Clinical Applications and Future Potential

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Listeners of this shel will get a seventy five dollars sponsored job credit at indndeed dot com slash podcast That's indndeed d. com slash podcast. Terms and conditions apppply. Need a hiring hero? This is a job for indndeed sponsored jobs. There are still questions and ethical issues surrounding the powerful gene editing technique known as CRISPR There's no doubt that it is already changing lives We're not talking here about designer babies although we will in this episode but editing human DNA to cure diseases and save lives I no longer have experienced severe pain and stopped my life just to be in the hospital for long periods of time My children no longer have the fear of losing their mom to sickle cell disease But the gene editing tool is only a decade old, and like all new technology, the implications are still somewhat of a black box. By using it to modify animal and plant cells, scientists are accelerating evolution and introducing novel genetic combinations that could transform our biological landscape in unforeseen ways But imagine ridding the world of milarious bading mosquitoes. So how do we balance the uncertainties of CRISPR technology with its promise This is Big Picture Science, and I'm Seth Shastak. I'm Molly Bentley. From practical hurdles to ethical challenges, we explore how a powerful gene editing tool is already rewriting DNA. This episode is CISPper Mosquitoes We've had unusually heavy rains in the past few weeks, which has been great for these plants, but it does prompt me to search around the yard for standing pools of water so we can avoid breeding a nuisance. Male and female mosquitoes will mate with each other and the females will lay eggs. Like here in this flower pot, I'll just pour this out I'll just pour it on the plant here. And typically females will lay eggs in bodies of water. Here's another not much water in that, but it doesn't take much. It just takes a quarter of an inch to create a mosquito incubator. then and then the next thing you know in the middle of the night is that awful wine and you're slapping your neck And females also have to feed on blood to help them to produce the proteins that they need to then produce eggs And that's why females will bite humans and other animals. males don't bite, they don't need to do that. Perhaps there's nothing that unites humanity so much as shared dislike of mosquitoes. and it's understandable that we do just about anything to get rid of them. We have. With the more discovered DDT and special sprayers, sections of the city are blanketed with the insecticide in the fight to stop the spread of the dread poliomolitis. Every suspected spot is sprayed did not work out. Aside from the toxic effects of DBT Mosquitoes do not carry Pio But they are vectors for many diseases, including malaria, West Nile virus, dengue, and Zika And so scientists have long searched for a safer way to rid ourselves of this pest. My name is Nathan Rose. I work for Oxitech, which is a biotech company based in the UK My title is the Head of Malaria Programs at OxyTch, and I'm a molecular biologist by training. Dr. Rose's team is controlling mosquito populations early in their lives in those breeding pools. By modifying male genomes with what's called gene limiting technology, they ensure that the baby females never reach adulthood So what OxyTch does is we release male mosquitoes which don't bite. They will mate with the wild female mosquitoes And then when those female mosquitoes lay eggs and produce offspring They only are able to produce male offspring They're not able to produce any female offspring And so that's a way of getting rid of the females, which are the ones that can actually bite and transmit diseases Oxatech is running the first open air release of modified mosquitoes in the United States But the company is not using the gene editing technique CISPR Scientists using CISPR on mosquitoes are restricting their work to the lab for now CRIPR and genene Limiting Technology Altered DNA. Identifying how the approaches differ though, will help us think about the practical and ethical implications of using CRISPR on all genomes, including human That is Is CISPR just another way of editing DNA or is it fundamentally different? Some people, Greenpeace and others will view any kind of genetic modification involving the outside world, involving non humans is a step down a slippery slope. Some of those slippery slopes are more slippery and lead to more dangerous places than others I'm Hank Greeley. I'm a law professor at Stanford University, where I directed Center for Law and the Biosciences He reminds us that we have been modifying genes for centuries. Everything we eat, everything we grow, are dogs and cats. We have modified their genomes with those brilliant geneticists named our ancestors. Our farmer and herder ancestors changed everything They just did it in a different way So let's look more closely at how Nathan Rose and his team are controlling the most irritating of all insects. And for that, we go to the humid, swampy southeastern coast So Florida is a part of the United States which has an invasive mosquito species called eighties Egyippti And this is the mosquito which can transmit diseases like dengue, Zika virus, yellow fever Broward and Miami Dade Counties both have a locally acquired case of dengue fever. And a couple of years ago, actually in the Florida Keys where we are now doing releases There was an outbreak of dengue fever. aboutbout sixty to seventy people got dengue in Florida That was before we started releases of our mosquitoes And this invasive species, unfortunately is not as effectively controlled by insecticides and other control tools as we'd like And so we need new tools to help the local mosquito control authorities to be able to stop this disease spreading mosquito He says that the company's release of around five million mosquitoes is a proof of concept that the technology works in the United States, and now the EPA has approved the company releasing billions of mosquitoes in the coming years We've already demonstrated it in Brazil for several years. So in Brazil, when we released our self limiting male mosquitoes We were able to reduce mosquito populations by ninety five percent in the areas will be released. And so it works really effectively. And in Florida, we've just been basically carrying out the same kind of demonstration to show that we can have an impact on the mosquito populations there. And did you have a similar result in Florida? What were the results in limiting the mosquito populations there So what we were doing in Florida was looking at a few different things. Initially, we were just looking at how far these mosquitoes were flying, how they were behaving, canan they actually mate with the local female mosquitoes And so we showed that that all happens as expected. And then in the last season, we were able to show reductions in the mosquito populations in the areas where all mosquitoes were released. So let's look more closely at how the technology of self limiting genes works Yeah. so what we did is in these mosquitoes, we used a kind of genetic editing method which allowed us to insert two genes into the mosquito's chromosomes And one of the genes that we inserted was a fluorescent gene, which basically allows us to which mosquitoes are modified Be when we put them under a microscope, they will glow a certain color and that way we can tell which mosquitoes have been released by us and which ones are Okay, but you have to put them under a microscope. You don't see them zipping around glowing like fireflies. No, they don't do that. When you stick them under a microscope with a certain color of light, then you will see them The second gene which we put into these mosquitoes is what we call the self limiting gene And this is a gene which causes female mosquitoes to stop developing when they're in the very early stages of development So the gene produces a protein, which then inhibits the general development of the female mosquitoes And mosquitoes start their development in water, so they will grow as larvae in water Then they become pupy and then they adults What this self limiting gene does is it basically stops the females from developing past the larval stage of development I wonder if you could say more about how you insert that gene into a mosquito genome. So what we do is we take the eggs of these mosquitoes and we put them on a microscope slide. and then what we can do is we can actually insert a very, very fine needle into those eggs and inject DNA into those eggs And what happens is that DNA that we inject carries these two genes, which I talked about And that DNA will then insert itself into the chromosomes of the mosquito eggs And then once it's inserted into there, we let those eggs hatch And then we can basically breed from those hatched eggs, which contain the two genes And once we've got the mosquitoes that carry these genes, we can then establish a breeding colony of them And you'll remember I said that the genes cause all female mosquitoes carrying them to die We can actually turn off that killing mechanism in the lab by feeding them an antidote. That allows us to breed male and female mosquitoes in the lab that carry these two jeans But when they're in the wild, they don't have access to that antidote and that means that the females will die And you said that this was a small scale release of these mosquitoes and it was in a limited area Nathan, what would a large scale release of these self limiting mosquitoes? look like So in Brazil, we actually now sell these mosquitoes commercially. And the way we do that is we ship to people bo which comes with some of these mosquito eggs inside and some food for the developing mosquito larvae And so when a person receives this box, they literally just add water They put this box outside in their yard And after about ten days, these male self limitting mosquitoes will start to fly out of this box and then they will fly out into their garden, into their yard, into the surrounding neighbourhood and mate with the wild females, and then that will stop the offspring So a large scale release would look like basically placing these release boxes throughout a neighborhood or throughout a city. that has a problem with this particular disease spreading mosquito. And what would you say are the biggest benefits of this technology? They Obviously they could stop or slow down the spread of certain diseases like dengue and malaria. But could you really put an end, say, to malaria transmission So we target just a few selected species of mosquitoes. Dengue and Zika virus and yellow fever are all spread by one single invasive species of mosquito. which is now found throughout South America. It's in the Southern United States. And it really shouldn't be there. It doesn't come from this part of the world. And so what we're doing is we're basically targeting just the single species without spraying chemicals which potentially could interact and kill other beneficial species like bees, like butterflies and so on So we really see this as a very targeted, environmentally friendly way to target just this invasive species And we're starting to apply the same technology to some of the other species of mosquito which spread malaria So malaria is spread by different kind of mosquito called the Anopheles mosquito genus And in different parts of the world, you get different species of the Anophelies mosquitoes And we're starting to work on a couple of those. One that's invaded East Africa recently, and another one that's found in Central America Experts see great promise in the work that Oxitech is doing. In fact, Hank Reeey thinks that the prospect of editing human genomes is drawing attention away from the areas where we will see major practical applications of this technology I actually think that gene editing is going to be most important with nonhans. We're going to take more risks because we don't care as much about mosquito babies as we care about human babies We will take more risks. We will do it for some good things like improving agriculture It's going to be a lot easier to change the genes of crops than to move, say the wheat belt three hundred miles north with climate change. Really interesting use is to try to cut down on diseases Malaria kills four hundred thousand people a year They're almost all little children in Africa, so we don't hear that much about them four hundred thousand people. They all catch malaria from mosquitoes That's all very promising, but what if something goes wrong It's not like you can recall millions of buzzing mosquitoes if an experiment goes off the rails. For example, could the modified genes escape into the environment? What about the fear that some people have that animals that feed on mosquitoes could take up these genes? Or could there be other unintended consequences So These mosquitoes are invasive species, so there is no particular animal in the environment which relies on these species for their diet. So if we reduce the population of these mosquitoes We're not going to have an impact on the food chain That's a really important aspect of what we do In terms of the genes being picked up by other species, that's not likely to happen. So you don't pick up the DNA from a chicken or a cow if you eat chicken or if you eat beef it gets digested in your stomach. And the same is true for any animal that eats one of these mosquitoes Um These mosquitoes also only breed with mosquitoes of the same species, so that means they're not able to pass on these genes to any other species because they can't breed with them effectively What is motivating you in this project right now? and what are you feeling most hopeful about? You've had success in Brazil, you've had trials in Florida with releasing these mosquitoes and they've been successful For you as a scientist What is motivating you about this project and is exciting to you about it So one of the biggest challenges globally right now is the loss of insect biodiversity because of the overuse of chemical insecticides So we found a way that we can target these species that cause huge public health problems around the globe without needing to do that. So we can help to address a major public health problem In South America, in Africa, in other parts of the world in a way that's going to have a minimum environmental impact and we're really excited about that. Do you think that the public understands your goals? And I ask because I know in some cases where Oxatec has conducted trials or proposed the release of these modified mosquitoes, the local residents have expressed opposition. and I wonder how you have addressed A their concerns? Have you talked to residents or to local communities directly? Do they understand what's happening? We do. We spend a lot of time talking to residents and local communities in Brazil where we've released these mosquitoes for over ten years We have more than ninety five percent public support in the cities where we release these mosquitoes So people see the problem with disease and they see this as a way to protect them. And so they're very, very supportive And we've actually seen the same in Florida. So in Florida, we spent a lot of time talking to local communities. We went door to door in the neighborhoods where we release mosquitoes And we actually invited people to take part in these releases with us by hosting some of these boxes that release mosquitoes, by hosting the traps that we use to monitor the impact of the environment And we were oversubscribed at all of those things. We had more people signing up than we knew what to do with So we've actually seen really positive public support throughout the project in Florida. So imagine one day, instead of lathering your arms with insect repellent and spraaying your backyard putut one of those boxes out back and let the self limiting gene technology go to work. Now, as we've said, self limiting gene technology is not CRISR, yet, both introduce a gene into mosquitoes that is designed to be inherited. So what is the difference For one, and it's an important difference passasses genes down with a method called a gene drive Ge drive is where you try to basically overcome the natural inheritance patterns in biology So naturally you would inherit Ge from your father and your mother And so you would have two different copies of a particular gene And then when your children inherit that, they would inherit one copy of those genes going forward Gene drive basically forces every single offspring to have two identical copies of a gene And what that enables you to do is to basically push a gene throughout the entire wild population of a particular species. So instead of a fifty percent chance of inheriting a gene, it's certain, it's one hundred percent. It's a hundred percent chance of inheriting that gene. And you can use CRISPA to accomplish that. So one of the concerns around that kind of gene drive approach is Is there a way to stop it if we needed to for any reasason? And so a lot of work is going into figuring out how could we achieve gene drive, but also be able to put an end to it if we needed to Whereas with your technology, the gene limiting technology could stop at any time It'll stop in any time and because it's causing all of the females that inherited to die, you'll see that those genes will disappear from the environment naturally very quickly Nathan Rose, what a pleasure to talk to you. Thank you so much for joining us. It's a pleasure. It's been great to talk to you as well. Thank you Okay, so if I've got this right, the primary difference between the technologies is how many generations forward each go. With CRISPR, there's no end, but with gene limiting technology, well, it's limited. Well, the CRISPR tool has been called revolutionary. It's so easy to use, it's been compared with the you, find and Rplace function in your word processor So, what happens when we start applying it to humans? An ethesis weighs in next. This episode of Big Picture science is CRISper Mosquitoes. This episode is brought to you by Accenture. When your advertising operations fall out of sync, everything else follows. Spotify and Accenture are working together to reinvent the rhythm of ad sales, using automation, analytics, and smarter workflows to simplify campaign delivery and access better data across the business. The result Less time spent on operations, more time connecting brands with the moments and fandoms that matter most Learn more at Acenture d. com slash Spotify appropriate gift for the ten year anniversary of a landmark scientific paper. twenty twenty two marked a decade since we learned about a gene editing tool different from anything that came before. Although, to be fair, credit for CISPR really goes back to something that came long before was invented by an anonymous bacterium. threeree billion years ago or so It's a bacterial defense mechanism It's a way bacteria used to cut up viruses. Viruses invade us and cause us trouble N so invade bacteria, but bacteria fought back with CISPR Here's how it works. CRSPR employs RNA called guide RNA in the task of search and replace RNA is the cousin of DNA And RNA can identify and bind to pieces of DNA protein cuts through both strands of DNA at that location. So the RNA grabs and holds ono the DNA, then the CISPR associated protein And there are a bunch of them, the first and most famous is called Cast nine. It cuts through the DNA And that's what viruses wanted to do. By cutting through the DNA, they inactivated the viruses That's what bacteria did to viruses When the targeted gene is cut, it turns it off Now you have the option to add new DNA to that location What are the possibilities this brrings for editing human genomes? Well, theoretically, you could turn off the DNA in germ cells that make eyes blue and insert one that ensures your child has brown eyes. CRISPR has been called the new frontier of gene editing because it is faster and more precise. And the implications of this causes consternation. We're devoting an episode to it, after all Bioethicist Tank Greey wants us to maintain perspective Arguably a more controllable method But it's not new. It is different. It does deserve our attention and concern But it doesn't require hysterical responses Maybe not, but it does require thought about its use practically and ethically So I think the questions we need to ask around CRISPR from an ethical perspective, the first two really important ethical questions that People never seem to recognize these ethical questions are, is it safe and does it work Safety and efficacy are fundamentally ethics questions. It's unethical to sell people things that are unsafe or ineffective. Once you get past that, it's really a matter of How much contontrol Do parents or societies want there to be over what offspring should be like Some people will say we should have none The Vatican says any kind of interference with natural reproduction is sinful Other people will say, go for it. The transhumanists say, yeah, I want to grow wings. There're going to be lots of different ethical takes coming from lots of different ethical perspectives. But ultimately it turns into a question of just how much control do we think people should be able to have over their offspring I'm a parent. Every parent has a duty to try to shape their offspring Is genetically shaping importantly different? Some people say yes, some people say no And there is not going to be a single ethics answer to that. It depends on what ethical starting places you take doror Greeley has given these questions a lot of thought. His latest book is CISPR People, The science and Ethhics of Editing Humans Ag, to what extent is this a significant breakthrough? I mean, I assume that people have been working for a while on the the problem of trying to edit a genome And is CRISPR really, you know, head and shoulders above the earlier attempts? Is this a major breakthrough or mean I realize it's a qualitative assessment, It's not head and shoulders above. it's redwood trees above It is enormously better than what came before. People had been able to do gene editing using a couple of things invented in the ots in the two thousands They would take three or four months of lab work of several postdocs and several grad students They might work a third of the time I remember talking to a friend at the medical school shortly after the CRISPR stuff came out and I said, Hey, man, you is your lab using this CISPR stuff He said, Yeahah, I said, how's that working? He said, Well, you know, new tools, I figured it would take us a couple of months to get it down. It took us one afternoon There are high school students using CRISPR It is fast, it is easy and it is cheap I have to say the idea of high school students using CRISPR does give me some pause There are lots of different cells, of course, in the human body, but there's a real distinction between using CRISPR for editing or for altering somatic cells and germ cells mayaybe you can explain the difference here This germ cell has nothing to do with you getting the flu or getting COVID or getting a cold, different kind of germ. This is Germ from the Greek word for seed And we have about thirty five trillion human cells in our body Probably around thirty four point nine nine trillion of them are what we call somatic cells. They're your brain cells and your skin cells and your gut cells and your fat cells kidney cells, your liver cells, etcer. The only ones that are germ cells Are your eggs and your sperm. and the cells that lead to the production of eggs and sperm That's it. What makes them different If I changed cells on the tip of your nose and gave you a different looking nose. That change dies if I change the DNA in him, that change dies with you If I change cells in your sperm And the sperm that I happen to change finds an egg and everything goes right And there's a baby born baby would get that changed DNA So the difference between somatic cells in your body is they die with you versus germ cells, they can be passed on to future generations Your children, maybe your children's children, children's children's children, etcetera. the dramatic take on this is that, you know reprogramming a somatic cell just affects that one individual Whas editing a germ cell could in principle change of species Yes, although, you know, to be fair, If we edit some somatic cells to keep you from dying, young That also has effects on your children It doesn't change their DNA, but it majorly changes their life. And fixing diseases changes societies in big ways. So Yes, it's a difference. It's not quite as stark a difference as people sometimes like to make it out. But in terms of DNA, yes, only changing the germ cells changes the DNA of the next generations has been around a little bit of time now. It's not, you know the work of last week or anything. What are the possibilities with this technique for, you know, for human good. What could it do that we can't do any other way It's already been used now for over a decade, just a little over a decade for basic research. Let's say you're interested in what a particular gene does Well, Use CRISPR to knock it out in a cell line and seells in a dish And that'll tell you what happens to cells if they don't have that gene Lots of basic research going on with lots of different kinds of cells and lots of different organisms The most important and exciting stuff is using it to treat human disease No as far as I know, no crIisper related drugs or therapies have been FDA approved Yet But there's some that are really close A lot of them are for cancer oddly enough to try to change the DNA of your T cells and your immune system so they'll attack the cancer But there are also trials in late stages for things like sickle cell anemia and for beta alisemia Heemophilia Now those are all blood diseases and there's a good reason for that. With blood diseases, you can take blood forming cells out of the body And you can change them outside the body, see if you made the right changes and put them back Potentially there are tens of millions or hundred maybe even a hundred million people around the world who have serious genetic diseases for which CRISPR could provide reallyally curative gene therapies Could you extend that treatment to also modify, for example the germ cells so that you know none of the offspring other people suffering these diseases. would even need CRISPR to forestall contracting those diseases So that's been done a lot in mice and in rats and some in non human primates. And We think it's been done at least three times in actual human babies Back in November of twenty eighteen at the secondecond International Human Genome Editing Summit in Hong Kong It turned out that a Chinese scientist named HoZhang Hui had crispered human embryos and that two of them had been born as non identical twin girls. shortly before that conference. This resulted in a great uproar. It resulted in changes in regulations and legislation It resulted in her being sentenced to three years in prison in China because he did not follow there were a lot of rules that he didn't follow As far as we know, it hasn't resulted in any more kids, and one of the really frustrating things about it is So there were the two kids announced in November of twenty eighteen. There was a third child born sometime the next summer We have no knowledge about how healthy those kids are The Chinese claiming that they're protecting the privacy of the babies not releasing any information about their health, which is As shame. Well You know, a lot of your book talks about the fact that this was really an unethical experiment And it was done apparently, somewhat secretively, you know, was only announced after the fact to somebody listening to this interview, they might think, well, gosh, CrISPR sounds like it has such enormous potential benefits Why the heck not try and improve the survivability of these twin girls, right? I mean, what's the danger here So Danger is this had never been done in humans before And We had no particular way of knowing whether it was going to work well or not The danger is you get dead babies or disabled babies babies who are very vulnerable to unforeseen diseases later in life Ha was in too big a hurry to be careful And as a result, the biggest ethical problem with this research wasas it put these babies at high risks, risks they had never consented to, of course. for minimal potential benefits to them Part of that has to do with the fact that these babies didn't have any particular genetic disease. What who was trying to do was increase improve their resistance to HIV Should at some point in the next seventy years after they were born, they be exposed to HIV Even if it works, it's not an enormous benefit. But the risks of doing anything that for the first time in humans are enormous. It flunked many things, but the first and the biggest was the risks greatly outweighed the potential benefits I hardly need point out, although pointed out anyhow, that this is really the first time in the three hundred thousand year history of homo sapiens. that we have a capability to change the human race Um You know, is there any reason not to say, look You know, we're not going to wait for evolution. I mean, we're no smarter than the the inhabitants of the Roman Empire Right? T two thousand years have gone by, we're still basically the same the same people Maybe we really do want super babies So the super baby story is, I think, an interesting and complicated one Um Biggest problem is right now we don't have any idea how to make super babies I'm not even sure that in thirty or forty years we will because brains are enormously complicated You know, change people's knees, change people's kidneys, yeah, maybe, but change people's brains in predictable and good ways Brains are a third genetics, a third environment and a third chance All those thirds are really, really complicated. If we could Should we If it's safe and effective I don't have a big objection to it, although I think that's a question that different Societies, cultures, governments D. Prospective parents will have to answer for themselves I think ultimately governments will have to decide if we can do this safely If we can't do it safely, we shouldn't do it. But if we cant and safely for the babies, if we can do this safely Do we want to and for what kinds of things Those are ultimately going to be political questions as well as at the level of the individual parents personal questions. And I think different countries will do Should we get to that point, different countries will make different decisions about that And I'm okay with that. I don't think there's I think People who say We shouldn't enhance ourselves are not paying attention to our history You and I are talking We're not actually in the same room. We're not in the same city. We're talking thanks to our devices In a couple of weeks, I'm flying to Seattle But my wings are not going to get tired We've been enhancing ourselves constantly. I would actually say Rather than Homo sapiens, homo enhansens or whatever the Latin root would be should be our name. So Is this different? Well, it's different because it's biological. The biological feels different But I don't think it really should be. Greeley is a law professor at Stanford University, where he directs the Center for Law in the Biosciences. He is the author of CRISPR People The science and ethics of editing humans While there have been leaps forward using CRISPR on people, a prominent example is a woman who is now free of a painful genetic disease. That story is next on this episode of Big Picture Science Cisper mosquitoes Hey, it's Kelly Rolan. You may not know this, but I have eczema. so I get how it can steal your time. But why let eczema take over when you can talk to your doctor about EBLS? EblS Labrab LBKZ, a two hundred fifty milligram per two milliliter injection is a prescription medicine used to treat adults and children twelve years of age and older, who weigh at least eighty eight pounds or forty kilograms, with moderate to severe eczema. Also called a topic dermatitis that is not well controlled with prescription therapies used on the skin, or topicals, or who cannot use topical therapies, EBGlS can be used with or without topical corticosteroids Don't use if you are allergic to EBGlS. Allergic reactions can occur that can be severe. eye problems can occur. Tell your doctor if you have new or worsening eye problems. You should not receive a live vaccine when treated with EBGlS. Before starting EBGlS, tell your doctor if you have a parasitic infection. Paid partartnership with Lillily. Respect your time. Ask your doctor about EBLS and visit eBGlS dot com or call one eight hundred Lillily RX or onene eight hundred, five four five, five nine, seven nine. Here's a development that may be surprising While scientists have not released crISper mosquitoes from the lab They have used CRISPR to change human DNA in the real world Here are two examples. One is the great potential of CISPR to improve lives. The other, as Hank Greey explained, is that of Chinese scientist Ho Jun Kui, whom the science community sanctioned after his shocking announcement at the Second International Summit on genene Eediting in Hong Kong in twenty eighteen He had used CRISPR to edit twin human embryos We want to give Dror Heay a chance to explain what he's done in terms of the science in particular, but also other aspects of what he hass done We didn't know The story that was going to break over the last couple of days The story broke thanks to this reporter who was writing about CRISPR research I'm Antonio Regleto. I am the senior editor for Biomedicine at MIT Technology Review What happened is I had gone to China the month before the conference or the summit, the second international Human Genome Eediting summit to interview all the people involved in editing human embryos, right Some people had started to just edit embryos experimentally And of course, you know, I wanted to see how far they had taken it. So I met Hojangkui When I was there He did not tell me he had made babies, of course. But then later on, I came back to Cambridge, Massachusetts, where I live. And a couple of days before the summit started, I discovered his documents online. So technology Review actually published a story called Chinese scientists are creating crisper babies, which broke the story that he had already started these experiments And about two hours later, he put his videos online, YouTube videos describing the experiment. Two beautiful little Chinese girls named Lulu and Nana came. So we pushed it out into the light. And of course, the consequences were intense. The experiment was not accepted by the scientific community, and Hujangkui actually ended up spending three years in jail But by the time scientists met for the third international summit on gene editing in London in twenty twenty three, researchers had moved on from Hoe's controversial experiment They were focused on another crISper breakthrough O celebrated as a milestone. Good evening. I'm Victoria Gray and I'm a thirty seven year old mother of four and a sickle cell survivor. Journalist Antonio Regolato describes Victoria Gray's case, which he also wrote about for MIT technology review and its implications for the future of disease treatment. Victoria Gray is an African American woman from Mississippi who is Among the first to receive a gene therapy using CRISPR gene editing to treat sickle cell disease, which he has As early as I can remember, severe pain and trips to the hospital was just as normal to me as sunshine on a school day And you know, she was kind of the star of the summit because she described her experience getting this treatment. Well, first of all, she described her experience living with sickle cells. And it was terrible to hear. terrible I would start having pain in one arm Then the next, in a matter of minutes, my entire body would be taken over with severe pain That would mean Long trip to the hospital for me receiving IV fluids High dose pain medicines and possible blood transfusions I return home and try to be a normal kid I've seen her presentation. if anyone wants to see her presentation, it is online, the presentation that she gave to the International Summit. And as you say, she tells the story of how she was born with sickle cell disease. How was it interfering with her ability to be a normal kid Well actually, the part of the story that really was the strongest medicine was her trying to live with this pain as an adult I mean, your heart goes out to a kid, but as an adult and having our own kids I also became a mom But my health began to decline at a faster rate. I can recall getting sick on my fall break in october twenty ten and not leaving the hospital until january of twenty eleven. Sickle cells caused by errors in the hemoglobin molecule, which result in sickling of your red blood cells, you don't get enough oxygen and this causes episodes of incredible pain And she's got kids. She's trying to hold out a job and she's constantly going to the ER. be treated often with you know strong pain medications. And finally, she got fed up She started a quest as many patients do to see what science could do for her. I think it started discussion about getting a bone marrow transplant from another person. Bone marrow transplant can be curative for sickle cell, but then she ended up enrolling in a clinical trial that was gonna to test a CRISPR treatment. It's run by Vertteex, phharmaceuticals here in Boston. and she was One of the first patient enrolled. I'm not sure if she was the first to get the treatment, but she's certainly the most well known recipient of it In june twenty nineteen, my new super sales was ready. That's what I like to call them. Full of hope and faith, I traveled back to Nashville with my dad by my side. And finally, on july second, twenty nineteen, I received my new super sales. Within minutes and the manual push of three valves of my edited sales My life changed tremendously I shaed tears and joy After about three months, I was able to return home to be my family. It took about seven to eight months for me to physically feel. and mentally accept that I was better. It's hard to say if she's been cured. I don't think she used the big C word. And I would be reluctant to use it either, but It certainly sounds like her life has changed. And in fact, you know, when she gave this presentation to the summit There was not a dry eye in the room What made her story particularly moving And maybe another way to put it is why do you think that her story is not only moving but also important? Well You know, I think there's been a lot of focus on bad part of CRISPR, the CISPR babies in China O things that people are scared of, gene drives, you know There's this fear about the misuse of technology or people using it in ways that society doesn't want when you're treating someone for sickle cell disease, that's something that everybody can applaud and everybody did That is the ambition of all those scientists and all those researchers and doctors in the room. I mean Why do they go to work in the morning? They're going there because they want to Telp patients. It's also exciting And it's also interesting and important because Victoria Gray is an African American woman from Mississippi.'s like she's far geographically far probably well far from the people that are developing these treatments, right? I mean, they're at Stanford and they're at Verttex. So it's quite interesting that the first treatment that's probably going to reach the market involving CRISPR is something that in the United States would really be primarily for African Americans So at this summit and just in general, there's a big discussion about, well, if these treatments are so expensive, how are we possibly going to get them to the people who need them And in the case of sickle cell those are people in the United States, but also sickle cells most common in along the equator in Africa. thoseose are poor countries. Vertex, the company has no intention of taking their treatment there. Not in itsnt not in its current form Well, stepping back from the treatment of sickle cell disease specifically and looking more generally What does the Victoria Gray case mean for how routine CISR might be as an avenue toward curing a host of diseases. It's very clear to me, very clear that scientists including the scientists at Verttex, are all looking for the next generation treatment What Victoria Grey got is Genation one. She is one point zero They are working very hard to figure out how to deliver these crisper molecules into the body You would basically get hooked up to an IV for an hour and the molecules would drip into your bloodstream and they would home in on the bone marrow cells and edit them where they lie I can't tell you how important this is because if gene editing technologyies ever to reach you know, for instance in The Democratic Republic of Congo, where there's like a high rate of sickle cell It be this bone marrow transplant. You know, you need hospitals and you know you need all this infrastructure to do that But if it's just a drip out of a bag That could turn CrisSPper into like a huge public health measure, just like vaccines have been You can imagine going around and gettingetting rid of these horrible inherited diseases for cheap for pretty cheap It shouldn't cost three million dollars, you know, why does it cost three million dollars? I can't I can't say, but the actual physical ingredients. It would only be like a thousand dollars. But some of these other stories that are emerging are exciting. There's some exciting stories with CRISPR. One of which has to do with In my opinion, with human enhancement, if you want to talk about that Well, I'd like to stick to the Well yes, okay, okay I will I will take that bait. in what way could CISPR be used for human enhancement. You mean things like perhaps you could get me to speak French fluently or have stronger arm strength or just in general, have better memory, that sort of thing? It's even better than that. Well, I'll tell you what, the controversy about the ed I't know what's better than better memory, but okay, go on Buz's long life The controversy with editing the embryos was, you know, enhancement. Are we going to create enhanced human beings, you know, designer human beings. These babies in China were edited such that they would be resistant to HIV, right? They would not be able to get HIV because the edit was to remove the receptor for HIV from their bodies It was kind of an enhancement Although people, you know, scientists strongly rejected this creation of the designer babies, on the other hand, there is a company here in Boston called VerV which has a treatment, a CISPR treatment. it cells in the liver The purpose is to lower someone's bad cholesterol levels, right All you have to do is break one gene, you knock out this gene. It's called PCSK nine And your bad cholesterol levels, LDL cholesterol are going to plummet. Who are they testing this drug in? Well, they're testing it in people who have an inherited condition of ultra high cholesterol, hyper cholesterolemia, right? Their blood looks like you know, it looks like butter And these people end up having literally a heart attack at twenty five or thirty,, it is a serious condition All of us have this bad cholesterol, right? I don't know what your level is. I think mine is like one hundred forty or something. You know all of us have aer than it used to be higher than it used to be. Yeah Eactly, exactly, exactly. I went into the doctor and I was shocked. like you know, I never thought I had a cholesterol problem and then you know, suddenly my level was a little bit higher. And so it turns out this is one of the best studied molecules in its relationship to heart disease O the things is the best studied in all of cardiology. And so basically the cardiologists are like, this LDL it's a toxin that kills you little by little. You know LDL is biggest is like the biggest killer in the world, this molecule slowly poisoning you and faster if you have high levels. So you can imagine this crISPR treatment that knocks out this gene Well, why give it only to the people who have like the most severe cases? Why not everybody when they're twenty years old or twenty five, undergo this drip that I'm talking about, a drip of some crISper into your system and lower your cholesterol permanently? This would be in life extension technology. And the scientists who were involved,, I approached them and I said, is this an enhancement therapy? And I expected them to kind of dodge the question and they said, no It is or it should be, and it can be. Because the enhancement therapies or anything that give you a leg up allow you to live longer and live stronger and healthier lives. Exactly Now we can think of other areas of enhancement like brain, you knowra brain genes. Certainly, in these huge studies that are going on population genetics, people have identified genes that basically protect you against Alzheimer's as well So that would be an interesting one to have, I would take that. What's interesting about this is we started talking about Victoria Gray and talking about sickle cell disease and inherited diseases And now we're talking about using in this conversation, CRISPR to help lower cholesterol and perhaps fight against Alzheimer's disease Does that flow as naturally as it seems to? Is Victoria Gray the face of the whole future in some ways, whether she wants to be or not The face of the whole future of the potential us live longer and have healthier lives. It does flow. I mean Wh Jennifer Down, one of the inventors of the CRISPR teechnology. I mean, she's said many times, she's tried to get the point across is that this is profound. like this is, you know, this is the technology to change the molecular basis of who we are. Um And that's why it generates controversy and upset when it comes to the babies. It's much easier to understand and accept when it's someone like Victoria Gray, who's so sick You know, the genome is the genome and it can be it can be made better Antonio Regoladto, thank you for this wonderful overview. Terrific. Thank you guys Antonio Regolato is the senior editor for biomedicine at MIT Technology Review Well, that brings us to the big picture question, Seth. And the question that we asked at the top of the show was is CISper fundamentally different kind of gene editing technology. Well, I think in some ways it is because Well, it has high precision and ultimately it could be, I suspect much more affordable, which would, you know, suddenly convert it from boutique medicine or a boutique treatment into something that could be perhaps even routinely done It is a revolution. It's like the Germ theory, right I think medical history will be divided into before CRISPR and after CRISPR. Well the show would not be possible without the editing talents of senior producer Gary Niederhoff and assistant producers Brian Edwards and Shannon Rose Gary I am the executive producer of Big Picture Science, Molly Bentley. And I'm Seth Shostak, senior astronomer at the SEI Institute. We'd like to give a big thanks to our listeners and to our Patreon supporters. The original music in the show is by Dewy Delleay and June Miyaki. This episode of Big Picture Science looking at how gene editing technologies are rewriting DNA is called CISper Mosquitoes. You may be listening to our radio show, but you can also listen to By Pi Sci by subscribing to the By Py Sci podcast. You'll find links on our website to the platforms that carry us. And if you crave more big Picture science, you'll find it in our archive at bigpictures science. org Looking to get the most out of your money, your time, and generally give your life an upgrade? 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