Coming.

This is on Crisper, the Story of Jennifer DOWDNA.

I'm Evan Ratliffe.

For our final episode, We're bringing you something a bit different.

It's a conversation that Walter Isaacson and Jennifer Dowdna had at the New Orleans Book Festival at Tulane University earlier this year.

It's a fascinating exchange that shows how, four years after the book's publication, the medical breakthroughs brought on by Crisper have only multiplied.

Isaacson and Downa also touch upon how recent cuts and science funding and researcher visas have shaken the field, putting at risk the very kind of work that created Crisper and is now saving lives.

If you've listened and enjoyed the series so far, thank you.

We would be grateful if you could take a moment to rate and review the podcast on your platform of choice.

Really helps us reach more people.

Here's the conversation.

Thank you, thank you, thank you, and Jennifer, thank you so much for being here.

Somebody who's written biographies, I tried people saying who's the nicest one.

I said, there's only one I've written about who well, Jennifer is the intersection of being a good person and a brilliant scientist, and probably the person most defining a future with biotech.

When you were a kid, you were an Ilo 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 eleven or twelve 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 Cure'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 of the Double Helix is he kind of minimizes and dismisses dismissively a bit rosalind Franklin, who did the great photograph that helped watching and quick understand the structure, calls her Rosie.

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 science.

That's true exactly.

So from there you decide to go to not be a French teacher, but go into biochemistry and chemistry mainly.

Why did you choose that that's not a usual path on chemistry?

Well, I think it started with my chemistry teacher in tenth grade.

She was a Miss Wong in Helo.

She taught us kids that science is about solving puzzles and not memorizing facts and 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 work, be working right at that intersection between chemistry and biology.

Now on the power of books, your father leaves on your bed, the double Heelix.

I think it was the old vintage paperback Penguin Blood.

Sorry, And if I remember, you thought it was a detective story because it looked like that, right, and then you find 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, and 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, 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 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, the something that I just I found myself drawn to that question of why.

When we get you get to Berkeley after a while, so along thank through Harvard, and but when you're there, you weren't doing RNA qusper 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 crisper, the first indication that there was something very interesting going on in bacteria known as as crisper 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 who at Berkeley works on RNA.

My name popped up and she called me and that's literally how we got together.

And there's why 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 Veneva Bush, starting in nineteen forty five, made part of what we as a nation do, which is curiosity driven basic science.

So when Jill Banfi, Jillian Banfield calls you up and says, I 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 Tom what was his name, right, or who who did the origins of life and figured the RNA world thesis that you worked on.

Well, Tom check was one person who I worked with in the past, but also my graduate advisor, Jack Shawstak, that's very interested in this question.

And it was he said, asked 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 it chicken and egg riddle to get there, right, which is we thought it was DNA that becomes the 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 nineteen nineties, approximately all the men, including dear Francis Collins 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 two thousand and yet if I look, there were almost there's no women on that project, but women like you Jillian Banfield Emano Chopantier.

All are focusing on the sibling or cousin molecule RNA.

Why is that?

And was that a gender thing or just happenstance?

No, 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 you got you an RNA.

Hmmm.

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 Crisper pathway.

Well, now that we're talking about Crisper, I'll start to give it, which means it's clustered repeated sequences that are in the back Chiera, You almost got it right.

Yeah, well I'm not going to do it clustered repeated inter's verse palandropic.

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 true that he is said, Okay, I'm going to call it Crisper, and then he had to figure out what with the cr I we want a nice acronym.

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 it's really as you said, it's a it's a series of repeated sequences of DNA.

So you probably all know that DNA is a four letter code and it is the you know, spelling out all kinds of molecular information that are required for cells to function.

But how to cells mark a particular set of sequences so they know what to do with them.

And what this is What happens in crisper 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 bugshots.

They say, hey, this one attacked me before exactly, and we didn't quite know we might need that as a human species.

While you were doing it right, I mean 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 crisper 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?

Yeah?

And uh 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, And we met at the Free Speech Movement Cafe at Berkeley in a quintessential place, and she arrived with a big, you know, stack of papers and she said, Jennifer, I've got we 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 ged 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 crisper sequences encode molecules of RNA that provide the molecular zip codes that tell proteins that are also part of the crisper 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 up molecules, 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 in sitting in my office in Berkeley, when Martin Yeneck, 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 Crisper CAST nine 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 cast nine 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 is you know, it 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 Crisper 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 DNA and 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 maybeturb 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 when maybe the simplest which is sickle sell anemia, is just a one letter mess up right, a typo, and it's you, Now your technology has done what with that?

Right?

Well, this is a disease that's been characterized for 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 till Crisper came along.

But with Crisper, 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 and 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 Crisper, 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, Hejuang Ki, 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 that we know of, and even China punished him.

It's like, okay, because you help get a consensus around the world, let's not cross the line of inheritance or heritable gene editing.

Do you think that should tell me about that line and how it can hold well?

I think the you know, the current state of the field, this is true even now, is that there's very little information about how genomediting 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, in 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 hallucinations as we call them.

An ai a lot to let me tell you a story.

When I was doing it, the book about You and gene editing, there was a young kid I'm blanking on.

His name is Pick in the book, and he loved playing basketball, except for when he crumpled over on the floor because he had sickle self.

David Sanchez, 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 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 happening?

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 to Nature documentary, and it's 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, you know, really appreciated the fact that, you know, 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 as a person and that he would be different without it.

So you know, it raises an interesting challenge.

Yeah, but we've always had those child I mean, I'm not sure Jonas Sack or Saban people would say, wait, if Franklin Roosevelt hadn't gotten polio, he would remain to an Upper East Side playboy.

So let's keep polio.

Interesting example.

Yeah, and from Darris Khan's good one, who's one of my next interviews here, But because she did the polio's effect on Franklin Roosevelt up.

But do you 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 in prices.

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 not probably not distant future, and we have to decide is that are we okay with them?

And one of the things I had tired about Jennifer and why I wanted to pick her as the subject.

I didn't know you're 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 worrying 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, and 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 a 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 right the Asilomar process.

So you said, okay, let's try it again for this Well.

I really admired that scientists in the seventies 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 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 nineteen seventies, and they came to an early conference we had and I think it was twenty fourteen, to discuss the ethics of crisper 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 could tail it, then we'd fall behind, as like the AI argument, let's I could tail it here because China will do it.

How did you try to make it international?

Well, we reached out to scientists and other countries, including in China.

We got the scientific academies 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 at least a consensus.

Well, I think one of the real challenges with something like this is that it's I mean, you know, we didn't say this earlier, but maybe folks here understand this already.

But you know, the thing that's so powerful about crisper really is that it's not difficult to use, and so that's meant that it could you know, take off very quickly as a powerful tool.

But the flip side is that it's you know, it's kind of readily deployable for these other purposes.

And in the case of the meeting that we had in California to discuss the you know, kind of the early days of Crisper and the ethics of it.

We really wanted to make sure that scientists would get on board with the you know, kind of the responsibility that we thought we all had, and so our approach has been to publish articles about this, to get the World Health Organization involved in creating a registry where scientists can be very transparent about work that they're doing, and also to get the scientific journals involved in ensuring that work that gets submitted for publication is reviewed with a lens on ethics.

Coming up after a break, Isaacson and down to discuss what it takes to keep doing scientific research in a fraud political moment, and how AI and Crisper are joining forces stay with us.

How worried are you or is there a reason to worry about what's happening now in Washington, both with Robert Kennedy Junior at h JASS and the government in terms of first of all, let's talk about regulations and science.

Well, it's you know, it's an interesting thing.

I mean, you know, there's a there's kind of two sides to that coin.

On the one hand, I think we appreciate the importance of regulations and especially when we think about approving drugs that are going to be used in US or our kids.

We want them to be safe, we want them to be effective, and that's the job of the Food and Drug Administration in the US.

The flip side is that if you have too many regulations or regulations that don't really make sense, then that can slow down the process.

And I think we all I certainly have seen, you know, both sides of that.

So it's you know, it's a it's a delicate balance.

How do you get the regulation regulations right so that they do what you want them to do and protect us but not impede progress.

And give me some examples where you've taken it from the lab to the bedside in a way by creating commercial companies to develop drugs.

Well, this is the thing.

I mean, companies play a very important role in that pipeline.

Academic scientists are great at innovation.

We love our students coming in with their ideas and having the freedom to pursue things.

And that's really I think what gave rise to something like Crisper.

But when it comes to expanding on an idea to the point where it can be globally accessible, academic labs are really not appropriate for that.

We don't have the funding to do it, we don't have the resources and the personnel to do it.

This is where companies are necessary.

So I've long believed that, you know, there's a really important partnership between academics and companies, and we have to figure out how to forge that effectively.

And Berkeley is very good at allowing people to commercialize and to start companies with the intellectual property.

Right.

No, Okay, they're not as good as Chilane, I mean, but yeah, oh yeah.

Yeah, they could be better.

But you know, well, I think I think there are a number of challenges.

You know, as we just said, universities are not set up to be companies and that means that intrinsically.

And I'll just speak for my own institution.

I don't know about Tulane.

To Lane maybe much better at this, but you know, really figuring out, really figuring out how to foster that connection.

How do you, for example, how do you train scientists that are coming out of academic labs, that are trained as academics to be good business people?

You know, how do you do that?

There's not there's no sort of easy answer to that.

How do you de risk an idea so that investors are now willing to put money into it where they think they're going to get a return.

That's also not not easy.

So and these are not unique to to anyone institution, of course, but you know, this was part of the motive for us to establish the Innovative Genomics Institute ten years ago, which is a partnership between different campuses of the University of California that's expressly focused on this kind of smooth pipeline between discovery and application.

That's something that's happened in a few places over the past fifty sixty years.

I mean, I teach a history of technology course here, which is when MIT and Harvard resisted the commercialization of the things.

Stanford University under Frederick Turman, who was the provost, encouraged graduate students starting with Hewlett and Packard and ending with Larry Page and so Gay Brenn that if you had a good idea, form a company, to what extent do you think that process can be improved?

Well, again, I think that we need to do better.

I'm speaking to myself here, really, you know, we need to do better at giving our students the training that they need to be effected in business.

And you know, one thing that's very interesting is that this is I see this in my own lab that people that are coming out of our labs, some of them are very focused on the science and they want to stay that way.

Others want to, you know, take a different lens to it.

They are willing to have or maybe even happy to let other people do the actual science.

What they really want to do is they want to think about the business model around it.

How do you how do you how do you expand it?

How do you develop it in ways that will solve real world problems?

And frankly you need both.

I ask all this because we are at two lane trying to BUYO Innovation Zone, a two lane innovation institute.

All of this is happening now.

And when you discovered this, you had two or three really great graduates.

I think Lucas was one of O Mecca and you said, Okay, we're going to just call a company Mammoth and we're going to make T shirts.

And they knew how to form a company.

Last time I was coming in from the San Francisco Apple there's a huge building that's Mammath pharmacut So explain how you picked the graduate students and said, you can form a company and I'll be I guess scientific advisor.

Well, they kind of are self selecting, you know.

These are often the students who recognize that that's their interest and that's what they want to do, and I feel like my job is to help them get there.

And I love, you know, working with people in the lab, helping them figure out what they're really good at and then do more of that.

And so in the case that you mentioned with Mammoth Biosciences, that was a wonderful situation where there were two graduate students in the lab, Lucas Harrington and Janis Chen, who were working together on a project.

They both recognized that there was an opportunity to commercialize it.

They wanted to be part of that, and they teamed up with another a third student coming out of Stanford.

Maybe the only history of a Stanford Berkeley partnership successful.

Yeah, right, and be done.

Can be done but rare, Yeah, And they started Mammoth Biosciences and they're going strong.

Getting back to the policy challenges we have now, we talked a little bit about regulation and trying to get the balance right.

The more pressing ones.

I'll start, well, there are two of them, I think, but I'll start with this NIH funding being cut radically and other NSF funding being cut.

Is that destroying the seed corn for the future inventions like crisper?

It's not a good idea, you know.

I mean, you're.

Not quite as forceful as Tony Fauci was stronger language than not a good idea.

Well, let me, let me, let me expand so you may appreciate that in the United States we are a leader around the world world right now in science and technology.

Why is that?

It's because taxpayer money for decades has gone into funding the kind of science that we're talking about here, you know, curiosity driven science that is asking questions about how nature works and then you know, taking those key insights that come out of that kind of work and turning them into applications.

Companies aren't going to do that.

Why not?

It's too risky, right, It's just the companies are not going to be able to invest in the kind of curiosity driven science that does provide that pipeline, but does so in a way that is, you know, kind of open ended.

And if we cut that off, I guarantee that we're going to see a big change not only in this country but around the world, because right now the United States really drives the discovery of all of the not all, but many of the of the medicines that we take and the kinds of technologies that have had such a huge benefit.

I would think that if you were an enemy of the United States and you wanted to destroy its future, one thing you would be doing is say, you know, they did the Internet, they did all these things at AI all because of these science grant even Larry Page and so Gay Brenn On National Science Foundation grants when they were graduates.

And you say, let's pull all these away so that China can be doing it.

Do you worry that competition a country like China will end up being in the foe if we keep this path.

Oh?

I not only worry about it, it's already happening.

I mean it's well, explain.

Give me some example.

Well, I think we're already seeing scientists being recruited to other countries.

They've been very, very proactive already about reaching out even to people in my lab about job opportunities.

We're seeing that some universities in the US are already cutting back on their graduate training programs due to NIH cuts or anticipated cuts, and it's not going to get better unless there's a real change in the approach in Washington.

And one of the related things is this, i'll call it cracked down on visas and people who are on student visas sometimes getting over I mean, so having foreign students studying here, that's going to be harder for them.

Have you seen any problem with that yet?

Well, you know, science is really international, and it's international, not just in the sense that there are people all over the world working on scientific problems, but it's international here in the United States in the sense that we recruit many of our scientists and our trainees from other countries.

Why is that, Well, again, it's because the US has been a real magnet for them, right, It's attracted them to come here because of the wonderful opportunities that they have had, and if we stifle that, it's going to be a disaster.

Have you seen stories of researchers who nail are afraid because they're not they're visas that they may lose.

Well, sure, I think that's happening all over and we're seeing some frightening examples of students even being pulled off the street, which is really shocking.

And does that have a ripple effect even at Berkeley?

Oh sure, I mean I think it, you know, creates an atmosphere of fear.

What would you do to try to make sure we became a magnet for the best around the world became you mean, yeah, well, yeah, we gain make sure we stay a magnet.

Well, I wouldn't be proceeding the way we are currently as a country.

I mean, I think we have to be welcoming to people from other countries.

We have to be willing to support science with taxpayer funding in ways that have been so valuable in the past.

I didn't mention before Walter, but you know, our very first grant that supported crisper research in my lab was actually from the National Science Foundation.

The NSF supported our work long before anybody appreciated that there was going to be human health value to it.

And they did that just out of curiosity.

Yes, yes, going back to Chrisper, we talked about sickle cell.

There's many other applications.

Tell me in humans first, I know there's for agriculture, climate and other things, but in humans, how will it be applied maybe even in cancer research.

Right.

Well, you know, I think one of the things that's very interesting about CRISPER is that as the first applications are coming to the fore we mentioned sickle cell disease, but there are also several therapies for liver diseases that are already in the last sort of third phase of clinical trial testing that are looking very promising.

These are all for genetic diseases that are relatively rare in the population.

But I think that what we're going to see over the next decade of CRISPER is increasingly this technology being deployed to prevent disease and to cure diseases that affect many people.

You mentioned cancer.

I think they're you know, we're looking at opportunities with programming the immune system in ways that allow targeted cancer therapies, and also thinking about ways that we can provide preventative changes in DNA that will protect us from disease.

Are you suggesting something that can to a cancer vaccines.

I think that's a possibility.

Yeah, And how would that work.

Well, the idea would be to program immune cells in a person so that those cells could find and destroy tumor cells before they form a tumor or before they metastasize.

Amazing, Yeah, and explain it works.

Let's say messenger RNA and guide RNA.

The guide RNA is what you did for gene editing.

Messenger RNA is what we use for the vaccines.

But it tends to tell our cell make this protein or something.

What are the implications of that of saying, okay, let's have let's code our molecules the way we code microchips.

Well, what's interesting about using RNA to do that kind of therapy is that it's a transient thing.

That means that it happens briefly.

And so with Crisper, if we were to use mRNA, for example, just as was used in the COVID vaccine to deliver Crisper molecules, then you could imagine a short term production of the genomeediting molecules that could make targeted changes and then go away, which is kind of ideal.

So then you'd have the the protective change made the editor goes away and a duration a lasting treatment.

But people looking at the mRNA vaccines, who are the anti vax people and whatever, and some of them in government now have been implying that a messenger RNA or some guide a thing like that will totally change your DNA and is a permanent thing.

How do you how could one get across the fact that no, RNA doesn't even go into the nucleus of the cell if it's building a protein, it just programs the outer I mean, it's complicated to make people believe that they're not getting reprogrammed.

I think this is where, you know, we scientists have to do better at explaining our findings.

Right now, there's zero evidence that there's any permanent changes that are made with mRNA use.

So there's just no data that would support that conclusion.

Yeah, you just said something interesting to me, which is we scientists are not good.

I mean, one of the reasons I wrote this book and others do is, wait, let's explain.

Scientists used to be better at being public intellectuals, explaining from the old days of Carl Sagan and others.

What should science instead of blaming on the people who don't get it, to what extent are scientists should they be doing more to communicate?

Oh, it's critical.

I think it's incredibly important.

I tell my students this regularly, and I'm sure you do too in your class, right, you really have to.

We have to be educating students to be not only great at what they do in the lab, but also thinking about how they explain the importance of what they do.

I tell my students, I want you to be able to say, in one sentence to your grandmother, you know why you're doing what you do and why it matters.

In one sentence to your grandmother, what are you doing now and why does it matter?

Thank you?

Rewriting the code of life to protect us from disease.

And you're doing it.

I do, okayday.

And what about rewriting it to protect us from climate change?

Well, I'd like to do that too.

Well.

You know, here's the thing.

So you know, CRISPER is a powerful technology in part because it works across all of biology.

We know that it works in bacteria, but it also works in humans, as we've been discussing, and it works in plants because you know, fundamentally they are all using DNA to encode their properties.

And so we realized in thinking about that fact that CRISPER could actually be used to make changes in plants, but also frankly in the microbes that support agriculture.

That will be beneficial in terms of protecting the climates.

I'll give you an example.

So cattle are harboring microbes in their gut, in their roomen that are important for digestion, but they also produce a lot of methane.

So methane is one of the most powerful greenhouse gases.

And it turns out that when you look at methane produced from animal farming around the world, it's about a third of the global methane that's released around the world.

Imagine that we could reprogram those microbes to not produce methane and in fact to use that energy to make more meat or more milk.

Great for farmers, great economically, and the right thing to do for the climate.

So that's what we're working on.

And tell me how close you are and how that would happen.

Well, this is where we brought on board a partner, a third partner campus partner at the Innovative Genomics Institute University California, Davis, one of the world's great agricultural universities, with experts working on this methaneroblem in cattle, and they had shown that you could change the cow diet to control methane production, but it wasn't It was clearly not an affordable or sustainable solution to the problem.

So we got together and we said, look, let's take your knowledge of cattle and ruman microbiology and combine it with the Crisper technology for reprogramming and make changes in the microbiome of cattle that could be permanent and could reduce the release of methane.

And that's what we're working on right now.

How do you feel, in this current climate, not just the politics in Washington, about saying all right, we're going to use RNA guided things to edit the biomes of our cows, etc.

Do you think there would be a backlash or you're going to have trouble getting people to understand that.

It seems like it would be deemedized right away.

Well, I think we have to be proactive.

I mean this.

We have a big public impact team at the Innovative Generalmics Institute to work on the communications about this, to explain the technology, to show the data that we have for the technology, and to really invite a partnership.

You know, you talked about scientists needing to be better kind of ambassadors, and I think that has to be not through lecturing.

It has to be through real partnership with our communities.

I'm going to talk about myself for a second.

What is it like?

I mean, I had to trail you for a couple of years.

I was in your lab all the time, in your hair all the time, so to speak, or Rubbert gloves, trying to learn how to do things.

What's it like to have books and other things written about you?

Does that you're you're not an out there person trying to get publicity.

Well, I'm still stunned that it got done.

Do you remember Walter that you know you called me so just It's kind of an interesting backstory because you know, Walter and I had met at the Aspen Ideas Festival where we did a chat like this, and you know, a few generations ago.

Now it feels like and and Walter a few months later called me up one day and he said, you know, I'm thinking about writing a book.

And I said, oh, that sounds great.

You're always writing books.

And he said, no, I mean about you.

And I said, I said, well, that'll never happen.

I couldn't imagine that it would come to pass.

But you know, Walter is very very uh you know, persistent and one thing led to another.

And I think what's been great about the book, Walter is that I think you did a wonderful job of telling a compelling story.

It's a you know, it's kind of a bit of a you know, it could be a tone, but it's not, you know, it's it's it's a it's a kind of a page turner, actually, And you did a great job of interviewing a lot of the people who were involved in the story telling their sides of it, talking about the way that science really works, the way it really gets done, and they're there's competition, there's collaboration that both plays into the things that actually happen in the laboratory.

So I think it's a great way for people to try to, you know, really understand the science that goes into a new technology that you might read headlines about but you don't have any idea where it emerged from.

I mean, you have that in history with great you know, advances in science.

The Double Helix being whatever you may think of Jim Watson just a wonderfully written book.

I mean, it is colorful, even if it's maybe too colorful at times.

Do you see a role at Igi, Berkeley, Tulane, whatever it may be, of just training science communicators, not people going to be great scientists.

But when people ask me how do I go into journalism whatever, I say, it's a tough time to go into journalism.

But pick a particular feel like maybe science.

Do you think Berkeley and others should have as science communication programs?

I do.

I think that's very important.

I also think that it's important to encourage people that you know, we're coming into contact with to pursue those ideas.

I mean, I think that.

I mean one one example from my own lab is a scientist named Sam Sternberg who was a former graduate student.

You know Sam.

You've interviewed Sam and when Sam was finishing up his PhD.

He's a wonderful scientist, you know, incredibly talented.

I asked him, you know, what do you want to do next in your career and he said, well, you know what, I think I want to write a book.

And I said, really, you want to write a book and he said, yeah, I want to write a book about the work that was that went into the discovery of crisper because I've lived through it in your lab and I think it's just an extraordinary story.

And so again I sort of thought, well that'll that'll probably not happen, but it did.

You know he did.

It's called the Crack in Creation and you should buy it, right, Oh no, it's you're talking about a cracking creator.

Yeah.

Yeah.

And so he took a year off from his research and he spent time, hold up, you know, writing this story.

And it was a struggle.

I mean writing is tough, you know, and editing genes is tough.

Writing it.

I've done both.

I think writing I've done both too, and it's I think writing is very hard either way.

But I did edit.

I think it was human kidney cells, right, Yes, I was able to add it in her lab, these cells so that they would phosphorus or blow in the dark.

As I'm not a scientist, and I thought, okay, I'm now doctor Frank.

And they made sure that we poured large amounts of chlorine and killed it.

So it's a type of thing.

Though it would be better if labs like yours or here or whatever could say the kids come in and just go to the bench and have a pipe and it's an experience.

Maybe, like you said, they don't have to be professional scientists.

In the future, but understanding a little bit about how science actually works.

I think it's very valuable, and then communicating that to people is critical.

Yeah, we have an anti science movement seeming to happen now, but it also comes at a time when uh, humanists are intimidated by science.

You know science, there's you know Twobe cultures system that I've been written about.

How important is it to sort of connect the sciences and the humanities.

I think it's very important again for the same reasons I think, you know, these are these are there fundamental ideas that we're all grappling with.

How do we how do we use technologies?

And we haven't brought a BAI yet, but you know, artificial intelligence, I think is the same kind of thing where it's you know, it's powerful, it's complicated.

You know, really understanding how these models, like large language models are actually working is non trivial.

And then to evaluate, you know, what's the what's the safety of these things, what the appropriate way to regulate them?

These are non trivial things to figure out, and so I just think that it's going to require a better effort between scientists and technologists and then the rest of us to work that out.

But I feel that humanists who care about the morale and they're going to be left out of the equation if they don't make the effort to learn some of the science.

That if you're clueless about the science, is going to be hard to discuss should we do arritable gene editing?

And that's why I love that you asked me if you could come to the lab and work with Chris Burd.

You know, it is great.

The two great historic advances of our time in science, just like you know one hundred years ago it was the age of electricity and then the digital revolution.

We're seeing two revolutions happen at once that I think are going to be the most transformative of the past five hundred years.

The life science is revolution, meaning gene editing at the core, and the AI revolution meaning artificial intelligence.

We saw the Nobel Prize this year being awarded both in physics and in chemistry to AI because that combination tell me what happens in your lab and your work and in your thought when you combine the power of the AI revolution to the power of the genetic revolution.

Well, when the work was done that was recognized by the chemistry Nobel this year, which is a program called alpha fold that allows prediction of protein three dimensional structures in a very accurate way.

Our lab and many many others began using it almost immediately because it instantly provides a tool that we can use to predict the functions of proteins, how they might interact with other molecules, and that's very valuable.

Used to be incredibly time consuming to work out individual shapes of proteins experimentally, and we don't.

We still do that, but we don't have to do it nearly to the extent that was required previously.

And as a result, it accelerates the pace of science.

And we're seeing this more and more with other kinds of AI driven approaches in technology approaches, is that we can do experiments faster, we can increasingly predict the right experiments to do and not waste time on the others.

And I think we're just going to continue to see this acceleration of the pace of discovery.

It's very, very exciting, but it's also it's a little bit scary.

To give me a very specific concrete way we get ahead of round and maybe take vaccine, where you use AI to totally say, handle a huge database that humans could never have coped with and discover something that could be a vaccine.

Well, it means that you can quickly evaluate all the molecules that are being produced by a virus or a bacterium that's infectious and try to figure out what are the ways to neutralize it.

And how might it work with cant or something.

Well, similarly with cancer, same thing.

You know, cancer cells often produce molecules on their surface that are not found on normal tissues.

So imagine that you could figure out what those are and what they look like, and then how to target them.

One of the problems with crisper is that it costs a whole lot I mean doing sickle cell I mean millions, so you can't really do it.

What is the reason the cost is so high and what could you do with delivery systems to get that cost down?

Yeah, thanks for bringing that up, because that's a very important point.

So right now, there's a drug castev that's approved by the FDA we mentioned earlier for sickle cell disease and it's extraordinary.

I've met one of the patients who is treated in the first trial using that therapy and it's completely changed her life in a very positive way.

So why and everybody with sickle cell disease able to get this if they want it?

And the reason, at least in part is the cost.

So it's about two million dollars of patient right now for this therapeutic Yeah good, not good?

And why is that?

Well, it's it's again in large part, it's for technical reasons.

It's because it's not easy to get those genomeeditors into the cells that need editing, namely the cells and the bone marrow that are the source of our blood supply and our bodies.

So imagine that you had a way to do that kind of targeted delivery into blood stem cells in the bone marrow by a simple injection or even maybe someday it's a pill that somebody could take.

That would be incredibly valuable and we change the whole field.

And it would also make it possible to use crisper for lots of other types of diseases.

So that's really one of the core mission goals of the IG is to figure out how to change the technology around genomediting delivery so those kinds of applications become possible.

So final question, you're at Pomona College.

You're thinking of being a French teacher maybe, but you're also holding the chemistry things and it's kind of fascinating you, and you figure out a path that takes you to the Nobel Prize.

For my students here, what should they be doing that will get them, if not a path to a Nobel a path to helping our society.

Well, all I can say is when I ask my French teacher about switching my major from chemistry to French, she said, no, stay with chemistry.

So it's probably good advice, but no.

I always tell my students you have to figure out what you're really passionate about and pursue it, just sort of doggedly, and not be dissuaded by naysayers.

You have to be able to identify what you really want to and your time on and then and then go after it wholeheartedly.

And I really see this over and over in my own lab, is that when students do that, they are they are successful.

Jennifer dowdno nowse both codes on Crisper.

The Story of Jennifer Downa is a production of Kaleidoscope and iHeart This show is based on the writing and reporting of Walter Isaacson.

It's hosted by me Evan Ratliffe and produced by Adrianna Tavia with assistance from Alex Joneveld.

It was mixed by Kyle Murdoch and our studio engineer was Thomas Walsh.

Our executive producers are Kate Osborne and my Guesttigador from Kaleidoscope and Katrina Norvell from iHeart Podcasts.

If you enjoy hearing stories about visionaries and science and technology, check out our other seasons based on the biographies that Walter Isaacson has written.

On Musk for an intimate dive into all facets of Elon Musk and on Benjamin Franklin to understand how his scientific curiosity shape society as we know it.

Thank you for listening.

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