The Origins Podcast with Lawrence Krauss - Jennifer Doudna: Scientist and World Changer

Episode Date: January 15, 2025

Jennifer Doudna changed the world. She didn’t do it intentionally. She pursued her curiosity about the structure and functioning of RNA as a research scientist, one who had been trained by some of the most impactful geneticists at the time, including two Nobel laureates. In the process, however, she and her collaborators discovered a genetic tool that has dwarfed all others for its potential to change both the human condition, but also what it may mean to be human. I am referring of course to CRISPR, the tool that Jennifer Doudna and Emmanuelle Charpentier helped develop and for which they were awarded the Nobel Prize. In our in-depth conversation we covered the scientific origins of Jennifer’s discoveries, and some of their possible implications. In a time when there is a misplaced notion that support for scientific research needs to be applied directly for certain goal-oriented activities, it is refreshing to have such a clear example of the benefits of fundamental research for our society, along with the need to prepare our minds for the possibilities of the future. It is exactly what the Origins Podcast, and the Origins Project Foundation are designed to highlight—the joy, benefits, and challenges of human intellectual inquiry for our society and our future. It was a pleasure and privilege to spend 90 minutes discussing these issues with this world-renowned biochemist and advocate for science. Our conversation was both a tutorial about modern genetics, and also an opportunity to discuss issues that society as a whole will have address as we come to grips with the new power of science in this century. With great power comes great responsibility, and I hope discussions such as the one I had with Jennifer will provoke and enlighten. Enjoy. As always, an ad-free video version of this podcast is also available to paid Critical Mass subscribers. Your subscriptions support the non-profit Origins Project Foundation, which produces the podcast. The audio version is available free on the Critical Mass site and on all podcast sites, and the video version will also be available on the Origins Project YouTube. Get full access to Critical Mass at lawrencekrauss.substack.com/subscribe

Hi, and welcome to the Origins Podcast. I'm your host, Lawrence Krause. In this episode, I had the long-awaited pleasure, finally, of having Jennifer Dowdna on the program. Jennifer won the Nobel Prize, along with Emmanuel Sharpentier, for discovering CRISPR, a technique of gene editing technique that's revolutionizing biology and offers the promise of being able to edit the human genome in ways that can cure disease and potentially do some things that. might sound dangerous like great designer babies. It's an important tool and it's changing not just biology but the way we may think about ourselves as human beings and it's therefore important for society and in order to understand it, it's important to understand the science. So what I wanted to do with Jennifer was talk about her own experience of discovery, which was based on curiosity-driven

research and not an effort to actually solve the problem of how to add the human genome, but also involved serendipity, many aspects of science that are really important. So I wanted to use her discoveries in microcosm to understand science and then to discuss the background behind the important questions that the important ethical questions that CRISPR raises. And we had a wonderful discussion of an explanation of biology, of CRISPR and her own experiences, both in the lab and outside the lab. It was fascinating for me. I knew it would be. It was a wonderful discussion and she was great. And I think you'll find this educational and also thought-provoking because CRISPR opens up the possibility of changing what it means to be human. And the Origins podcast is all

about bringing you closer to these discoveries that affect the challenge that produce the challenges of the 21st century. And the only way we as a society can address those challenges is by understanding and communicating the fundamental science. And this, in my mind, was just a perfect example of that. And I hope you enjoy it as much as I did. You can watch it ad-free on our substack site, Critical Mass. Or you can, and if you, if you subscribe to that site, you will support the Origins Project Foundation, our nonprofit foundation that produces the podcast. Or you can watch it on our YouTube channel. And if you do, I hope you'll subscribe to our YouTube channel, or you can listen to it on any podcast listing site.

No matter how you watch or listen to it, I think you find this discussion with Jennifer Dowdna, this great scientist, talking about a great discovery, remarkable, as remarkable as I did. So with no further ado, Jennifer Dowdna. Well, Jennifer Dowdna, thank you so much for coming on. I've wanted to have you on for a long time. Obviously, I've admired your work, and it's really nice to connect, if at least virtually. you're being here. It's a pleasure to be here. And I want to, and we'll go a deep dive into the remarkable science that you've been involved in and its implications, but this is the Origins

podcast. And what I like to do is really begin by finding how people got to where they are, to the point of why we're talking about what they're doing. And I do know some aspects of your childhood, which you talk about in the book you wrote, that Cracking Creation and some other research I've done, but I want to go into it a little further. Clearly, it's clear that your father had a big influence on you, that you mentioned two things that I can remember. One, giving you Jim Watson's book when you were 12, I think, and the other was connecting you. He's a professor of, what was he a professor of again? American literature. And in spite of being a professor of American literature, He didn't seem to mind you were going to science, but when you were a fresh person,

he got you a summer job in a lab, and that hooked you up. So he knew, given the Watson's book, he must have known you like science. Where did your, where did your interest in science get kindled? Was it through discussions with him or anything else or reading or TV? Well, I grew up in an interesting place. I grew up in Hawaii, but not in the fancy Hawaii. I grew up on the big island in a town called Hilo. It's very rainy, very beautiful.

It's kind of a working class town. It has a branch of the University of Hawaii campus on it. And that's why my father was there, because he was a professor at that branch campus. And I had the opportunity to experience that culture, to explore the island. and all of the fascinating biology there. But I also, you know, my father was a professor of literature,

and so our household was quite intellectual in the sense that there were always discussions going on about all kinds of topics. My dad was an avid reader. He read everything, as far as I could tell. There wasn't really a topic he wasn't interested in. And so he was always reading things, and he would often, you know, toss books my way. and I think it was partly just to see what took. And so with the Jim Watson book,

it actually took me a little time to pick it up. I'm embarrassed to say. But once I did, I couldn't put it down. You know, I was really fascinated. And I think that was something that, you know, my father noticed and realized that, you know, I had a real interest in science. Now, clearly he was a big reader.

Were you a big reader too? Did you like to read everything? I noticed you first thought Jim Watson's book was a, mystery story, which it sort of is, did you read literature primarily, or did you read popular science other than that book? Yeah, I did read a lot. I did. Everybody has to recognize this was before the internet. It was before TikTok. It was before any of that. When I tell my son this, he's shocked. The world existed before those things. But yeah, and so, and being in a small town, you know, we didn't have a lot of entertainment. So, yeah, I did a lot of reading.

I read, yeah, pretty much everything. I read westerns. I read histories. I read a lot of fiction. I read young adult fiction. I did, to be honest, I did not read a lot of science fiction. But when I did read science fiction, I read the classics. You know, I read Arthur C. Clark and, you know, Ursula Le Guin.

And I read things like that. So I really enjoyed stories and nonfiction that featured. that featured people doing interesting things. Absolutely. You know, well, one of my books is called The Physics of Star Trek, I wrote many years ago, which became very popular. But everyone thinks I'm therefore fascinated with science fiction. But I used to read it when I was a kid.

But until I got to the point where I realized that science was much more fascinating than science fiction, and then I switched over. So I know about your father, but what about your mother? I don't know much about her influence and what she did. So why don't you tell me? She was a lecturer in Asian history. So she was a history buff. And she was, you know, originally kind of a homemaker, I would say, in our, when we were really little kids.

But after we moved to Hawaii, she started teaching at the local community college. And she got fascinated by, with Asian history. And so she ended up going back to school in her 40s. And she got in Asian. history got a teaching degree. And then that's what she taught for the rest of her career. So interesting. She wasn't one of the one, she went back to her school in the 40s. It wasn't one of those things that where she graduated around the same time you did or anything like that. Were you and your... Actually, it probably was, actually. Yeah, I think it was. I had already

left home. I think I was maybe in college. And yeah, we probably did graduate around the same time. Interesting. Interesting. It probably meant a lot to her that you did. So, as you say, you didn't read science fiction. You read science books. But now I want to ask the important question, and I always have to ask people. Why biology and not physics? That's a great question.

Actually, it's a great question. I think, well, it actually, I have to tell you that initially it was neither. It was chemistry. Chemistry. I was really interested in chemistry. I had a great chemistry teacher in high school. That is such a rare thing because if you look at high schools, among the worst teachers, it always seems to be chemistry teachers.

Chemistry? No, ours was great. Miss Wong was her name. And she was someone who really emphasized discovery and experiments. And it was the first time that I had this concept that science was not about memorizing a bunch of facts. It was actually about figuring things out. And I always loved solving puzzles. That was another thing we used to do in our house.

a lot was we always had a jigsaw puzzle going. We were always working on crosswords and, you know, solving other kinds of game, work game kinds of things. And so for me, realizing that science was figuring out the answer to puzzles was, was great. Solving puzzles. Yeah. Yeah, no, and it's interesting you say it wasn't memorizing. It's the first time. I want to ask you about this because a, a, Leon Letterman, who was a friend and colleague in mine, Nobel Presumini physicist, and I have worked a lot to try and change the way science has taught, because schools tend to teach science biology first, then chemistry, and then physics. And we argued it's the exact wrong order, because physics is the basis of chemistry,

chemistry is the base of biology. And we know the reason they do it. I mean, biology seems friendlier and touch-feely stuff. But it does give you the impression because, you know, at these concepts that you're just told exist and that you sort of have to memorize it, whereas if you learned it the other way around, you'd realize, you know, where it came from. Have you thought about that much at all? I think you have a good point there, honestly.

It actually does make a lot more sense to teach it in that order, but somehow they don't. And actually, that was true in college too. Yeah, but it was the same thing. We tended to, you know, study the more touchy-feely science first and then get into the hard stuff later. Yeah, I mean, obviously the reason is they somehow think math is the scary part and there's not as much math in biology at the beginning. And unfortunately, though, because the way things work now, a lot of, because it's taught in that order, people, you know, they take their electives. And so they take their first science, they have to take biology. Most of them never get around, maybe even to chemistry or much less physics at all.

It's true. Yeah, I know. It's too bad. Now, so that's interesting. I think that, well, the chemistry, well, you became a biochemist, so you, you, chemistry remained your primary interest. So did you, did you, did you, you got turned on to chemistry? When you went to college, did you know you wanted to do chemistry first, or did you, how to,

actually, I knew I wanted to do biochemistry. You did? Yeah, because in high school, I, well, in high school, I had just, you know, I, yeah, I loved chemistry, but I realized that what I was really excited about was learning about the chemistry of life. And that did kind of start with the Watson book, but it continued to thinking about the chemistry of cells and all kinds of questions that come up when you start to really dig in. And we also had a series of scientists that came in from around the state of Hawaii to talk to our high school class. and one of them was a biochemist who explained that she was studying how cancer cells grow

and why normal cells become cancer. And I thought that that's so interesting. I want to work on that. Oh, that's, okay, that's great. Yeah, well, that's, I mean, and getting exposure to things like that is really important. You know, there are many things I, I don't much sure I regret, but my mother wanted me be a doctor. and for many reasons my brother, a lawyer, he became a lawyer. But she told me doctors were scientists and I got interested in science

and discovered in high school that maybe doctors weren't scientists. But the big point was I dropped biology because when I took it, I'm a little bit older than you, maybe a decade or so. It was where I was taught, it was just memorizing. It was just like memorizing the parts of a frog. Because the chemistry of life hadn't yet permeated, this was in the 60s, and that explosion, that fascination, which I've had to learn after the fact, wasn't there. But I can, you know, it's just amazing. I mean, it's just amazing how things change.

And it's also satisfying because, in a way, because the fields of like physics and biology emerged in many ways, because in so many ways, and they're not so different, but they used to be. So you knew you wanted to biochemistry. You went to Pomona. Is that just because you wanted to stay in California? Or you were, you were in Hawaii because you didn't want to go too far east or was it a liberal arts college aspect? Yeah, my parents really wanted me to go to a liberal arts college. They were both Oberlin College graduates.

I taught Ohio. No. I was a chair of the fitness department of case Western for a while. So I know what that. I mean, it's a great school that I thought. Ohio, yeah, I know. So far from Hawaii and a little bit cold in the wintertime, a little flat. So I ended up looking for opportunities elsewhere.

And we had family friends who had also attended Pomona. And they told me that Pomona had a wonderful science program. So I looked into it. And actually, it was very interesting because Pomona at that time, this was in the early 80s, they had one of the only undergraduate biochemistry professors. that I could find at a college like that. It was a relatively new discipline. And so most colleges had people who were strictly biologists or chemists,

but not somebody doing both. So that was very exciting for me. Oh, yeah, it's really important, you know. And, you know, kids often ask me where to go. And generally I say that, you know, it doesn't even matter where you go. You can get a great education anywhere. And, you know, go to a place where you're challenged by other students if you can find a place like that.

And generally get to know professors. And if you do well, you can go to the best graduate schools. I mean, I went to a small college, and then I went to MIT. You went to a small college, then you went to Harvard. And it's a great way to get excited if you can work with the professor. Now, you did your, you worked that summer in a lab in Hawaii that your father got you hooked up to. And that was the first time you sort of got that joy of discovery, which we'll talk about it later, I think. But did you, were you able to work in labs as an undergraduate at Pomona?

I certainly did. Yeah, I did from the very beginning. I worked in several different labs. I did some interesting things. I washed dishes. Yeah, of course. That wasn't so interesting. Actually, it was kind of fun. I washed dishes. And I also worked in an orchid lab, a lab that was studying how viral infections occur in orchids and how to prevent them. I worked in a lab that was studying how muscle cells contract and we were working in mice. So we were working in mouse tissue. And then I landed in my biochemistry professor's lab where I was studying soil bacteria. So quite a range.

Okay. Yeah, now that is quite a range. Now, what, I mean, other than reputation, did you choose Harvard because, I mean, did you know about Jack Shostack or did you just choose it because of the department? and okay. Yeah, and my undergraduate professors told me that, you know, that they thought that program was really strong. You know, it was interesting because I didn't apply very many places. I think I only applied to three or four graduate schools, which, you know, nowadays

sounds kind of crazy. But I couldn't, you know, you had to pay, I don't know, $70 per application. I didn't have a lot of money. My parents didn't have much. And so I couldn't afford. to apply to 10 or 15 or 20 places. And furthermore, I guess I, you know, I sort of imagined that I might end up at my father's alma mater, which was the University of Michigan at Ann Arbor. Oh, okay. So I applied there. I also applied to Penn. And then kind of on a lark thinking

I'll never get in, but, you know, what the heck, I threw in an application at Harvard. I was very surprised when I got accepted. Yeah, no, yeah. Well, I grew up in Canada. I didn't know about the American system. I also only applied to a few. And, yeah, and didn't get into any except for MIT, but that was okay. Not too shabby. Yeah, it was okay. It worked out. Okay. And then, and then true serendipity, which is a story of many things that we'll get to in terms of the science you discovered, the term serendipity just coming up in my mind as I was reading about your work. you ended, you, you, you end up working with Jack Shostack, which was a, which turned out to be a really, was that again, did you choose that area or was it just, I mean, I know what it's like for graduate students. Sometimes you just end up in, in, in, and you luck out. But did you, were you for, beginning to focus? Jack had already moved to the origin of life at that point or daddy. Actually, he, he was kind of in transition. So he was, you know, he was, you know, he was, uh, known to all of us graduate students as a kind of a young, prodigy type, you know, professors. Very young is very smart, doing really interesting work.

He was at that time working on how DNA molecules in cells recombine. Because we know that, you know, when cells divide, and this is, of course, very important for inheritance, chromosomes will recombine. And, you know, they kind of make up an amalgam of, you know, genes from mom and dad. And then that's how traits get passed along and how the species is able to ensure that there's enough diversity that you can avoid deleterious mutations and things like that. So he was fascinated by those kinds of questions.

And he was studying this process in yeast, so in a fungus, yeast cells, actually using the kind of yeast that bakers and brewers use. And so I went to his laboratory to, learn a little bit about working with yeast, which I had never done before. And when I got there, he said, actually, I've gotten very interested in the origin of life. And I want to, you know, I want to start researching this. And I have some ideas. And would you like to be the first student to move in this new direction? And I said, sure. And it was great because, you know, he was very,

very excited about this. He was reading a lot about it. It was an exciting time in the field when there were some new discoveries coming along that we could act on. So it was a great decision, but, you know, it was quite serendipitous, to be honest. Yeah, no. And was the yeast, with the experiments on yeast, is that what he won the Nobel Prize for later on? Well, not exactly. Let's see. Not exactly. He actually, but it was sort of related in a way because what he won the Nobel Prize for was for how the ends of chromosomes are maintained. And it turns out that in yeast, the chromosomes are, you know, the chromosomes are somewhat, unique. But he was studying how chromosomes are maintained and other kinds of organisms that are

a little bit more similar to the way human chromosomes are copied. And that was the work that was recognized for his Nobel Prize. Now, he'd gotten interested in the origin of life. At that point, had Czech and all minorities sort of discovered what led to the RNA world, that RNA is both a work that you later got involved in, essentially, that RNA is both a genetic coder and also an enzyme or at least her catalyst. Yeah, they had. They had just published that work when I arrived in Shostack's lab. And in fact, this is what Shostak was so excited about, like, you know, sort of pursuing so my ideas that came out of that because it was a time in the field when it was very new to think about the way that a certain kind of molecule, in this case, RNA, could have been the primordial

molecule that allowed life to get started. And this was the idea that he really wanted to explore. Yeah, no, that's when focus went from DNA, which had been since Watson and Craig had and the big thing, to suddenly RNA becoming of interest. And RNA in one way or another has been a great focus of your career. And we'll go into that. I want to, I want to, we're going to do some biology lessons. So I want everyone to be up on the same page before we talk about CRISPR. And then the consequences.

And we'll try to do it in less than a full term. But I was intrigued. it's probably worth mentioning. You know, you start the book in a sense talking about this case, Kim, who had had a disease and basically was spontaneously cured. You want to just talk

about that for a second? Or a minute. Yeah, I mean, I think you know, what's fascinating is that when people have studied genetic diseases, it's often been through investigating rare cases that we've made

fundamental discoveries. And That includes finding genes that are causal for disease, and there are probably about 7,000 genes that, or diseases in humans, you know, where there's kind of a clear, no single genetic basis for it. And then occasionally, there are spontaneous cures that happen because of sometimes this process that we just mentioned, DNA recombination, where DNA molecules will, recombine in such a way that the mutated gene is corrected or removed. Just amazing.

And it's those kind of, you know, initially before, you know, before it was possible to do anything fancy in human cells, you could observe these cases rarely in the human population and draw inferences about what genetics were for a particular disease. And interesting. And it's basically, you know, it's the story of control versus evolution in the sense that that yeah, by recombination by accident, you might, you might cure something. And the idea is, can we, can we learn from that and maybe make it happen in a controlled way, which is really what your CRISPR discovery allows us to do. Now, let's just talk biology. So, okay, DNA, four base pairs,

and, and, and they can connect up, GC and AT. And that creates this double helix, okay? But I just want to explain some terms which maybe we'll use later, which is, first of all, transcription. Well, that means making a copy of a gene, which is originally in the form of DNA, and copying it into a molecule of RNA. Okay. And RNA is like DNA except two of the base pairs are different, but it can hook up to DNA and transmit that genetic information because it has the same, it has the same a series of letters. Chemical structure. Okay, translation. Translation means making a protein.

And the way that that happens in biology is that there's a code that is originally in genes in DNA. That code is copied into an RNA molecule, as we just said, by transcription. And then that RNA can be translated, meaning that there's a machinery in the the cell that will read the genetic code in the RNA and link together the components necessary to make a particular protein. So proteins, probably people know are made of amino acids. And so what the code does is it tells the machinery which order and which amino acids to hook together to make a particular kind of protein. It's a very, very incredible process. It is really an incredible process.

You know, you'd almost think there was intelligent design if you didn't know better, which we do. It is amazing. Three, you know, these codons, three letters turn into an amino instruction making amino acids. And then one uses one of these, what, 21, 20, how many amino acids are used? How about 20? Yeah, 20. Yeah, 20. Maybe in 21, you know, a couple of rare ones.

Okay. And then just for just since we'll talk about the human genome. Yeah, what you're asking me, what is? I'm actually to define these terms just so we, you know, I want to put everyone the same wavelength because I think it's important. It's very important. So what is the human genome? The human genome is the entirety of DNA that's found in a human cell. So it's the code of life. It's the set of instructions that tells cells how to develop into a human being, meaning making our brains and our hearts and our lungs and all our other tissues. And then not only that, but functioning together as a human being, meaning making our brains and our hearts and our lungs and our, you know, all our other tissues. And then not only that, but functioning together as. an organism. It's, again, it's truly incredible that a molecule like that could contain the instructions to build such a thing. It's remarkable indeed. And, and, okay, mitochondrial DNA, which is, which turns out

to be important later on. Right. Well, people might have heard of mitochondria because sometimes you see that mentioned in the news because of things like aging and, you know, what happens or mitochondria when we exercise and things like that. And that's because mitochondria are the little energy factories found in cells. So they are responsible for taking chemical energy in the form of food that we eat, so sugar molecules in particular that go into the mitochondria and they're converted there by a chemical process that turns those, breaks down the sugar molecules into much simpler molecules and allows things like our muscles to function and our brains to think and all of those

good things to happen. But the mitochondrial DNA, which I, the fact that it comes from the mother, maybe you, I just want to. Oh, right. Yeah, no, of course. I mean, the DNA is, is interesting because, like you said, yeah, it's inherited through the mom. And it's, it's a very small instruction set compared to what we find in the rest of the cell. It's an instruction set that is geared mostly towards what we just said, kind of energy harvesting, energy conversion. And it's a, it's a, because it's such an important part of the cell, these mitochondria, when somebody inherits a defective gene from, from mom,

that is a mitochondrial gene, you know, that, that, that can cause disease. So we know there are a number of diseases that are inherited in that fashion. Yeah, and I think it's important what we get later on that, yeah, normally we think of 50% of our genes come from mom, 50% of our genes from dad. And that's in the chromosomes, but there's this little extra bit that just comes from mom and the mitochondria. And mitochondria also, I guess, are important because they're a great example of evolution, right? I guess since the worker Lynn Margolis or maybe others that, you know, that they probably got this function to be able to handle oxygen and generate power by

eating another, you know, basically a symbiotic relationship of eventually combining two entities and making one. The kinds of cells, yeah. They probably came from bacteria originally. Yeah. Yeah. Okay. Last two things.

Recessive genes. Those are the genes that can be superseded if you have a, you know, kind of a good copy of the gene. So just to put that into context, so all of us have in our cell, in all of our cells, except for our egg and sperm cells, we have two copies of every gene. And so you could imagine a situation where somebody inherits a defective copy of a gene from one parent and a, quote, normal copy from the other parent. Well, if that gene is recessive, as you just said, then it might not actually matter for the person in terms of their health, right? It's kind of almost like it's hiding. It's hiding in the cells.

It's, and you don't notice it. You only might notice it if that person goes on to marry someone or have children with somebody who also has a defective copy of the gene and their offspring inherit those two defective copies, right? Then you'd have two copies and you would observe an effect. So it's a, you know, it's kind of a, it's like a, uh, uh, a, uh, a little bit like a Trojan horse in a way. Yeah, it's there, but it doesn't always manifest it.

And then dominant inheritance is the opposite, right? The opposite, right? You have one bad copy? You're in trouble. Yeah, it'll always take over. Okay, I think that's the tools we need probably for the rest. Now, viruses, um, part of the fascinating parts of this story is that, is that, is that, um, what, what is now a tool that's changed.

biology and changes and may change the way we we are as human beings began thinking about viruses and bacteria which is which is wonderful um what a viruses do and also i want to ask you a question do you think viruses are alive i mean i i know they're not but i you know what i i i guess the question is what's life you know and i have one of the chapters in my last book is about that. I mean, they don't have the machinery to reproduce on their own, but they can hijack machinery of a cell to reproduce. And I, you know, it seems to me that's pretty almost, almost likely. They can. And, you know, you bring up an interesting point because I think what's happened is that as we study viruses and cells more and more, and this is a lot of the work of some of the,

some of my colleagues here at the Innovative Genomics Institute are working on this kind of thing. We find that, you know, the lines are blurred in a way, right? So you can find DNA, that seems to belong to a virus, and yet it seems to also encode most of the machinery, but maybe not quite all, that you would need to be self-reproducing, and vice versa. You know, there are cells that are very, very small, and they're very streamlined. They're almost virus-like, except that they do seem to have all of the necessary components for reproduction. So it's a bit of a glory line. But you're right. I mean, people have been fascinated by viruses ever since we've, you know, we've had biologists because they are able to

take over cells and hijack their machinery to produce more viruses. Yeah, no, I mean, it seems to me, it's almost like cuckobards. I mean, it seems to me, like, all they are is a kind of life that's learned how to be more efficient. Why bother having all that extra baggage when you can, when you can, when you can just find a handy cell to do it for you? It's a great solution, yeah. Yeah, it is a great. It's a great solution for life. And I wonder, well, in terms of thinking about life's evolution, that obviously played an important role. Now, viruses obviously edit genes because they go into a cell and they cause it to make more viruses. And there are two types of recombination of after, you know, long

sequences of DNA, they get cut or moved around. There's homologists and illegitimate. I want you to tell me about the two of them. Well, let's start with homologous. Okay. So this means that you have two segments of DNA that are the same, and so they can overlap with each other, and they can allow an exchange reaction to occur that allows one DNA strand to swap into the other or kind of replace the other. And so that's the type of DNA recombination, we call it.

That happens a lot during, for example, you know, after a cell, an egg cell is fertilized and you have cells that are dividing very quickly, those cells are growing and their chromosomes are recombining. And that type of recombination that we just talked about is typically what's going on. whereas illegitimate recombination is... Is where we have a situation where maybe there's, you know, there's often just a very, very small section of DNA that is similar in letter sequence to another piece of DNA, but it leads to a recombination event in any case that maybe

shouldn't have really happened, but does. And this is the kind of thing that, for example, can happen when... when a chromosome breaks due to chemical or even physical damage that happens, and that means that there's a piece of DNA that needs to be repaired, occasionally that repair can happen through this sort of illegitimate recombination process, and sometimes that leads to cancer. This was actually how that type of recombination was originally studied, is that people were investigating what happens to DNA,

and cancer cells. And they noticed that in some cases, it's through this kind of illegitimate recombining that you can form genes that are, you know, cancer causing. Now, you know, I have a question because I was, that it never occurred to me before. I was always reading your book. Illigitimate recombination, you say happens a lot more

than homologous recombination. If that in cells, right, you know, that's sort of random combining. But it occurred to me if that, if that's a much more prevalent process, How come in sexual selection, how come it with eggs and sperm, how come they manage to do this beautiful homologous recombination and not, and not the other? What causes that? Right. Well, let's just define when, you know, there are different situations when recombination occurs.

What we're referring to in the book there that you're talking about is the kind of DNA repair that happens after there's a double-stranded break in DNA, which is, you know, DNA damage. Yeah. And in that instance, the cell is very eager to repair that broken DNA. And so it's really just looking for a quick way to, you know, fix those ends, seal them up, and allow the DNA to continue to be copied as DNA replication is happening as cells are dividing. And so, you know, it's one of those things where there's kind of pressure in the cell to figure out how to quickly fix those broken ends. But what you're talking about was with, you know, development, human development, and sort of, you know, egg fertilization and what happens at that stage of development is a process that's quite distinct because there we're not typically, at least,

worried about DNA that's broken. We're actually just worried about DNA that is being very quickly copied and then is available to recombine using homologous recombination to make the kinds of recombined chromosomes that result from, you know, from sexual selection. When it's being copied, but it has to take parts of the chromosome from father and part from the mother. Those those must be cut, then I would, right? When, you know, I guess at some level. They do, but it's a, it's a much more controlled cutting process, I guess is what I'm saying. Okay.

Now, speaking of controlled cutting processes, which is, which is what this is all about, CRISPR and your work and part of your work. The whole idea is, obviously, is if you can edit, if you can edit the gene, that means you can, you can determine the letters that are there and either correct mistakes or change it to make it better. And then we'll talk about all of that. But I was intrigued. You know, you describe gene editing as three segments. One, first recognizing the DNA sequence you want to edit, then cutting it.

And then you say the third element is having an editor, which can be reprogrammed to look at different DNA segments. And this is what obviously Christopher eventually is all about. You have a reprogramable device that can recognize DNA, go to that place and cut it. And that's, and you describe that. But the first thing occurred to me in thinking about that is, why isn't there the fourth part, which is also putting add, at a DNA sequence part of that? The cutting, so you go in and you cut, but then, and we'll get to the fact that, as you say, cells like to repair and there's other ways to it. But if you really want an edit, you've got to be able to make either add letters or add a sequence, and that's a central part of a gene editing. And I was surprised it sort of doesn't thought of as a central part of that whole process.

Right. Well, I think it's because it's a, you know, it's a, it's a little bit harder to do that as we, as we discuss. So what typically happens when DNA is broken in cells is that there's, you know, this quick fix that occurs that is, kind of this illegitimate recombination, if you will. And, you know, more rarely, more occasionally, there's a situation where there might be a piece of DNA that does have the kind of overlapping sequence, the homology that allows recombination that's more similar to kind of the normal recombining that we just discussed. And so I think that, you know, that's really the point of that explanation was to point out that, you know, in many cases, there simply isn't that piece of DNA available to do that kind of

recombination. Okay. Yeah. No, it's interesting to see how, how the different therapeutic applications depend upon whether you can add something or just cut or cut in two places and, etc. I was going to go into the precursors, this ZFN and Talon, but I think given time, the point is that, look, obviously it's a holy grail. which has now been discovered, but a holy grail of, you know, if you can obviously manipulate the human genome at will, you can do lots of wonderful things. And there were a bunch of tools that had been developed that have been used in variety of things and were, you know, in vogue around the time that you were thinking about something very different. You'd already moved to Yale. I noticed

I was a professor of Yale. You moved to Yale a year after I left Yale. I was a year after I left Yale. looking at that. And then you... Which department were you in? And then you too had the wisdom to leave Yale. But anyway... Which department were you in? Physics department. Physics, yeah. Up on the hill there. My dean was Sid Altman, actually. Oh, that was all right. My college dean and I always thought, well, college deans, they don't do anything. And then after he stepped down, that's when they won the Nobel Prize. But anyway, you were, you, so you were studying RNA. And in fact, one of the, one of the first claims to fame

of yours was to find the precise location of every atom in a part of RNA that self-splices, which is the kind of thing that I guess Tom Check had won the Nobel Prize and Altman and won the Nobel Prize for for discovering that RNA can be chemically active as well. And so you were the, am I correct, you're the first person, your lab was the first lab to understand that atomic structure directly and exactly, right? That's right. And the motivation, there was to understand the shape of the molecule, shape of the RNA that would allow it to work like a protein, even though it's not a protein. In fact, it's a very different chemical entity

than a protein. And it's hard to kind of imagine now based on all the research that's come since then. But in those days, people really argued about whether RNA would even have a three-dimensional shape associated with it. People thought maybe it's more like a spaghetti molecule. or something. I was convinced that it must have a particular shape to it that would allow it to function like a protein, except nobody knew what that would be. And so that was our motivation for trying to figure out the structures of these RNAs. What tools did you use for, did you, did you use to do that chemical structure? No, primarily something called x-ray crystallography, where you literally form a crystal of the molecule that you want to visualize and then show.

shine x-rays on it that are diffracted through the molecule, through the molecular structure in the crystal that can actually provide the data to back-calculate the structure of the molecule. It's a really fun process. Physics in action. Physics and action. It's poetic, of course, because it's exactly x-ray crystallography that led your early hero, Jim Watson and his college to discover this. And Rosalind Franklin.

Don't forget her. And Rosal Franklin. I was just going to sit call you. And Rosal Franklin, her work, in fact, they interpreted it. to discover the structure of DNA. Yeah. And I think you just answered my question. I guess I wasn't clear to me.

You said that RNA can fold up into three-dimensional structures was incredibly important. And I didn't get that. But now I do. It's really that because proteins fold like that. And so it's that three-dimensional structure that makes it resemble a protein. And that's why it's incredibly important. Good.

That's right. I mean, I didn't quite understand. That's right. And, you know, and sort of through the history of sort of modern biology has been driven in many ways by understanding these kinds of molecular shapes. And in fact, I don't know if people paid attention to the Nobel Prize announcement this year, but in chemistry and in physics, actually, the Nobel Prizes were given out for artificial intelligence-based methods that allow, for the case of the chemistry prize, the prediction of protein structures.

Yeah, no, and yeah, and that's obviously protein structure. is very important because if you, because that tells you, you know, proteins do things, and if you can understand how their structure makes them do things, then you have a fundamental understanding, a chemical understanding, which is really what it's, what I guess has been your focus. And as a physicist, for me, the most interesting part of this is sort of the fundamental dynamics of how things work. Agreed.

But your discovery, your personal discovery of CRISPR, not CRISPR as a tool, but CRISPR itself happened by serendipity. And a colleague who was looking at sort of Earth-based science, Earth and planetary science, looking at early history of life and looking at something that was, and she was interested in you because you'd been looking, she wanted to look at someone who knew about RNA interference, which is, I understand, the suppression of the expression of the expression of genes, the genes turning into proteins.

And suppressing that as an immune response. You want to walk through that a little bit? Yeah, wow, you're good. You have a lot of the details there. Right, but I'll fill in a few that you didn't mention. I'm going to take your time. It seems I should do my homework, too. No, no, not at all.

This colleague of mine, Gillian Banfield, here at Berkeley, was investigating bacteria that grow in the environment, and the viruses that they co-eater, exist with. And she discovered examples of CRISPR systems, which are natural bacterial immune systems. This was before anybody knew that's what they did or anything about how they operated, except that it was pretty clear that these were somehow adaptable, meaning that they were mechanisms for cells, bacteria, to capture short pieces of DNA from infecting viruses and then make little copies of RNA of those viral DNA segments and somehow use them to protect cells from future

viral infection. So it all sounded very mysterious but also very interesting. And Jill did not, you know, she's not an experimentalist herself and she doesn't work on RNA, but she knew that I did. And so she reached out to me to ask if I would like to study this with her. And that's actually how we got introduced to both each other and to CRISPR. Yeah, it's a wonderful, it's a wonderful, there's a few things that I want to, a few themes that I want to come back to near the end, but one, one is curiosity-driven research. The other is science as a social activity, that it's, this, and physics is responsible for the misconception of because of Mr. Einstein, and how it's due to, due to someone sitting

alone in a room at night, discovering that, but that's not how science works. It's, it's a deeply social process, and we'll get to that. But now I want to talk about CRISPR, it's, which is, I mean, and it's a pity we can't show the diagram here, because that kind of kind of makes everything clear. CRISPR stands for clustered, regularly spaced, interspers, short, palindromic repeats. And by the way, I have to say, it's another reason I didn't go into biology. I couldn't remember all the names. The acronyms. I know. It's terrible, right? Yeah. But when you see the picture, it tells you what that means. So why don't you walk us through what that picture means? Well, the, the, the The acronym and the picture refer to this process that I just kind of mentioned briefly, which

is that bacteria capture short pieces of DNA from viruses, and they store them. They store them in their own chromosome. And they don't store them randomly, but they store them all in one place in the chromosome. It's like putting them all in a drawer of a bureau or something. And so in this, in the case of CRISPR, these are places in the bacterial chromosome that have a whole series of these little stored pieces of DNA that are inserted between a sequence of DNA that is repeated over and over. So it's a very distinctive pattern, and it probably is there to help the cell know that, you know, this is where I've got my, you know, my, my, my, my, my, my, my, my,

my, uh, my, my, uh, my mutativey genes stored. And they are there to serve as templates for the production of molecules of RNA that are then able to find those viruses if they show up in the cell again, because as you mentioned earlier, RNA and DNA have very similar sets of letters, and they can pair with each other and use that as a basis for recognition. Yeah, I mean, you know, in retro, things are always easy in hindsight. But when you see that and you see that the more of these, you know, these, you know, unique DNA sequences that a bacteria has, the more it can fend off viruses. I mean, it kind of jumps out, at least in retrospect, that, hey, this must be because it's been exposed to these

viruses and it's learned how to build up immunity. And obviously something about that chemical composition allows it to have the immunity. I mean, it just sort of stands out and therefore that chemistry is somehow, you know, it just, in retrospect, when I was looking at it, hey, this is clearly the thing you should be looking at that somehow going to be attacking, or manipulating RNA and DNA. And, and, and, and, and, and, and, uh, but again, in retrospect, it's probably easier to see then. And you know, there's a beauty to it as well, don't you think? It's so elegant. It's such an elegant way to, unbelievably elegant. And in fact, so, um, um,

And the interesting thing is that these are present in archa and bacteria, the oldest life forms on Earth. So the immune system, so even these very, one could say primitive, I don't think that's the right word to use, but it is in a sense of at least temporarily primitive life forms. They have this remarkable chemistry and this immune system. It's just, it's amazing. It is amazing. Now, now the things that attack bacteria are bacteria, bacteria, Phages, right? That's right. And they basically cut apart. The way they attack bacteria is act like little scissors and they basically go in and they're viruses and they cut apart the DNA of the

bacteria and kill it. Okay. Yeah, that's right. And they take over the machinery. They make more viruses. And the process, just they're a virus. So they kill it and take over the machinery and make more viruses that can go and kill other things. It's just, you know, again, it looks like, you know, It's just, yeah, it's just amazing that they, they officially do what they need to do. One thing in your book that amazed me is that you said there are 10 to 31 bacteriophages on Earth. I'm born. Now, I don't know if anyone's ever, maybe they have because you probably, you know, you've talked about this a lot in different ways. But there, you know, there are 10 to the 22 stars in the universe.

So this is, this is a billion times more stars than there are in the universe. It's amazing to think about that, isn't it? Yeah, it's a very big number. Yeah, I know. I mean, I try to put it in terms of there's a billion, 100 billion stars in our galaxy, 100 billion galaxies, 10 to the 22. This dwarfs that by a factor of a billion. And those are, and so they're the fundamental.

It's obviously not only the fundamental, but it was essential. If you think about the history of life, I guess, now that we're talking about, it didn't occur to meets those now. Life had to develop an immune system if there are so many of these. Oh, it was essential. We would be around today if we didn't have a way to handle that. That's right. And so it was a requirement.

And undoubtedly, a lot of bacteria died until that requirement was developed by natural selection. And by the way, some people think that, you know, this is one of the drivers of evolution, too, is that viruses are, you know, they're a big, think of all the genes in those 10 to 31 phages, right? It's a lot. And so they are an incredible library of genetic material that, you know, provides. a resource for cells. So occasionally, we know that actually maybe more than occasionally, cells take up genes from viruses if they're useful. So is it not true? I don't know, is it true that perhaps a large part, I mean, the large part of our genome comes from eventually having built up from virus? Absolutely. Absolutely. That's true for humans, yeah. Yeah. Now,

associated with this, weird, this sequence, this clustered, regularly spaced, interspers, short, ballendromic repeat are other genes called cast genes. And they are, so they're always nearby. And what's clear, again, in retrospect, I guess it had to be discovered by people, is that they're involved in slicing up DNA and RNA, right? That's right. Well, they encode proteins, right? So they encode proteins that combine with the little pieces of RNA that are coming from these stores, viral segments, and together that protein and RNA are able to search the cell looking for viral DNA sequences latching onto them if they're found and then cutting them up. And so this CRISPR DNA gets converted to by translation, transcription, I forget.

Well, the DNA gets converted by transcription. The transcription into CRISPR RNA. And so CRISPR RNA is the thing that seeks out the relevant DNA of the virus. But not on its own. It has to do it with these cast proteins. Yeah, yeah, no, yeah, the cast proteins. And apparently with another RNA, which we'll get to, which it was essential part of your lab's work. Right, right.

And they basically pair together to seek out and ultimately seek out and destroy. Seek and destroy, like Mount Missile. It is an amazing, I mean, as you just said, it's an amazing defensive system and it's remarkably complicated and elegant at the same time. And yet it happens in bacteria. Yeah. You know, when I have to, when I thought of that, it reminded me, I don't know if you this quote from Bertrand Russell who said from protozo to man, there's nowhere a very wide gap in either structure or in behavior. So true. Yeah, I know.

It's so true in so many ways. So many ways. And it's fascinating. I guess I want to jump ahead. I had notes later on. But the thing that really occurred to me is your chemist, you're a biochemist. This amazing mechanism, which we'll go into a little more detail, is chemistry in action. Life discovered this chemistry.

Bacteria discovered this elegant chemistry. And in some sense, I guess the interesting question is, scientists like yourself and other people had, obviously gene editing is a power, is an amazing holy grail. It is interesting that you learned how to do it for bacteria. Do you see any way maybe with AI now? Do you think it could, is there any way that you think a smart scientist would have said,

oh, I can develop this molecular machine by putting these things together to do that? Or is it, or did we have? to learn from life? I think we had to learn from life, you know, because I don't, first of all, I'm not sure anyone would have had the idea for how to do it. And secondly, I'm not sure it would have been possible, even if the idea, even if conceptually you could imagine something like this, how would you actually build it? You know, and this is, this has been one of the challenges in biology for forever, really, is, you know, how do you, how do you, how do you, how do you, how do you, how do you construct molecules that have a particular property or behavior?

Scientists have been trying to do this for all kinds of reasons, right? Whether it's, you know, that you want to understand just fundamentals about how life works versus, you know, maybe you want to be able to create molecules that do new things or are useful industrially. And yet, it's really hard to do that. And the thing about cells and viruses and evolution is that they've had a lot of time. A lot more time than any of us have had. So they've had a lot of time to do trial and error.

And that's what they do. They basically do trial and error. And if something gives cells or viruses an advantage in some way, meaning that it helps them to grow or replicate better, then those kinds of molecules and traits tend to get selected. Yeah, no, I mean, that's the big feature of natural selection, which is so non-intuitive. And Richard Dawkins and I've talked about that on the stage, so long with people who don't understand evolution, don't realize, long time is something we just don't have, we can't appreciate.

No. It's just so non-intuitive. Billion, not just thousands of years, but hundreds of thousands or millions or billions of years. It's just so long. And so necessity is the mother of invention. The fact is, you just said, it's not just, they were interesting. What bacteria were interested in this, it's an essential tool of their survival. And you can imagine, you could have imagined lots of failed trials and those life forms died out for that very reason.

And it's just like natural action, the only ones that survived were the ones that through trial and error managed to develop this incredibly amazing, sophisticated tool and technology. but again, it was necessity. That's right. And, you know, that does remind me of something that I was going to ask about. A colleague, I was going to say a friend, and we actually met at the World Economic Forum when I used to speak there, which I understand you spoke at. But Francis Arnold won the Nobel Prize for basically as a chemist learning from evolution, right, using directed kind of natural selection in her laboratory.

to help develop chemical processes that you might not have thought of in events. It's an amazing tool if you can use it. And now, so the, but the key thing was having seen these things, I mean, what your, what your lab and what the goal was was to learn exactly how CRISPR RNA and Cass, what eventually would be called Cas9, but how they seek out, how they pair, and, and, and, and, and, and, you know, and, and do that. And so there was another sort of a bit of serendipity that led you to this. So, you know, the serendipity of meeting someone who was interested in CRISPR and introduced

you to it. And then, and you knew the tech, you knew that you were working on RNA and had the technology to understand and try and explore those things. But there was this thing called type one cast genes. And then there were these other, which, which as far as I can tell, those cast genes, just ask like scissors and and cut everything in sight. But there's another cast gene called type 2 cast gene. And there was another bit of serendipity that led your,

Leo in that direction. You want to talk about that for a second or a minute? Yeah, I mean, I'm not, there were a few. Someone you met. I mean, again, you know. Yeah, let's start there. So we, you know, we, in my lab, we were working on these CRISPR systems and trying to figure out their chemistry, how they worked, how they protected cells from viruses.

And it was a small project in my lab in those days. And I found myself, you know, invited to meetings that I didn't typically attend. And one of them was a meeting being held by the American Society of Microbiology. And it was being held in Puerto Rico that year. This was in 2011. And so I had been invited to give a lecture there. And I'm not quite sure why I went. And I was kind of wondering at the time, is this really, you know, should I really spend time doing this?

But it, I don't know, it was an interesting place. Yeah, that's a nice place to call. Interesting topic. Yeah. And I went to this conference and I ended up meeting a woman, Emmanuel Charpentier. And Emmanuel is a scientist who is a, I think she would define herself as a medical microbiologist. So she's very interested in bacteria. that infect humans that cause, you know, various kinds of, you know, sometimes very severe or lethal

infections. And in studying bacteria that can do this in humans, she had come across a different kind of CRISPR system. And so she was curious about how this might work and what it might have to do with the biology of this infectious bacterium. And so when we met at the conference, She asked me whether I would like to work with her lab to investigate the chemistry of a new kind of CRISPR protein, a caste protein called CAS 9. And I was intrigued. It sounded very interesting. Nobody had done much research on this particular form of CRISPR at the time.

And so that was the really important. It was one of the really important things that happened in our careers because we were able to begin doing science together that probably neither of our labs would have been able to do independently. Yeah, it was a symbiotic relationship, just like mitochondria. And, well, before, I have some questions about that. Before I do, I wanted to, I mean, the final step then, I want to jump to the final step, which was, which is the realization that your collaboration ultimately realized that in order to basically produce CRISPR RNA in bacteria and attack DNA of phages, you needed three components.

The CRISPR RNA, which was created by the CRISPR, you know, from the CRISPR DNA, CAS 9, which unlike the other cast proteins, does a single cut. I guess, is that the key point about cast 9? Well, it cuts DNA, and of course DNA is a double-stranded molecule. making, you know, it's cutting both of those strands. But it, I guess the important point is that it, it cuts once and it cuts precisely. It cuts precisely, which is obviously a position. And then the other aspect is that, and people just try CRISPR RNA and CAS 9. It didn't seem to work. You discovered you need another bit of RNA, trace RNA. And is the purpose that trace RNA to keep the

cast nine and the CRISPR RNA together? Is that what it? Yes. That's its purpose. Basically. Yeah. That's fine really what it does. Otherwise the, the, the, the, the Cas9 isn't finding the RNA, the CRISPR RNA. And so that's the key point, that it holds them together. That's right. And you do that, you can make a double stranded cut. And then you're in business. And that basically, then you have a virus seeking missile. And that was, that was ultimately the, the work that you then wrote a paper, the science article, which was June 8th, I think, 2012. And that was, I think that that's the, I assume the paper on which both you and Emmanuel won the Nobel Prize. Yeah. I mean, you know, obviously did a lot of work after that. Now, I do want to ask about two aspects of that.

I've already asked about, isn't it amazing that bacteria found the chemistry that science couldn't, but I think that's great because they're smarter than you think. And they also have behavior. That's the other thing that that that that that Bertram Russell was talking about it's and it's amazing you you can't tell from behavior you can't tell about consciousness that's because bacteria behaves but it doesn't have consciousness but what was it about but I have two questions what was it about your lab and your skills that caused Emmanuel to want to work with you what was it specifically that your lab could do well it's that we're biochemists and we work on RNA Because, you know, again, it comes back to the way that these virus-seeking missiles, as you just said, how they're guided. How are they guided? Well, they're guided by RNA. So if you want to understand how the missile works, you've got to figure out the guidance system.

And but, but, you know, given your history and understanding structural, I guess what we can call structural biology, I mean, the structure of molecules was, was that an essential part of understanding how the missiles guided? Did you do much structural work there? Or was it experimental work on RNA directly? We did eventually, but initially in those very early months working together, we were focused more on biochemistry. It was really about testing how it was that these RNA-guided proteins could find viral DNA and what they did when they got there, how they cut it up. Okay, now I want to get, there are a bunch of morals I'm trying to get across here. And by the way, I mean, you later on talking the book about the important,

of explaining the public, the public can be informed about these things. And I mean, that's one of the reasons, that's one of the purposes of this podcast and the kind of things we're talking about, is to try and give people the tools to understand what, what the basis of these things are so they can make informed decisions and equally importantly vote for people who might make informed decisions. But so that's why, you know, that's why it's so interesting to talk about these details. But the other aspect of, of this, which I think is so important is that it was based on curiosity-driven research. It's, it's, it's, it's, you were, you know, you were asking fundamentals about RNA. Jill was asking questions about, you know, about ancient

bacteria. And it wasn't, it wasn't as if people said, well, gee, is, I'm going to take money to develop a gene editing scheme. Okay. And I like to, and I use some examples in your book, but I like to think the same thing. If you had paid Bell Labs in the 1940s or early 50s, make better computers, well, they would have had cogs and wheels and it would have, you know, and then the transistor was invented. And the importance of curiosity-driven research is really something I want to, I want to spend a few minutes talking about because of the times in which we live, because of what seems to be such pressure to produce economic benefits, to, for science to be applied and for governments to fund science that's applied.

We see in the United States, I suspect, I'm not sure, but given the composition of the advisors to the new administration, I suspect we're going to see a lot more pressure to, you know, to look for economic benefits to science. In spite of the fact that years ago, I was involved when we're trying to get governments spend money on fundamental research with a study that was eventually done for the National Academy of Sciences, something before the Gathering Storm, it was called. But one of the things that was discovered was that, interestingly enough, half the GNP of the United States now could be traced back to curiosity-driven research a generation earlier. So I'd like you

to talk about the importance of this a little bit, because I think it's something when we think about one of the, you know, what may be some of the lessons that come from this podcast, that may be one. And I think the history of how this unbelievably important application, a tool that can change medicine and biology, was not developed for that reason, or it wasn't discovered for that reason at all. So sorry, but that's the prep. Yeah. No, it's, it's a great point. I mean, and actually, this is, this is the way that a lot of fundamental breakthroughs and discoveries have been made. They're somewhat serendipitous. They're due to, scientists being curious about something. Think of penicillin is a great example.

Absolutely, another one. You know, I saw another interesting statistic recently related to what you just mentioned about government-sponsored research, and that is that, so you know, you know, but, you know, hopefully your listeners are aware, but if they're not, you know, there's a major taxpayer-funded organizations in the United States known as the National Institutes of Health and the National Science Foundation. Yes. These are both government agencies that are responsible for distributing taxpayer money to people like me that are doing fundamental research.

So we write grants. This is the way we fund our laboratories. We write grants to these agencies and we propose projects and they get reviewed by our peers. Now, here's the statistic I saw recently. It turns out that for every dollar that the National Institutes of Health in the United States invest in that type of curiosity-driven fundamental research, there's at least a two-and-a-half-dollar return in the economy later. And why is that?

Well, it's because of what we just said, is that a lot of discoveries come from working on fundamental questions in biology or in other areas of science, and then making discoveries that have implications far beyond what the discoverer could have imagined. And, you know, another great example is the MRNA vaccine that was used during the pandemic. That science, again, came out of work that was initially very fundamental and wasn't designed to develop a vaccine per se, but in the end, when we needed it, we had the knowledge to do so, and we only had it because of that kind of funding. Yeah, and, you know,

you just remind me of another, when I, a colleague, mind when I was at Harvard, I moved there from MIT and an amazing scientist named Ed Purcell, who won the Nobel Prize for presenting NMR, which of course is relevant. But when he and Block invented NMR, nuclear magnetic resonance, he was asked about it and said it'll never have any applications. You couldn't, you know, it was like it just, it's a fascinating way of, you know, understanding how nuclear work and how to manipulate them, but didn't realize those applications. And, you know, one of the reasons is important, just yesterday the day before, I was reading that the government of New Zealand has just, do you hear this?

They just took, they said, we're going to cut funding, and half of the funding of science has to now go directly to economic benefits. and it's the most misguided kind of action that a government could take, I think. Yeah, because the problem is, I mean, it sounds like a great idea, doesn't it? Yeah. The problem is which things are going to be those things. We don't know. Exactly. You don't know till you know. No.

And that's what makes science so wonderful. You don't know until you know. And it's that thrill, which you talk about in your book and anyone who's done science is the thrill of exploring the unknown. And you never know where it's going to lead. Yeah. And another aspect of making sure these agencies, scientific agencies, which are ultimately directed by the public because governments determine the heads of those agencies, is that they spend money on science. One of the things that I've spent some time recently lately is that agencies like the NIH and NSF

have devoted a lot of their energy instead of science to social engineering. and it's unfortunate, I think, personally, because you're so little dollars anyway. The NSF, you know, I mean, NAH gets a lot more, but the NSF is maybe $8 billion, and it's just, and you take a billion dollars of that or $1.5 billion that and spend it to trying to do social engineering that's probably more importantly done somewhere else, and you've lost a lot of the importance. Yeah, I agree. Yeah.

Just to that time check here, because I'm going to have to sign up. in just about 10 minutes. Okay, yeah. I'm looking, we were 114, and I was thought it was going 130, but okay, we'll go 125, but okay. Well, let's get, I want to talk about general trends then. I mean, okay, before we, the other thing I do want to talk about, this led, science, that discovery obviously changed your life as well as changing science, and it hasn't been

the same since as you talk about in the book at great length. But one of the things you did have been involved is creating companies. everyone I know in that your field seems to great companies. And it's okay. That's good. That's, you know, there's a lot of possibilities. But I was going to ask, you know, when I was chair of the physics department, we created a program in physics entrepreneurship. And we didn't know anything about that.

And so one of the things we did was got to get physicists to become entrepreneurs to come back. And the one thing that they taught, they said, we didn't teach. We wanted to find out what we should teach students. We're doing a master's program. And they said, you've got to teach people how to fail effectively. That's the one thing that, you know, because we give problem sets and undergraduate classes. We give graduate PhDs to, you know, this is a problem that's likely solvable. But then you go into the real world and it's not done that way.

And a lot of the times, in fact, the tools you develop for one thing, as your story is a perfect example of, ends up solving something that you had no idea, and you may have come up against a brick wall here. So I wanted to ask, was it, how much of it is a shock for you to become an entrepreneur or become, what was your greatest learning curve or surprise in that regard as you went out of academia to business? I mean, you didn't leave academia, but as you opened up that option. Yeah, yeah. I mean, I'm an unlikely business person in a way because I just, it wasn't my goal at all in going into science or scientific research. But maybe we should just say a little bit about, you know, why start a company?

Why do people do this? Are they just wanting to get rich or what are they doing? And really, you know, it's what's interesting is that we've been talking about how a lot of fundamental discoveries are made in academic labs. That's, you know, that's kind of what academic science is really all about. and but but as as we also talked about sometimes those discoveries have real world impact and and they have problem-solving abilities and they could be scaled and they could have you know they could have they could change things in the world in in positive ways and yet academic groups for

the most part are not they're not you know they're not set up to to do that kind of scaling or development. And so that's really when I think companies make sense for science, is when you have a discovery that has real-world potential. It can do something and you can see it. You know, you can see it being able to cure a genetic disease or change the microbes that are producing methane, which is a powerful greenhouse gas. So you know the science behind that. It's just that in an academic setting, you don't have the resources to develop. into an actual tool that's going to solve those specific problems. And so then I think it really can make a lot of sense of that stage to found a company

because what a company can do is to attract the people and the money and the space and the other resources that are necessary to do that kind of scaling. And so for me, you know, in this whole process, I think that, you know, when we, way back, actually before we started working on the type of christmas, that became the genome editing tool, we realized that a lot of the molecules that you find in these CRISPR immune systems are very useful. Bacteria used them, but we realized, no, scientists could use them for other things, except that, again, as academics, we're not really set up to develop them in that way. So that really led to the initial founding of a company called

Caribou, Bioscience, which is now is a therapeutics-focused company. And then, later to founding other companies that would solve particular problems using CRISPR and CRISPR-related technologies, but do it at a scale and at a level that would be difficult or maybe impossible to do in an academic lab. Okay, but the question, that's great. But beyond that, though, I mean, as an academic, as someone who's been brought up as an academic and a professor, one learns a certain skill set. Is it clear that, or I mean, it's sometimes, I guess, I guess a rude awakening, presumably the skill set to run a successful company to be a CEO is a very different skill set or it's not always the same skill set. And so is it, you know, is it, is it,

is it advisable or is it easy for scientists to make that transition? Was it easy for you to make that transition? I guess you didn't be, did you ever, were you ever the CEO of any of these companies or did you just become an advisor? No, never a CEO. Good. Okay, yeah, because that's a very skill set. I tell some of our company's CEOs that, you know, I really admire their abilities as business people, you know, because it's a, you're right. It's a completely different skill set in some ways. In some ways, it's not. I mean, you know, I think just like a CEO, an academic research leader has to, a professor has to lead a team. You have to, you know, advise people.

You have to set goals. You have to set deadlines. You have to raise money. You've got to produce something. In our case, our product is to. typically publications. And so those are, you know, there's some parallels there. But I agree with you 100%. I don't think in academia, we are not trained to have the kind of skills that you typically need to run a business. Yeah. And the entrepreneurial. I remember our business school being when we

created this master's program in physics entrepreneurship said that was an oxymoron. But in fact, scientists have to raise money. They have to do all these entrepreneurial things. They do. The other thing I'm worried about it, but I'm worried about time. I do want to, look, you've given short shrift to obviously, people can imagine the implications of CRISPR, but the possibilities of are immense, you know, and your book talking about, I mean, in plants and agriculture and food and potatoes, which I live in PEI here are very important. And in actually engineering animals and maybe in making designer animals. And ultimately, changing the human genome and in different ways. I mean, not just changing the genome, but editing to help cure diseases. And that's happening.

And that's the great excitement about specifically diseases where you know that there's a genetic cause, not that there's about 3,000 genes that cause it, but immune or deficiencies, hunting disease, sickle cell, cystic fibrosis, resistance to HIV, perhaps, muscular dystrophy. and maybe even cancer in some ways. So it's incredibly. I mean, I don't want to give short shrift to the, obviously that's why this work is so important. I want to ask three questions

because I think we have three minutes left about if it's okay. And maybe one minute, a question apiece. One, Richard Feynman said, you know, when he won the Nobel Prize, that that wasn't the exciting part. It was, it was the discovery that was more exciting. Is that the way you feel? Yes.

In a word, yes. It's the process, you know. It's the whole experience. One thing, you know, you spent a lot of the last part of the book talking about this key question of affecting human genome. And I was happy to see, because I totally disagreed with you. I don't see any real problems of doing research or curing disease. I think it's ultimately important. And sure, there are risks and people are going to abuse it, but you don't have control of that over science. And it seemed to me that when you talk about your own evolution, it more or less came around to that. But there is one thing that hit me. When you said that CRISPR has made basically for $130, you can get a gene editing kit now. And I was a chairman of the board of the

Boltony atomic scientists for over a decade that set the atomic clock. And we used to look at all the existential threats to humanity. And we got Matt Messelson, who you probably know, to talk to us once, this was 10, 15 years ago, and we were talking about bioterrorism, and he said, you know, I'm not so worried because you need, you know, to do these labs for genetic, you really have to have an incredible lab. And it's not the kind of thing someone's going to have in their basement or whatever. But now one can do gene hacking in a basement. And so should we be more concerned about bioterrorism as a result? No, I would say not. I still think you have to have a certain. level of skill and and it's not it's not something that is is easy enough to do that you know that I would worry about it in particular relative to all the other things that people can get access to that can cause harm so okay well you know when you were thinking about whether it's ethical to to to affect humans you know basically the embryo and change the human genome

as you point out when you talk to people who either had relatives who had a disease that might be cured, in some sense the attitude is it ethical not to do that? Right. And it reminded me of a more serious ethical problem. But it's that kind of problem. I went to when I was an undergraduate, I met someone who worked on the atomic bomb, a physicist, well-known person. I won't mention his name.

And I said, do you regret working on the atomic bomb? He said, you know, my brother was in the Pacific. and he and two million other people would have died if we hadn't you know i mean if we hadn't developed that horrific weapon so when it comes down to this that it's not so it's not so clear or crystal clear um you know the if you can save lives is it ethical not to and you can't control no one can control the the the results of their work and no one can and people say science is bad but my friend stephen pinker pointed out you could say architecture architecture is bad because architects created the Auschwitz, you know, and, but it's, you know,

you can use science for good or bad. And I think I'll give you, I want to just read, I know we've got to end, so I want to just read the last lines of your book, okay? It comes to CRISPR, the possibilities of this new technology, good and bad, are limited only by our imaginations. I firmly believe we can use it for the former and not the latter, but I'm also cognizant that this will require determination from us individually and collectively. As a speech, We've never done anything like this before, but then again, we've never had the tools to do it. And I thank you for helping create those tools, you know, for better or worse, to potentially help our society. And I hope that our discussion has talked about, you know, some of the aspects of science has been fascinating for me.

I wish we had more time, but it's been a real pleasure. So I want to thank you for coming on. I hope you enjoyed it. Thank you for inviting me. What a great discussion. And like you said, lots to do. There's a whole future ahead for this. People, everybody should stay tuned.

Yeah, stay tuned. And good luck to you and your colleagues. Thanks again. Thank you so much. Hi, it's Lawrence again. As the Origins podcast continues to reach millions of people around the world, I just wanted to say thank you. It's because of your support, whether you listen or watch,

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