George Church Interview Transcript

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BRUCE MCCABE: Professor George Church, welcome. [laughter] You are one of the people I've wanted to talk to for so long, because you are one of the founding fathers of just about everything that's happening in genetics and genomics and really you've had a hand in everything that's touching on the whole biotech industry today if we look back. The Human Genome Project, sequencing technologies, editing technologies, including editing the whole genome. And I hope we're going to get into that today. I believe you've co-founded more than 50 companies and I think you've got a hand in perhaps 100s more in terms of being an advisor or on the board or involved with your students. So, in terms of impact on humanity through biology, I can't think of anyone better placed to talk to us about the future. So I just wanted to say what a privilege it was and thank you.

GEORGE CHURCH:  Thank you.

BRUCE MCCABE: George, before we get into the future, because that's what I want to spend most of the time on, where we're going, and I'm sure that's what most people want to talk to you about, I just wanted to very briefly look at the origins of your passion for chemistry and biology. Because I read your bio and I see that you start as an undergrad, straight into this space, but was that something you had for as long as you can remember? Or was it something that was triggered by an event or a person or a mentor? Where did it come from?

GEORGE CHURCH:  It definitely comes from before undergrad. I was pretty obsessed with all of the sciences but with an emphasis on biology and chemistry, a little bit of biophysics from probably 10 years old when I went to the New York World's Fair. If I had to pin it on something, it was that the World's Fair, it was kind of a very clever Potemkin village that convinced you that the future is here. And at 10 years old, I didn't have enough common sense to know that it was just a facade. They had some real stuff behind it. They had like a light pen where you could design a fabric real time. They had animatronic mammoths and Lincoln, Abraham Lincoln's, which I thought were the future of computing, having people. Computers that looked like people and the pets and ... But anyway, so I went back to Florida from New York and just couldn't get over the fact that the future was locked up in New York somewhere. And I didn't have access to it. And so I just, basically on returning to Florida, I just started making it myself if I could possibly could. So that motivated me all the way through high school. I was in a big rush to get through college so I could get into research.

BRUCE MCCABE: It wasn't just the discovery. It wasn't the curiosity. It really was, already, thinking about how to change the future from the very beginning that was inspiring you.

GEORGE CHURCH:  I think I was an engineer from that moment, because most of the things that were on display weren't really science. They were engineering. I didn't call it engineering until, gee, probably into my postdoc or maybe even starting my lab as professor. It just was, we called it science, just like at Cape Canaveral, they called it rocket science. There was almost no science in rocket science. It was all engineering. The principles had been worked out in the '30s and '40s. But anyway, once I did recognize that I was an engineer, who happened every now and then to make a scientific discovery, just because we had better tools for a moment. And that made it easier to do my job, knowing what it was I was actually doing. But, yeah, the drugs and syringes and stuff in my father's doctor's bag inspired me. Everything having to do with computers back in the '60s. Didn't seem to inspire anybody else [laughter]. I would ask, "Wouldn't you like to have a computer?" And they'd look at me like I was from Venus or Alpha Centauri or something, it's like, why would you want to have a computer? [laughter] And now you try to buy one of these things loose from their hand, and forget about it, right?

BRUCE MCCABE: [laughter] Exactly. You have billions of people addicted to them, but so much power in this cross-disciplinary thing, right? And you were cross-disciplinary from the start. You're interested in everything. And so many things happen at the intersections.

GEORGE CHURCH:  Yeah. Some people would call it ADD. But in addition to a marginal case of ADHD, I also had narcolepsy and dyslexia, so I jumped around and I got used to it enough that when I went to find my research, I wanted something that combined all of those so I could have an excuse for not focusing.

BRUCE MCCABE: Yeah [laughter]

GEORGE CHURCH:  And I found that in crystallography. Crystallography of RNA, and proteins, you really had to know biology to say what the crystal structure meant. And then you had to drill all the way back to physics and mathematics to do those Fourier transforms, to get the phases to solve the structure. It wasn't like microscopy where we just looked through the lens and there it was. You had to do all this math in order to, and then you could see it on a computer screen. Back in the time where there really weren't that many computer screens that could display a rotating molecule, say.

BRUCE MCCABE: Well, I want to interrogate this multidisciplinary brain of yours about some forward thinking. Because you're involved in so much and so many projects, there really isn't anyone better that I could think of to talk broadly about the future of medicine and biology and some of these more impactful things. And we had an email exchange before this, and that very first question. I'd love to start with that. Just very broadly, what are your hopes and wishes, what are those dreams for what you could hope biotech could accomplish for humanity in the next 20-40 years? What would be the big things?

GEORGE CHURCH:  Well, scientists have to be cautious to separate from what they think is possible, what is likely to happen and what they want to happen. Because very often when people will ask me whether such and such is possible, and then down the road everybody will say, "Oh, that's what he wants to happen." All I did was answer the question of whether it's possible or not.

BRUCE MCCABE: Yeah. Yep. Definitely.

GEORGE CHURCH:  But if we focus on your question, which is, what would I like to see happen? Which isn't usually the question. It would be really nice to have a virtuous cycle, rather the vicious one, where if you eliminate some of the diseases of poverty like Guinea worm and malaria and tuberculosis, then you have fewer family resources dedicated to just staying alive and keeping the family alive, and then you have a little bit more resources to pay for education of the children and the women and then that leads into better micro-finances. And then that leads to better health practices, hygiene, prenatal care and so forth. And you just get this virtuous cycle where you lift everybody up out of poverty, without necessarily having to spend enormous amounts of government money, which is kind of a political hot potato, right? …

BRUCE MCCABE: Yeah.

GEORGE CHURCH:  … Giving money to the poor, somehow, is much less acceptable than giving money to the rich. And so what you have to do to fix the poor without it looking like a handout, is you create new technologies which are a lot cheaper. So that's number one I would like to see going forward. And in fact, it's been one of our obsessions just bringing down the price of everything so it's affordable to everybody. And then the other thing is, in addition to the diseases of poverty, which will probably kill 10% of us, there are all the other diseases that affect everybody including the poor, which is diseases of aging. And if we could fix those, then we would at least get ourselves a few decades of longer youthful, productive life. 

That's the important thing. So, we don't want necessarily to just prolong the very expensive, very painful for the whole family of having somebody that's almost dead and you have to keep them in life support, which is way more expensive than ... But instead what you're doing is you're keeping them youthful, which means that they don't have to retire. In fact, they wouldn't even want to retire ...

BRUCE MCCABE: Absolutely.

GEORGE CHURCH:  … They might want to switch jobs, they might want to get retrained, go back to school, but why retire if you're at the peak of your career. And I think what's underappreciated as society has progressed, the age at which our education stops is getting older and older. So I think that, for example, my education is peaking somewhere around my current age.

BRUCE MCCABE: [laughter]

GEORGE CHURCH:  And it would be kind of a pity to like shut down the supercomputer right after you filled up its data bank, and turn it into scrap metal. It just doesn't make economic sense. And that's how I feel about myself right now. I could be wrong.

BRUCE MCCABE: No, but that's interesting because it's this is a huge …

GEORGE CHURCH:  So those are the two main things I'd like to see happen, is affordable healthcare to get us up out of poverty, and then something that will solve the 90% of disease that will get us past our normal retirement age.

BRUCE MCCABE: Yeah. I love the economic sort of flow-ons from these things. If I look at … one is, yeah, so the intellectual machinery still goes for longer, and that would have to be good for humanity, right? We'd all be a little wiser on average, as a population. And then there's just fixing the whole economics of healthcare, if we can extend cellular youth for longer then it actually impacts the instance of every single disease, right? Pretty much. Statistically. So the entire cost of healthcare could be brought down as a system. It just suggests so many changes.

GEORGE CHURCH:  If we extend life by 30 years, and we extend retirement by 30 years, then we get 30 years to get our act together, prepare for whatever comes after that. But right now we'll just go from emergency to emergency, economically speaking.

BRUCE MCCABE: Yup, it's crazy, isn't it? And my understanding of this, I want you to correct me if I'm wrong, but my understanding is, there's lots of people think about rejuvenation reversal, which is possible, but complex, and has all sorts of additional difficulties attached. So it's a longer process. And then there's a bunch of therapies we're developing now – and we're going to extend and we're going to have multi-drug therapies, we're going to get better at it – which are all about simply prolonging the youthfulness of cells, if you like, extending the health span of all the cells in the body, and that statistically reduces all the diseases we might get. So it naturally increases average lifespan, because you're starting that way. And that seems to be the more probable, more likely and the least complex pathway forward. Would that be fair?

GEORGE CHURCH:  I don't think they're that different, really.

BRUCE MCCABE: Really?

GEORGE CHURCH:  I think the two major divisions in aging research, is one is epigenetics versus damage, and the other is longevity versus age-related disease reversal. And a lot of it boils down to pragmatics. Which is epigenetics... the main reason that young cells repair better is epigenetics, they think they're young. So for example, you can actually repair a damaged heart if you're a fetus or a newborn.

BRUCE MCCABE: Okay.

GEORGE CHURCH:  But you can't if you're my age, not easily. So that's the short version of epigenetics versus damage, that if you make the cells think they're young, they have the wherewithal to repair almost everything, proteins and nucleic acids, lipids, and so forth. Then the longevity versus age-related disease reversal axis is it is simply easier to do clinical trials ... So if you have a cardiovascular disease or a kidney disease, or diabetes, obesity disease, you can in principle reverse that to a healthier state in a matter of weeks and months. However, if you want – and you can prove that in a clinical trial and in a couple of months you can restore a healthier version of these different organs – if you want to prove longevity, you have to recognize that each of us is unpredictable how long we will last, and on average, the standard deviation is 15 years. And so if you want to be safe [with testing the hypothesis] then you do two sigma, which is 30 years, and a 30-year clinical trial is just unaffordable where the endpoint is. You didn't die.

BRUCE MCCABE: Yeah.

GEORGE CHURCH:  Right. Well, the other one, the endpoint is your kidney's better, right?

BRUCE MCCABE: Yes.

GEORGE CHURCH:  And so nobody really can afford a 30-year clinical trial. And Oh, and by the way, if it doesn't work, then you go back to square one and you have another 30 year, so that's 60 year double clinical trial. Well, we've seen clinical trials go as fast as 11 months. I mean, that's what happened during COVID, we got some approved things that looked a lot like gene therapies, that were vaccines. And they got approved in 11 months, and they got applied to 5.6 billion people.

BRUCE MCCABE: Yeah. That's true.

GEORGE CHURCH:  But that's the record we're looking for, not the opposite direction where we start doing 30-year clinical trials. So those are my outlines for those two dichotomies.

BRUCE MCCABE: Yeah. Interesting. Interesting. And yeah, when you don't, when you say you don't see much difference, I get it as the way you put it in words there, is that the more “stemness” you have in your cells, the more youthfulness, I guess, the capacity to make those repairs is there anyway. So it's, yeah. Okay. And I've had these discussions about differences between health span extension and rejuvenation, but also maximum lifespan. Where, Professor Vijg at Albert Einstein College of Medicine – he’s very big on, look, there's probably a biological maximum built into our design, so it's an evolutionary outcome. It's part of our programming that there probably is something we wouldn't be able to break through. It might be around 120 years statistically, but something we couldn't fundamentally break through without completely re-engineering what a human organism is. That was his argument on that. Do you feel the same? Do you feel is perhaps a fundamental barrier no matter how healthy we are that we'll start to die? Or do you think ...

GEORGE CHURCH:  Well, I totally agree with the concept that there's a programmed death date, with of course a standard deviation. There are some rats that live a year and a half, that's when they die. A little bit of variation, whether they're dying in the wild or in the lab. And then there are bowhead whales that last 200 years, and that's clearly in their, built into their evolution and DNA. That I agree with.

But that doesn't mean that you have to change radically. I don't have to become a bowhead whale in order to live 200 years. That I don't agree with. I think that there are a small number of pathways we need to get right. It's not one pathway. It's not some simple one drug. It's polypharmacy. It is multiple drugs. Probably gene therapies or cell therapies or both. And but we're already used to multiple drugs. It's like HIV, cancer, antibacterials, three to five drugs at once is standard of care, right? So, I'm not worried that we have to have a lot of things. 

And we will change. In a certain sense, we won't be human anymore. In the same sense that we're not the human beings that our ancestors would recognize. Our ancestors lived in fear of 20 infectious diseases that we don't even think about, for the most part, because, essentially they're either extinct, like smallpox, or there's adequate vaccination to provide herd immunity. And that makes us superhuman with respect to our ancestors 200 years ago. 

So the same thing will be true here, but it'll involve very complicated – and to a certain extent we can change our species definition through gene therapy, somatic gene therapy on adults. We can't change everything, but we can change a whole lot of things. In fact, that's one of the things that my lab focuses on is so-called “multiplex editing,” where you can change a number of genes at once in a mature individual.

BRUCE MCCABE: Yeah, yeah. Okay. And the other thing that keeps coming up whenever I raise this topic with people, is the cost and accessibility economics. So on the supply side of this, do you feel it's realistic we can get longevity-related drugs down to very low costs, so we can have broad access.

GEORGE CHURCH:  We've already done it, but we've already done it, in the sense not exactly that, but we have brought down the cost of gene therapy, manufacturing and delivery down to $2-$20 per dose. And that's an unusual statement because most people think of gene therapies as being the most expensive category of drugs in history. They cost like $2-$3.5 million per dose. But if you look at the top five COVID vaccines, three of them were viral capsid and then a viral capsid on a double-strand DNA payload. And two of them were lipid nanoparticles with a single-stranded RNA payload. But basically the whole R&D and manufacturing and delivery is straight out of the gene therapy playbooks. That means that 5.6 billion people have, you know …

BRUCE MCCABE: Wow.

GEORGE CHURCH:  … did the acid test and all these things, and it was safe and effective. So that'll make the next set of gene therapies much easier to develop. Well, some of them we will call vaccines, we'll have vaccines against cancer, we'll have vaccines against senescence, we can call it whatever we want. But that path has been greatly expedited by the emergency use authorization acts during ...

BRUCE MCCABE: I've never thought of it, but it's a perfect metaphor for where we could be, in scale for some of these drugs, and when you get to that scale.

GEORGE CHURCH:  And the main difference between the $3.5 million a dose and the $2 a dose or $20, is the economies of scale. There's a fixed cost for the research and development and for the clinical trials, that you just can't go below a certain level. And then you divide that by the amortization over the population that will benefit, and some of these orphan drug diseases have only 100 people a year in the whole world that could benefit from it, but have the right combination of wealthy nation and rare disease. But then compare that to these COVID-19 gene therapy like things, and 11 billion doses were manufactured. That's the denominator for that.

BRUCE MCCABE: Yeah. And the amazing thing is, the economic payoff at the other end, is probably the biggest mankind will ever see, because we're lowering the incidence of all the diseases.

GEORGE CHURCH:  Yes, exactly.

BRUCE MCCABE: Even if it was more expensive per person, you'd probably get that payback out of the health system. That's incredible. Yeah. There's huge changes of afoot. I mean, and I guess we're going to see a gradualism here. We're going to see more and more therapies that are more effective, more multiple multi-drug approaches as time marches on. And we'll get a family of therapies that gets bigger and bigger, I guess. Yeah. Realistically. Oh, that's how I'm imagining it, I'm hoping you'll say, "No Bruce." Or "That's reasonable." [laughter]

GEORGE CHURCH:  I think it's, yeah, it's reasonable. Yeah.

BRUCE MCCABE: Yeah. There's not some big inflection point coming, it's really just a gradual sort of thing.

GEORGE CHURCH:  Well, it may look like. I mean, there are going to be a series of inflection points that'll get smoothed out, yeah, I think.

BRUCE MCCABE: Yeah. Now, the other thing is getting back to organs, right? There are a number of ways of tackling organ failure and, you know, we can do the transplants, and I'm so interested in the xenotransplant work that you're involved with. I've been down to see Anthony Atala down at Wake Forest where they're looking at how do we build [organs] from the bottom up as well, which quickly reaches complexity limits with vascular systems and nerves and all the rest of it: when you're trying to print a kidney you can't really do it from a design point of view [so] you've got to be able to grow it and harness the genetics. And then we've got also rejuvenation, which we touched on a little bit earlier where we target the optic nerve, for example, to rejuvenate it for a glaucoma patient, or perhaps we target hearing loss. 

So just tell me where the big, what are you most excited about there? And this idea of “organs on demand” through xenotransplants. It does seem like a realistic possibility and within a decade or two. So where are we at?

GEORGE CHURCH:  Well, so the two things that are exciting, one is the obvious thing, which is there's a crisis in getting access to organs. As we get better and better at preventing fatal accidents, like head trauma, that means the number of the organ donors drops, which is a good, it's a mixed blessing.

BRUCE MCCABE: Yep.

GEORGE CHURCH:  So that's one thing is just, is dealing with this crisis, but the bigger deal is that we can have enhanced organs, organs that are less likely to fail than human to human transplants. And keep in mind that some things aren't called transplants [but] they're basically transplants. So transfusions and hematopoietic stem cells are probably the most common transplant and transfusions affect like 16 million people per year. So these are big numbers, and if they're enhanced, that means that they can be cancer resistant, pathogen resistant, immunologically privileged, senescent resistant et cetera, and the list goes on of desirable features that could be put into them, things that you can, and if they're made in pigs, you can actually do germline engineering. Which we don't want to do on humans, but we do want to take advantage. And some of the advantages are, so you can completely debug it, you can make sure that it's fine. While with somatic gene therapy, you kind of throw in this virus, you throw in billions of viruses ...

BRUCE MCCABE: Each time.

GEORGE CHURCH:  … encapsulated in nucleic acids, and you hope for the, and that each of them is going to go into the genome or go into the cell and have a short-term or a long-term effect and you hope they don't cause cancer. But with this you can completely debug it in the pig, and then move them into humans. So those are the two things that are exciting. 

The status that you asked about is that we have three or four major groups that are committing resources to this. It's not like a government mandate, like the war on cancer keeps getting, but in a way it may solve that indirectly. What it is is, just a couple of private citizens decided that they would have their own efforts, like Joe Tector, Martine Rothblatt, David Sachs, these are all pioneers that invited us to join. Which was very gracious of them. Back when they saw our 2013 CRISPR papers and they said, "This is what we need. Instead of editing one gene, let's edit a bunch of them." Because each had their wish list. And so anyways, fast forward to today – that was a decade ago – today we've taken everybody's wish list, we've made 69 edits in a pig germline, and they're healthy and they're eating just like pigs. Which is very fast. It's like three months and three weeks gestation period, and then they're sexually mature in five months. And all the organs are the right size in that short period of time, so that they're growing organs faster than any other related creature could do. And we've now got up to two years survival of these organs in non-human primates, which is really good, because...

BRUCE MCCABE: Right. Okay. Yes, we've done this.

GEORGE CHURCH:  … because the preclinical trials in primates is by all accounts likely to be pessimistic relative to what will happen in humans, because doctors work harder on their human patients, they, it's easier to explain to them and listen to them what the symptoms are …

BRUCE MCCABE: Yeah, yep. And to follow a diet ...

GEORGE CHURCH:  … and there's no way of saying, "Hey doctor, I think it's right here, in the spleen." And then finally, you can't reason with them that don't pull their sutures out, you know. You have to like bind them, and that cause there's all kinds of stress in a monkey that doesn't happen to human. Anyway, the fact that we're getting such good results with fairly large non-human primate trials, means we're really ready to go into a big human cohort. So that's going to happen very soon.

BRUCE MCCABE: So it looks like the most...

GEORGE CHURCH:  Not 10 years from now, much sooner than that.

BRUCE MCCABE: Okay. Yeah. So it looks like the earliest and most promising pathway is the xenotransplant pathway through the pigs.

GEORGE CHURCH:  Yeah. And I think it's very flexible too, and with one pig, you could get a dozen organs and skin and blood cells and that you can carve it up a lot of different ways. Even within blood there's lots of different components of blood that you... So, and all of them enhanced, it's just as almost all drugs and preventatives and vaccines are enhancements.

BRUCE MCCABE: Wow. Ready to go. I remember having a chat with Rodolphe Barrangou, and we were chatting about organs and I was asking him, I knew a little less at that stage and I was asking him about the printed organs and he immediately dismissed me and said, "You've got to look at what they're doing with pigs, because if I needed a new kidney, that's where I'd be getting it from." And, yeah, and he directed me to your research, so brilliant ...

GEORGE CHURCH:  Thank you, Rodolphe.

BRUCE MCCABE: Yeah, yeah, yeah. He's wonderful. So and I want to talk about his world in a minute, in agriculture, because I know you're doing so many things more broadly across all organisms ...

GEORGE CHURCH:  He and I are both involved in Inari and agriculture.

BRUCE MCCABE: Oh, right. Well, perhaps that's the segue. Let's talk about that world of agriculture, animals, carbon. Again, what are the priorities there? Because I know the woolly mammoth project is a HUGE exercise ultimately in positive, let's say, geoengineering, to try and keep the tundra frozen. And most people just think about it as bringing back woolly mammoths, but I know it's got that bigger scale. When we had our back and forth, you mentioned sequestration. I wondered whether you were talking about that particular project? Or you're talking about engineering plants on a broader scale? Or what's in your head about what you'd love to see.

GEORGE CHURCH:  Well, when we talk about sequestration, we're talking about vascular plants, you know farm plants [and], algae which grow much faster. So the doubling time of our fastest organism that we've discovered is 17,000 times faster than corn. So just imagine your cornfield, you've got a mature cornfield and then 80, 90 minutes later, you've got two cornfields, that's mind boggling. But so, anyway, we're thinking about all these different ways, but the problem with using farms, colliding farms to sequestration is, the farmers typically don't want to give up even a fraction of a percent of productivity.

BRUCE MCCABE: Okay.

GEORGE CHURCH:  And there's almost no way you can sequester, I'm not – I want to apply this to my entire conversation – I don't say anything's impossible, I'm just saying it's challenging ...

BRUCE MCCABE: It's harder, yeah.

GEORGE CHURCH:  … to sequester carbon and still improve yields, and I know that because I'm deeply involved in Inari which is a genetic company that is improving the yields and the pest resistance and drought resistance and so forth, of standard big crops like corn and soybeans. So that makes farms hard.

There's deserts, and one of the biggest "deserts" is the Arctic, but it's not really a desert in the same sense in that it's the best way to sequester carbon historically. Because what happens is, every summer you get a pretty fast growth season followed by, you freeze that, and then the next season you layer animal excrement and dust and stuff, and you build another layer. And it builds up to the point where you've got say 500 meters of topsoil, and you compare that to the rainforests of the world, all over the world, you know, Amazon, Borneo, so forth, and those have one meter, because they're so active, they're just like constantly turning over, and there's never a winter and there's certainly never freezing. But the Arctic is like the perfect recipe, but it's also the perfect recipe for disaster in the sense that over the years, the Arctic has sequestered 1,400 gigatons of carbon. And now it's melting, and it's temperatures going up faster than the rest of the world.

BRUCE MCCABE: The ultimate negative feedback loop awaits us.

GEORGE CHURCH:  Exactly. And it's releasing the carbon in the worst possible form. Instead of carbon dioxide, which is bad enough – we're all freaking out about 10 gigatons of carbon turning into carbon dioxide in the human anthropocentric world – there’s 1,400 gigatons that's getting 80 times worse, in the form of methane. Okay. And you can dramatically see this by just taking a lighter to any of the lakes in Siberia. Last time I was in Siberia we showed that you can make a little methane fire out of water. And it's in all the lakes, all the land, almost all the land, and offshore in the salt water, just tons and tons of methane. So if you could restore the Arctic to something not so long ago, where it was a vibrant ecosystem, a lot of measurements have been made about how many more species and how many more animals per hectare were grown back in the heyday of herbivores, of the mega herbivores. If you could, and that's mainly a matter of just a slight shift in the ratio of trees to grass. Grass is much more efficient at fixing the carbon and it's much better at allowing the herbivores to go in and there do their thing, in terms of keeping the temperature cold after the summer's over.

BRUCE MCCABE: And a win-win for extending populations of elephants, or in this case, hybrid elephants to other geographies.

GEORGE CHURCH:  Right.

BRUCE MCCABE: What would be the next priority, in terms of sustainability, after that project? Are there any other targets that you wish new people, wish people would perhaps think more broadly about or deeply about? Opportunities, let's say?

GEORGE CHURCH:  I am totally a believer in letting all the flowers bloom and encouraging everybody to do whatever they can, change their light bulbs, drive their SUV a little bit less. But we need to also, while we're being encouraging, we need to also be realistic, that even if all the humans left the planet, that would only save us 10 gigatons a year of in the CO2 form, versus 1,400 gigatons that is in its own little loop that we need to stop, and a lot of it's in the form of methane. So I guess my second target it's...

BRUCE MCCABE: There's a big gap between target one and target two, is what you just told me.

GEORGE CHURCH:  Well, certainly a big gap between turning off your lights and converting the...

BRUCE MCCABE: All that methane.

GEORGE CHURCH:  Permafrost back to grass. But I wouldn't say in between, I would say in addition, something at the right scale. You have to sequester carbon because we're already past the point where we should be. So it's not a matter of slowing down things, we need to reverse them. It's kind of like the argument with aging, you don't want to slow it down, you actually want to reverse it, is probably deserts. The edges of the deserts have some chance of, it probably won't be exponential, but it could be a fast linear. You either have to figure out how to trap the rainfall, so it doesn't run off or desalinize the ocean and pump it in. These are expensive projects, probably more expensive than “manufacturing,” if I can use the word, tens of thousands, hundreds of thousands of elephants and then letting them do their thing.

BRUCE MCCABE: Yeah. From a biology point of view, looking at the desert issue, I guess, heat resistance, salt resistance in plants, are opportunities there, right? I mean, to at least help, as a percentage in this, some one or two percent contribution?

GEORGE CHURCH:  Yeah, and this falls into the letting all the flowers bloom category. But in a way, it's betting against the home team. In a way, that's hedging your bets – you're doing it by saying, given that we're going to have high temperatures, we're going to do this. It's a good, it’s a strategy, it'll kind of take care of itself in the sense that farmers are always looking for that 1% improved crop yielded improvement every year or two. And as the temperature rises slowly, then the seeds they want will be … I don't think it requires government handouts necessarily.

BRUCE MCCABE: Yeah. I understand.

GEORGE CHURCH:  And to some extent, a lot of these, I don't think necessarily the Mammoths do either – sorry, the cold-resistant elephants – these are things that will have their own economic incentives. And so every other method that's competing with those, that involves a lot of belt tightening and capital expenditures, are not going to be very popular politically, compared to things where the farmers seed selection does its capitalistic thing, and repopulating the Arctic with fairly natural biology.

BRUCE MCCABE: So a little pet one that I wanted to ask you about, because I got excited about it some years ago, looking at the spread of energy sources and biofuels. Biofuels are seen as a particularly important one in aviation, for example, where it's very hard to do the substitution with electrification yet [and] hydrogen has its own issues there. But with biofuels, there were all these projects 10 years ago that I saw, which were about genetically engineering cyanobacteria to excrete methanol and ethanol, and then you could do, have your fuels being produced in situ, and there's no harvesting costs. And there was this lovely on-gain, cascading set of gains. Is there still – because they haven't scaled, none of these things have scaled – I'm wondering if there's still hope there, in your mind, for that kind of way of producing biofuels?

GEORGE CHURCH:  Well, better than ethanol, is that a couple of companies figured out how to make alkanes so you could make diesel, gasoline, and jet fuel without requiring new chemical source, debugging new chemicals like hydrogen or ethanol.

BRUCE MCCABE: Yep.

GEORGE CHURCH:  The problem I don't think was scaling – it was perfectly scalable – the problem is that it's very hard to compete with pulling stuff out of the ground and sending it through pipes ...

BRUCE MCCABE: Economics.

GEORGE CHURCH:  … It's incredibly low cost. Especially when the costs to the environment are not really factored in. You have carbon credits, but the carbon credits are about 10 times cheaper than the gasoline or the diesel or that fuel, which is already commoditized beyond almost all other chemicals by a factor of 10. So you've got these two factors of 10 that take you down to, it's just not, the economics is not properly lined up.

BRUCE MCCABE: Yeah. I get it. Totally. And especially...

GEORGE CHURCH:  And I'm not saying it can't be done. Again, I don't think that it can't be done.

BRUCE MCCABE: Yeah. The science part with no obstacles, necessarily. But the economics, yeah.

GEORGE CHURCH:  It's not even necessarily politically impossible, it's just hard. It's just hard.

BRUCE MCCABE: Yeah. Yeah. I got it. I got it. So, moving forward.  I'm sort of getting into my little checklist here – carbon sequestration was one, agriculture was another, biofuels. You mentioned in our email exchange, genome recoding as a research pathway that you wish more people knew more about. Can we get stuck into that then? Because I understand recoding to be basically creating a whole phenotype that doesn't exist in nature, and so we're modifying the whole genome, but it's a very simplistic understanding, and I'm very interested in what's in your head about applications for that.

GEORGE CHURCH:  Well, we're just now entering an era where we can synthesize genomes, mostly small genomes. And just barely – the difference between multiplex editing that we were talking about in the context of drugs and aging, and so forth – multiplex editing kind of overlaps genome synthesis. And we haven't had our eyes on the target. 

What is the real payoff for synthesizing a genome? And we realized, I don't know, somewhere between 2002 and 2009, that there are three payoffs. One is being able to have cells with new amino acid chemistry, the building blocks of almost all the proteins. Having new chemistries. Having biocontainment so you can do things in the wild without worrying, like inside of our bodies, or in cleaning up chemical spills and things like that. 

And then the third and biggest of the three, I think, is multi-virus resistance. Is if you change the genetic code, the code that goes from DNA to RNA to protein, enough so that the host is happy, you've changed it with the host's permission of the bacterial cells is in on the game, then the viruses aren't in on the game, and their genetic code is broken in every single one of their proteins, in every single virus in multiple ways. And the only way you can fix it is to get to a mutation rate which would break everything else, so that it can't even evolve around it, it's so fundamental, and this was a dream that we had since 2002, and we finally showed that we could do it just this year, published, where we swapped two codons out of 64 triplet codons. Two of them, we swapped it from coding for serine to coding for leucine. And in doing so, that means that every viral protein that expects a serine in that position gets a leucine or a mixture of serine and leucine, both of which are fatal. And again, multiple places in every protein of every virus. And then we can't show that it's resistant to every natural virus, but we can show that it is resistant to all the laboratory viruses, which is a lot of different kinds. And then a particular category of viruses that would've been able to break through all the previous candidates for multi-virus resistance, and then a random sampling of viruses from sewage and farm waste and things like that. And the short version of this is, it's resistant to all of those.

BRUCE MCCABE: Wow. Super organism.

GEORGE CHURCH:  Yeah, and the method is generalizable, we think to any organism. Any plant, any animal, any bacteria, any microbe that's used industrially or agriculturally, we can make them resistant to all viruses. And this is a big deal economically.

BRUCE MCCABE: [laughter] It's huge!

GEORGE CHURCH:  Right. So we were talking about 1% improvement in yield. Well, if you get the wrong virus, your entire crop is gone. It's not 1%. Yeah.

BRUCE MCCABE: Yeah. Or your entire – your livestock, for example.

GEORGE CHURCH:  Yeah. In fact, even if the virus doesn't kill your livestock, you have to kill your livestock because, if they have foot and mouth disease or African swine fever virus, you have to contain your whole livestock herd and then burn them in a way that that keeps them from contaminating adjacent. And so it's lethal even the virus isn't lethal. Yeah.

BRUCE MCCABE: That's amazing. So is this a realistic scenario that you could have a population of swine or cattle that are entirely virus resistant? That's sort of a realistic scenario?

GEORGE CHURCH:  Well, we haven't done it, but we've done a proof of concept in an industrial microorganism. And so it's not too far stretched to get industrialized. 

BRUCE MCCABE: I love it.

GEORGE CHURCH:  So the problem is the number of codons – so these are the stuff of the protein, how you code for the protein – is about 10 times more than in bacteria. So you might have 4,000 proteins of the bacteria and 40,000 in pigs but we're probably going to want to do it in pigs anyway because they're organ donors now, and we don't – if your patient lost their liver due to hepatitis, you don't want to get infected by hepatitis.

BRUCE MCCABE: Yep.

GEORGE CHURCH:  Or cytomegalovirus ...

BRUCE MCCABE: Which is what happened with the first patient.

GEORGE CHURCH:  … or other viruses. You just want to be resistant to all of them. And it's one of the reasons that you have organ replacement is because you are susceptible to a virus. Anyway, so, I don't know how far off that is, but it is, it provides a nice impetus for developing better engineering genome synthesis tools. So, my guess is since all these things are on exponentials, that what seems very hard for us today, two years from now will seem plausible. And five years from now will be seem routine.

BRUCE MCCABE: That's the story of your career, isn't it? I mean, so many of the things you started. We sequenced one genome and then [laughter] look where we are. I mean, that was how long ago now?

GEORGE CHURCH:  We sequenced one genome for $3 billion and we didn't even do it by a method that was usable in the clinic. The method we used, even if it had been free and not $3 billion, it only sequenced one genome. And all of us are made up of mother and father genomes. So we have two genomes, and that's a little harder to sequence because you have to keep them straight. Anyway, $3 billion, now it's $300, yeah.

BRUCE MCCABE: And now we're shooting for this to become part of really standardized personalized medicine for anybody.

GEORGE CHURCH:  Absolutely. And it's already cheap enough that you actually make money by sequencing people rather than losing money. It's a net positive for society to sequence them, probably a tenfold return on investment.

BRUCE MCCABE: It's incredible. And now I've seen the human cell atlas where they're saying, well, we're going to do the whole genome, so we're going to understand the epigenome and the spatial relationships between 37 trillion cells in a body [laughter]. There's exponentials on exponentials still to come.

GEORGE CHURCH:  Yes. Yes. All this keeps the technologists employed.

BRUCE MCCABE: [laughter] Yeah that's right, sells a lot of computers. Now we're coming to an end. I don't know, are there any other messages that you wish people knew more about, in your field, that would just help in terms of creating a better future? Any research pathways that you think, gosh, I wish people knew more about this, or would read more about it and it would help?

GEORGE CHURCH:  I think we've covered quite a few. The use of gene therapy in vaccines, the age-related disease reversal, virus resistance, enhanced transplants. These are things that not everybody knows about as deeply as this conversation. And hopefully they'll be prompted to go even – there's even there's even more depth, it's even more fun. Yeah, carbon sequestration, we covered that.

BRUCE MCCABE: Yeah, we got the big ones.

GEORGE CHURCH:  You've covered the landscape.

BRUCE MCCABE: Can we cover one that, I read, you sent me this paper. I'll link this paper. And this is a very recent project of yours, looking at interstellar exploration using biology as a mechanism to do that, and it blew my mind! It just, I mean, just an example of how big you think. I've never, I don't think I've ever read a paper that made me think bigger about so many parameters than this paper! [laughter]

GEORGE CHURCH:  Thank you very much, Bruce.

BRUCE MCCABE: Yeah, no [laughter] you've got to, let's try to do the one minute version of it. I don't know how you can, but I've got the title here somewhere and I loved it. It's Picogram-Scale Interstellar Probes via Bioinspired Engineering, is what that paper is called, if anyone wants to look it up.

GEORGE CHURCH:  Yeah.

BRUCE MCCABE: But in summary, you're talking about using microorganisms because we can get everything small and distribute it far and explore lots of places, right? And then having them communicate back in aggregate, like via bioluminescence, of what they found on other planets. I mean, that's extraordinary.

GEORGE CHURCH:  Right, so part of it was just to discuss the economics of accelerating things to a fraction of the speed of light, let's say one fifth, one 10th the speed of light ...

BRUCE MCCABE: Which is horrifically expensive.

GEORGE CHURCH:  … It's extraordinarily expensive if there is a human being in there somewhere. I mean, because you need to have shielding from radiation. And it's incredibly, you're talking about tons of matter that you're sending it some fraction the speed of light. But if you reductio ad absurdum, there are living organisms that have everything, all the manufacturing they need, to make copies of themselves in picogram amounts. So the difference between tons, hundreds of kilograms and picograms is enormous. You can accelerate many picogram packages with fairly modest lasers, with light sails, very inexpensively, so that means you get more shots on goal. 

It doesn't have to be microorganisms, this could be multicellular. The point is microorganisms themselves can be multicellular. But the point is almost everybody starts at the nanogram or picogram stage. 

The article was intended both to think differently about interstellar travel, and the need to have an outpost that has technology that can “phone home.” But it was also, it was kind of a roadmap to getting synthetic biology better at inorganic chemistry. So, biology and even synthetic biology does do it. And I summarized, a couple dozen examples. But we should be able to do as much or more inorganic and bio-inorganic chemistry via synthetic biology. And we could already harvest the incredible number of environments that current organisms can handle so that even if they don't know what kind of environment they're going to aim for, they'll be able to handle it, turn it into either bioluminescence or bio-lasers.

BRUCE MCCABE: Yeah, bio-lasers.

GEORGE CHURCH:  Some way of communicating back to earth. And that will, the return trip will be even faster than the forward. The forward might be a 10th of speed of light, but the backwards will be exactly the speed of light, in terms of information content.

BRUCE MCCABE: I loved it. It made me think so much bigger on about five axes at once. So my brain was hurting, but I was enjoying it. And that's the thing, challenging us to think bigger. Especially, in your whole career, like this whole, what we'd might call loosely biotechnology now, but it's really genomics and all these frontiers. I think every 10 years, everyone's got to recalibrate how big they think. The idea of even age reduction or slowing or reversing therapies was completely off the table for a sensible dinner conversation 10 years ago, and now everyone has to recalibrate and understand it's coming, it's absolutely coming, and they're real [laughter].

GEORGE CHURCH:  Yeah. It's greatly enabled by our ability to read and write at a genomic scale.

BRUCE MCCABE: Exactly. So, look, do you ever reflect on just how many lives you've impacted on this planet? Have you ever thought about that? 

GEORGE CHURCH:  I think that's, I'd say an immodest and usually inaccurate thought. Everybody's a hero of their own story, so I try not to be.

BRUCE MCCABE: [laughter] Well, I'm putting it in the, minimum tens of millions, but I think hundreds of millions on this planet because of all the technologies that touch their lives through medicine and so forth. 

GEORGE CHURCH:  I think it's a team effort that involves just a lot of people.

BRUCE MCCABE: Yeah, I know you're going to say that. Of course there are a thousand people around you, but in terms of the name that keeps popping up over the last 40 years, with everything that I sort of read or see, you've played a role, either inspiring the research or mentoring or whatever, so we need you to take …

GEORGE CHURCH:  I'm very proud of my alumni, the graduate students and postdocs that have gone off and either started companies or started their own academic labs. It's a wonderful crew. And they're very nice to each other. I mean, that's one of the fundamental things that we encourage, so it's lovely to see them populate the world.

BRUCE MCCABE: Well, if we do say, in aggregate that community around you, which is vast now, their impact on humanity has been profoundly positive and profound in scale as well. So we need you to take the anti-aging therapies and give us another 60 or 70 years, George, because then you can multiply it by 10 or 100 or 1000 and keep helping us out [laughter].

GEORGE CHURCH:  I'll try. We will try [laughter].

BRUCE MCCABE: Alright. Professor George Church, thank you so much for your time. This has been an absolute privilege for me, a real joy. So, thank you so much for making a full hour of your time to talk to me.

GEORGE CHURCH:  Yeah, thank you. I think you do the terrific job of making it accessible to a lot of people. Thank you.

BRUCE MCCABE: My pleasure and my privilege. Cheers, George. Bye for now.

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