The Life Scientific: George Church

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0:30at Whole Foods Market. If your best finance people are doing expense reports, chasing receipts, or spending time on month-end clothes, it's time to get Brex AF, a gentic finance that eliminates that work before it starts. Learn more at brex.com slash AF. Hello. What if we could bring back the woolly mammoth, not for spectacle, but to help save the planet or improve the success rate of transplants by growing human-compatible organs in pigs? What if everyone in the world could have their genome sequenced as easily as getting a blood test, so we could spot diseases before they even appear? These ideas might sound like science fiction, but they're being made reality by today's guest, who makes a habit of finding solutions to the seemingly impossible.

1:19George Church is a geneticist, molecular engineer, and one of the pioneers of modern genomics, a professor at Harvard Medical School and MIT, He developed the first method for direct genomic sequencing, helped initiate the Human Genome Project, and founded the Personal Genome Project, making huge quantities of DNA data publicly available for research. Today he's working on some of the most headline-grabbing and often controversial science on the planet, from de-extinction to virus-proof humans to slowing down ageing. Clearly he's not a man to be slowed down himself, not even by the fact that he has narcolepsy, the neurological disorder that causes sudden sleep attacks.

2:01In fact, George says some of his best ideas come in the moments between waking and sleep. Perhaps we could all afford to do a bit more dreaming. Professor George Church, welcome to The Life Scientific. Thank you. Great to be here. Now, George, I'm going to have to pick up on the woolly mammoths, because I think people will have heard stories quite recently about your work in so-called de-extinction. We're going to come to the science later on, but for now, can I just ask why? What's the motivation here? The largest motivation is restoring ecosystems and helping endangered species by restoring

2:37George Church:genes that are extinct and providing diversity to those endangered species like elephants. So if woolly mammoths were brought back and roamed the Arctic, how is that of benefit? So the idea here is that there's a lot more carbon at risk in the Arctic than anywhere else. There's 1 ,400 gigatons, which dwarfs the 10 gigatons of human activity per year. And so it's not just keeping that 1 ,400 frozen. It's also adding to it by having more active organisms like grasses rather than trees that allow it to be sequestered over a vast amount of space. But now it's hard for them to be reintroduced because a lot of the grasslands have been turned over to trees.

3:23George Church:And the only species on the plant that like knocking down trees are elephants, and they do it with great gusto in every environment they're in. So that would be helpful to shift the balance slightly back towards grasslands. It'll still be a mixed ecosystem, but it'll be much more productive. So restoring grasslands in the Arctic is a way of keeping the permafrost frozen, keeping the carbon trapped underground. Not only keeping the 1 ,400 gigatons frozen, but also bringing it in faster. Right. Now, George, I mentioned in the introduction that you're narcoleptic, and you actually get inspiration during your brief naps.

4:05Yes.

4:06George Church:Mostly waking up. Very often I'll fall asleep when something's going wrong. So, for example, if my computer starts acting up or crashing, then I crash along with it. or if there's some tough math problem or something like that. And then I just wake up thinking orthogonally to where I was stuck. You told my producer that your ideas are often labeled as impossible or useless or both. And it's when people make those comments that you know you're on the right track. It's not a guarantee I'm on the right track, but it is amazing how often that means that I'm just the right amount out of the box. Right.

4:43So, George Church, you were born in 1954 in Florida. and I gather your mother was a very big influence in your early life.

4:51George Church:Slightly bigger influence because I had three fathers sequentially. So there are periods of time where she was a single mom and she was extremely bright and loving. She got both a jurist doctor in law and a PhD in psychology and she was just always interested in intellectuals. So even though we were in a remote, intellectually speaking, part of Florida, And somehow we had some pretty interesting people stopping by the house. So what were you like as a kid? I was, you know, a little socially awkward. I was dyslexic. So I mostly learned by looking at pictures. I wasn't really narcoleptic until I hit my teen years.

5:33George Church:But yeah, I was fairly isolated from other kids living on the bay and very curious. So as a teenager, you were clearly very bright. but dealing with the challenges that come with dyslexia. So your mother and then stepfather decided to send you to his old boarding school in Massachusetts, which I hear was a pretty progressive place. Oh, it was amazing. It had a layout like a college campus. It was more beautiful than most college campuses I've seen. And the classes had no upper limit. I mean, we were essentially doing college work in high school. It was like the scene in The Wizard of Oz where it goes from black and white to color for me.

6:10George Church:It was just wonderful. Yeah. You went on to study zoology and chemistry at Duke University in North Carolina and completed that undergraduate degree in two years, then started a graduate fellowship in biochemistry. But after a year, you had to leave. Tell me what happened. Well, so in addition to the two degrees, I also did research in a third topic, which was x-ray crystallography. And I got so excited about that. I was working over 100 hours a week. And I just didn't show up for any of my classes, most of which I had taken already as an undergraduate, but I didn't want to take them again. Right.

6:49George Church:And that resulted in me failing. They didn't like that. Completely. And yes. Well, in 1977, you started a PhD in biochemistry and molecular biology at Harvard under the great Walter Gilbert, who would win a Nobel Prize in chemistry just three years after that. shared with Fred Sanger and Paul Berg for developing methods of sequencing DNA. And here you also made a significant breakthrough developing the first direct genomic sequencing method. Now talk me through what that involves and how it improved on the existing method. All the existing sequencing methods at that point depended upon recombinant DNA amplification, So essentially cloning.

7:34George Church:So you had to take the gene from one place, move it into what was called a recombinant DNA vector, and then amplify it to very large amounts of DNA in a bacterium. And then you could sequence it. And I changed it to you can essentially sequence the whole genome without cloning. And a variation on that became what was now called next-gen sequencing. And it's the one that we use to this day. Well, after your PhD, George, you were involved in kick-starting the Human Genome Project, the huge international effort to map, sequence, analyze the entire human genome. How and why did that come about? Well, so I was invited to a very tiny Department of Energy meeting in Utah.

8:22Congress had asked DOE to become a shepherd for any way of measuring the mutation rates of populations exposed to various sources of energy, most notably atomic energy and even atomic bombs.

8:37George Church:So the Department of Energy was responsible for following up on what the United States had done to Japan. And 10 experts convened in Utah in a ski resort. And we concluded in the first few minutes that we couldn't really estimate mutation rates if we didn't have a gold standard genome as a reference point. And even then, it would be hard. So we spent the rest of the time describing how we would go about getting a reference genome. And then that sort of failure to meet our mandate became the Genome Project. And listeners will probably remember the project succeeded in mapping and sequencing the entire human genome, all 3 billion DNA base pairs in 2003, which has been a huge help for medical science.

9:25Now, George, after your postdoc, you joined the Harvard Medical School as an assistant professor. Let's talk about some of your early work at Harvard. In 2005, you officially launched the Personal Genome Project, an open access platform sharing individuals' genome and health data sets. What was the inspiration behind that? Well, part of that we did as part of a grant where we said we'll do at least a small bacterial genome, But if we can improve the technology fast enough, by the end of the grant, we'll be doing human genomes.

9:57George Church:But in order to do that, we need to do human subjects research authorization at the Harvard IRB. And when I studied their protocols, they struck me as antediluvian, you know, anachronistic. Things like if we find out something that can save your life, we can't tell you that. Had to protect the patients from their own data, keep everything private. So we developed a protocol where we did the opposite. We gave them their data and we gave the world the data. So we weren't making false promises, but we were getting very thorough consent. The following year, you became subject number one and shared your own information online.

10:39Another year on, the first group of 10 volunteers were added featuring high profile names like the cognitive psychologist Steven Pinker, who was in fact the second ever guest on this show nearly 15 years ago. And your decision to be subject number one certainly paid off because I gather a doctor who'd accessed your records came up to you at a conference and gave some helpful advice.

11:03George Church:That's right. I had started statins about a year or so earlier to deal with high cholesterol. And so this person sitting in one of the front rows said to me while we were waiting for the meeting to start, you know, you really should get a checkup on both your cholesterol levels and muscle markers. because statins can have a negative effect on your muscle markers and can fail to have a positive effect on the thing you want it to, cholesterol. And this was really weird because this is a complete stranger in the front row. And so I went back after the meeting and did get my blood analyzed. And in fact, he was right on both counts.

11:41George Church:There were negative consequences in the muscles and there was no positive consequences on my cholesterol. And so we adjusted things and eventually got a good system. Goodness. Well, I know a long-term ambition of yours, George, has been to make personal genome sequencing affordable. The idea being that people can get information about their inherited genetic risks from cancer to allergic reactions. How is that going? So that has dropped the price from$3 billion to maybe$300 for individuals. and it continues to drop, it could easily be basically the price of getting saliva, which is where we get the DNA from.

12:24That is remarkable. I mean, it is something then that can benefit the whole world, provided, of course, nations take it up. A number of nations are taking it up. It is intended to be a democratizing force.

12:37George Church:I think nations like Iceland, the UK, UAE, these are leading the charge in getting all their citizens sequenced. So I think it's having a big impact. In particular, for very severe inherited diseases, which affect maybe 3 % of the population, which is a huge fraction and costs trillions of dollars, those can be avoided by genetic counseling. Well, so the UK government, it was only earlier this year that they announced that every newborn baby in England is going to have their DNA mapped. I think it may be still a few years away before that actually takes place. But that's incredible. No, it's unaffordable not to do that for a government.

13:19George Church:And England has really paved the way in many genetic technologies.

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14:26Time to get to the woolly mammoths now, George. We covered the whys earlier, so let's hear a bit about the science, because you're not resurrecting woolly mammoths. You're creating a new version using ancient and modern genes. How does that work? What's the process?

14:43George Church:So we're really resurrecting genetic variation. We want diversity of particular types. So, for example, we want the genes that can make them resistant to cold, things that affect the 10 centimeter fat everywhere and the smaller ears and the blood and nerve adaptations to cold. And we want some things that are not present in the modern nor in the ancient DNA, things that make them stay, for example, resistant to a deadly virus, EAHV, which is killing maybe 20 % of the youth, which is enough to tip the balance towards extinction. So that's something where we don't want to be limited by the old or the new.

15:24George Church:and all the engineered genomes will be part of the same species in the same sense that the pigs we make for organ transplant are part of the same species as regular pigs. I wanted to ask you about that in fact because that actually laid the groundwork for the Woolly Mammoth Project this work on pigs making their organs compatible for human transplants. Yes and we now have a patient that benefited from this and a clinical study for a lot more patients. We have survival since January of 2025, a very healthy, active, happy kidney transplant patient. And it de-risks a lot of our other projects in that it's multiplex editing, where we have 69 different edits in the pig genome.

16:11George Church:A lot of them are to eliminate viruses that are built in the pig genome, and it could be quite hazardous to an immune-suppressed organ transplant recipient. and then we have a few that make them more human-like and then three of them that make it less rejected because of sugars on the surface. And so showing that we can make all those edits at once in a healthy pig increases the probability we can make a similar number of edits that could make a healthy, cold-resistant elephant that would have a lot of the properties of mammoth and would help the elephant live in an environment without human conflict in the Arctic.

16:48You've also successfully engineered woolly mice and most recently, I think, a litter of dire wolf pups. How have they helped progress things?

16:59George Church:Well, the advantage of mice and canines, wolves, are that they have more rapid development. Mice have a gestation period of 20 days, while elephants are 22 months. So you can do rapid prototyping in mice and wolves. And so you can test aspects of fat metabolism and woolly hair. So if their woolly hair is really working and they look like beautiful, very cute little fuzzballs, if that makes them like colder temperatures, then we'll detect that by a variety of methods now. With the wolf, we're testing more environmental issues. You know, most ecosystems are thought to benefit from apex predators.

17:42George Church:And back in the day when there were mega herbivores like the giant ground sloth and the bison and the mammoths, they needed a comparable sized predator. so we could test all sorts of new alleles more rapidly in mice than wolves. As you know very well, George, there are scientists and others who've criticised this project. Some take offence at your claim that you can bring back extinct animals, which I think we've mentioned is really a misleading shorthand one finds with clickbait headlines. But others argue that long extinct animals should be left extinct, that our planet has changed too much.

18:20they've questioned the ecological necessity of this project suggesting we should focus on saving existing animals and environments instead what's your response to them well i try to listen very carefully to critiques and come up with my own as well i mean we have to take those one at a time you know for example if you say that their environment doesn't exist anymore the response is that it's still minus 40 in the winter and that the vegetation is very similar and they're

18:50George Church:So a lot of their socialization and microbiome in their gut and so forth is going to be essentially compatible with elephants. We also check with the people whose environment might be affected by these revived species or proxy species that have a lot of the traits and a lot of the genes, not necessarily all of them. So we're choosing areas that have close to zero population density, but still we talk to the indigenous people in each of the continents that's affected by our different projects. And to a large extent, we have a lot of enthusiasm from indigenous people, including investment in the projects and collaboration on projects about modern endangered species.

19:34Another recent breakthrough in your lab has been modifying an organism's entire genetic code to create an improved version. And you tested that out just a couple of years ago with E. coli bacteria. Right. So we have a series of projects that require extensive genetic engineering, not just one gene.

19:56George Church:So most pharmaceutical products that have been developed with our genome editing and engineering technology are single genes. But there are a few that involve multiple. One of them is the de-extinction. Another one is the pig organ transplant. And the third one is making virus-resistant organisms. And so we've been dreaming about this since, you know, the turn of the millennium around 2001. And now it finally delivered in 2023 where we have an industrial bacterium that has a problem with viruses and has just hundreds of different viruses that infect it. And we made it resistant to all of them, including viruses we haven't seen yet.

20:34George Church:And by changing the genetic code, we make it so the host bacterium is fine, but the viruses are broken in every gene in multiple ways so that they can't evolve around the changed genetic code that we installed in the bacterium. And that works like a charm. We've taken hundreds of viruses from the wild as well as all the lab ones that have been isolated. And it's resistant to all of them with no escape noted so far. Very, very clever. Things are changing very rapidly. People always get nervous with rapid advances in science and technology and medicine. How do you respond to people being squeamish about this, about genetically engineered products being used in the human body?

21:23be they therapies or transplanted organs?

21:26George Church:Well, I don't try to reassure or change minds, but I do answer the questions. And there's nothing forcing people to take these medicines, right? So I think we will see their safety and efficacy tested in preclinical trials and then in clinical trials. You know, it's worth being cautious. I completely support people that are being cautious. But what's important is that we embrace truth, that we hunt it down. You know, Google search and AI tools and so forth, the average person can get the facts. But that's also part of freedom is that if you don't like the facts, you know, you're free to ignore them, but at your own risk.