Instant Genius - CRISPR, with Prof Fyodor Urnov

Episode Date: September 12, 2021

Prof Fyodor Urnov tells us how CRISPR is already changing the lives of people with genetic disorders, and why it’s essential that gene editing therapies are accessible to all. Once you’ve mastered the basics with Instant Genius, dive deeper with Instant Genius Extra, where you’ll find longer, richer discussions about the most exciting ideas in the world of science and technology. Only available on Apple Podcasts. Produced by the team behind BBC Science Focus Magazine. Visit our website: sciencefocus.com Hosted on Acast. See acast.com/privacy for more information. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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In 2020, Jennifer Dowdner and Emmanuel Charpentier won the Nobel Prize in Chemistry for their development of CRISPR, a revolutionary method of gene editing. In this episode, I talked to Professor Fyodor Ernov. He works with Dowdner at the Innovative Genomics Institute at UC Berkeley in California, and he featured in Human Nature, a 2019 documentary about CRISPR. He tells me how CRISPR is already changing the lives of people with genetic disorders and why it's essential that gene editing therapies are accessible to all. CRISPR is something that probably most of us have heard of,

if we're at least vaguely aware of science news, but it might not be something that everyone knows exactly what it is, and it's a very complex topic. So just to start, could you please, in one sentence, just describe what CRISPR is? CRISPR is the equivalent of a word processor for the genetic material of any living organism from cow to human that allows us to change that genetic material in a way we specify. So CRISPR is a form of gene editing, but there are other forms out there as well, aren't there?

So how is it different to other forms of gene editing? I will admit that asking yours truly this question is a bit like asking a koala to speak about the different kinds of eucalyptus leaves that can be kind of Australia. Targeted genetic engineering was first practiced in smaller organisms such as yeast in the late 70s. And what then happened is scientists attempted

to use it in other systems and it just didn't work, including in the parts of the living world where we would most want it to work, like repair a mutation that causes disease, or change, let's say, a gene that causes a rice plant to become susceptible to drought. So fast forward to 2012 here at Berkeley, Jennifer Dowdna,

discovers that CRISPR Cass can be used for targeted genetic engineering. Now, it happens to be the case that genome editing was put together and named before that discovery. But in all practical terms, as far as the real world is concerned, looking out the window, what will that look like 10 years from now in terms of what has been gene edited? The vast majority of those things will have been done using CRISPR. And the reason for such a long answer to such a simple question is it's one of those situations where I think we need to be mindful of the broader outcome of a technology rather than its specific instantiation. In other words, I have no idea whether people will share music via Spotify or something else. The point is that

online music is a thing. CRISPR is today's non-dujure for the most efficient gene editing technology we have. So you work for the Innovative Genomics Institute. What is it that you do there? Try to use CRISPR to make for a better world. there has been $11 billion with a bee put into the overall sector of genetic engineering just in human health, so I'm not mentioning agriculture or discovery of drugs. And that shows that the for-profit sector is very excited about what you can do with gene editing. as we have learned through the pandemic of COVID-19, there is no global counsel for the equitable and just distribution of technologies to the planet

in a world where everybody benefits equitably. So Jennifer Dowden's vision for founding the Innovative Genomics Institute is to make sure that this extraordinary tool that we have is also used and applied and made available to settings where, I suppose, spontaneously emerging market-based processes may or may not lead it to. For example, the engineering of crops for parts of the developing world where climate change and other circumstances are creating major challenges, or doing better diagnostics for things like

SARS-CoV-2, where it's pretty clear that we're still lagging behind in terms of being able to rapidly and in the real world diagnose whether somebody has the virus or not. And the part where yours truly spends all of his life, how do we deliver medical treatments based on CRISPR to those who are most in need and who for reasons that will probably require five episodes of instant genius, the current, I guess, for-profit space in healthcare may not address. The most obvious sort of use of CRISPR of gene editing is in treating genetic diseases. So what kind of diseases could it be and is it being used to treat? You know, if you had asked me this question 10 years ago, I would have gone on a long string of hypotheticals with featuring words like we are hopeful

to and perhaps or someday here we are in September 2021 when I can give you specific example. about human beings walking the earth that has been CRISPRed. And not only has that happened, they are feeling better. And thus, we are sharing our planet with our fellow genetically engineered humans, which is an amazing thing to say. Earlier this year, we learned that the most prevalent type of genetic disease on Earth, which are disorders of red blood cell production, one is called sickle cell disease, and the other is called beta thalysemia

has been, as best as we can tell, safely and effectively treated by using CRISPR, where people's blood stem cells were removed. They got CRISPRed, put back in, and major disease symptoms, such as needing blood transfusions or experiencing pain, appear to have resolved.

Now, everyone who works in this field will tell you that nobody who works in this field is doing a victory lap. it will take years to make sure that these treatments are actually safe. And then, of course, we have the formidable challenge of how to make them accessible. But, you know, we learned about sickle cell disease in Western medicine in, I think, 1910. We've known that sickle cell as genetic since the 1930s. Vernon Ingram told us about the molecular cause of sickles in 1956, I believe.

And yet here we are only in 2021. a long time before we can say to the world, okay, after more than a century of study of this disease, we have actually built a technology that appears to be able to not just treat it, but as best as we can tell, cure it. The challenge with what I just described, and the reason that it's expensive to administer such a therapy has to do with, as I mentioned, taking the cells out of the body,

then crispering them and putting them back in. And let's just say that it's a laborious, and sophisticated operation, which involves dozens of people, large specialized facilities where people wear the kinds of protective gear you see in science fiction films. And that's, you know, because of a need to make sure that the therapies are made properly. But what if we could just inject CRISPR? And CRISPR would somehow go to where it needs to go and fix the gene it needs to fix and then go away, you know, quoting Eliza Doolittle, wouldn't that be leverly?

that's happened. So the first clinical trial I just described for sickle cell disease was done by a U.S. biotechnology company and European as well, CRISPR therapeutics. What I'm about to describe was done by a biotech company called Intelia. And they took a number of people, including some in the United Kingdom, who have a disease with a long name, TTR amyloidosis, which most of you, audience, has not heard. of. It's one of those things that used to be called genetic doom or genetic destiny. It's like, you know you have the disease and you kind of know what's going to happen to you and you're like,

you're looking with a sense of dread at the bleakness ahead. Well, so Intelia has engineered a CRISPR to get rid of the gene that causes the disease. That's not enough. They figured out a way how to get it into the human body literally via an injection. Okay, well, we've been able to to do injections for a long time. But the best part is they figured out how to get CRISPR to the organ, which needs crispering, and that's the liver. Last but not least, if an average person on the street with a disease says, would you like to carry some CRISPR in you? Most people would say, well, I wasn't planning on it. And the beautiful thing about gene editing, and this, I think, is really what sets it apart from anything else we've ever had in this space, is the genetic edit that CRISPR

makes in your DNA is permanent. But the CRISPR itself has gone. It's like literally a repair person. Imagine you have something wrong with your house or apartment, like you have a leaking roof. The repair person doesn't move into your house to stay there after the repair is done. They just leave. Similarly, in this clinical trial, CRISPR got injected, went into the liver of six individuals, got rid of the gene that needed to be gotten rid of, and then basically vanished. Or the technical tremors got rapidly degraded.

So I will admit to you, if you were asking me five years ago to write a utopia that says, Fyodor, why don't you just fantasize about how great the future could be with the CRISPR clinical thing? I really couldn't write a better story than reality has brought us. You know, here we are with more than 35 people who have been crispered for their severe disease of the blood, safely and effectively, early days but still. and six people got CRISPR for a severe disease of their nerves and heart, and they appear to be quite well. So no victory laps, nobody's eating scoops of ice cream, you know, at 2 in the afternoon,

but the palpability of the excitement is there, is there. I'm amazed that you can just inject CRISPR and it can work. work in the body. So I always imagined you would, you know, take a sample and then you would, you know, do the gene editing in a lab and then, you know, put that back in the body as you, as you described with the sickle cell disease. So how is it exactly that CRISPR actually works that allows you to be able to just inject it into the body and it can cure what it needs to cure? Sorry, I realize this may be a very complex question. Not in the slightest. Happy to explain. Think about this as a set of directions to a party,

counting backwards from when you've walked into the room and you give the host, you know, a bag of cookies you baked. So in order to do that, you need to get through the door. In order to do that, you need to get to the house. And in order to get there, you need directions from where you are to where you're going. So for CRISPR, the Nobel Prize winning discovery by Jennifer Dowdna and her colleague Emmanuel Chauphanier

has to do with the last step, which is when inside your body, when inside your cell, when inside the nucleus of your cell where your DNA is, how does CRISPR get to the destination? You know, when there's this person on American TV, her name is Marie Kondo, and she talks about this concept of things having to spark joy. This is the part of CRISPR that sparks joy. because, you know, your audience, of course, is familiar with a classic structure of DNA where one strand pairs with another in a way that James Watson and Francis Crick figured out in formidable part based on data from Rosalind Franklin and Maurice Wilkins and others. And your audience will remember from, you know, elementary school that there are these very simple rules through which one strand matches with another where if one strand has an A, the other has a T, if one has a G, the other has a C, it's, you know, It's one of those facts like Pythagoras' theorem that you kind of learn when you're 11 and forget for the rest of your life.

Jennifer and Emmanuel discovered that if you arm CRISPR with a tiny snippet of nucleic acid with a string of 20 letters, then CRISPR will run around the nucleus in a way we still don't completely understand. And then we'll find in this enormous stretch of genetic text, which is human DNA. And let's remind ourselves that human DNA is very long. If you read a letter of it a second, you know, like A, G, C, T, it'll take you a century to read the whole thing, a century. It's a very long text. So now imagine having a molecular machine, you give it a 20-letter string, and it runs around the entire human genetic text and finds a match. I mean, you know, I suppose we humans think of this quite naturally.

You know, if you give, if I tell your audience, what is the origin of the phrase, oh, brave new world that has such creatures in it, you know, everybody will say, oh, my goodness, it's the tempest. That's what Miranda says to prosper, right? Well, I use that quote on purpose. Talk about Brave New World that has such creatures in it. CRISPR, it's Mother Nature's machine to take a tiny snippet of nucleic acid, genetic text, and run around any amount of genetic information and find a perfect match. Okay, so that's how CRISPR gets to the gene. Now, how does CRISPR get inside the cell? So it gets inside the cell because it got packaged in a little droplet of a lipid. And the lipid is built to fuse with the cell and release, so fat basically, and the fat releases the cargo into the

cell. How does the, I'm starting to sound a bit like, you know, this is the house that Jack built. How does, how does that lipid droplet with the CRISPR get to the liver? It was engineered to go there. So the way that is technically done is scientists. And I should also say this is one of those amazing examples where people from different disciplines have to converge to get this to work. You know, you have to have different skills, different superpowers. And so a group of people separate from the CRISPR engineers have spent a lot of time figuring out how to package things and then inject them into the body in a way where they go to a specific destination.

And they're the ones who figured out how to get something to the liver. So the long answer to your very short question is CRISPR gets packaged in a special libel droplet, which is technically called a lipid nanoparticle that has been engineered to, A, get to the liver, in this case, B, release the CRISPR cargo into the cell, and then Mother Nature takes over, armed with Jennifer's and De Manuel's Nobel Prize-winning insight,

to then route that CRISPR to the gene of interest to do to it what we need to do. That's example number one. A shorter example is, in some settings, it's actually beneficial and logistically better to put CRISPR inside a virus. Viruses are Mother Nature's way to get into things. Now, let's just be clear. This is not a disease-causing virus.

This is an inert virus that has been gutted of all its viral virality. Instead, its gut has been replaced with CRISPR. The only thing that is left of its virusness is the ability to get into a particular cell type. And I'm really excited in about two weeks we should hear from a biotechnology company called Editus. And they're about to tell us what happened on their clinical trial when they put CRISPR coronavirus and injected it into the eye of somebody who, I hope, I'm using the word right, had congenital blindness, because if our hopes and dreams are fulfilled, they should be able to

see. We don't know yet, fingers crossed. So I can kind of intuitively understand how gene editing could be used to treat genetic disorders. You know, you can just, in some way, you can go in and you can change the genes or you can turn off the genes. But are there any diseases it can cure that aren't specifically caused by genetics? That's the big hope. You know, there are 5,000 different genetic diseases and collectively they affect, you know, 200 million people, at least on Earth. You know, it's a, it's a raw fact of the living universe that, you know, everyone will at some point succumb to a disease. How do we deal with those? There is clear promise on two fronts. The first one has to do with cancer. We've made,

remarkable progress over the past two decades in understanding the molecular basis of what causes cancer. And, you know, there are some remarkable examples where that understanding has led to very strong medicines. So, for example, melanoma, especially when it metastasizes, is a horrific cancer. And there is a medicine called Ketruda, which is a protein, which causes the human immune system when injected into a human to attack the tumor. Incidentally, I bring this up because that fundamental notion was discovered and reduced to practice by Berkeley's previous Nobel laureate, Jim Allison, I meant previous before Jennifer's discovered. But, you know, to be honest with you, we don't really have cures with a capital C for most cancers.

And so this is where a remarkable new direction has emerged, which is using CRISPR to genetically engineer human immune cells to attack the cancer in a specific and potent way. There have been some early stage clinical trials with a bit of promise. Now, before anyone in your audience starts to frantically search clinical trials.gov for a CRISPR, and I think they're absolutely coming,

this field is, while very rapidly developing, needs, I'd say, about another two to three to four years to start delivering on the promise of what we think would happen. But in the big picture of the vision is this. The vision is to make cells that have been crispered to attack a cancer and critically resist the cancer's attempts to defend itself. And a really good example, I keep mentioning Berkeley, well, I wonder if you can tell why I'm a professor,

But it just so happens, it's a center of innovation. So there's a biotech company in the Bay Area called Caribou. And it came out of work at UC Berkeley. And they're one of the companies along with others, for example, such as allergen and others who are trying to build these off-the-shelf T-cells to fight cancer. I want to be clear. We need a few years for this to play out. So that's sort of non-simple genetic disease number one.

The other, and for this, I will admit, to having a sort of an end-a-moment. emotional conflict of interest. Heart disease runs in my family, and I'm not excited. So there is a biotech company called Verve, and they're doing what I think is some of the most interesting work in putting CRISPR to use for a common disease, which, as you guessed, it happens to be cardiovascular dism. So you will say to me, but Fyodor, but cardiovascular disease is not genetic, or at least not trivially genetic. It has to do with history and diet and this, that. We don't know, right? right, except that there are people who are genetically protected from it. I mean, I don't want to use the word one, the genetic lottery. There is no genetic lottery. But there are rare individuals who lack

a normal form of a gene, and nothing appears to be wrong with them, except they appear to be really resistant to heart disease, no matter what their lifestyle. And, you know, if I were speaking with Mother Nature, I would definitely ask her for that gene, but it's a bit too late. I'm already here. Well, so the remarkable thing is it's not too late. So what Verve is doing is they are developing a way to put CRISPR into humans to give people that heart disease protective gene. How do you actually do that in the world of medicine where it's kind of hard to do a sort of a preventative treatment when what you're doing is so experimental? So it turns out that there is a charted path for this. And it's also in the cardiovascular disease space. I strongly suspect that a good fraction of your audience takes

statins for cardiovascular disease prevention, it so happens that they weren't developed or approved for prevention. They were developed and approved to treat a rare, severe form of heart disease, that is genetic, because they were so novel at the time, this was the early 80s. And so scientists developed this thing called statins, and they tested it on people who are really succumbing to genetic heart disease, and they improved. Then scientists and medists, physicians, turned to the regulatory authorities, such as the Food and Drug Administration and the U.S. and said, hey, this is working really well in genetic heart disease. Can we try it for sporadic heart disease?

They tried it and it worked. And then the physician said, look, it's working so well. Can we prescribe it for prevention? And that's why, you know, I think there were like 220 million prescriptions, including one for my dad, who's 86, to take a statinous disease prevention rather than treatment. So the path that Verve is taking with CRISPR is conceptually similar.

They have developed a way to use CRISPR, again injected into the bloodstream, to get rid of the gene. And we know that getting rid of it should protect against heart disease. They've shown some pretty magnificent data in the most important non-human model that you have to do this experiment in, which is non-human primates. And they have spoken publicly about the fact that sometime next year they are intending to take folks, you guessed it, with genetic heart disease and try to use CRISPR to give them this protective variant. If that works, I am certain that what they're going to do is try to follow in the footsteps of statins, which is to turn to the Food and Drug Administration and say, hi.

This is working really well in genetic disease. Can we try it for sporadic? So that's example number one. Example number two has to do with pain, which is you like talk about and now for something completely different. The reason I bring up pain is the theme is similar, you know, like tens and tens and tens of millions. of folks in the states and certainly worldwide, suffer from chronic pain of that sort or other. And some of it's severe, like trigeminal neuralgia

can be terrible or pain when you have cancer, which really resists opioids. So right now the way this has managed, quote-unquote, is using very strong medicines such as fentanyl, which unfortunately is addictive, and addiction to it, you know, has killed tens of thousands of my fellow Americans in this past year and continues to. So is there a way, is there a crisper play here?

there is. So it turns out that there are rare individuals who experience no pain. They lead a terrible life. You can't live without pain. Having said that, when people looked at their DNA, it turns out that the reason they experience no pain is they don't have a function in copy of a gene, which makes a protein, which lives in your spine, which sends the pain signal from wherever you're pained, like a knee or your face, to your brain. And so the pain signal is the transmission of the pain signal. The transmission of the pain signal is broken. Now that you've heard me speak about Verve, trying to create a natural protective variant for heart disease and people who don't have that variant, I'm sure it will not surprise you that a company called Naviga is trying to do the same but for the pain gene.

Namely, they are trying to use a different form of CRISPR to inject it into the spine, to tune down in people who experience severe pain for one reason or another. The gene, that drives the pain sensation, not to the point where they don't feel any pain, that's not good, but where the pain is tolerable. So taking a step back, I've described two specific examples, one in heart disease and one in pain, with the same underlying theme. We study human genetic variation. We find rare individuals who are either susceptible or protected to a disease.

And in the case of finding variants that protect us, what you then do is you use CRISPR in its various forms and you develop a plan, speaking with the Food and Drug Administration or the European Medicines Agency, to try to give a person without the variant that genetic variant using CRISPR to treat existing disease. And if that works, to then expand the scope of that use to less severe forms. So, frankly, I am hopeful. You know, I'm 52, I think. You know, I am hopeful in 10 years to please be CRISPR for my heart disease risk. It would be amazing. I strongly suspect I will develop chronic pain of some sort, other than my heart. I'm just kidding.

I will experience chronic pain, and I'd love to be crispered for that as well. And I want to be clear, I'm joking. Of course, it has nothing to do with me. The dream, of course, is that folks, that this would be broadly and equitably available. And what I think is really inspiring about the promise of CRISPR is it could be a one and done. Right. So statins have to be taken daily. Opioids for pain have to be taken frequently.

the vision for CRISPR as an amazing way to help the world is you get CRISPR at once and then you wish that person a happy, healthy life. And that, of course, going back to telling you about the Innovative Genomics Institute is, is really what we're trying to achieve here. We want to build ways in which CRISPR can be affordably developed and delivered to make sure that it's not just, you know, some Berkeley professor daydreaming about being CRISPR. but like the rest of the world. Right, absolutely. Thank you. This is a really, really massive topic. So we could talk about this for hours, I'm sure, but I'd just like to wrap up this first episode

by asking you, what three things do you really think that everyone should know about CRISPR? It came out of human curiosity. Jennifer Dowdner was not trying to build a revolutionary gene editing tool. She's just deeply curious about how the world works. And so I think your audience should take comfort in the fact that the formidable investment

that governments around the world make in such fundamental research gave us such an amazing technology to affect human health. Two, the promise of CRISPR to make a better world is much greater than the many worst-case scenarios that you hear out there. When I speak with folks about CRISPR, the very first thing that comes out of their mouth, oh, designer babies. And I go, no, no, no, no, no, not designer babies. Nobody's making designer babies. This is, and nobody ever should. I tell them about cancer and heart disease and sickle cell disease and blindness. So thing number two to know about CRISPR is the real world uses to treat genetic disease and other disease

are the thrilling future of this technology. And three, for all of the astonishing promise of CRISPR in human health. Our vision here at the Innovative Genomics Institute and frankly worldwide in everybody who works with this is that the bigger impact will be in the context of global warming. We can make

crispered crops and animals in a way where they have no foreign DNA so they're not, they don't have a different gene. They just have a natural variant which protects them from drought or disease

So we are not, you know, as some people say, quote, playing God. We're collaborating with Mother Nature. We are listening to her language and speaking with her on her own terms and respectfully taking her discoveries and just putting them to good use. So the promise of CRISPR to address global warming with a particular angle on engineering the crops and animals that we hear, humans need to lead an equitable and sustainable life is very formidable. And I think this is something we work on very hard at the IGI and many people work on

and that your audience should be excited. Thank you for listening to this episode of Instant Genius. That was Professor Fyodor Ernoff. If you want to know more about CRISPR, check up documentary Human Nature, which is available on Netflix or Amazon Prime video. Or to hear him tell me more about gene editing, head over to see you. to the Instant Genius Extra podcast. The September issue of BBC Science Focus magazine is out now.

Pick up a copy install or visit ScienceFocus.com. This podcast is sponsored by Name, Audio and Focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name Audio believes you can have digital precision with analog warmth. Alongside French acoustic specialist vocal, name creates high-end audio systems. combining innovation with craftsmanship, so you can listen to music, just as the artist intended. Discover more at name audio.com.

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