We Made This Bacteria Immune to EVERYTHING (ft. George Church)

Today's guest made bacteria immune to every virus that exists. This breakthrough could revolutionize medicine by creating virus proof cell therapies and potentially extending this protection to human cells, while also demonstrating that we can fundamentally rewrite the language of life itself. Something that was previously thought impossible.

We had been dreaming about this since 2002, but just in the last couple of years, we delivered, engineered, and secured an organism that was resistant to all viruses. Every gene in every virus is broken in multiple ways, and so they can't even evolve around that.

George Church is a Harvard Medical School genetics professor and pioneer of synthetic biology. He's an entrepreneur who has founded multiple biotech companies and is known for pushing the boundaries between science fiction and reality. His team just did something that sounds like pure science fiction. They made living cells completely immune to.

Every virus on Earth.

Not resistant, immune. Every single virus that tries to infect your cells just fails. The viruses can't evolve around it. They didn't add anything new. They just removed a few letters from the genetic Alphabet. But George isn't stopping there. He wants to do this to human cells. He's talking about engineering astronauts for Mars missions, bringing back woolly mammoths, and maybe in just maybe making humans virus proof too.

The implications are staggering. The ethics are murky, and the timeline. Well, if Church's track record tells us anything, it's happening far faster than we think.

All right, welcome today to this episode of into the Impossible. So I want to start off with some of the curiosity that you engender in me and your wonderful book, which we'll get to. We'll talk about different challenges. We'll talk about the relevance of biology, genetics, gene information, and so forth to an audience that has a lot of astronomers and a lot of cosmologists and a lot of people that think about life on other planets. And that's sort of where I want to begin and asking a question. Eventually we'll get to whether or not Elon Musk is sending the wrong species to Mars. But first I want to ask you, how do we grow or engineer life like tardigrades or rotophores, or how do they indeed have natural resistance to radiation that would liquefy my cells? I know, for one, how do these creatures come about? Why was this so necessary at one point, and why is it still in the, you know, in their genetic record to this very day?

It's hard to definitively answer questions about the past or about intentionality. But I think there's fairly convincing speculation that much of the radiation resistance in naturally occurring species is due to desiccation. Desiccation causes DNA damage and the repair processes that deal with that also work for say double stranded DNA breaks that would cause be caused by ionizing radiation, gamma rays and desiccation. And this applies to single cell organisms like Dianococcus and to multicellular organisms like the tardigrade.

Could we learn from them? Could we use tools that you've invented like mage multiplex genome engineering to add kind of a repair kit, rotifer style, you know, a bolt on to our DNA essentially upgrad or out of this world, out of this earth biology.

Yeah. So there is some work in the literature and in our lab on seeing what sort of the minimum number of genes required to get an increase in radiation resistance or better repair. And a lot of the, you know, a lot of the repair proteins are known. There's, there's as few as four or five genes can result in 10,000 fold, 100,000 fold improvement in radiation resistance in a starting organism like E. Coli, which is, has very low tolerance for radiation and turn them into something that is comparable to, you know, things that we thought required billions of years of evolution to become that radiation resistant. You can do it in a small number of mutations, which gives us hope. We haven't yet, we've started to, but haven't finished extending that to mammalian cells. But you know, assuming that goes as well as it did in bacteria, then that's something that could at least apply to cell therapies and organ therapies.

Whether that would be enough to protect the entire body is an open question.

I know you mentioned that, you know, it's hard to make predictions about the past kind of inverting Yogi Berra. But if we look at the inherent ability for our species or for even, you know, lineages that we're not directly related to, but share, you know, some massive amount of chromosomes with. I forget a fruit fly has something what 50% of similar variety of chromosomes to a human being or something like that or a banana. I forget which one if it's the fruit or the fly.

Well, it's kind of a, it's kind of a slope, you know, it's different levels of relatedness. But we have, you know, a fruit fly basically has one copy of each gene where we have four copies of those genes and they do four different things. So but you know, we have roughly the same composition of at least for core essential genes.

So does that hint at something in the deep past that perhaps as you mentioned, one of my favorite words, I think you Know, originally coined by Fred Hoyle or one of his colleagues. You know, panspermia, the, the notion that life arrived on, you know, meteorites or comets, not unlike the kind you get at my website, Brian Keating.com and George, I'll, I'll bring you one because you have a dot EDU email address and that automatically gets you one. Does that point to perhaps, you know, evidence for life originating not on Earth? In other words, the fact that we have this radiation resistance? We know the sun is an active star, but to survive interstellar distances it would have to be very hard. And I think a trip to Mars, you said in an interview, is about 180 days worth of Earth exposure. So does the existence of latent, even latent unexpressed information or abilities within our DNA to resist radiation and vacuum and so forth, does that point to an origin perhaps from another world?

Well, in a certain sense it points away from it in the sense that, yes, you have all this, this radiation that's galactic. But you know, the main things that protect the three main things that protect us on Earth is, is our magnetic field and then the atmosphere and any additional layers that could come if you're subterranean and then, and finally then active metabolism. So if you're in a tiny frozen rock without a magnetic field and without much mass to protect you and you're frozen, so there's no metabolism, that's the worst case scenario. But there are many larger rocks that have, in principle, a planet could come, could break loose and it would have all the magnetism and the atmosphere and so forth that it had when it was part of a solar system. And those can go at, you know, at very high velocities that, you know, slowing them down and transferring them to another solar system is a non trivial thing. The other possibility is if you can, if you're going at relativistic speeds, let's say 5% speed of light or something like that, there's some calculations that indicate that you can decelerate. And so then if you just accept a certain number of mutations, if you accept the frozen state, you can have a very small package in the order of single cells or small cluster of cells, nanogram amounts, and you can cover distances like say from here to Proxima B in dozens of years. And you just accept the number of lesions.

And then as soon as you get into a warm place, then you start repairing those lesions. And so I think that those kinds of solutions to the triple problem of magnetic atomic shielding and repair processes could allow at least short trips and we don't know what the upper limit is. You know, most of the, of the failure of repair processes are because there's a compromise where the evolution has been cheap or you know, has hit a, it's hit a trade off between saving energy for other things like reproduction rather than spending huge amounts of energy keeping a perfect copy of your, of your genome in every cell in your body. It's basically. But in a scenario where you have great abundance as we do in the modern world and might have in a, in a panspermia world, then you would, you would spend that energy wisely on repair.

What about the prevention is worth a nanogram of cure? Is Elon being reckless by sending unmodified humans to Mars? Or should we be editing astronauts before engineering rockets?

Well, I think I, I wouldn't lay this at Elon's feet just generally, ethically, he's, he's putting effort into the physics mainly. But yes, I, I think it's almost inevitable that since, you know, we consider medicine as being appropriate to a certain environment. So if you, you know, live in a very cold environment, then doctors are going to be treating frostbite and if you look, live in a very humid environment, you might be dealing with fungus and so forth. And I think as we go into space there's going to be a whole new set of problems, mostly having to do with weightlessness and radiation that are, that will merit new medicines. And an increasing number of medicines are now gene therapies which are kind of a once and done which can apply to an increasing fraction of your body. So I suspect that that is, that will happen and in a way that will be kind of independent of the. It doesn't have to be independent, but so far it has been independent of the physics problems. I mean, for example, there are known solutions for the, let's say the gravitational issues.

You know, these are very serious things. Even after people return to Earth after a year or more, they have kind of irreversible damage to the bone structure and even the distribution of fluids in the body that could be solved by having simple rotation, centrifugal forces that end up being one unit gravity. For some reason that's been deemed not cost effective so far, even in the International Space Station. But that's. Now that becomes a more difficult problem on moons and planets because then you have to set up the equivalent of a rotating space station which is already unaffordable in a gravitational force field anyway. I mean, all these things have physics solutions, but they also have biological ones. So we'll see which which ones are respected.

Speaking of billionaires, soon I'll ask George whether or not billionaires will live 50% longer than U.S. public university employees.

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But first, I want to do what we're not supposed to do in life, George, which is to judge books by their covers.

Hey book lovers, we're judging books by the covers.

We know we're not supposed to do it better into the impossible.

There's nothing to it. Let's take a look and judge some books.

You know, in a probabilistic sense. What else do we have to go on? So for those that have not encountered. Your really delightfully written, highly nerdy, but highly informative for lay people as well. Your book ReGen ReGenesis, which hearkens to many different aspects. So I want you to go through the title, the COVID art and the subtitle and what went into all those with you and your co author.

So the title is regenesis subtitle is How Synthetic Biology Will Reinvent Nature and Ourselves. This was co authored with Ed Regus who's a popular science writer. It was a great pleasure to collaborative. You wanted me unpack some of those words?

Yeah, the title and the subtitle and they are.

So the regenesis refers to the regenerative processes that occur within our bodies all the time. I think most non biologists are blissfully unaware of what's going on. We're constantly getting cancer and having our blood vessels break and they're all constantly getting repaired. So that's one meaning of regenesis. The other meaning is the genesis. The creation of life from non life is something that we're quite interested in from an astrobiology standpoint is how many times did that happen, how different were the outcomes and so forth. And we can get a feeling for that on Earth by creating lots of alternative synthetic biology. So that's for the subtitle is How Synthetic Biology Would Reinvent Nature and Ourselves.

Reinvent, I think is intended to be a modest term. That is to say that even if we come up with biology that's not at all like our current biology, it probably is a reinvention because of the vast amount of real estate present in the. In our galaxy and beyond. So. But nevertheless, with that modesty in mind, it's breathtaking how fast the synthetic biology is going. It's going at an exponential curve that's typically faster than Moore's Law where costs are dropping by factors of 2 to 10 per year and quality is going up a similar pace. So. And we think that some of these will affect manufacturing of essentially anything.

I teach a course at MIT and Harvard and actually globally students globally called how to grow Almost Anything. And that's the idea is that biology can manufacture even inorganic materials and computers and so forth, computer, electronic components. So that's what we mean by nature and ourselves.

And the artwork on the COVID I listen to the audiobook. So I have a microscopically sized cover. Can you go through what, what the description of the COVID looks like to them?

I actually didn't choose this cover. It is a, it's a refactoring of, of a, of a A famous painting that, that I actually figured out what it was. I reverse engineered what the painting was when it was presented to me by the publishers.

Of course you did.

I didn't veto it. But you know, it's, I think it represents, I think the connection with the topic is that is, it represents Genesis in some sense the biblical version of it. But it's abstract enough that it, it could be something else. Again, the point was to be modest, not to be arrogant about, about what we're reinventing.

Okay, we're going to do a couple of quick, quick questions from my audience. First, what's the biggest myth that people believe about genes and traits like intelligence or aging? Can you get into the. What's the difference between polygenic and environmental factors that lead to different complexity, factors that we see not just in ourselves, but in all species?

Yeah, I think one of the, I'm not sure, a myth, it's certainly a potential source of confusion even among scientists is that you can establish with well known tools like genome wide association studies, you can establish that there are, let's say 9,000 genes involved in a polygenic trait like height. Height is one of the favorite ones because people collect height information and weight, even when they're studying some disease unrelated to height and weight, because it's just easy to do. Anyway, 9,000 genes are involved. And so you sort of say, well that's so complicated, it's going to be hard to predict, much less influenced. Right. But in fact, there's one gene that doesn't turn up as being particularly special in those 9,000 that does influence it tremendously in all sorts of animals and in humans at the extreme values of tall and small. And that's the somatotropin gene or sometimes called the human growth hormone. And it's so powerful that it's actually used in seven different clinical settings, diseases.

And it works. It's like part of standard medical care in these seven cases that shows that something can be multigenic, polygenic and also monogenic in a very practical way. And it can be a germline or it can be something that happens somatically. So for example, some of the giants, the historical giants over 10ft, sorry, 8ft tall, had pituitary tumors. This is not something that kills them, it just makes them very tall. And if it continues late enough in life, it causes acromagaly which, where you have coarse facial and hand features. So anyway, that's one of the complex things that's misunderstood, but we could look into others if you want.

I want to ask another question, you have this unique ability to combine physics, engineering, obviously biology, bioinformatics, even AI, which we'll get to. But I want to ask first, what's something that you would have thought was science fiction 20 years ago, but now in your lab and your collaborators labs is routine? Effectively?

Yeah. Almost every project that we're proud of had that nature to it. You know, it was called science fiction in a pejorative way, not in an admiring way that it was either useless or impossible or both. Some examples were, you know, when I was starting as a graduate student, I had the pleasure of typing in most of the DNA sequence, an RNA sequence that was known at the time. And that was easy back then because there wasn't much known. And I thought, wow, wouldn't it be great to do this? You know, I learned some things then I said, wouldn't it be great to do this for everybody on the planet and do their whole genome? And that was completely out of the question because the biggest things that had been sequenced at that point were 80 base pairs long C's, A's, G's and T's. And the human genome was 3 billion times 2 for each person had mother and father inheritance. So 80 to 3 billion.

But we did it. So we're now sequencing lots of millions of human genomes and hopefully we'll get all 8 billion at least subset of people who want their genome, which is I think going to be most people, but we'll see that's science fiction. Particular ways of doing it, like what's called nanopore sequencing, where we just look at single molecules that just seem like, you know, doing single molecule anything, much less, you know, reading the detailed structure from a single molecule seen. But that's now also the routine. It's the best way of getting really long reads, you know, making organs and pigs that could transplant humans. We now have someone who's getting close to six months with a pig kidney that seems quite healthy, happy. So that's, that's, that's science fiction. And the list goes on and on, you know, of things that, you know, even surprise the people doing it.

Tell me about your relationship with past guest Craig Venter. What's that like? Because you guys are in a very similar space, very, you think very much alike in some ways, but I sense of friendly degree of maybe competition or admiration without directly having collaborated. If you feel comfortable.

Yeah, I feel comfortable. I don't think we're exactly competitive. We're kind of synergistic. Craig, when we were meeting Together, he answered somebody's question, and he said, george helps invent these technologies and we deploy them and, and use them on a scale that's useful. And. And I'm certainly not unique as inventor, and he's not unique as. As a consumer. But we do.

We do have similar tastes, which I think are good tastes. That is to say, you know, we both worked on. On ocean ecology at one point with a genomic flavor. We both worked on human longevity and wellness. We both were involved in synthesizing genomes. He did mycoplasma and we did E. Coli. I don't think it's simple enough to just say that one is doing industrial and the other one's doing academic, because we've both done a little of each.

And in fact, I think very often his industrial projects end up being very academic. Like, you know, sequencing the human genome wasn't immediately commercializable, even though they tried to patent all the CDNAs. In the end, it's just the. It was mostly very basic research that came out of the genome project, while some of the things that. That I did that were kind of academic, like multiplex editing, end up producing CRISPR and. And these organs from pigs and. And things that were genuinely useful. Anyway, I think, you know, I think we help populate.

We represent extreme values in the genomics field with similar goals, which is to, you know, help the environment and help people.

Quick story about Craig. We went to. I used to be involved with a project that Jim Simons, my late mentor and friend, sponsored, called Math for America. And we had a branch here in San Diego. And Jim came out for one of the first fundraisers that we had trying to raise money. And Craig was there as well. This is before he started the Veteran Institute down the road from ucsd. And he spent the whole time talking to Jim Simons.

And at the end, Jim said, you know, Craig's very interesting, but, you know, you should be very careful inviting people to talk to me, especially the smarter they are. And I said, that's weird. I thought you like smart people, Jim. And he said, well, no, because the problem is every time I meet somebody, they tell me that they're a genius. They asked me for money, and even if I, at my wealth, gave a dollar to each person who said they were a genius, I'd be broke. But, you know, Craig was not, not too shy about fundraising for his own ventures at someone else's fundraiser. So I want to ask about genome rewriting and the resistances of viruses and basically the question between editing and Rewriting it just seems strange. I heard Jennifer Doudna speak two weeks ago at the Simons foundation for a retrospective, you know, tribute to Jim Sim life.

And I really can't understand how you guys do what you do because it seems like if I went to Mars and sprayed Mars with a bunch of koala bears, it wouldn't just take over the planet, but somehow you guys are able to change a single gene or a part of a gene, and then it rewrites the entire genome grammar like what you did with codons. Can you explain that to a simple experimental cosmologist? How does the body know you inject in a couple of trillion particles maybe, and that it takes over 10, 10 to the, you know, 24th particles?

Yeah. So actually how biology does what it does is rightfully mysterious to non biologists. And it causes some of the, you know, some misunderstandings. You know, like physicists might say, oh, you're defying the second law of thermodynamics if you live forever or something like that. And the fact is, no, we're obeying them by burning energy and entropy into the outside world in order to keep the thing in the middle, you know, youthful or for that matter, to some extent there's a continuum of life from billions, 3 billion years ago to today where there's no dead thing anywhere along that pathway anyway, that reproduction and the process of evolution is also a little counterintuitive where you can a bunch of small increments, even in the lab you can see, accumulate and make new phenomena. So anyway, it's a real gift to we synthetic biologists is that so many things self assemble, they've been selected by evolution to, to bind and to catalyze and so forth. So you literally can throw something in there and it says, well, I've never seen this before, but I've seen things like it. I'm just going to run with it.

You can put a little piece of optic nervous tissue and put it where it doesn't belong, in the tail rather than the head, and it wires up and it senses things and it reacts as an organ, as an eye would, and the same thing at the genomic level, you can change the genetic code quite radically. And it will, it will do its best. And you can, and you have all kinds of great debugging tools that you just, just unimaginable for most people in a mechanical world, you know, having a self repairing any, anything mechanical. But in biology you take it for granted and you use it. And so synthetic biology is really, it's not like all other engineering protocols. So if you're going to build a bridge, you might build some scale models, but maybe one or two. And then you build the big thing and hope it doesn't fall down. But with biology, you can make billions of model prototypes and then you could literally let them compete with each other and then pick the winner.

Imagine if we could build a billion bridges and then pick the winner. That would be great. Or take. Yeah. Anyway, so what we did with your other part of your question was how did we make virus resistant cells? By changing the code. And put that in the simplest possible way, but not too simple, is that the genetic code contains 64 triplet codons. So every possible combination of ACG and T, like AAA is. Each of these 64 codons encodes a different amino acid.

Sometimes they're redundant. The same amino acid at different triplets. Anyway, you can change those triplets because of redundancy. So some amino acids have six different triplet codons, and we can take two of them and move them up with the other four and then clean out every use of that. So every protein in your body is made up of these triplet, or the gene is made up of these triplets and you can clean up. So it's not using two out of the 64. Once you've done so, that's radical surgery. You've done that throughout the genome.

The organism is now just basically as healthy as it was before, but it's only using 62 of the 64. Or you could use 63 out of 64, which was our first genome that we engineered then. Now that it's freed up, it might have resistance to viruses because the viruses needed that code, that particular one out of 64. And we had been dreaming about this since 2002, but just, you know, in the last couple of years, we delivered. We eventually we engineered and debugged and made it biosecured an organism that was resistant to all viruses. Because of the changes in a code, the virus still has the old code, the cell has made a new code without consulting the virus. And so the virus is broken. Every gene in every virus is broken in multiple ways.

And so they can't even evolve around that, as far as we can tell, both theoretically and experimentally.

And what is it about these codons? I mean, can you explain again to a lay audience, what is a codon? What are the different functions of them? I kind of analogize them to almost like a colony of bees where you've got drones and workers and honey and a Queen and, and they do different things and you have to implant certain things in the hive to make them stop. And there are stop codons and start, but there's also redundant codons and so forth. Can you talk about how these, you know, kind of magical combinations of, of just tiny amounts of, of, you know, chemical content do so many different varieties, well beyond the number of permutations, say that at least as a, you know, a physicist, I might think are possible to express.

Yeah, I like the, the specialized casts of the, of the social insects. As a, as a metaphor, we do have start signals and stop signals and, and so forth. Another way of thinking about it is like a computer program, but, but here's a single molecule which has a, you know, it's linear like, you know, computer tape or. Actually, most programs are written linearly historically. But anyway, you'll, you'll, you'll go along the tape until you find the start, start signal, which will be a start codon of three letters, A, T, G. And then you'll take the next one and it'll. What you've, you've now started. And then the next one, you know, might be aaa, which is lysine, and the next one after that might be ggg, which is glycine.

And they, and you just add them on and there's a machine that does this. And if you had to pick something that is the secret of life, I would say it's a ribosome. It's this machine that does this decoding of this single molecule, linear tape, metaphorically. And it goes along and it keeps adding amino acids. And so you're converting from a simple, kind of a simple information molecule, which is DNA and rna, into a folded molecule that has catalysis and sort of architectural features to it, regulatory features that the typical linear DNA doesn't have. You want to keep those functions separate, just like you want to keep the computer codes separate from the, the bulldozer or the manufacturing process that it regulates. So anyway, the ribosome is amazing. It takes single molecules of RNA and turns them into single molecules of protein.

And it does that trillions of times per square millimeter per minute.

Towards the end of the book, you talk about storing it, encrypting it, and all the attendant concerns that you might have with making a book out of DNA. I think DNA is, is unique. Certainly a lot of people talk about. I heard David Reich speak again a couple weeks ago at the Simons Foundation. You know, it's always analogized that, you know, DNA is the software, but. And Then, you know, the, the cells, the hardware, et cetera. But, but DNA and rna, especially, as past guest Thomas Check has pointed out, you know, they are software, but they're also hardware. So I always find the analogy kind of breaks down.

But, but what do you think about, you know, the replacement of the physical world, which, which has not yet happened. We do have proposals by my friend David Spergel and others to make dark matter detectors out of DNA sequencing kits for various reasons. But can we replace hard drives? Could we eventually have this podcast hosted not on Riverside, but on, you know, DNA fm? What are the prospects for using, you know, this magical substance that is hardware and software like proper properties? Is it truly unique and what possibilities beyond writing your book in DNA is possible beyond that?

Right. So yeah, the book that I held up earlier, we did encode an early draft of it into DNA and made 70 billion copies of it, which is some kind of record. And you beat God, you know, in.

Terms of book sales. If you can sell each one of them, you'll beat the Bible.

Right. And, you know, the industry kind of got inspired by this and there's now a worldwide consortium that's, that's trying to push this because it has certain key properties that are good and some that are not so good. So the good things is that it lasts a long time. So our record for DNA storage is over a million years and our record for disk drives is decades. It also is easy to make copies. It's very compact. It's like millions of times more compact than most storage media. And it's easy to make copies.

You can make 70 billion copies. We made for a few pennies that, you know, even if you, yeah, even if you had a market for 70 billion books, you would have trouble manufacturing it for pennies. So the downsides are it's not fast. I mean, to the extent that it's cheap and you can do it in parallel, you can make lots of copies of a book. That seems fast, but in fact, if you want to make one, if you want to read one copy of a book, we have limitations on the reading and writing phases of. But the copying phase is really fast, the reading and writing, since we're kind of interfacing with a digital physics based world of data storage, that's the slow part. So one of the things that I think is an interesting application of it is in, is leaving the physics and digital world out and just recording in a biological world so you can record all sorts of physiological data in an, in an animal or a human. And Then human cells, and then you can take, then you can store that in wherever it was recorded.

So every cell in, let's say a mouse has its own recording device and records lots of, you know, you know, gigabytes of data. The whole mouse then can encode an exabyte of Data that's say 10 to the 18th bytes of data. And, and it's very intuitive, that is to say the recording of events that's relevant to the heart is in the heart and recording events that are important to the tail are in the tail. And so the three dimensional aspect is record is, is there. And so I, so I think that, and you don't need to read it all at once. You can just. Only when something goes wrong do you read it. And so it's analogous to a flight recorder in a plane or a camera that you, a surveillance camera in a bank or something like that.

Most of those things they just store them for a while and then they recycle them. But if something bad happens, then they'll go through it in great detail. So I think that kind of, it's kind of like a living camcorder that's just taking lots of data in and then, and then the slowness of writing is replaced by, because it's biological, it's just as fast as you need. And then the reading is compensated for the fact that you only read it rarely. So I think that's an interesting combination. But most of the industry right now is just trying to compete with disk drives, as far as I know, and I think that's challenging.

Yeah, even the dark matter detector is sort of curious, but may not ever have any real scalability. And despite the trillions of dollars that have gone into sequencing and so forth and, you know, soon I want to get to our favorite topic around the water cooler these days and maybe the watering hole, the woolly mammoth, the dire wolf and creatures like that, perhaps from people's nightmares. But I have a couple more lightning round questions from my audience, if you don't mind. Which film, in your opinion, gets genetics hilariously wrong?

You know, maybe I, maybe I've been too selective. You know, I think movies like Gattaca and Jurassic park are actually pretty, pretty good. You can pick little nitpick things, but I wouldn't say they're hilarious, for example. I mean, one example that shows how it's, it's somewhat amusing, but it's not. They, they had a thing called a lysine contingency in Jurassic park where if the animal, if the dinosaurs escaped, I Don't think I have to prep this audience for 20 years old, almost 35. If the dinosaurs escape, then they, they have a dependency on lysine, which is one of the amino acids they were talking about in the genetic code and they, and they'll starve. Effectively nutritionally deficient. The problem with that is that every food on the planet has lysine in it.

Plenty of it too. It has 20amino acids and lysine is one of them. And it's fine. So what we did, we did eventually implement a real world version of this. Again, science fiction turns into science fact. We made a version of that which instead of lysine uses a different amino acid. We call it bip A doesn't really matter. It's a, it's one that's only chemically made.

It's only, you can only make it in chemistry labs. It's not made in nature. So in that case, if they did escape, then they would run out of bipay and they would, they would do, they would, they would die. So, and this is important for biocontainment, not just for bio containing dinosaurs, but for biocontaining. Let's say you want to clean up an oil spill with a, with a new bacterium and you're not really sure, you know, not sure you want to release that bacterium on the world forever, but you want to release it on the oil spill. Then you want to bio contain it. So, so that's, that's, maybe you, maybe you have a favorite one. Do you think is hilariously wrong.

And I could address that. I've got plenty in physics and astronomy. You know, anytime there's a multiverse or a wormhole, you know, that, that'll always trigger my, my annoyance. But, but you know, they do a decent job. Yeah, I mean a Jurassic park you quote from, you know, quite with, with high praise in the book. And I think it was like a, a great movie. I mean I can't vouch for the, you know, the ninth sequel that, that's coming out this, this next, next month.

I hear it's really great.

Anything with Scarlett Johansson, you know, can't be bad. Tell me George, is it possible, you know, as an extrapolation of what you wrote in Regenesis, very presciently almost, you know, 12, 13 years ago now and it was, was written what, what is it going to be the case that we're going to set out to produce unintentionally or, or not a, a hierarchy, a caste system where, you know, billionaires will live 50% longer than ordinary thousand heirs like, like me. How will that pan out in your opinion?

I think I have consistently felt that this is negotiable. This is something where we, where as scientists, if we choose to make it inexpensive, we can and we have. Almost everything that I've worked on, we've brought down the price by 20 million fold, for example, for reading and writing DNA. And I think that will also be true for gene therapies. And gene therapies are a very, look like a very viable way of dealing with age related diseases. So for example, vaccines are now being formulated in a formulation of gene therapy where you have a wrapper that allows you to target particular tissues and then you have a single gene in the middle. And that's been tested now on 6.5 billion people successfully for the COVID vaccine, for example. So I think, and that's on the order of $20 a dose.

So there are examples of gene therapies that are not just for the rich. They were affordable for essentially the whole population. And so I think that the main thing that made that inexpensive was the, the large marketplace. In other words, you have a fixed amount of money you're going to spend on research and clinical trials and then you divide that by the denominator, which is the number of people that will benefit. And if 6 billion people are going to benefit, then you can get it down to $30 a dose. And I think the same thing is true of aging. Essentially all of us are going to die of aging, 90% of us. And so that can be brought down to a similar price range.

So I'm working hard to make sure it's not just the super rich or even the moderately rich that benefit. I want everybody to benefit. I think it's within the capability of synthetic biologists to do exactly that.

So I want to go from shallow layperson level to beyond Nobel prize winner level here with a discussion about these induced pluripotent stem cells. And I want to first start off with people that aren't so familiar with what are they and how do they allow, you know, the turning of, you know, skin cells or umbilical cord blood as they guilted me into with my, with my youngest kids, you know, freezing this stuff, you know, for who knows how much money I'm still paying off along with my college loans. What are these things and what can they be used for at a layperson level?

Right. So stem cells have things in common with the earliest embryonic cells. I worked on this in the 80s with Gail Martin, who was One of the pioneers in this field. And they can differentiate into every cell in your body. They do in every baby, every embryo, every fetus grows and develops. And they also replenish. Some parts of your body have stem cells built into them. So if something gets damaged, they will use the stem cells to repair it.

It's not the only repair process, but it's a very powerful one. We've harnessed them since the mid 2000s. We've harnessed them into making cell therapies and even, you know, for a variety of different diseases. And these are making their way into clinical trials. The very first two came from spin offs from my lab. One of them is that's already in phase three. So there's phase one, two and three are the stages that you have to get through to have a therapeutic approved by the FDA for general use. So phase three is the last phase.

And the first stem cell derived therapy to do that is, is granulosa cells that are used in IVF clinics now. So another one that's coming along that's in phase one has to do with autoimmune disease using natural parts of your immune system. But these can be engineered the same way. We were talking about making bacterial cells resistant to all viruses. You can do almost anything to these stem cells. And then from that you can make any cell in the body, in principle, all cells of the body. We use the stem cells sometimes to make whole organisms like mouse or pig or so forth.

Could you in principle use them in some vast 3D printer to make mirror humans? And maybe you could describe what a mirror human is first of all, and then whether or not a stem cell from a, a non mirror human. I don't know what that means. An ordinary human could be used to make a mirror image of that, of that organism's DNA.

Yeah. So, I mean, it would be very challenging to make even a mirror ribosome, the hero that I talked about earlier, much less a bacterial cell, much less a human, but they all have the same principle, which is that your right and your left hand look a lot alike, but they're not directly superimposable. They're, you know, when they, when you line them up, they're actually backwards. They're from each other. You put it up against a mirror, then you can, you can see what, what's meant by mirror. And this happens not just at the level of your hands, but the level of molecules. You have molecules which are mirror images of one another. And they can't just interconvert by rotation.

They have all to make one into the other, you'd have to break a bond and reform it. So those mirror. So all of life has a particular mirror form. So the helixes, the helixes of proteins and DNA are all right handed as say they screw like this. If you could make, and we can make mirror images of, of the DNA and some of the proteins and the proteins that you can even get mirror image proteins to make copies of mirror image DNA. But no one has yet made a cell that has all of its molecules mirror image. And part of that is we wrote a co author on a paper that warned about this is probably not a good thing to do in that it could be misused. It's probably quite safe if there were no evil people in the world.

But it's just like jets are generally safe if you don't run them into buildings. So anyway, the advantages of mere molecules, not necessarily replicating cells is that you can make things that are more stable in the environment, things that don't rotate in the environment, things that don't get degraded inside your body so you can make medicines that last longer, things like that. And so I think there's considerable enthusiasm for making mirror molecules and there's low enthusiasm for making mirror image, you know, bacteria or fungus or. And for humans that's off the table ethically for now. I mean ethics does change as we get comfortable with technology. But right now we don't want to, we're not, don't want to make genetically engineered humans in the germline, meaning via babies, but we routinely make genetically engineered humans in the soma in the body that's not inherited and that's what gene therapy is all about.

Last question before we move on to talking about the mammoth in the room. And I guess this question will really revolve around the risks as you talk a lot in the book about risks and how we've overcome them and how ludatism has never really worked. But recently we learned about the bankruptcy of 23andMe and that I was now in receivership. And supposedly the Wojcicki foundation is gonna take it over. But there was a lot of concern for people like me. And luckily I didn't, you know, go too deep into cataloging everything in my life. But, but I did subscribe to that. And you know, you also have had even more, you put, you know, your whole genome is online, I believe.

Are you worried about, you know, targeted super villains and the ethics of, of having these data, you know, from billions, I mean literally Facebook's had billions of you know, of people's personal information, passwords leaked. I mean, what happens when, you know, they, they buy up your genome or something like that? I mean, could they make targeted superweapons to just, you know, the anti church missile? And that would be the ultimate, you know, kind of terrifying bioweapon evolution of this massive revolution that genetics have, has brought on. So you obviously weren't worried, you know, 12 years ago, would you do it today?

Yeah, my genome is still available, along with medical records. To make it useful, we have a project that's intended to make packages that represents individuals so you can develop software that a physician would use. Physician has to see the whole individual. I worry about everything. I worry about technology and usually accompany each new technology we develop with a prior paper on safety considerations, not just in the book, but academic papers. And when we found companies, we try to have safety be one of the founding principles. In this case. If you are concerned about the privacy of your genome, your problem isn't so much whether it's posted on Facebook or not.

The problem is that you're dropping your DNA all over the place every day. So the only way you could keep your DNA truly private, now that it's getting dirt cheap to sequence it, you could just pick up somebody's coffee cup or their dandruff or something and sequence it. You would have to stay in your house or completely seal yourself in a moon suit or something, which is not practical. That said, if you want to assassinate somebody, there's a lot easier than building a personalized weapon because most people have so much, they have a lot more in common than they have different. And to make something that would only work on one person would be challenging. I'm not saying it's impossible.

Yeah, I mean, it depends on who the person is.

Just easier to shoot them or poison them or, you know, there's a variety of ways. So I, I'm not recommending that anybody kill anybody ever. But certainly I think it's unlikely that, that you would go through this exotic method. And if you, and if you did, it would be hard to. If that developed as a technology, it would be hard to protect yourself just by keeping your data private. You would also have to keep your, your pieces of your body also private.

All right, so here we go. When you set out to bring the dire wolf and the woolly mammoth back to life, or in some sense resurrect them, regenerate them, de extinc them, as you call it, what was the single most unexpected roadblock that you hit? And how did cutting edge gene editing actually help you push past that obstacle?

Right. Well, some of this was de risks by the work that we did in pigs. So we had to make 69 edits to the pig in order to make it safe and effective for transplant in the humans with kidney failure, heart, liver. And so that gave us some experience. You need to make a lot of edits to, to, to get key to de extinct multiple genes. So we're not talking about de extincting species so much as genes to help increase the diversity of, you know, of modern species that are endangered. So a lot of, you know, a lot of endangered species have gone through population bottlenecks where, you know, because their environment has been crisscrossed by pipelines and highways and things like that, so their population has become inbred and hence less adapted. Also their environment has changed.

So anyway, we're trying to make, give endangered species some superpowers like resistance to killer herpes viruses that are, you know, part of the reason they're endangered species, to make them cold tolerant so they can huddle, you know, now have suddenly millions of square kilometers of space that's far away from poachers and from humans in general, but, but, but full of plenty of, of, you know, delightful plants that herbivores like. So the surprising roadblocks that you asked about would be, I think one of them is that when you're working with endangered species, the rules that you have to follow, and we do, and we respect them, but that slows things down a little bit. I wouldn't say it was unexpected. We want to eventually make possibly thousands of changes in the genome. And we're still for most purposes stuck in the low numbers for bacterial genome engineering. We've synthesized the whole genome. And so in principle, we could have changed the whole genome, but the more you change, the more debugging you have to do. So in the tens of thousands is a reasonable number edits, whether they're made by editing or whether they're made by genome synthesis.

But that's changing. I think it's changing. These are all exponential. They're going faster and faster. So I think it won't be long before we're not only synthesizing microbes, we're also synthesizing mammalian genomes accurately. And then, but we've overcome it by, you know, we're really trying to make the species healthier and to improve the environment, which means we're actually not trying to make an identical copy to something this long ago. We're using the old genes to help the new ones. We're trying to make things that fit a particular environment and that's, you know, we're getting better and better at it.

You know, I don't think we're were perfect but we can test, you can test things out with easy organisms like mice. So we made a woolly mouse that had a lot of the features that we wanted to have in terms of cold tolerance like make cold tolerant elephants so they have their new home and possible they can help the environment. And then dogs and wolves are also easy, not quite as easy as mice to engineer but, but relatively easy. And, and many ecologists will claim that, that you need a major, you know, you need to major predator is a keystone species in any environment. You know, as, as occurred in, in Yellowstone. We did an experiment where we removed the wolves, returned them back. It's not a simple story but it is, it is an instructive one anyway. So those are some of the, the roadblocks and surprises that we've overcome.

The main question I have now is the possibility of virus proofing humans. Is it possible to virus proof a human? And then concomitantly on the other side living well, living longer. Can we reverse aging using gene therapy?

Right. So I think gene therapy is only recently become, you know, come into something that, that looks like a very reasonable medicine. It's been used for, you know, saving millions of people via vaccines. It's, it's, it's saving individual people. You can make it n of 1 a highly designed gene therapy that just happened thanks to Kieran Musunuro and his team at Penn where within just a few months you could go from kid being born, sequenced and cured. So for gene therapy for viruses, we've shown that we can make virus resistant cells. We've got to upgrade that to human cells and then got to deliver those human cells to enough parts of the human body to make it virus resistant. It depends on the kind of virus.

So if it's something like HIV that just infects T cells, that's relatively easy to replace our T cells either by gene therapy or by cell therapy. If there's a virus that can affect every cell in your body, that would be quite challenging to do it by cell replacement, but not out of the question. I'm not going to say impossible for age related diseases. I think we're entering a golden era where a lot of information is turning into practical therapies and preventatives. We have a couple of things going into clinical trials now at Rejuvenate Bio that look incredibly promising. The gene therapy is once and done, so you don't have to be paying for it for the rest of your life. And we've seen that gene therapies can get into the $30 range, probably more, at least initially, until the full population can use it. And that's because we have learned a lot about the components of aging, the things that are deep underneath almost all diseases, almost all forms of death.

We can now get at the core of those and even reverse them at a cellular level, so called this. You can make stem cells from, from fairly old cells that are not stem cells. And we can do that in the body as well. So and we can extend life in preclinical animal trials. So I think we're going to have very interesting near future for genome engineering for with respect to infectious diseases and age related diseases.

Very rapid question. Arthur C. Clarke, who's the namesake not only of this podcast, but of all podcasts. I don't know if you knew that, but the word podcast comes from the ipod, which comes from the pod bay doors, which is in the background over here on my wall. So Arthur said many things, including the only way to know the limits of the possible is to go beyond them into the impossible, which is the namesake of this partner and the aim of this podcast. But I want to ask you a different take very quickly. You might not be familiar with another quote that Arthur said, which is that when a distinguished scientist says something is possible, he's very much likely to be right. When he says something is impossible, he is likely to be wrong.

I want to ask you, what have you been wrong about? Is there anything, you're so prolific, so generative, just incredible mind, have you been wrong about anything? Or what would your critics say if pressed to do so?

I'd like to believe I'm one of my best critics. And I try not to say something's impossible. I'm just very disciplined about that. When you tell or even say that it's a bad idea, you do have to prioritize a little bit. But with my students, I try to say, well, this is maybe a more promising direction. But I think what I've been wrong, even though I'm. I've become a fairly good communicator of science, I think early on and even, maybe even to this day, if somebody asks a question just the right way, I will give an optimistic answer like how long will it take? Is the worst question. And most my colleagues like to dodge that question.

I try not to dodge any question, but occasionally I'll say something, you know, where I've got all the caveats in my mind, but I'm not articulating them, right? Like, how long would it take to do this? Well, it takes two years to birth an elephant. Okay, that's true. It's 22 months. And that's true. But then taken out of context, it's like, well, that's how long it takes to complete this project, you know, and. Or I'll actually believe that it might take two to 10 years, and it actually takes a little bit more. I remember somebody was. Was a critic was saying, you know, he's been saying that you have pig organs in people any day now, you know, and there.

I don't see any pig organs in people now. I can say, okay, there's. There's one survivor of six months now, and he's. He's happy and enjoying his life. So, you know what? Okay, so maybe I was off by a year in a when a project that's been going on since the 1960s. I don't think that's a gigantic sin, but I do plead guilty.

Well, George, thank you so much. This has been a real treat for me.

Okay? Thank you.

The genetic revolution, George Church has accelerated, has made things faster than Moore's Law, and the line between biology and technology is disappearing entirely. If you want to understand where this convergence is heading, check out my episode with Nobel Prize winner Thomas. Check. We explore how AI and other revolutionary tools are making machines that can design medicines better than even humans can. Click here. And don't forget to, like, comment and subscribe.