Kara Swisher and Dr. Jennifer Doudna on CRISPR and Its Possibilities – The New York Times

Posted: October 28, 2020 at 9:56 am

[MUSIC - THEME, SWAY]

(SINGING) When you walk in the room, do you have sway?

Jennifer Doudna just won the Nobel Prize for Chemistry. Its for her work on something called Crispr. Shes the smart one so shell explain it in a minute. Doudna and her collaborator, Emmanuelle Charpentier, are only the sixth and seventh women in history to win chemistrys highest honor. Their work is groundbreaking, a fast and precise way to edit the genome. Its already been used to grow seedless tomatoes, double a dogs muscle mass, and treat people with sickle cell anemia. Someday, it could be used to make designer babies. But before we get to the complex ethics of playing God, we started with the basics.

Lets explain the basic idea of Crispr. It stands for and I want you to say it because youll say it correctly, and Ill bollocks it. But it stands for

Clusters of Regularly Interspaced Short Palindromic Repeats. Say that three times fast. [LAUGHS] Or dont.

You lost me at palindromic. But I know what a palindrome is, so thank goodness. So explain very basically how its different from before. Because you didnt discover Crispr. Francisco Mojica did. But talk about this breakthrough now.

Well, I think its important to point out that in bacteria, Crispr works as an adaptive immune system, analogous to the way our own bodies fight infection. The mechanisms are different, but the principle is the same. Our bodies can adapt to viruses, learn how to fight them. And similarly, in bacteria, the bacteria use the Crispr pathway to do that. The characteristic of all of these Crispr immunity systems is a distinctive pattern of DNA sequences that represents the storage mechanism for learning about a new virus, and then learning how to fight back against it.

So its bacteria protecting itself.

Exactly, yep. And I was interested in this because I thought it was incredibly exciting that this whole kingdom of life that namely bacteria might have adaptive immunity that had never been studied. Previously, nobody knew about it. And so we wanted to understand it. And this is where the technology comes in because in working with Emmanuelle Charpentier and her team

This is your colleague who you won the Nobel Prize with?

Correct, and so we were able to figure out exactly how this Crispr bacterial immune system operates. And it works using a protein that can cut DNA precisely. And importantly and this is the key to the technology the cutting, the position, the sequence of DNA that gets cut is defined by a small molecule of RNA, which is a chemical cousin of DNA that can be, after our work, controlled by scientists to allow this Crispr protein called Cas9 to cut DNA at a place of our choosing.

Right, and youre injecting this RNA in, correct?

Yeah, there are different ways to put it in. You can inject it. You can program the cell to make it. Its rewriting the code. Its taking an editor to the code, like you might edit a Word document. And so that just gives scientists the ability to address questions they couldnt address before. And I think that its fair to say that human beings now have a tool for manipulating DNA precisely in cells. That puts in our hands the ability to control our fate, control our genetic fate, and that of all other organisms that we occupy the planet with. So it is a profound opportunity and also a big challenge to make sure that its used responsibly.

And so essentially, when you were discovering this, when this was your breakthrough, you compared it at one point to a good suspense novel. Can you explain that?

Well, science for me is always a good suspense novel. And this was a particularly interesting volume of it. First of all, we thought, OK, theres evidence that this protein cuts DNA. But how does it do that? And so we did experiments to answer that question. It was a very cool answer. It was, well, this is a programmable protein. We can program it with these RNA molecules to cut a desired DNA sequence. And then I think the leap to the technology was appreciating that we could actually engineer it to be simpler than nature has done by creating a simpler way to make this little RNA molecule that does the programming.

These bacteria were protecting themselves, and then they had a map for you of how they did it.

Yeah, Id call it a map, sure. Yeah, yeah. But heres something very important to appreciate. In bacteria, bacteria do not use Crispr for genome editing, as far as we know. They use it to destroy viral DNA. Thats what they did.

Coming at them.

Its coming at them, and they cut it up and destroy it. But once we understood how that worked, we realized that we could use it differently in plant and animal cells and human cells because of fundamental biological differences in the way those cells deal with DNA breaks.

So essentially, what you invented is gene editing technology, but with scary precision.

Well, I didnt at the time, I wasnt thinking scary. I was thinking, cool, you know? Exciting, wow.

Well get to scary in a minute. But what was the question you asked yourself when you saw that?

First question was, what is it doing? And then once we knew what it was doing, you could start to make connections and say, well, if it does this, then if we put it into these other types of cells, its going to do that. Its going to do genome editing.

So where was the suspense moment?

I think for us, the suspense was kind of twofold. One was, how does it work, and figuring that out. And the second was, is it actually going to be useful for genome editing? And testing that and showing that was just incredibly exciting.

And so you worked with you mentioned is it Dr. Charpentier?

Yeah.

Talk to me about that collaboration. I know Ive heard about you meeting and everything else. How did you work together on it?

Yeah, so we were in three different countries. Emmanuelle was in Sweden at the time. Her student was working Krzys Chylinski working in Vienna and Martin Jinek and I working in Berkeley. So it was a lot of international coordination there, different time zones, et cetera. And it was a lot of fun. It was a lot of fun because the project took off very quickly. They started to get exciting data right away. And so we were communicating back and forth, initially email and occasional Skype calls. Experiments and ideas and thinking would be going on in one time zone, and then wed go to bed. And Emmanuelle and her team would wake up, and they would take over. And we felt like we were sort of working 24/7 that way.

Right. I want to run through some of the high hopes people have for this technology and get it straight, what is actually possible. I kind of think of it, like, you dont know what people are going to make once you invent, say, the iPhone. You dont know what the killer app, so to speak, is. So lets go through some things. Now, could it solve world hunger? How would it do that?

Yeah, no question. I think there is a lot of excitement about that. How do we increase food production? How do we increase the nutritional value of food? I mean, I would just start by saying that when we talk about plants, everything we eat is genome editing, in my opinion, because its been bred to have properties that are valuable to us. And how does that happen? Well, its because plant breeders are introducing random changes into DNA of plants and then selecting for desired traits. So thats been going on for a long time, obviously, for eons, probably. And the difference now with Crispr is that now we have a technology that allows precision. So we dont have to wait for random mutations to crop up, along with all sorts of other things that are maybe undesirable. But we actually can go in and precisely alter a gene or a set of genes and nothing else. And so thats very important.

Drought resistant crops?

Yeah, exactly. In the Innovative Genomics Institute that I founded, which is a Berkeley UCSF partnership, we have a very active program on that. And theyre focused on things like increasing the number of pores in plants or decreasing them to control the amount of water flux into leaves. I mean, its a very practical thing that one can now do with genome editing.

So lets move onto something else. Could you help someone regenerate a lost limb or

Thats going to be tough. Even if we could, for something like that, there are going to be many, many genes involved. So thats part of it. And we dont know what they are. So thats a big jump.

So that would be a challenge. Could you revive extinct animals? The woolly mammoth thing has always seemed to interest scientists.

Yeah, that comes up a lot. I think George Church may disagree with me on this, but I think the wooly mammoth is going to be a big challenge. More power to him if he can do it. But I think

This is a scientist I think at Harvard, right?

Yeah, hes talked a lot about this. I think more realistic, though, is to revive species that have gone extinct recently, like the carrier pigeon, for example, is one that gets discussed. Because it has a genome thats not that different from existing animals, other birds, where you could imagine being able to reengineer changes into an existing genome to recreate the original properties of that bird.

What about future babies smarter, healthier, more beautiful, taller, whatever you want?

Yeah, its a very intriguing idea. Its also one of the most fraught topics in Crispr because of the echoes of eugenics, thinking about safety, and I think just the challenges, honestly, of who decides and how do you monitor health of somebody whos had genes edited when they were an embryo. Its a very big challenge. And so, of course, the field has been working on this for years now in terms of thinking about appropriate regulation and guidelines. And its an ongoing topic. And Im sure many listeners are familiar with the fact that there was an announcement about Crispr babies a couple of years ago that really did galvanize, I think, international cooperation to ensure that that sort of inappropriate use doesnt happen again.

Right, so a couple more of the future possibilities. Coronavirus something youre working on. How would Crispr be applied to that?

I think its most useful in the current pandemic certainly as a diagnostic method. So this is another one of those things that came out of just doing fundamental biochemistry and understanding the mechanisms of these Crispr proteins, was discovering that some of them have the ability to detect and kind of report on a DNA or RNA sequence that they encounter. We think about it in the context of pandemic preparedness.

So for testing.

Yeah.

For testing, but what about actually putting a gene into people, fixing the gene so they dont get it, rather than flu shots and things like that?

Yeah, interesting possibility. I think not something that will happen in a timeline that will affect the current pandemic, but I think this is a very interesting idea in the future, is, will we understand enough about, for example, how the immune system deals with a virus like the SARS-Cov-2 virus that causes Covid-19 to be able to program cells to get ready?

To get ready before.

Yeah.

So we wouldnt need vaccines. So its vaccination for whatever comes along, correct?

Yeah.

Right, fascinating. So this is this idea of an adaptive immune system. So possibilities, those are more far away, but the day-to-day applications like my brothers a doctor in San Francisco at CPMC, and he has muscular dystrophy. And he was talking about that. Some of these diseases like sickle cell anemia, muscular dystrophy can you talk about things that are in the immediate?

Yeah, well, sickle cell is maybe the one to mention first.

Its a blood disease, right?

Yeah, because its a blood disease. Its also its been well-known for decades that its caused by a single genetic mutation that affects red blood cells. And so Crispr is, thats the right tool one gene, fix the gene. And in fact, that is roaring ahead. There are multiple clinical trials ongoing currently for sickle cell disease. Weve already seen the announcement about Victoria Gray, a patient who received Crispr therapy for her sickle cell disease and has apparently been cured of her disease, which is just extraordinary. In fact, just a couple of days ago, I heard from her doctor on the East Coast writing to me about just his thoughts about it as a technology after the Nobel announcement. So I think many of us feel very excited about those opportunities.

So single gene problems are things that are less complex.

Exactly, and muscular dystrophy is another great example of that, right? Thats another disease well-known, single gene that causes that disease. And Crispr is a tool that can be harnessed for that purpose as well.

Any other areas?

Well, I guess the other two I would mention, one is cystic fibrosis. I think thats a little further down the line because we dont, today, know an easy way to get the gene editing molecules into lung cells, where they would be necessary for cystic fibrosis. But that is a disease where, again, theres a well-known single gene that causes that disease. And then the other area of biology that I think is likely to be impacted by Crispr in the coming 5 to 10 years, I would say, is neurodegenerative disease in the brain. I mean

This is dementia.

Yeah, Dementia, Parkinsons, familial forms of ALS. I mean, these are all diseases where, again, at least in some cases, we understand the gene, or genes. Sometimes its a few genes that are involved. And Crispr in principle could be used to make corrections.

And breast cancer?

Well, breast cancer is harder. I think any cancers, there, I guess, the way I think about Crispr for a cancer treatment is more in the context of cancer immunotherapy as a way to help the immune system fight the cancer.

Yeah. All right, well, lets talk about the darker side of Crispr, obviously. Its something you think about a lot in your book, A Crack in Creation. You describe waking up in a cold sweat from a nightmare. Youre introduced to Adolf Hitler whos wearing a pig mask OK. He wants to know more about your amazing technology. Do you still have nightmares like this? And what do you take away from that?

Yeah. I mean, I think that dream, for me, came kind of relatively early on in the evolution of the development of the technology and, for me, was kind of a crystallization, I guess, of unease that I had and just things that I was thinking about, kind of nebulous fears that kind of all came together in that dream. And I havent had a dream quite like that since, but maybe thats why it really stood out for me. It just it really was kind of this moment, in a way, of, oh my gosh, this

You woke up.

Yeah.

You had this dream, and you woke up, and then did what?

Yeah, and I was sweating. And I just thought, oh my god. I mean, what have I done?

Yeah.

And realized

Its your little Dr. Frankenstein moment, right?

Kind of, yeah. And I just think that, for me, that was one of the kind of stepping stones to getting comfortable, if I ever did. I dont know if I am comfortable, but getting more comfortable, at least, with realizing that, OK, I need to step out of my lab, and I need to start talking about this publicly. Because this is a technology that has great risk.

Right, so lets talk about that. Because, again, we talked about you are fine with gene editing for alterations that arent passed on, that essentially dies with the patient. Then germline editing, which is explain what that is, and why did you want a moratorium, because you declared that five years ago. And it feels a little like Oppenheimer opposing the H bomb.

Well, lets start with what germline editing is. So it means making genetic changes that are heritable. That means they can be passed on to future generations. And so if you introduce a genetic change using Crispr, lets say, in sperm or eggs or an embryo, that is then used for either fertilization or for then implantation and to create a pregnancy, then those genetic changes become part of all the cells in that individual. And they can be passed on to future generations. So its a profound thing to think about because its one thing if youre tweaking a gene for I dont know eye color or something. It sort of sounds pretty innocuous. But its very different if you start thinking about changes that might affect somebodys fertility or their intelligence or their other properties that they might have, even their physical properties. And then how that might be misused, where you can certainly imagine lots of misuses of that.

Oh, one can always. Theres been hundreds of science fiction movies where thats misused, right? Its been imagined.

Its been imagined, yes.

So have you become more flexible on germline? When you just said eye color is innocuous, is it?

Well, is it? Yeah, its a great question. Personally, would I ever use Crispr to change color in a child of mine or advise someone to do that? No. I wouldnt. And I think that with any technology, one has to balance risk versus benefit. And with something like embryo editing, theres still a lot of risk that goes along with it, that inadvertent changes are made. Or even if it was perfect at targeting the gene youre targeting, we dont really know what the long-term effects of a lot of mutations of that nature would actually be in an individual. So I just dont I dont think one could condone that. But I have to say that when I first started thinking about that use of Crispr, I felt really opposed to it. I just thought I just cant I cant see anyone justifying that. But in the intervening years, I guess I have come to appreciate a couple of things. One is that theres a lot of fundamental biology that is not known about early human development that might only be possible to discover using Crispr in embryos that are being utilized for research under appropriate guidelines, and not being allowed to develop beyond a few days, essentially, in the laboratory. And so Ive come to feel that there is value in those kinds of experiments, if theyre conducted under appropriate ethical guidelines. But I certainly dont think that the timing is right or that theres really any justification right now for using Crispr to edit embryos that are then implanted to create a pregnancy.

Right, so this idea of designer humans or genome-engineered humans. What do you think we lose if we start playing with genetics? Do we need genetic variation in life like this? Theyre not imperfections, if you think of it that way.

Absolutely. I mean, I think thats what makes human life so rich, right, is there is all this incredible variation. But I do think that, again, thinking some period of time in the future, lets say that we get to a point where Crispr use in embryos is well understood. Its possible to and we understand genetics of certain diseases. Ill give you one example. There is a gene that is clearly involved in high cholesterol in individuals. And heart disease is still a major killer in many countries, including the U.S. Imagine that you could use Crispr in families that have this gene that makes them susceptible to heart disease to give them the form of the gene that is protective against that. Would we do it? I think its possible, right? I think when the technology is clearly safe and were making that one tweak to one gene, I think that could be something that some families might decide they want to do.

Who decides, from your perspective, when its dangerous? Because the National Security Agency released a report on threat assessment and include genome editing in there as a potential weapon of mass destruction.

Yeah.

What scares you the most about where the technology could lead, without any laws in place?

When I think about how it could get rolled out, I think it could happen in the context of in vitro fertilization clinics that, for example, offer a menu of traits and say, check off. I want my baby to have this, that, the other thing. And then were going to use Crispr to make those tweaks. I think that makes me uncomfortable certainly now, partly because, technologically, its just not realistic to do that without a lot of risk, but also because of what you just said. Who should decide that? And how would you monitor the health of individuals who were born after that kind of treatment? And I think these are very big questions

So who should?

that have yet to be addressed.

Who should, from your perspective?

I guess I do feel that if we look at the history of in vitro fertilization, that does offer a road map. Is it the right one? Im not sure, but it is a roadmap. And as you may know, that technology developed, in many ways, in kind of a very grassroots sort of way. There was no top down prescription of, heres how were going to do it. It was more just initial efforts to use it, kind of in a one-off way. Louise Brown, of course, a very famous first baby born as a result of IVF. And when it was clear that she had sort of developed normally, I think many people that were facing infertile lack of fertility, this became a very realistic option. So I think that we could see Crispr getting deployed in a similar fashion, where there will be kind of one-off uses here and there. And depending on the outcomes, that will start to be more widely adopted. [MUSIC PLAYING]

Well be right back.

Two years ago, a Chinese scientist shocked the world. A pair of twins had been born to an HIV positive father. And Dr. He Jiankui announced he had modified their embryos to make the newborns HIV resistant. They were the worlds first Crispr babies. The scientist who engineered them was found guilty of illegal medical practices and is currently serving a three-year prison sentence in China.

What levers and regulations exist in the scientific community?

Well, lets start with here in the U.S. In the United States, since the 1970s, weve had regulations in place that really make it impossible for anyone here to get regulatory approval to create a pregnancy. So what I understood from talking to the scientist who reported this, He Jiankui, is that I think he really felt that this would be OK. I think that he didnt think that he was breaking any laws or that he was doing anything illegal at the time. I think he saw himself, in a way, as somebody who was bringing this technology to people that might, in the future, want to use it with their babies.

Yeah, and he e-mailed you to tell you about it. Is that correct?

He did, yeah.

Can you recap that? Youre getting that email. What did you think?

Yeah, well, I got that email. I was actually here in the U.S. I was about to leave for a conference on human genome editing, the second international summit, which was happening in Hong Kong. This was two Novembers ago. And it was Thanksgiving weekend, in fact. And I received an email with a subject line, Babies Born.

Oh, no.

And yeah, it was kind of one of those nightmare emails that came in.

But not a nightmare, a real one.

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Kara Swisher and Dr. Jennifer Doudna on CRISPR and Its Possibilities - The New York Times

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