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(upbeat music) - [Narrator] Thank you for joining us for the Crosscut Ideas Festival.

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- Hello and welcome to Crosscut Festival.

My name is Carl Zimmer.

I'm a columnist at the New York Times and also the author of 14 books about science.

Today's talk is about the gene editing technology, CRISPR.

It's got the potential to let scientists make precise changes to DNA, and is being used to treat a wide range of diseases.

It's already being used to develop new treatments for HIV, sickle cell diseases, and other disorders.

It's also being used to create new crops that are resistant to pests and diseases.

So we're gonna explore today the potential of CRISPR to help humanity, but also the ethical challenges that it poses to us.

And today, we are joined by one of the people who actually won the Nobel Prize for CRISPR.

Jennifer Doudna is a professor at University of California Berkeley, and she brings a huge wealth of knowledge about this subject, and we're going to go into all these different directions in the next half hour or so.

So, Dr. Doudna, welcome and thank you for joining me today.

- Hi, Carl.

Great to be here.

- So, you know, CRISPR has been around for... You know, it's been over a decade since you did some of your first experiments on it, but, you know, there probably are some people who maybe have heard the phrase CRISPR, but are like, "What is that exactly?"

So maybe we could do like a real quick, just tutorial for people about what exactly it is that we're talking about.

What is CRISPR?

- Well, it might sound like where you store your vegetables in the refrigerator, but it's actually a technology, and it came out of fundamental science around the way that bacteria fight viral infection.

So it's kind of a classic example of curiosity-driven science going in an unexpected direction.

So it's now being used by a scientist, as you said, in the introduction, to make precise changes in the DNA of cells and organisms.

And really what this means is that we now have the ability to tweak or even completely rewrite the code of life in cells in a way that gives us precision control over the genes that affect how we live our lives, how we interact in the environment, our health, and as you mentioned, the way that crops and plants are developing.

So it's a really powerful tool.

- So these are molecules that bacteria were making on their own, and you and your colleagues have been figuring out how to tailor them to actually change DNA in the way that you want?

- Right, and you can think about it almost like a scissors, you know?

It's sort of like a way to cut DNA, that triggers DNA repair in cells, and that repair is a way that you can actually edit the genome and make targeted changes.

And what's great about CRISPR, and here's the thing to remember about it, if you remember one thing, is that it's programmable, so it can be targeted to particular places and the scientist can control where it goes, so that makes it a really useful tool.

- So if people have heard about, you know, recombinant DNA, these kinds of tools, like in the 1970s, like, the fact that, you know, bacteria can make human insulin, for example, that people can use to treat diabetes, that's an earlier kind of technology, and we're talking about something that's more precise?

- Exactly, that's right.

Yeah.

- So, I mean, when you were working on these early experiments, I mean, essentially, you know, you were, like, working in test tubes with these really, you know, simple systems to see if you could just zero in and make these molecules work in the way you wanted.

And now, you know, here we are talking about medicine and applications to food, and, you know, there are people who are frightened about CRISPR babies, which we'll get to later.

But did you have a sense when you were, like, there with the test tube with your colleagues that, like, this is something that you would be talking about, that this would be a reality?

- Well, maybe not those details, but we certainly had a sense that this was a powerful pathway in microbes, a way that microbes acquire immunity to the viruses that are infecting them in real time, which is, you know, kind of extraordinary.

And, so, you know, that was really what sparked our interest in working on it in the beginning, because clearly bacteria had found a way to capture the genetic information from viruses quickly, and then use that for cellular protection.

And so that was the impetus for doing this work.

But, you know, where it went after, you know... And all the kind of directions that it's gone in over the last decade, wow, I mean, it's amazing to see.

- Yeah, I mean, I guess, you know, once people figured out how to get CRISPR into human cells, I mean, then things really start to take off in terms of the possibilities for medicine, if you're looking at something, a situation where you've got some kind of condition, medical condition that has something to do with how your genes are spelled out, essentially.

And I guess now, I mean, we're kind of at this amazing point where, you know, the FDA is pretty quickly, potentially, going to be approving some CRISPR-based medicines.

Maybe we could, like, talk a little bit about, say, for example, how you use sickle cell anemia...

I'm sorry, how you use CRISPR to treat a condition like sickle cell anemia.

Kind of walk us through, you know... Let's talk about the disease and how CRISPR can actually help.

- Well, we could start with, what is sickle cell anemia?

So it's a very well-characterized genetic disease that occurs in people that inherit two copies of a gene that contains the sickle cell mutation.

And so that turns out to be a single letter change in the DNA code, in a gene that encodes a protein essential for carrying oxygen in red blood cells.

So when somebody inherits two copies of that sickle gene, then they are subject to this disease, and, you know, it's a disease that has terrible consequences for their lives and their health.

Up until now, it could be diagnosed, it could be, you know, treated, sort of, you know, mitigated, some of the conditions, often with things like blood transfusion, so requiring hospitalization, but we really didn't have a way to address the cause of the disease.

And that's really where CRISPR comes in, because the technology allows scientists to actually either directly correct that disease-causing mutation, or to turn on the production of another protein that can suppress the effects of the sickle cell mutation, and that's actually how this first therapy is working.

It turns on production of a sickle...

Sorry, a fetal form of the protein hemoglobin that can suppress that sickle cell mutation, so it's an extraordinary path forward that basically offers a cure for patients.

- So the adult version of hemoglobin that we make, that is in our red blood cells, that's got a mutation that causes this faulty thing to happen, but we also have this gene for a second kind of hemoglobin that we make as fetuses, and that shuts off after we're born.

And so the secret here is to change that switch with CRISPR, so now people can make that fetal hemoglobin, and that's gonna work well enough for them?

- Yeah, it seems like it's a one-and-done kind of therapy, working just the way you described.

So you turn back on that fetal gene and now people are basically symptom-free.

- I mean, you know, we're describing something, you know, just very briefly and concisely, but, obviously, that journey was not brief and concise.

I mean, what were some of, like, those key steps to actually get something that you could confidently inject into someone and feel confident that it was gonna be something that was going to be, you know, safe and was gonna do what you wanted it to do?

- Well, you're right.

Not a straightforward path at all, and certainly requiring many, many people, and their ingenuity, and their hard work, so there was not only the CRISPR technology itself, of course, but also all of the research that went into understanding the biology of sickle cell disease, and the way that it would be possible to activate the production of fetal hemoglobin, so that you could suppress the effects of the disease.

Then, you know, figuring out how to use CRISPR to do exactly that and do it precisely and safely.

And then, as you said, figuring out how to actually do it in a patient.

And it's probably worth mentioning, right now, the way that works in patients is that the CRISPR technology is put into cells that are first removed from the patient, so the genome editing is actually done outside the body.

It's done in a lab.

And those genome edited cells can then be reintroduced into the patient.

So, you know, it works well, but it's expensive and it takes time.

- Right.

Right.

So these are cells that you can take out of someone's body.

These are the kinds of cells that will give rise to red blood cells.

So you take them out of someone's body, you do the CRISPR in a lab where you can control the conditions, and you can screen them, and then you can put them back into someone, where they're going to start to supply this population of red blood cells that can really do the job.

Is that the idea?

- That's the idea, right.

And, so, it's like you described, it also involves, essentially, doing a bone marrow transplant, because you have to kind of create a little space in the bone marrow for these new edited cells to take over, you know, take residents.

And of course, that, you know, is a difficult procedure and requires weeks of hospitalization, so it's non-trivial to do it.

On the other hand, it looks like it's truly a one and done procedure.

So it's quite extraordinary in that regard.

And, so, I hope we'll talk about this a little bit, but I think one of the issues right now is, you know, this works really well, but how do we make sure that people who can benefit from it get access and can afford it, right?

- Yeah.

- So, yeah.

- Sure.

I mean, we kind of have a glimpse of what we might be dealing with CRISPR medicine, with these other kinds of therapies, gene therapy, where you use other techniques to just, you know, insert a whole gene into somebody's cells to do something that their genes can't do.

And there are some impressive results for, like, hemophilia, and so on with that.

But I believe...

I mean, you know, it's literally one shot, those things need, but they're like $3 million for the treatment.

- Yeah.

- You know, the companies say, "Well, you know, it's cost effective over the long run, because hemophilia is such an expensive disease to treat," but I imagine that we'll be wrestling with these issues with CRISPR too.

I mean, what do you think...

I mean, you know, you're a biologist, not a health economist, but, I mean, have you had thoughts about what might be the best way forward for this?

- Absolutely, I mean, that was actually a motivation for starting the Innovative Genomics Institute a few years back, which is a nonprofit based at the University of California in the Bay Area, was to think about exactly that question.

"How do we take what's clearly a very exciting, very powerful technology, that has extraordinary opportunity, and bring it to a point where it is widely affordable and available?"

And, you know, that's a tall order.

How do we do that?

It's non-trivial to do.

Certainly will involve companies.

I think what a nonprofit can contribute to that is really thinking about what the breakthroughs are in accessory technologies that will enable more widespread distribution.

And so, for example, one of the things that we're working hard on right now is how do we get around having to do a bone marrow transplant?

Wouldn't it be amazing if you could provide a patient with a one-time treatment that was delivered by, say, an injection, or even potentially orally, where, you know, they get the editor, it goes to the cells in the body that need editing, and then they're cured?

Again, you know, today that sounds kind of fantastical, but I think we can bring that into reality with the right focus on the delivery technology that will be needed.

- So the idea is that these molecules you call the editor, you'd put it in some sort of package, and that package, when it's injected or swallowed, it would be able to make its way through the body, you know, to these sites where the cells that they need to edit are, that they would actually...

I mean, it does sound a little like science fiction, I have to say (laughs).

- Yeah.

Yeah, it does.

Yeah.

But, you know, it's worth recognizing that cells in the body have molecules on their surface that marks them as particular kinds of cells.

And so it's not maybe out of the realm of possibility.

In fact, we know that viruses are very good at doing this, that they can actually figure out what those little molecules are on the surface of blood cells and blood stem cells, which are the cells that would need to be edited for sickle cell disease, and hone into those, and leave all the other cells alone.

(Carl moans) So it's possible we may see FDA approval of a treatment for sickle cell anemia or some blood disorder this year.

I mean, are there other diseases that you think are particularly good, sort of low hanging fruit for CRISPR, things that, you know, we might be looking for in the next few years?

- Well, Carl, I think certainly other blood diseases are on the docket there, and also diseases of tissues that are relatively, you know, easier to deliver to.

And the two that come to mind right away are the liver and the eye.

And in fact, you know, there already are are clinical trials that are looking very promising in for genetic diseases in both of those organs that involve CRISPR.

So I think that's a really exciting path forward.

In the longer term, I think... A couple things I'm really interested in, and, you know, it's gonna take time, but I think we have some really exciting opportunities in areas that include neurodegeneration, so thinking about how we could... And, frankly, not just treat patients that are already suffering from neurodegeneration, but potentially make corrective changes to their DNA before they are symptomatic.

You know, as we get better and better at predicting and understanding what the genetics are of diseases like Alzheimer's, let's say, being able to use CRISPR to provide protection against a terrible degenerative disease like that would be extraordinary, and would be, you know, really a different way of thinking about treating a disease like that.

- Mm-hmm.

- Another possibility that I think is very interesting, and was certainly contemplated extensively during the pandemic, is could we program the immune system to be, you know, prepared in ways that might give us pandemic protection in the future?

So these are... You know, I would put these in the category of, definitely, kind of futuristic opportunities, but things that academics really should be working on, because they are the kind of hard, but important challenge that, you know, nonprofits can tackle.

- You know, are there particular risks of using CRISPR in medicine that CRISPR scientists are gonna have to be careful about?

I mean, are there things about using CRISPR that might have particular, you know, side effects that you're gonna have to be looking out for?

- Oh, yeah, certainly, I mean, you know, it's a serious thing to change DNA.

It sounds pretty permanent, right?

And so you'd wanna be sure that the right genes are getting altered and nothing else, so certainly the accuracy of the system is important, as well as, frankly, just understanding enough about human genetics, that we can be confident that when we make a particular change in the genome, that we're having a desired impact and not, you know, something unintended or unexpected.

So that really means that, you know, hand in hand with thinking about applications of CRISPR, we just need to continue to use it as a research tool, as many laboratories globally are now doing, to understand our genetics better.

- So I wanna just shift gears a bit, because you have been working on some new applications of CRISPR, which are really intriguing.

They have to do with the microbiome.

And the microbiome is something, again, that people may be hearing a lot about, you know, that sort of collection of microbes that call our bodies home.

So, I mean, tell us a little bit about what this project is, where you want to use CRISPR to use it on the microbiome.

- Well, this is a project that really stems from work that has been done for a long time by laboratories, including that of my colleague Jill Banfield, here at UC Berkeley, and at the Innovative Genomics Institute.

So, you know, the Banfield lab has been, really, a global leader in investigating what those microbes actually are, not only in our bodies, but also in our environment.

And they do this by reading the genetic code of all of those organisms, kind of, you know, together, and then assembling the pieces and figuring out which organisms are present, and also which viruses are present in their midst, as well as, you know, what those organism genes are doing.

And because of that, we realized that, you know, we actually had an interesting opportunity with CRISPR to take a technology that, you know, actually came from these microbes, and turn it around, and apply it in those microbes, but in a way that is very new, in the sense that, you know, traditionally microbes have been studied one organism at a time in labs, but that's not representative of how they actually behave in our bodies or in the environment, where they're growing together with many different species, and, you know, that certainly affects their behavior and their biology, as well as their, you know, interactions with us.

So we're excited about being able to use CRISPR now to modify these microbiomes, where we can make targeted changes to individual genes and, you know, particular species, but in the context of a natural microbiome.

So that's really what we're looking to do, both for human health applications, as well as thinking about challenges of climate change.

- So I'm gonna get back to that little climate change teaser there, but just to be clear, so you might, say, have a mouse with a thousand species of microbes in its gut, and you would give it sort of a treatment where, you know, the editor would not just go to bacteria, but would go to, say, one particular species of bacteria, change one gene in that bacteria, and then you would sort of sit back and see, okay, how does that change, like, how the microbiome helps the mouse's immune system develop or digest food, or something like that?

- Exactly, so, you know, let's compare that to... You know, you take an antibiotic, it typically affects the whole microbiome, right?

Or many of those organisms.

So it can, you know, alter things a lot more broadly than one might like.

And then for people that have certain kinds of infections, and especially intestinal disorders, they can use a fecal transplant, which can work very well from a therapeutic perspective, but certainly not scalable, and, you know, not very appealing.

So we're pretty excited about the opportunity to make targeted changes using CRISPR, where you could really kind of fine tune the microbiome.

And there's already some really intriguing evidence that microbiomes are producing molecules and, you know, they're being produced by particular species in a microbiome that you might be able to turn off, for example, and have a real impact on human health.

- So I get the human health.

Now, where does climate change come into this?

- Yeah, great question.

So, well, you know, I was...

When we started this project, I was astounded to discover that methane, which is a very potent greenhouse gas, much more potent than carbon dioxide, is produced by livestock.

And in fact, it's one of the big livestock or one of the big contributors to global methane emissions every year.

And there's really strong evidence that methane is, you know, one of the major contributors to global climate change since pre-industrial times.

So what do we do about that?

Because, you know, there's a lot of farming that goes on, and I don't think we're gonna be getting rid of farm animals anytime soon.

So we're contemplating a future where CRISPR could be used in the cow rumen to make, again, those same kinds of targeted changes to the microbiome that would reduce or even eliminate methane emissions by fine tuning the metabolism of that organism in that microbial community.

And if we could do that at the birth of a calf, you know, by adjusting their feed or even providing a pill that would provide that kind of change, we could establish a healthy gut microbiome from the get-go and have a positive impact on reducing methane emissions for the animal's entire lifetime.

So this is something that, you know, could be very appealing to farmers, because it actually also means that you get more efficient conversion of, frankly, feed into food, you know?

- Mm-hmm, mm-hmm, right.

I mean, speaking of food, how does things seem to be growing in terms of using CRISPR to develop new kinds of fruits, vegetables, other kinds of foods?

- Yeah, it's really interesting right now.

I mean, we're seeing...

I feel like there's a real ramp up of the application of CRISPR for that type of use.

And, you know, there's some interesting hurdles there, you know, regulatory barriers that are different in different parts of the world.

But I'll just give a couple of examples.

You know, in Japan recently, a tomato was approved, a CRISPR tomato that produces more of a compound that's thought to be protective of human health.

And, you know, because CRISPR has the precision that it does, that kind of genetic change can be made without messing with any other genes, which means you still have a tomato that has the same size, shape, flavor, you know, all the other properties that breeders have been, you know, interested in preserving over time.

But you have this one little genetic tweak that now allows this tomato to make, you know, a compound that is linked to human health.

So I think that's an interesting one.

And then, you know, there also are examples in crops that are used commercially, for example, making adjustments in rice and wheat that lead to more productive plants under drought conditions.

And again, you know, the tweaks are very small, right?

So crop yields are preserved, all of the flavor and, you know, nutritional properties are preserved, but you have a plant that can grow well under low water conditions.

- So just before we finish up, I mean, we're talking about, you know, these really, you know, tremendous potential changes in food we eat, the way we could carry out medicine.

There's, you know, been anxieties, which, you know, you've expressed yourself about the possible abuse of this for, say, you know, tinkering with human embryos.

Do you think that kind of the world's governments have really kind of grappled yet with the potentials of CRISPR and the need to be regulating them in a way to sort of take advantage of these benefits without running afoul of potential risks?

I mean, how do you see kind of the world's governments, where their thinking is now in 2023?

- Well, I would say... You know, the good news is that I would say many governments are well aware of the CRISPR technology.

And how do I know that?

Well, because, you know, we're fielding questions frequently from government groups from around the world about CRISPR, you know, technology, just fundamental questions about how it works, but also specific applications of the technology.

So clearly regulatory agencies are paying attention.

And, you know, there's also really been an important global effort among scientists to figure out how to get ahead of, you know, this discussion and encourage a community of transparency around the applications of CRISPR, because as you mentioned, there definitely are ethical challenges when we think about uses in humans, in plants, in the environment, you know, and really making sure that we're staying on top of that, because the technology is moving very quickly.

- Well, we are out of time.

We could've talked much more about all this, but I think we really got a taste for CRISPR, so thanks so much, Dr. Doudna, for talking with us today.

- My pleasure.

Great to be here, Carl.

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