseling can save millions of dollars and a certain risk, a very definite risk of something that isn't covered by the million dollar gene therapies.

I, I think the trend is going to be towards everybody getting IVF as the main way of having babies. I think that's a plausible future.

Noor: Yeah, I think it's super exciting. Obviously pharma has created so many medical miracles for managing so many different types of chronic diseases, but it just really cooled the idea that at the time of transfer, the time of pregnancy begins.

So many risks can be mitigated all at once. I don't, it's just something, it's just something, obviously I'm super excited about it. Anyone who's had a family member or themselves have their life hijacked by one of these typos. And then unfortunately, just like you're saying, the fixed costs and the the end is usually really small for each of these rare diseases individually.

So it's really hard for there to be an economic incentive for a company to go in and design a much less secure, even medication that you can take for life to just treat the symptoms rather than addressing the root cause. Yeah. So that's a future I think is super exciting. And then the other thing that's really interesting about IVF is that there's already a population of people who aren't infertile that are doing it.

There's women who are egg freezing who they, they have no documented infertility. They haven't even tried to get pregnant yet, but they're freezing their eggs. And people don't realize that egg freezing is exactly the same as IV. You're just, it's the first part of it. You're freezing the the eggs and then you can choose to fertilize them with your partner's burn.

But that procedure, people are already doing. I don't wanna say recreationally, but essentially just to preserve optionality. So the idea of anyone who's trying to have kids, whether they wanna do it to basically change their timeline or to mitigate disease doing it. It doesn't seem like too far of a leap from where we're already at today.

Another thing I wanted to switch gears to is just so there's a fertility crisis happening right now, people aren't having enough kids and I think there's a, people have a lot of concerns about, is this going to derail my career? When is the right time? Do you wanna talk a little bit personally about how you, you and your wife made that decision?

Like how did your life change? Obviously you guys have both had still super successful careers, but how did you guys decide if this is the right time to have kids? This is how things are gonna change or stay the same. What is, could you like just walk us a little bit through your thinking there?

George: Yeah. I'm, uh, I think anecdotes are not the way we do science, but they are the way we make personal connections and think things through.

And in our case, we were both very interested in science and Andy's other were not in a rush. Until we realized the biological clock was ticking and we were actually past the age where you would have to get an amniocentesis back then, that was the only game in town for prenatal. And we did, we got, we decided after 11 years being together that we wanted to have a child and, and got in and found out it was a healthy eulo girl.

And so that meant we couldn't name it. Name her Marie. Whilst she was still only 18 months, you know, weeks old, and, and it was a good experience. It really made real our, we were both geneticists. It made real, this whole idea that you can look at the chromosomes of your baby when there's barely even a bump on your belly.

And it was just very, very moving personally. And then when she came out, was such an amazing person. Could relate. Little thing you could barely see in the ultrasound and chromosomes that were nicely arranged in the karyotype with a real person. That has turned out well and we now have grandchildren.

Noor: Wow.

Congratulations. That's amazing. So how did it change, basically, becoming a father? How did it change your relationship to your work?

George: So our child didn't sleep much. She wasn't cranky, but she just was wide awake. Maybe sleep five hours a night. So we took turns with everything. And I think overall, you, you, it doesn't really, it does consume time, but it doesn't feel that way.

It feels like you're gaining time, you're gaining perspective on the world. The hours that you're not at work are just as motivating as the hours as you are at work and just keeps feeding forward. Now, obviously if you have a very problematic birth. Child and so forth, you are gonna be changing your profession from whatever it was to taking care of the child and, uh, raising money for studying the disease so forth.

As we've been talking about that, that, that may be a thing in the past or growing 'cause for every heroic. Parent that did that in the past, they solved the disease one way or another. They figured out what caused it. They figured out what could prevent it and so forth. And then the next set of parents won't deal with that.

So I think that's inspiring to me. And the parents that gave up their job in order to advance the science and take care of their own child really benefited all of us. They didn't really quit their job. They did. One of the most important jobs in the world, they became amateur geneticists, which really had just as much impact as some of the professionals.

Noor: Yeah, absolutely. It took decades of making sequencing cheaper and thousands and millions of people pouring over all of this data to be able to curate these databases so that it's standing on the shoulders of giants are required so many different developments in different domains so that we're outta state now where all of this literature has been compiled for the benefit of the next generation.

So. That's super exciting. So yeah. I guess I just wanna close with kind of your other sci-fi ideas. Bringing back ancient species is, is obviously something that I think has captured everyone's imagination. What are the, we've obviously had a long track record of making things that sounded like science fiction turned real.

Are there other things that are on your to-do list where like, I really wanna make sure that this one gets a little bit further and stops being just a movie, but we get some animal models or we get some patients. Is there something like that's brewing for you that. It's a quite area, but you think it's gonna be there in the next five or 10 years?

George: Yeah. Almost everything in our lab at some point mm-hmm. Gets branded as impossible or useless or both? Um, yeah. Yeah. The thing about the elephant project is not, it's not just about extinct species, it's also about endangered species and about climate change. So it's three science fixes stories at once.

Noor: Mm-hmm. We shouldn't

George: get too ahead of ourselves. Uh, we haven't delivered on any of the three. Uh, although the, the main point is to deliver technology, it could be applied to a number of, uh, agricultural species and even humans, and it's already having impact on adjacent things like we're making some of the reproductive technology we're developing or also useful in, in human.

Some of the, some of the, the, the methods we have to develop for multiplex editing is having multiple advantages. For example, engineering elephants is not that different from engineering pigs, which for which we get super safe and in some cases enhanced organs for transplant.

Noor: Maybe. Maybe just to focus on the reproductive technology side, what do you think is exciting there?

Obviously people have been talking a long time about in future gametogenesis the idea of taking stem cells and converting them to egg or sperm cells. Where are we there? What are some of the things that your lab is doing and do you think maybe walk us through what the introduction into clinical care would look like for, for those projects?

George: I still think we're. We're not there yet for Gametogenesis. There's only one species that has in vitro gametogenesis, which is mouse, and even there GA are extremely inefficient as maybe two, 3% success rate, but we live in exponential times. Almost every technology I've been involved in has gone exponential at with doubling times close to a year.

I think that may be happening with Ga Meto Genesis as well, but it has to go through the same safety efficacy tests that every other medical treatment goes through. But we'll see. It's if we are making this major transition to society towards, uh, IV it would be nice to, this might be part of it, is being able to go from skin or blood is so far easier on the patient, on the mother.

And then is the hormone treatments, but that, that could change. Both parts of that could change. So it's just, it's just symbolic that the progress's happening. Uh, we also have developed granulosis cells that help the ma in vitro maturation process. For, for some people that's a bigger deal than for others.

Maybe you're older. We're also developing artificial wombs, which I think is mainly aimed at veterinarian and endangered species. But if that, if you get enough experience with that and people notice how well it works for endangered species, they might say, okay, time to start carefully considering that for clinical use in certain extreme cases for of, of high risks, say gestational diabetes or something like that.

Or you where you don't wanna have a surrogate. Um, who knows where that goes, but, but again, that if that is safe and effective and, and widely accepted like IVF, it could be a game changer for the, the different, the, the gender biases that intrinsically come from, sacrifices that are differentially made by the, the woman.

Noor: It's incredibly exciting. I just think that reproductive technology is this, this slice that I think has just incredibly high impact, right? Everyone has a mom and one of the things that most people self record as the most meaningful parts of their life is, you know, having kids and the actual process of it hasn't changed very much in four years.

I'd say one of the biggest advances was the introduction of IVF. There was this, there's 5 million people right now who would never have existed that this wasn't have had, this hadn't. Been invented, and I think that we're at this really interesting tipping point now where hopefully genetic testing will totally change and reshape and radically reduce the amount of disease the next generation has to face.

But to your point. The burden of pregnancy on women and, you know, a fraction of them, uh, are just not able to carry or have extremely complicated pregnancies. Like the fact that you guys are working on that is really exciting. And I hope you get that your successes will inspire more funding, more research, because it's such an important problem.

And I, I still think enough, there's enough people working on it, enough excitement around it that it deserves. Yeah, thanks so much for the time. It was a, you know, really wide ranging topic, uh, conversation from startups to research to IVF, so it was amazing to get the chance to, uh, chat with you. I'm looking forward to seeing all the, all these developments go, come from, go from preprints out into the world and hopefully into the wild.

Hopefully we get these endangered species back pretty soon.

George: Yeah. Yeah. Thank you very much. It's been a great pleasure talking to you and good luck on all of your. Contributions to clinical medicine.

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