The Two Sides of Gene Editing

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Kevin Davies: Now we can think about surgically just fixing one letter of the DNA sequence without even having to completely cut the double helix. So, new flavors of gene editing called base editing and prime editing. There are companies in the clinic now with different diseases. The next five to ten years are going to be very exciting.

Zachary Karabell: What Could Go Right? I’m Zachary Karabell, the founder of the Progress Network, joined as always by Emma Varvaloucas, the Executive Director of The Progress Network. And What Could Go Right is our weekly podcast where we look at, yes, what could go right. Or at least we look at what’s going on in the world with an eye toward things could go right, not just the assumption that things will go wrong.

And this is all framed by a belief, and I think a legitimate belief that most of our contemporary commentary about everything that’s going on in the world is more framed by an expectation of all the things that are about to go wrong than framed by the expectation that things could in fact go right, that human beings are capable of solving human problems. So today we’re gonna have a conversation about technology and science, and health and medicine. And we don’t, I think, talk quite enough about health and medicine and the nitty gritties of science and innovation. And today we’re going to look at something that is on the verge of, if not already, going to affect the very warp and woof of our health and lives and longevity and medicine is the endometriosis.

in ways that has happened really quickly, really in the past decade. So who are we going to talk to today, Ms. Varvaloucas?

Emma Varvaloucas: So today we are going to talk to the CRISPR guy. We’re talking to Kevin Davies. He’s the executive editor of the CRISPR Journal. And he has been writing about genetics for a very long time.

He’s the author of five different books on it. The most recent is called Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing. So that’s what I mean by he’s the CRISPR guy. He’s also working on a book now about the biography of sickle cell disease and the relationship between CRISPR and sickle cell is a very important one.

We’re going to talk about that very soon. So are you ready to talk to Kevin?

Zachary Karabell: I am. And for those of you listening. We ourselves at The Progress Network have engaged in our own mini me form of CRISPR because we do occasionally edit these conversations and these videos in ways that you would never know, but which our team at The Podglomerate is in charge of.

So, I like to think that we’ve, we’ve done our own form of kind of very, very early stage CRISPR, but now I think we should talk to someone who really knows what he’s talking about.

Emma Varvaloucas: The dad jokes, the dad jokes are out of control.

Zachary Karabell: Oh well, gotta live with them.

Kevin Davies, it’s a pleasure to have you with us. We probably haven’t done quite enough science given that we are, If you had to force us into one camp or another, we’re a little more techno optimist than not.

That doesn’t mean we’re kind of in love with Silicon Valley as an ethos or culture. It just means, you know, if you’re going to look at the potential of human beings to solve problems that human beings have created, look to technology as much as anything else. And granted, a lot of what you do is solving problems that the universe created, or God, if you believe in that, not human beings.

So, we probably don’t touch on science quite enough, and it’s probably because neither of us are scientists, you know, we are guilty as charged as full blooded humanists. For those people who don’t understand what CRISPR is, except as a way to order their bacon, maybe you could illuminate people as to what it is you are focusing on, what it is you have dedicated your career to, and what the hell all of this means.

Kevin Davies: I’ll be happy to give that a shot. So, I trained as a geneticist, and certainly for a while harbored dreams of coming to America from London, where I’m originally from, and building this fantastic academic career. I did my PhD in London with a group in the 1980s, hunting the gene for cystic fibrosis.

We didn’t know it at the time, but we were competing with a chap named Francis Collins, who, I don’t know whatever happened to him, but we’ll come back to Francis later, perhaps. The idea to find the gene that is mutated in patients with a terrible, fatal genetic disease was inspiring, and we thought by landing on the gene, isolating the DNA, that’ll give us the clue to the mechanism and then we’ll be able to cure it.

And we were beginning in the mid 1980s to think about gene therapy as a possible solution. We would take this mystery piece of DNA. put it in a Trojan horse of some sort of a virus, let’s say, inject it into patients, or in the case of CF patients, maybe give them an aerosol, they would breathe this in, the virus would go into the cells that are abnormal, and somehow this gene would get to work and we might cure the disease that way.

Maybe we could cure Parkinson’s disease, or Alzheimer’s disease, or muscular dystrophy. But we never, when we were having these strategy meetings often. down the pub one evening, we never thought that we would have a tool, a scalpel, a genetic scissors, as the Nobel Committee called it a few years ago, that could actually go into the nucleus of our cells, identify the precise section of DNA that needs to be repaired, and effect, basically repair the pothole, repair the single letter of the genetic code that needed to be fixed in order to restore the normal function of that gene.

And so in a nutshell, that is the new power that CRISPR has given us. It’s really, I think the best way to think about it is this is DNA surgery. We do all kinds of amazing 21st century surgeries. We have heart surgery and brain surgery and whatever organ you’re interested in. But we can now perform DNA surgery, as I’m sure we’ll talk about during the course of this program.

We will. We’ve seen the effects, we’ve seen cures, essentially, of patients with sickle cell disease and thalassemia as just the first in what I hope, over the next 10, 20, 30 years, will be just a litany of treatments. genetic diseases and cancers that are potentially successfully treated and cured thanks to this technology.

Emma Varvaloucas: Yeah, so maybe let’s fast forward a little bit as you did towards the end there and talk about, it seems like, you know, while the ideas and the research for CRISPR have been around for 25 years plus, all of a sudden in the last few months there’s been a big fast forwarding of like what’s actually on tap, let’s say, what’s actually available.

You know, you mentioned the FDA in the US approved the treatment for sickel cell beta thalassemia. I think it was December of 2023. So I wonder if you could tell us a little bit more about why now, right? Like what’s happened in, in the recent, very recent past, and what can we look forward to in the very recent future, as you were just referencing?

Kevin Davies: Sure. This CRISPR revolution, it’s really happened very, very quickly. The breakthrough paper that really got the ball rolling was published only a little over a decade ago. This was a collaboration between Jennifer Doudna and Emmanuel Charpentier. They published their paper in 2012. CRISPR is a naturally occurring system of bacterial immunity.

So over a couple of decades, scientists figured out sort of the mechanics of how bacteria are able to defend themselves against viruses. When I was doing my PhD 40 something years ago, we learned about one immune system that bacteria have called restriction enzymes, and these little guys enabled the first revolution in genetic engineering, really the whole recombinant DNA era of the 1970s and 1980s that gave rise to the biotechnology industry.

We would never have guessed that lurking in plain sight was this other immune system that was discovered in the 2000s. And Jennifer and Emmanuel were able to, with their colleagues, were able to adapt this system to say, if bacteria have a tool, a protein and a little bit of RNA that they can use as sort of a heat seeking missile to identify an invading virus piece of DNA and cut it to essentially inactivate it, why can’t we adapt that system and now use it to target any piece of DNA in any organism that we want? So that was the sort of the essence of their paper. Within a few months in 2013, scientists were able to show that this could actually work in human cells. That was not at all a foregone conclusion because the context of human DNA is vastly different, completely different planet to a little bacterial genome.

That worked, and then biotech companies started to be launched, all the key players launched companies, and it’s really the beginnings of those companies that led to, okay, what diseases, what’s going to be the low hanging fruit as we perfect CRISPR gene editing and put it into the clinic? Sickle cell disease was one of the choices of CRISPR Therapeutics, one of this for the first wave of companies.

Other companies chose different diseases for different reasons, and we can touch on those a bit later. CRISPR did therapeutics later on, partnered with Vertex Pharmaceuticals, which had already shown its strengths in developing a whole range of drugs for cystic fibrosis, which we were talking about a minute ago.

But they said, let’s get into the gene editing space. And if there’s ever a patient population in the United States that really deserves to feel the benefit of modern medicine, having been essentially ignored for over a century, the sickle cell community is it.

So the trial, the clinical trial, began in 2019. The first patient, first American patient in that trial has become quite well known. I’ve had the pleasure of meeting her a couple of times now, Victoria Gray, and she told her story in a series of great interviews on National Public Radio. So she’s now more than five years out as the first patient in literally now dozens of patients on this trial, and they’re all reporting spectacular results, which is why the FDA with very, very little pushback from any of the experts who were looking at this gave the final formal approval for Casgevi and another gene therapy drug developed by a different company, Bluebird, in December of last year, as you said.

So now we’re seeing and hearing about the first patients who are now with, thanks to their own or their family’s insurance companies, finally beginning to see insurance companies offer coverage so that they can now receive the same benefits as Victoria and the other patients in the trial did over the past few years.

Zachary Karabell: I want to go to a minute to, like, Jennifer Doudna and CRISPR and COVID. My understanding is the way the world, particularly the United States, particularly with Operation Warp Speed, responded to COVID was to do what we had done with infectious diseases for a long time, which is to look for a vaccine or cure, but that there was an alternate path that’s more in the immunotherapy land, that rather than being a shot that you take that boosts your immunity, you know, you could essentially use CRISPR enhanced technologies to create lasting immunity to a whole spectrum of, let’s say, coronaviruses or other stuff.

But that the commercialization of that and the way you would do those and distribute them doesn’t line up the way vaccine development, procurement, and selling does, so that there’s like a mismatch between what we’re on the verge of being able to do scientifically and immunologically and kind of what we’re able to do commercially and, I don’t know what the word would be, but like within the system of how we distribute these solutions.

Is that an accurate question? Is it inaccurate? What’s your response to that particular conundrum?

Kevin Davies: As the pandemic broke out in early 2020, Jennifer at her lab at UC Berkeley and many of the other leading scientists who developed CRISPR gene editing technology were increasingly interested in using CRISPR as a diagnostic, and they were beginning to develop the first CRISPR based kits that could potentially one day rival all the at home and PCR kits that we’ve all become so depressingly familiar with over the past few years.

But they had to put, or they elected to put their labs on hold and just use their resources, use their personnel to fill the gap in basic routine testing for their local communities. So this happened in the Bay Area, this happened in Boston, and I’m sure it happened in many other facilities as well.

So I think there is a lot of hope down the road and potentially if we face future pandemics that CRISPR will have its uses. I think the, as far as developing some sort of super immune vaccine or something like that, I think that’s probably at least a long way, a long way out. So that’s not something I think we’ve heard too much about, at least from legitimate sources just yet.

Emma Varvaloucas: That reminds me, actually, there’s quite a funny New York Times review of your book, Kevin, that came out in 2019. And if you read the review, the whole thing is essentially like, well, CRISPR was really not that helpful for the pandemic, so I just really don’t see the use of this going forward. It has aged incredibly poorly, so if anyone reads that review.

Kevin Davies: Yes, the book came out in 2020, on the eve of the Nobel prizes, ironically, for Doudna and Charpentier, and the New York Times, Carl Zimmer had written this review. They’d expedited it to sort of, you know, catch the wave of the Nobel prize announcement. So I was very happy about that. But yes, it did have a sort of a bit of a, twist, sting in the tail, where he said, you know, if CRISPR is so great, yes, how come we’re still, you know, all suffering here, stuck at home?

So yeah, I don’t think CRISPR has solved that just yet.

Emma Varvaloucas: Well maybe you could tell us a little bit about why you do think CRISPR is so great. I mean, you know, you mentioned like the very little FDA pushback, which I’d like to come back to. I mean, part of the reason for that is because like the results are so amazing for sickle cell. So there’s that, but also what’s coming next?

Like what are your, what are you looking at?

Kevin Davies: Yes, I do not mean to give the impression that the FDA weren’t taking a very stern, long look. They absolutely did. But I think, Emma, you said it beautifully. Yes, the results were so compelling. Obviously, the scientists and the clinicians involved in the trial had been publishing in peer reviewed journals, the New England Journal of Medicine, interim results, so the whole world could see and were pretty much unanimous in thinking and judging that these results were about as good as anybody could dream up.

When the patients go into the trial, they were, by definition, very ill. They were experiencing multiple pain crises. The pain that a sickle cell patient experiences, as I’m sure you are aware of, is literally off the charts, it is absolutely excruciating, and this can result in weeks, sometimes months in hospital, and there’s so little effective therapy.

So as more and more patients underwent this cell therapy and came out the other side, they were experiencing a newfound energy and health that they had literally never experienced before. Pain crises disappeared, the need for blood transfusions disappeared, hospitalizations disappeared. And this was repeated patient after patient after patient in both the Vertex trial and at the Bluebird trial as well.

So six weeks before the ultimate FDA approval, there was a big, it was all open to the public and I watched with great interest and anticipation, an advisory committee meeting, to really dig into one, perhaps for some, still unanswered question, which is just how safe is this therapy? You’re giving patients a little RNA heat seeking missile to go into the nucleus and identify the one stretch of the single gene or chromosome region that you want to, you want to edit, you want to cut.

And the hope is that you’re not somehow seeing that same sequence somewhere else in our 23 pairs of chromosomes, our 3 billion letters of DNA. But Vertex did a very compelling job of showing at that meeting, as they had for years before, there was simply no off target effects that they had to be worried about.

So while this was a theoretical concern, there was literally no practical reasons. And over the last few years, the FDA, I think, has been, the bigger issue has really been the manufacturing of some of the viruses and some of the reagents that have been needed. That, that is where some of the FDA holds in some other trials have been found, not because of concerns about off target effects. So we’re all basking in the early glow of the success of the Vertex and Bluebird trials. Other companies are also developing slight variations of these approaches. We’ll start to see those come up before the FDA in the next year or two, I have no doubt.

And other companies are using CRISPR to attack other diseases. So liver diseases, liver is a very spongy organ that is very good at taking up viruses and other particles. So it’s a very attractive organ to target for liver specific diseases. So a company called Intellia Pharmaceuticals has a couple of programs there.

Another company up in the Boston area called Verve Therapeutics is looking at heart disease, and although they had a slight setback, their long term goal is that gene editing could be, again, attacking the liver, could be a way to genetically reduce levels of bad cholesterol. And the number of applications is going to grow, as is the fundamental technology.

So all of these systems, or most of the systems I’ve just very briefly summarized, have used the flavor of CRISPR, that for which Doudna and Charpentier won the Nobel Prize. But scientists don’t stand still, and just because CRISPR has shaken up the world of gene therapy, that doesn’t mean we sort of sit back and say, okay, we’re done here.

On the contrary, we are constantly iterating and looking for other ways to either expand on the CRISPR chassis, the CRISPR platform, or look around nature for other ways that we can kind of modulate DNA. And we’re seeing amazing progress in both of those. So, final point on this question, when the Nobel Committee gave out the Nobel Prize in 2020, they referred to CRISPR as the genetic scissors, which was quite nice, but the way it works is it literally cuts both strands of the double helix of DNA. Since, well, even before the Nobel Prize, other groups were starting to work on other flavors of gene editing that are much more delicate and potentially even more precise. So now we can think about surgically just fixing one letter of the DNA sequence without even having to completely cut the double helix.

So new flavors of gene editing. Cool. Base editing and prime editing. There are companies that are promoting these. They’re in the clinic now with different, different diseases. So the next five to 10 years are going to be very exciting.

News Clip: Joni is now one of the first people in the world to have his genes edited using CRISPR to treat his disease.

I’m like, wow, that’s, that’s pretty cool and scary and freaky.

You feel like a medical pioneer?

I don’t know, I feel like, I feel like a guinea pig.

In sickle cell, a genetic mutation causes red blood cells, which carry oxygen around the body, to be misshapen, like crescents or sickles. They can get stuck in the blood vessels, causing severe pain and decreased oxygen to organs.

CRISPR allows you to make a precise cut in DNA. In this case, cells are removed from the body and edited to turn on production of a different form of the oxygen carrying protein hemoglobin.

Zachary Karabell: So it’s interesting in the kind of court of public opinion that CRISPR has, for whatever series of reasons, enjoyed largely very positive reception.

Maybe because it is seen as ameliorating diseases that have confounded the ability of previous generations to deal with, whose amelioration is perceived rightly as an unalloyed positive. And then you juxtapose that with the incredible negativity about genetically modified organisms, which in many ways is a slightly earlier and rather different way of dealing with the genome, which is rather than using a scissors and editing, you insert foreign DNA into an organism, often plants and crops, to have a desired outcome.

And as we know, particularly in the European Union, generic feeling about genetically, about GMOs is an unalloyed negative, right? I mean, if you asked person X on the street in Germany, France, Great Britain, what they feel about GMOs, you would be hard pressed, I think, to find more than one in 10 who would have a favorable response.

And yet you’d have a lot of people having a favorable response to CRISPR, which is interesting in that they’re both essentially the manipulation of the genome. One is inserting foreign, which I guess strikes people as inherently more I don’t know, creepy, threatening, frankenfoodie, even though as we know, transgenic mutations do occur naturally and have occurred naturally, meaning it’s not just a function of contemporary science that foreign DNA can enter into a genome, although we accelerate it and target it.

What I find interesting is, I’m writing a book about corn right now, so this has been on my mind. And that the EU in particular has started to recognize in their generic suspicion of these technologies, that edit once and you maybe help sickle cell, edit twice and you do something else, edit 20 or 30 times and you’re kind of creating a new genome via editing, right?

Meaning you can manipulate into something new if you edit enough. So there’s like discussion of limiting the number of snips to somehow bound the process. I mean, I’m just wondering what you think about, eventually this stuff’s going to confront regulatory and or ethical and or moral questions. And we may be at the beginning of a kind of a efflorescence of optimism about this, which I think is great, by the way.

But you’ve got to anticipate some degree of both regulatory and cultural, eh, wait a minute.

Kevin Davies: Well, I think you’re absolutely right. There is most people, including I think many people listening and watching this podcast, would probably say they would be loath to knowingly eat GMO food. I would probably argue that, you know, if even inserting a piece of inert DNA, even if it comes from a foreign organism, is probably not something to be overly concerned about.

And yet, if we’re going for shopping in Whole Foods or some fancy grocery store, we see all the non GMO labels, and we sort of think almost instinctively reach for the, Oh, that’s, that’s, that’s going to be good for me, you know, along with all the other labels that they put on. And it’s being taken, to ridiculous extremes.

We have now, you know, non GMO water and non GMO salt substances that literally cannot be genetically modified. So somebody’s having a bit of a laugh.

Zachary Karabell: I’ve seen gluten free water.

Kevin Davies: Gluten free water. I have to try that.

Zachary Karabell: You know, non GMO gluten free water. You’re like, right on.

That’s great. Thanks so much.

Kevin Davies: I think, Zachary, you said it nicely.

The whole, the major selling point of CRISPR, with regards to engineering crops, is that it’s a completely precise tweak of the genetic code. We’re not putting in anything foreign, we’re simply making a very subtle, but nevertheless important single base change that may be the difference between this crop surviving drought, or a pest, or a parasite.

And we’re seeing countless examples around the globe where if we don’t take and use the technology that we’ve developed over the last couple of decades, we’re going to really struggle even more than we are now to feed the planet. There was a case recently where, I think largely due to Greenpeace, which meant well, I’m sure, but their campaign against golden rice, a vitamin A enriched rice, has blocked the growth of that crop in the Philippines, which could be potentially disastrous for thousands, if not millions of people.

CRISPR, yes, if you, it’s taken to extreme, perhaps some of the concerns that you raised, Zachary, would have to be looked at. But the pro CRISPR lobby would say, we are simply using our ingenuity to make a specific precision edit to affect an outcome rather than the alternative, which is bombarding genomes of plants with x rays and other mutagens and crossing them and taking decades to get to the same point.

So why are we using our heads here? Unless somebody could absolutely prove there is some safety concern, I’m waiting for that day. And I think I’ve been waiting a long time.

Emma Varvaloucas: Well I guess like some of the moral considerations, you know, that we’re talking about here is like, well, if you can go in and precisely edit just one thing, why not precisely edit away Down’s Syndrome? Why not precisely edit away ADHD? Why not precisely edit away, it’s the slippery slope argument, right?

I know the really big case that many people think of when they think about this is the Chinese scientists who edited the human embryos, and I think there’s three kids now that are, what, six years old out there living their lives, but anyway, yeah, I’d love to hear some of your thoughts about some of those arguments where this just kind of turns into like a weird, eugenics, creepy science thing.

Kevin Davies: All of the cases, all of the examples we’ve talked about in the last 20, 30 minutes have been what we call somatic gene therapy. We’re just affecting the cells of the actual patient. There is literally no chance of any of these edits being passed on to the next generation. But six years ago, a young, very ambitious Chinese scientist named He Jiankui, I’ll just call him JK for ease, who trained in America, did his PhD in Texas, did a postdoc at Stanford, so, he’d been training and mentored by some very smart, very influential scientists. He got lured back to China to start his own group. He launched a DNA sequencing company. He was doing great. He really didn’t have to go down this slippery slope, as you, I think, rightfully call it. But a number of other Chinese groups had published, in 2015, 16, 17, early experiments applying CRISPR on non viable human embryos, just for scientific reasons, to see how gene editing might work in that context, but with no, importantly, no obvious desire to then re implant those embryos.

This is purely for scientific research purposes. He Jiankui didn’t see why he should stop there. It was, I think, for his own ego, for his country’s reputation. This was the way he felt he could smash through the ceiling. So he decided to tackle a disease, HIV, that is still a major public health issue in China.

And the idea was, if he could make an edit of a specific gene that is the lock to the HIV key, then it, any child born with this particular edit, even if exposed to HIV, they would be resistant. The science was sort of well established, but nobody, nobody thought that anybody should go ahead and actually try to pull this off.

So I spent three or four chapters in the middle of my book, Editing Humanity, which is peeking over my shoulder, talking about this case, which flared up in late 2018, a week I will never forget. I managed to persuade my company to send me to a bioethics conference. That takes some doing, particularly when it’s far away in Hong Kong.

And as I landed and opened Twitter, I’d never seen, you know, my phone, the closest my phone’s ever come to blowing up, I think, as it emerged that JK had announced that he had actually overseen the birth of a pair of twins, gene edited twins, Lulu and Nana. He was outed, in a way, by a brilliant piece of scientific journalism by Antonio Regalado, an intrepid investigative journalist at MIT Technology Review.

He’d actually met JK in an off the record meeting, and one of my favourite parts of the book is describing this meeting, because Antonio was in China making a documentary film. And the director of the film shared with me footage from after this off the record meeting where he opened his, opened the camera, put it on, and asked Antonio and his other colleagues to quickly summarize what they had just heard from JK. He hadn’t said he wanted to bring about gene edited CRISPR babies, but he’d said everything but that, and they were all pretty much convinced that this was inevitable. When Antonio went back home to the United States, he began a sort of three week crusade to find any traces online of what this scientist JK was doing. And Thanksgiving weekend, 2018, he finally found the smoking gun, a backdated clinical trial registry, other incriminating documents, and so his story, although he didn’t know that the CRISPR babies had been born, he knew that that was the ultimate plan. And ironically, it turns out that JK had been working with an American media consultant who had brought in the Associated Press in confidence to write up and orchestrate the big reveal.

So Antonio was able to scoop the Associated Press, which then had to sort of belatedly come out with its own story revealing the birth, as well as JK uploading to YouTube a series of quite extraordinary pre recorded videos announcing the birth of these children. Later that weekend at this conference, he was, he’d been previously invited, there was a lot of questions as to whether he would show up.

He showed up. I give him credit for that. One entire side of this huge auditorium at Hong Kong University was filled, filled with media, photographers, camera crews. It was more like a rock concert than a scientific convention. Yet he walked onto the stage in almost complete silence. I had snuck from the media pen at the back of the conference down to the front row, and I, there’s a post on YouTube of my sort of shaky handheld iPhone footage of this entire walk of shame in a way, as he then tried for 20 minutes to defend what he had, what he had done.

So what happened after that? He was eventually tried and sent to jail. The world came down on him. Nobody really supported the experiments that he had done, because, of course, the changes, the edits that he made in these twins are now part of the fabric of their DNA in every cell, including their germ cells.

So if and when these girls, Lulu and Nana, and as you say, correctly, there’s a third child who was born a few months later. If and when they reach reproductive age, those edits will be passed on to their future children, or there’s a 50 50 chance that they’ll be passed on. And it’s one of the, I think, most damning pieces of criticism that was levelled at JK in the aftermath of this episode. How could you dare to tamper with the gene pool of the human species without consulting other members of the human species. That still gives me goosebumps. Ironically, he did consult a few members of the species, but he swore them to secrecy. And one of the bizarre sort of side stories of this whole debacle is that a number of very prominent American scientists who swore to, sworn to confidence, taken into JK’s confidence, and even though I think some of them, or maybe all of them, wanted to spill the beans because they felt it was wrong, what he was doing was wrong, they didn’t know where to go. Who do you call? The director of the NIH? The president of the World Health Organization? The New York Times? Elon Musk? I mean, what do you, what do you do?

I don’t, I don’t think we’ve even solved that question. There’ve been a number of ethical panels and blue ribbon reports published. And interestingly, I think the experts, the report convened by the National Academy of Sciences that came out a couple of years after this, said, let’s not, no pun intended, let’s not throw out the baby with the bathwater.

Let’s not completely ban human embryo editing. There may come a point in the coming years where there is a medical scenario where this might be the only way that a couple could have a biologically healthy child. Those scenarios are very few and far between, but let’s not be so tempted to just, you completely exert a moratorium on this technology.

Meanwhile, after serving his almost three years in jail, JK was released. And a point I made in my book, and I think the reason that the book was actually censored and never published in China, even though I had a real Chinese publishing deal, is that, He was not the rogue scientist that I think many experts portrayed him to be.

He had friends in high places, and I think that’s borne out by what has happened since. He’s been rehabilitated before our eyes. He’s landed another gig at another university. He’s openly talking about reinstigating gene editing programs for muscular dystrophy, for Alzheimer’s disease, which he says his mother had.

He’s talking about helping to pay out of his own pocket the healthcare for the CRISPR babies, to which I say, well, you know, you broke it, you fix it. I mean, of course you should do that. But what their actual medical status is, we don’t know. Nothing has been revealed. And of course, they’re entitled to their privacy.

They may not know, their families may have no wish to tell them. So there’s so many still unanswered questions. And could this happen again? I mean, I fear, yes, at some point, I think it’s almost bound to happen again.

Zachary Karabell: I would be stronger than that, than your English modesty, which is, it is inevitably certain, unequivocally going to happen again and happen again in vast proliferation.

If the history of technology, containing technology seems to not be in the human societal DNA. Slowing it down? Potentially, yes. We have obviously these conversations about AI and how we want that particular set of technologies to evolve and with guardrails and there’s a lot of discussion about that.

There’s been more discussion about that in the bioethical community for a longer period of time with the recognition of, we are soon, I mean, people understood we were, we were going to have these tools, right? When the Human Genome Project started, all of this, I mean, you’re obviously have been around kind of present at the creation as it were, but there’s been an awareness that we’re heading in this direction and that this is going to happen.

And I think we’ll look back at this episode of JK and the firestorm that greeted him as a failed attempt to hold back the tide. Because you certainly have a lot of people in Silicon Valley who are with their own obsession with longevity and, and escaping death, you know, the temptation with both money and technology to pursue the death dream or the immortality dream seems to me it’s going to be just too powerful to contain and there’ll be government acts.

I mean, just like now you can spend a million dollars and get a Passport to Malta.

Emma Varvaloucas: In Greece is like 250 K or something to get a residency.

Zachary Karabell: Malta’s more expensive. I think people like want the Malta one more, you know? Note, note to our listeners, if you’re looking to bargain shop, go to Greece. Like some countries gonna go, Hey, you know, we’ll build a lab.

We’ll set them up, we’ll make this legal. Right? I mean it, so what are we gonna do about that?

Kevin Davies: If JK could do it, any scientists can do it. I mean, one of the, the, one of the reasons CRISPR became this global sensation is that it’s so easy to use. There were other flavors of gene editing before CRISPR came along, and before Doudna, Charpentier, Feng Zhang, and others did the great science that they did.

But CRISPR just proved to be so easy in comparison with these, with its forerunners that every lab was able to very quickly make progress with it. JK had no experimental track record. He’d published one theoretical paper about CRISPR during his PhD, and yet there he was literally trying to meddle with the genomes of human embryos.

Six months after the JK debacle, Russian scientists got a lot of press. Quite a well respected medical geneticist from everything I can gather, Denis Rebrikov, he said to anybody who put a microphone in front of him that he wanted to do exactly what JK had done, except rather than tackling HIV, he was interested in tackling a hereditary form of deafness, which in parts of Russia, it was quite a common genetic disease.

And with CRISPR, you could change the sequence of one of these genes that would render these newborn children hearing enabled, even though their parents were deaf. And he had enrolled patients, couples ready to embark on this clinical trial until the Russian health authorities told him to put his plans on pause.

I’m almost shocked that those haven’t been rekindled. I think what potentially worries me more is the sort of medical tourism aspect, that if we can do that for health diseases, genetic diseases, that’s one thing, potentially, you could make a case for that, but someone’s going to set up a clinic to change hair color or eye color or lighten complexion or whatever.

Emma, you raised a number of points and an easy pushback is, well, they can’t do that yet because the genetics aren’t that simple. We haven’t figured that out. But if there was, what if there was a longevity gene or some variant that we said, this isn’t the only gene that controls lifespan, but we know that this particular sequence at this particular point of the gene can give you a 10 percent or 20 percent increase in lifespan on average.

Would wealthy people be willing to take that chance and do that?

Zachary Karabell: The other question, which we do need to ask, I mean, at least, even if it seems like we shouldn’t is, A, what is exactly wrong with that, and B, it’s already beginning to happen in an acceptable way in that plenty of people are doing IVF, they’re freezing embryos, and they’re choosing the sex. Now, they’re not editing the sex, but they’re choosing them.

They’re saying, look, we want a boy, we want a girl. You know, we’re going to choose embryo A, not embryo.

Emma Varvaloucas: They scan all those embryos for various kinds of genetic abnormalities. clashes between your genes and your partner’s genes and all that. So it’s even a step further than the gender.

Zachary Karabell: And most people, I mean, at least from what I can gather, seem basically comfortable with that, right?

I mean, they’re going to be basically comfortable with the next iteration of it too. And I guess we do have to ask the question of, there is a gut reaction of, oh my God, no. But then you just have to ask, well, is that the right gut reaction? You know, is there something wrong with getting rid of hereditary deafness?

Kevin Davies: I think attitudes probably will evolve and change over time. And many other authors, Hank Greely, Eben Kirksey, Françoise Baylis, there’s a lot of very, very good books that probe this aspect of the story even deeper than mine. So I urge viewers and listeners to go and check out those, some of those sources.

Yes, IVF, which seems like it’s going to be a big part of the upcoming. presidential race here in the United States, is an interesting one because we do have this type of IVF where we can do pre implantation genetic diagnosis. So for families that have a very severe genetic disease, they can undergo IVF and then the doctors can take literally a biopsy, just aspirate a cell from the little bundles of each individual embryo to determine the genetic code at the gene in question in order to sort the embryos and decide which ones are suitable for implantation and which ones are just going to be put into suspended animation or even discarded. So we are, I think most people are comfortable with that, and it’s resulted in the birth of healthy biological children for thousands and thousands of couples. But because we have that technology that will work in 98 or 99 percent of any scenario that you could give me, so why we need to now start playing around with scissors in human embryos is a very, very troubling question. And we don’t even know if it’s safe. And the final point on this, I think, the first few papers where really respected scientists have looked at the fidelity of gene editing in human embryos, they’ve come away pretty scared, because the genomes end up far more jumbled than they would have anticipated.

So performing CRISPR or any type of gene editing in a human embryo, we’re going to need to do a lot more basic research to figure out just how safe it is to get the same sort of results that we’re seeing when we take stem cells and put them in a dish and take them to the laboratory and prepare gene edited cells to implant into a sickle cell patient.

Emma Varvaloucas: Do you think that that information might come out of China at some point about those three people, or it’s just going to be locked away forever?

Kevin Davies: It seems locked away right now, and as you said, it’s been almost six years since they were born, and I think, you know, we’re entitled to a certain amount of medical privacy in Europe and in the United States.

I don’t, that shouldn’t be any different in China. But I think there are a lot of clinicians who’ve watched this story who feel they would really like to know because they would like, if there’s anything that they can do to help these children, we just don’t know. We know that the edit that JK was trying to do with this one particular gene did not go as planned.

It never had a chance of going as planned. He was trying to mimic a naturally occurring variant. This is how we know this gene is part of the HIV entry process. There was no way he could just precisely cut out 32 letters of DNA. That was never going to happen. So by definition, he was creating walking human experiments.

And so that’s why it’s so troubling. We just don’t know how healthy they are. We know that he didn’t fix the gene in question, and we have yet to see data on all the other potential unforeseen edits that may have happened elsewhere. So I think everyone who is concerned about the long term health of these young children has every right to be concerned.

And I hope that JK, who’s shown very little contrition, he’s never apologized for this, he just simply says, it was too early, it was, the time wasn’t right. I hope he can find a way to, while preserving their anonymity if necessary, make sure that they get all the help that they need.

Zachary Karabell: So is this the next frontier, you know, if you think about what the debates are gonna be in the next few years, is this really where the locus is gonna be, which is how far do you take this in human beings, driven by the same set of desires that have led to lots of medical breakthroughs?

Kevin Davies: I think not, only because there’s so much more positive good that this technology can do, and all the other technologies that are still being developed that sort of take the essence of CRISPR and say, okay, now we can do that a little bit better or a little bit more precisely. Some technologies are looking to fix just single letters of the genome.

Others are saying, if we have a genetic disease that can be caused by literally hundreds of different mutations, we’re not going to fix them one at a time. Why don’t we just remove the whole brick out of the chromosomal wall and put in the healthy copy? That way, it doesn’t matter what mutation you have, one solution will fix all.

So there’s technologies making fast tracked, so, make those sorts of repairs. So we have thousands of known genetic diseases. We have patients with cancer where CRISPR is now being used as part of the CAR T regimen to immunologically help these patients, that’s also showing great promise. We really don’t need to be going down this sort of distracting blind alley of germline editing.

I mean, I say that, and then we’ll get a headline next week that says someone’s tried this again, and so we will be obliged to. But there’s so much good that this can do as part of the medical toolbox, and of course, plants, and you know, there’s so many other applications as well. You know, George Church up at Harvard Medical School has launched a company to resurrect the woolly mammoth.

That could be a whole other episode of this podcast, so we can come back to that another time.

Emma Varvaloucas: Jurassic Park, coming to real life near you, it’s very soon.

Zachary Karabell: Kevin, I want to thank you for your, your time today, it’s been, I think, an illuminating traipse through the CRISPR universe and its expanding boundaries much as we’re told our universe is, or I don’t know, maybe our universe has stopped expanding.

I guess we’re a little unclear for the, uh, the point of expanding or contracting, but for now we know CRISPR is definitely expanding. I think people should look at your book. I know you said it’s four years old, but it remains acutely relevant. You’ve been a wonderful communicator and a bridge somewhat between a locus of scientific debate within the scientific community, but also a way of communicating some of that to a lay audience that is deeply impacted by all this, but often doesn’t understand what the hell’s going on. So I want to thank you for that as well.

Kevin Davies: Thank you for the opportunity. I appreciate it.

Emma Varvaloucas: Yeah. Thank you so much, Kevin.

So I’m glad that Kevin turned things back around into a positive note there because we, I think it’s really important to discuss the moral considerations, especially when you’re talking about a public that by and large post COVID is very skeptical of the public health authorities, and the public health authorities are going to be the ones that are establishing regulations for this, right?

We didn’t get so much into that point about the FDA approval process for this and what they’re going to have to establish down the road but, as Kevin said, the reason why they approved these new treatments is just because, as he mentioned, you can read at NPR, what has happened to these sickle cell patients, it’s like basically, for all intents and purposes, a cure.

I am hoping, as he said at the end there, that the next 5, 10 years, the general public debate is going to be like, wow, amazing.

Zachary Karabell: You know, there’s another thing we didn’t get into, and this is something I’m focused on because of the book I’m doing, which is the applications of this in, in crop science, where you have a lot of bioengineering, which is not necessarily replacing GMOs, but it’s the next thing that a lot of companies are looking at as a way of, you know, drought resistant crops and nutrient crops that can grow with far fewer artificial fertilizers, and that seems to be creating far less public unease than the GMO issue, right?

So the CRISPR editing of, of seeds and crops is somehow not triggering the same frankenfood fears, but there’s a lot of breakthroughs there that are quite positive. Again, if you’re legitimately concerned about the effect of climate change on crop yields and soil depletion, you know, if you can, if you can tweak the genome of a lot of these crops such that they are, they don’t need as much water, they don’t need as much fertilizer, all these things are.

At least in theory, quite good for the planet if you’re worried about resource consumption. And that’s a whole other area too where this, this technology is having very positive applications in my view.

Emma Varvaloucas: Well, a question for you. Do you think that there’s been a lack of public furor around that because it doesn’t lend itself so easily to that like visual image of, as you said, frankenfood, like tomatoes with arms and like bubbles on them.

Do you think it’s just that or do you just think it’s that people are less aware of the fact that they’re doing that.

Zachary Karabell: I think it’s probably both, but I think the lack of awareness is that it doesn’t have the same, I mean, there was a really concerted sort of campaign in the 90s against GMOs because it had that resonance of like, foreign DNA, you know, alien DNA in your food.

As Kevin talked about, the editing, the snipping, the scissors, right, just doesn’t have the same visceral hook for people. So it’s harder even for people who are, I guess, legitimately concerned about science run amok, and particularly, this had a lot to do with the GMO campaign, concerned about the fusion of capitalism and technology or fusion of capitalism and science that at the end of the day, basically companies trying to make money will use whatever technologies they can use to maximize their profit, whether or not that actually benefits the health and safety and longevity of mankind, humankind.

So I think that’s the root concern. It was easier to seize on that with GMOs and it has been for gene editing and CRISPR. Maybe that’ll come, right? We just may be at a lull moment awaiting the tsunami of protests, but maybe the excesses of, you know, we’ve talked about this a lot, you and I over the podcast and throughout the Progress Network work, some of the extremes of both climate activism and apocalyptic, we’re destroying everything because of our technology, has its own counter reaction. So it may be that, I mean, we’re not the only ones to know the absurdity of saying non GMO water, right? At some point, even most people are kind of going, really? As these things become more ubiquitous, you know, we do calm down and start to try to integrate these things in a more balanced way.

Like there are things that we shouldn’t do that are harmful and there are things we should do that are helpful and we probably can be mature enough as a society to find a balance. It’s just takes a lot of imbalance to find that balance.

Emma Varvaloucas: Yeah, I think one, one final point that I’d like to make before we completely wrap up is that the other discussion we didn’t really get into is the accessibility issue, meaning, you know, you were kind of pointing to this in one of your questions is, we have all these amazing things and how many people are actually going to get to utilize them? And that’s kind of an unanswered question right now. I know just from research, so we did an article on this, um, back in December when they approved the sickle cell therapy, that insurance in the US has agreed to cover this, but it is expensive, you know, and it’s a process. It’s not like you just go to the pharmacy and take a pill, right? That’s going to be a question, a big question as well going into the future.

Zachary Karabell: Yeah, I mean, if we were going to continue the ethical question, the one that really is going to emerge is exactly that one, which is the thing that people feared, I think, legitimately for years, that you’d basically have wealthy people who create their own, their own bespoke babies or their own bespoke universe of health, and then everybody else is like looking inward, maybe with better health or worse health, but with the legitimate resentment of there’s like one standard of human innovation and biology and medicine and treatment for the wealthy, and then there’s basically everybody else who suffers what they may. And given current trajectories, that’s exactly the pathway we appear to be on.

Emma Varvaloucas: Wow.

Zachary Karabell: That’s a non optimistic, non What Could Go Right coda to a general What Could Go Right.

Emma Varvaloucas: Wait, wait. Why do you say that? Because I was going to say the opposite, which is that, you know, again, we need to get into this in the discussion, but the other kind of cool thing about this being the first CRISPR treatment to be approved for sickle cell is that Not only is there a history of sickle cell disease being ignored in the U. S. because it was mostly black Americans that suffer from sickle cell disease, there’s also a history of prejudice against them because they used to screen, well they still screen everybody for sickle cell now for health reasons, but they used to screen people for the sickle cell trait because they didn’t want to give them jobs.

So, in fact, like there could actually be a really effective treatment for this seems to be going in the opposite direction of what you’re saying, but.

Zachary Karabell: Well, that’s a good point.

Emma Varvaloucas: Yeah.

Zachary Karabell: I retract my negativity. Yes, there will be some wealthy people who benefit disproportionately or have access to new technologies because they can pay for them.

Emma Varvaloucas: Yeah.

Zachary Karabell: But then there’s everything you just said about sickle cell and that just overrides it. So I feel much better now.

Emma Varvaloucas: Okay, good. All right, did my job today.

Zachary Karabell: On that note, thank you all for listening to another episode of What Could Go Right? We’ll be back with you week by week by week through the election.

And send us your comments, sign up for What Could Go Right? at theprogressnetwork.org if you have not already. Send suggestions, ideas, you name it. We’ll listen. 

Thank you, Emma.

Emma Varvaloucas: Thanks, Zachary.

Zachary Karabell: What Could Go Right is produced by the Podglomerate, executive produced by Jeff Umbro, marketing by the Podglomerate. To find out more about What Could Go Right, the Progress Network, or to subscribe to the What Could Go Right newsletter, visit theprogressnetwork.org. Thanks for listening.