Thank you. Thank you. Thank you. And Jennifer, thank you so much for being here. As somebody who's written biographies, I tried. People say, 'Who's the nicest one?' I said, 'There's only one I've written about who I...' Well, Jennifer is the intersection of being a good person and a brilliant scientist, and probably the person most defining our future. So, thank you with biotech. How did you... um, when you were a kid, you were in Hilo, Hawaii, I think you had a guidance counselor who once said, 'Girls don't do science.' How did you end up thinking, 'Okay, there are women scientists. I can do this.'
I think when I, you know, I think back to my upbringing, my father was a literature professor. He gave me a copy of The Double Helix, a book about the discovery of the structure of DNA, when I was probably 11 or 12 years old. And that book really showed me that science is a process of discovery. And I was fascinated by that description of how scientists could figure out the mystery of something in biology by doing experiments. And then I learned about Marie Curie's work and was inspired by her story. And together, I think those two ideas really spurred me on to thinking about a career in science.
One of the things in James Watson's book, The Double Helix, is he kind of minimizes and dismisses, dismissively a bit, Rosalind Franklin, who did the great photograph that helped Watson and Crick understand the structure, calls her Rosy. Most people when they read that book they say, 'Oh, you know, it was dismissive.' But when you read the book, what did you think?
When I read the book, I thought, that's ridiculous. Of course she was doing important experiments, and that a woman could be a scientist.
Yes. Which you told me at one point that up until then you hardly knew that there were women scientists.
So from there you decide to go to, not be a French teacher, but go into biochemistry or chemistry mainly. Why did you choose that? That's not a usual path, biochemistry.
Well, I think it started with my chemistry teacher in 10th grade. She was Miss Wong in Hilo. She taught us kids that science is about solving puzzles and not memorizing facts in textbooks. And I thought that was so interesting, and I thought to myself, wouldn't it be amazing to understand the chemistry of life? So that was really the first inkling I had that really what I wanted to do was be working right at that intersection between chemistry and biology.
Now on the power of books, your father leaves on your bed The Double Helix. I think it was the old vintage paperback.
Penguin. Penguin. Sorry. And if I remember, you thought it was a detective story because it looked like that, right? And then you found out it wasn't. And then you found out it was.
Yep. That's right. I thought it was a detective story of one type, but in fact, when I read the book, I realized it is a detective story. It's just about something very different than I expected.
Tell me, growing up, you're taking hikes and you're seeing things in Hawaii that we kind of have here too, out in the, you know, which is weird grasses that if you touch them, they curl up. And one of the things I like about you, Leonardo da Vinci, and others, is a curiosity about things that we all see every day, but we don't go, 'Oh my god, why is that?' And when you touched, I can't remember the name of the grass, and it curled, you just become fixated on how does that happen, right?
Yeah, I, you know, I think when I was in Hawaii I was amazed by all the plants and animals that had adapted to that island environment. So you're mentioning sleeping grass. That's one of the organisms that I was fascinated by. But we also had blind spiders that lived in lava tubes. And this was, you know, something that I just found myself drawn to that question of why.
When we get, you get to Berkeley after a while through a long thing through Harvard and U, but when you're there you weren't doing RNA CRISPR type stuff. I mean it was not yet a full field. How did you end up starting to study that? I mean who called you and said let's do something?
Well, you know, this is the great thing about doing research is that ideas come out of all sorts of directions. So in our case with CRISPR, the first indication that there was something very interesting going on in bacteria known as CRISPR systems was the work of Jill Banfield, who studies bacteria in their native environment. And I think she was really one of the first people that noticed that bacteria can acquire immunity to viruses that infect them in real time. And she wondered how that works and why. And she had a hypothesis that involved molecules of RNA, which are the chemical cousins of DNA. She Googled, you know, who at Berkeley works on RNA. My name popped up and she called me, and that's literally how we got together.
And this is why a great research university is so good because you have a lot of people together and somebody says, okay, I need to know about this molecule, and you form a partnership.
Right. That's right. Collaboration.
And one of the problems nowadays is so much of that is funding of basic research, not applied research, just funding for curiosity's sake, that the federal government under Vannevar Bush starting in 1945 made part of what we as a nation do, which is curiosity-driven basic science. So when Jill Banfield, Jillian Banfield, calls you up and says, 'I've got this molecule. I know you're interested in it, but maybe it has something to do with the sequences in bacteria.' Were you all thinking of an applied application or were you just basic research?
Oh, certainly not. It was pure, you know, curiosity-driven science.
And what was it you were trying to figure out?
Well, the question at that time for me was, well, first of all, I guess I was amazed that bacteria would have an adaptive immune system. We're all familiar with our own bodies working that way, but nobody had any inkling that bacteria could do something like that. So, I was fascinated by that possibility and also by the role of molecules of RNA, which are thought to be some of the most ancient molecules on our planet and perhaps even the source of life on Earth.
Well, source of life. So, we're all trying to figure out how did life begin? You had a great time, Tom Cech was his name, right? Or who did the origins of life and figured the RNA world thesis that you worked on.
Well, Tom Cech was one person who I worked with in the past, but also my graduate adviser, Jack Szostak, was very interested in this question, and he said, ask big questions.
Right. He did. And what was the big question?
Well, the big question was where did life come from and can we study it in the lab?
And why does it... The answer is yes. But you have to do a chicken and egg riddle to get there, right? Which is we thought it was DNA that becomes a code for replicating species. But you can't have... How did you figure out that chicken and egg thing?
Well, you know, the fundamental question is DNA is the code of life. Yet it is replicated by proteins that are encoded by DNA. So, sort of sets up this conundrum of, you know, which came first. And some scientists think that in fact neither one. It was really RNA molecules that might have had the ability to both encode information, which they do, but also copy information originally, and that that union of activities in one molecule could have given rise to early life.
Yeah. I mean, the main thing is to be able to replicate itself, which I guess is what distinguishes a rock from life, right? Yeah. And so, one of the things I say in the book, but you've pushed back on, but I'll let you do it again, is when you look at when you were doing that, say, in the 1990s approximately, all the men, including dear Francis Collins, who I think I see here, and others, they're doing the Human Genome Project. Eric Lander. Anyway, it's a very alpha male thing to figure out DNA and to sequence it by 2000. And yet if I look, there were almost no women on that project, but women like you, Jill Banfield, Emmanuelle Charpentier, all are focusing on the sibling or cousin molecule RNA. Why is that? And was that a gender thing or just happenstance?
Okay. But you played soccer and you said you always knew to run where the ball was going, not where the ball was. And I figured that was part of what got you into RNA.
I think what got me into RNA, just frankly, was just curiosity and this question about its role possibly in evolution that I found so fascinating, also in the CRISPR pathway.
Well, now that we're talking about CRISPR, I'll start to give it, which means it's clustered repeated sequences that are in the bacteria.
Yeah. Well, I'm not going to do clustered regularly interspaced palindromic repeats. By the way, it was a whatever it's called where somebody comes up with a name and then tries to come up with the words that will spell the name. Wasn't it the case that he said, 'Okay, I'm going to call it CRISPR.' And then he had to figure out what would the C-R-I... he wanted a nice acronym.
So yeah, it was a nice acronym. It's called a backronym or something where you go backwards to get the acronym.
But what it is is repeated sequences in the genetics of a bacteria. Explain why bacteria would waste a lot of time repeating sequences.
Well, what's interesting is that it's really, as you said, it's a series of repeated sequences of DNA. So, you probably all know that DNA is a four-letter code and it is spelling out all kinds of molecular information that are required for cells to function. But how do cells mark a particular set of sequences so they know what to do with them? And what happens in CRISPR sequences is that there's a repetitive region in the DNA that tells the cell this part is special. This is where I'm storing information about viruses that are infecting me over time. So it creates a genetic vaccination card.
It's a little bit like bug shots. They say, 'Hey, this one attacked me before.'
And we didn't quite know we might need that as a human species while you were doing it, right? I mean that we were going to be hit by viruses that way.
Well, we always get hit by viruses, of course, but humans don't have a CRISPR system. They do immunity differently, but in bacteria, this is a very effective way in real time for cells to acquire immunity to viruses and then use it to protect themselves.
Well, they've been at it longer than we have. Meaning bacteria have been fighting viruses for four billion years or so roughly. Yeah. And so is this an evolutionary thing that the smart bacteria figured out?
And so where did... So Jillian Banfield calls you up. Take the story from there.
Yeah. She called me on the phone. This was in the days before we were all, you know, texting each other.
Yeah. Yeah. Yeah. And we met at the Free Speech Movement Cafe at Berkeley, kind of a quintessential place. And she arrived with a big, you know, stack of papers and she said, 'Jennifer, we've just noticed something fascinating in these bacterial genomic sequences.' And we don't know what it means, but she showed me these signatures of repetitive DNA elements that flanked unique sequences that came from viruses. And so the question was why? Why would bacteria be storing little pieces of viral DNA in their genome? That was the question. And she was so passionate and so excited about this that I couldn't help but, you know, be drawn to it.
And how did that start leading to a gene editing tool?
Well, that led to a whole project that initiated in our lab biochemically to figure out how these sequences might be protecting bugs. And what we figured out, and this is the royal we with other people working in the field as well, is that these CRISPR sequences encode molecules of RNA that provide the molecular zip codes that tell proteins that are also part of the CRISPR pathway where to go and what to cut. And so what they do in these cells is they cut up viral DNA that gets into the cell and prevent it from causing an infection.
So these are proteins, sometimes called enzymes in this case, right? That know how to cut. They're just like scissors, but they're made of molecules, right? Right. And so you see it cuts DNA. When does it occur to you, oh wait, if I can cut and paste DNA, I can edit genes?
Well, you know, Walter, I remember this morning sitting in my office in Berkeley when Martin Jinek, who was the scientist in Berkeley working on this project, came into my office and he said, 'Jennifer, you know, we figured out that this protein called CRISPR Cas9 is an RNA-guided enzyme that has the ability to recognize viral DNA that matches the little letter sequence in these RNA molecules and make a double-stranded DNA cut just like you would cut a rope.' And when we looked at the data, we realized that we had in our hands the knowledge of how to reprogram these Cas9 proteins so they would cut DNA where we wanted. And if that one could do that, you could trigger DNA repair in other cell types like plant or animal or even human cells to make targeted changes in the genome. And this was really the synthesis of a lot of other scientists' work in the field. But realizing, putting all of those pieces together with our knowledge of this CRISPR enzyme made us recognize that we were probably sitting on a very powerful technology.
And what did you think at first that this ability to edit DNA in humans would be good for?
All kinds of things. I mean, people were already able to use earlier forms of genome engineering to make targeted changes in DNA. So imagine that you could, you know, perturb a gene and understand its function or maybe perturb a whole set of genes. But even beyond that, what if you could actually change a DNA sequence to correct a disease-causing mutation? I think that was really one of the things that first attracted our attention.
Well, give us, I think what may be the simplest, which is sickle cell anemia is just a one-letter mess up, right? A typo. And now your technology has done what with that?
Right. Well, this is a disease that's been characterized, understood for a long time at the genetic level, but it was impossible to cure it certainly and not trivial to treat. And of course, if you know anyone with sickle cell disease, you know that it's a terrible disorder that causes repetitive cycles of crisis where patients have to get blood transfusions. That's really the only way they can be treated up until CRISPR came along. But with CRISPR, it's now possible to override that mutation and give patients back a normal blood supply, which means that they're free of these repetitive crises.
How big of a deal is it to cross the line between doing that in a patient and doing that in the, I'll say, the inheritable genetics of a patient, so that the children and grandchildren will have been edited?
Well, now you're talking about something that I think is really interesting and fundamental about a technology like CRISPR, which is that it enables making targeted changes in the DNA of an individual, as is being done currently for sickle cell treatments. But in principle, it could also be done in embryos where it creates a change in DNA that can be passed on to future generations. We call that a heritable change. And to me, that's really kind of in a different category.
One guy who has done it in China who visited some of your seminars out at Cold Spring Harbor. He's the only person who has crossed that line, right? Or the only person we know of. And even China punished him. It's like, okay, because you helped get a consensus around the world, let's not cross the line of inherited or heritable gene editing. Do you think that should... Tell me about that line and how it can hold.
Well, I think that, you know, the current state of the field, and this is true even now, is that there's very little information about how genome editing would actually work in embryos to the point where it's really not, I think, technically safe to use it in that setting. So many scientists think that it's irresponsible to proceed with that kind of an application until we have really vetted the technology and also determined under what circumstances and which conditions would it really be the right way to proceed.
But in some ways that begs the larger moral question, which is suppose it was something you could technically do, as you can easily imagine that in five or ten years we'll be able to do it without, you know, mistakes or off-target effects as we call them in AI. Is there just a huge moral question? The book about you and gene editing, there was a young kid, I'm blanking on his name, picture is in the book, and he loved playing basketball except for when he crumpled over on the floor because he had sickle cell.
David Sanchez. And so he's working in the Bay Area being treated. And one of them says, 'You know, we'll be able to edit this out someday. In fact, we'll edit it out so that neither you nor your children or anybody's grandchildren will ever have it.' And he said, 'That's great.' And then he comes back and he says, 'Well, wait, shouldn't that be my child's decision?' They said, 'Well, didn't you hate the pain?' He said, 'Yeah, but there were things I learned, including resilience and getting up off the floor when I fell down, that maybe we should be careful about editing for future generations.' So, that seems to me the larger issue than can we technically get it right.
Yeah, I agree. It's a really moving section in the story of David. You know, David, his story was told in the film Human Nature documentary, and it's a fascinating reflection that he has even as a young boy about what is it that truly makes us individuals, makes us who we are. And I think he really appreciated the fact that his disease had, you know, it was a terrible, terrible disease, and I'm sure he wouldn't wish it on anyone, but he also reflected that it had helped to shape him as a person and that he would be different without it. So it raises an interesting challenge.
Yeah. But we've always had those... I mean, I'm not sure Jonas Salk or Sabin people would say, wait, if Franklin Roosevelt hadn't gotten polio, he would have remained an Upper East Side playboy, so let's keep polio.
Yeah, it's from Doris Kearns Goodwin, who's one of my next interviews here, because she did the polio's effect on Franklin Roosevelt. But let's go back to sickle cell. You can change the letter so the cells aren't sickled. In theory, I know we haven't done it in practice, you could probably change it so that the cells carry more oxygen rather than less, more oxygen than on average, and you could edit so that your children would win the Olympics or be sprinters. Is that morally acceptable?
Well, let's just first point out that you could only do those things if you knew which genes to edit and which mutations to make. But you know, if we say for the sake of argument, suppose you did know those things. I think you're right. It brings up a very important question we all have to grapple with because I think this technology will be capable of making those kinds of changes in embryos in the probably not distant future, and we have to decide, are we okay with that?
And one of the things I admired about Jennifer and why I wanted to pick her as the subject, I didn't know you were going to win the Nobel Prize, which helped the book a bit, but was that once you do this and you have this tool, you start learning about these questions. And in the history of science, we have so many examples. Oppenheimer the movie is somewhat about it, which is the Prometheus problem that we have snatched a technology from the gods and who knows what we're going to do with it. And early on in biotechnology, I'll call it bioengineering, there was a group called the Asilomar group in California that said, okay, this could be dangerous, and they met a few times and said, we don't want government to regulate it, we don't want to let the genie out of the bottle. And they did that process. And what impressed me about you is that when you got this discovery and technology, right, you almost replicated the Asilomar process. You said, okay, let's try it again for this.
Well, I really admired that scientists in the 70s had grappled with these sort of fundamental ethical questions about biotechnology. In that case, they were looking at examples of modification of bugs that live, you know, bacteria, E. coli, that live in the human body and wondering whether there could be health risks to making those kinds of modifications that had become possible. So we actually contacted Paul Berg and David Baltimore, two of the scientists who were some of the leaders of those original group discussions in the 1970s, and they came to an early conference we had in, I think it was 2014, to discuss the ethics of CRISPR and how we should think about it and how we should proceed as a scientific community.
And how did you enlist it? Because if it was only US scientists curtailing it, then we'd fall behind here because China will do it. How did you try to make it international?
Well, we reached out to scientists in other countries, including in China. We got the scientific meetings involved, and this was, I think, really critical to bringing together a global community of people who could think together about how to proceed.
And what lines have you sketched out or drawn on the use of this technology that have been agreed to or at least the consensus?
