Plain English with Derek Thompson - The Gene-Editing Breakthrough That Saved a Baby’s Life

Episode Date: May 23, 2025

Last year, Kyle and Nicole Muldoon welcomed their baby KJ into the world. Almost immediately, doctors realized something was wrong. KJ had been born with a genetic mutation that made it impossible to regulate the amount of ammonia in his system. The rare disease had the potential to kill him or cause severe brain damage. But KJ is almost 10 months old today. And he’s doing better than ever. Because this little baby has become a piece of medical history: the first patient of any age to receive a personalized gene-editing treatment. It's truly remarkable. In the hundreds of years of modern science, no human being had ever received a medicine designed specifically to correct their genetic mutation. A medicine built for one. That is, until KJ Muldoon. Today, we have a very special guest: Dr. Kiran Musunuru, the gene-editing researcher at the University of Pennsylvania at the center of this breakthrough. We talk about the full story of saving baby KJ, what this breakthrough means for science, and what we need to learn or change to make personalized genetic medicine possible at a larger scale. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Dr. Kiran Musunuru Producer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

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Royal Port Rush. Away we go. Today, the medical science breakthrough of the year. In 2024, Kyle and Nicole Muldoon welcomed their baby KJ into the world. And almost immediately, doctors realized that some, something was very wrong. KJ was born with a genetic mutation that made it impossible for the baby

to regulate the amount of ammonia in his system. This is a rare disease that was likely to kill him in weeks, maybe months. Today, KJ is almost 10 months old, and he's doing better than ever. Because this little baby has become a piece of medical history, the first patient of any age in any country to receive a successful

personalized gene editing treatment. I want to contextualize this accomplishment for a second. All of us have in our DNA a series of genetic mutations. Mutation, after all, is the engine of evolution. We wouldn't be here without it. Some of these genetic mutations are benign. Many of them we don't even notice. But some of them cause terrible diseases like sickle cell anemia.

In the hundreds of years of medical science, in the decades of genetic research, in the many years of CRISPR gene editing technology, no human being has ever received a medicine designed specifically to correct their genetic mutation. A medicine built for one. That is, until KJ. Maldoon. This breakthrough got started when Kieran Musunuru,

a gene editing researcher at the University of Pennsylvania, was asked by his colleague, Dr. Rebecca Aaron's note, Nicholas to develop a bespoke therapy for KJ last summer. Dr. Musunuru and his team put together an Avenger squad of academic researchers and private sector companies who pulled together to save KJ's life and possibly create a blueprint for fixing other genetic diseases. Today we have a very special guest, Dr. Kieran Musuniru. We talk about the full story of saving baby KJ from his perspective, what this breakthrough

means for science, what its lessons are for other scientists working on their own breakthroughs, and what we need to learn or change to make personalized genetic medicine possible at scale. I'm Derek Thompson. This is plain English. Karen Musanuro, welcome at the show. Thanks so much for having me. Tell me about KJ. Muldoon. When did doctors first realize that something was wrong? So he was born at the hospital of the University of Pennsylvania, my hospital. It's actually an adult hospital, but his mom was giving birth there. A very, very savvy physician on his case realized, oh, you know, like he was two days old.

He just wasn't looking good. He was lethargic. He just wasn't moving properly. Something was up. And so there's a whole list of things that could be. The savvy physician realized, okay, I need to check for all these various things and found that the ammonia level was very, very high, over a thousand. And it's hard to know what that means until I tell you that the normal level of ammonia is like 10 or 20 or 30, right? So it made total

sense that something really bad was happening. And so he was immediately transferred across the street to the Children's Hospital, Philadelphia. And there's an underground tunnel. So they quickly like took them underground through the tunnel to chop the Children's Hospital, got him into the intensive care unit and start dialysis, because that's the only way you can deal with this on an emergency basis. So the doctors run tests, and they realize that KJ has a rare disorder called CPS1 deficiency. What is that? CPS1 deficiency is the most devastating of a group of related diseases called urea cycle disorders. What it effectively means is that he has an enzyme deficiency in his liver. The purpose of this enzyme is to help detoxify the breakdown products

of protein. So anytime he eats protein, anytime any of us eats protein, it gets broken down into different metabolites. And we use a lot of those for our nutrition to, you know, to maintain our body's health or in the case of an infant to grow, to grow well. But they're waste products. And one of those waste products is called ammonia, which we've all heard of. And, And ammonia is normally cleared from the body by a series of enzymes that turned it into another metabolite called urea. And urea actually leaves the body through the urine. In fact, that's why it's called urine because it's high in urea.

So for the vast majority of us, it's no problem. We can eat as much protein as we like. In fact, most of us, at least in the United States, are eating vastly more protein than we really need, probably. But it's okay. Our body can handle it just fine. KJ could not. because he had a missing enzyme entirely absent.

And because of that, ammonia, immediately after his born, ammonia was building up in his body. And within a couple of days, you could tell that it was actually causing real problems. So he would get like a common cold or, you know, like a rotavirus, like a bug, a stomach bug. His ammonia level would shoot up. And this is exactly what we expected to see. And it was clear that this was going to get worse and worse over time. and that if nothing happened, it would eventually catch up to him. Every time the ammonia goes up, there's the potential for irreversible injury to the brain.

Then you start to lose cognitive function. You start to not be able to feed on your own. Then you have to have things like feeding tubes permanently placed so you can get nutrition. And then when you grow older, you're not hitting developmental milestones. And then that obviously has a lot of downstream consequences. On August 8th, you get an email from a close colleague at CHOP, the Children's Hospital of Philadelphia. And a doctor there tells you, we have a big. baby with a rare genetic disease, and is there something you can do to save this baby's life?

What happened next? To be very clear, the person who called me, or really actually emailed me, Dr. Rebecca Aaron's Nicholas, my colleague at CHOP at the Children's Hospital, Philadelphia, we've actually been working together for a year. So this wasn't, you know, random doctor, like has a patient, oh, let me reach out to this guy and see if he's willing to help. We've been working together for a number reviewer. So, you know, that one email that, you know, has gotten a lot of attention. It's actually one of probably like dozens and dozens of emails we exchange on a daily basis. I mean, we've been working towards this goal of trying to make personalized gene editing therapies and doing what you

might call time trials, trying to figure out how to streamline the process. You get a new genetic diagnosis. You have a variant in hand. It might never have been seen before anywhere in any person. how do you quickly come to a solution using gene editing for that particular genetic change, that variant? And then if you can do it quickly enough, can you actually then embark on the process of getting that drug manufactured and actually getting regulatory approval from the FDA? And so there was a lot of prior work that led up to this email on the evening of August day. But exactly as you said, I get the email from my dear colleague back. as she goes by, saying, you know, we have this patient, here are the genetic testing results.

But she gave me the information, and I took a look at the variance, and she was looking at the variance as well. And we thought, wow, one of the variants, there are two variants, one from mom, one from dad. And the variant from dad, it was a, if you want to talk about like the actual letters in the DNA code, it was a C to T change, a cytosine to thymine change for what that's out of the billions and billions and billions of letters in the DNA code in every cell of his body, that was enough to cause the very devastating disease that he had CPS1 deficiency. And so we saw the C to T variant. We looked at the sequence around it, and we quickly realized,

hmm, I think there's a good chance we can make a therapy to correct this particular variant, to reverse that change, go from T back to the C that ordinarily you would expect to find in that position. and the vast majority of people have in that position in their DNA code. Right. And so that started the clock ticking. Before we pick up that ticking clock and describe the breakneck speed at which this therapy was developed, can you slow down for a moment here and help me understand how this gene editing therapy actually works? Yeah.

So that's the key question here, right? So he has a misspelling effectively, if you want to think of it that way, in his genes. in the CPS1 gene, the specific gene that makes this broken enzyme. As I said, it's like a misspelling from C to T. And so what this therapy does is it corrects that misspelling. It goes from T back to C. And now that gene can make the normal enzyme. And so it basically fixes the enzyme.

So the problem with the enzyme that results from that genetic change, that makes it broken, that makes it absent, is now in principle corrected. And now you make the normal enzyme. and now you can start processing that ammonia in the appropriate way and turn it to urea and then get rid of it from the body. Now, every cell has a misspelling, right? So the key is you want to try to correct that mispelling as as many cells as possible. And it's really hard to do like 100% of the cells.

But the goal is to try to get as many of the cells. And the more cells you can correct that misspelling, the more cells can make the normal enzyme. And the more normal enzyme you get in aggregate across the whole liver, the more you can process the ammonia. And so it's a little unclear how much you need. Is 20% enough? Is 30% enough?

We know that 50% is more than enough because of the nature of the disease. But where between 0% and 50% is it's a mystery. And so you just have to kind of do the best that you can. I think some people listening are conceptual thinkers. And when you provide a really clear concept, like base editing is sort of like word processing. We took the C, we turned it to a T. You can take the T, you turn it to a C. They understand that at the conceptual level.

I think other people, myself included, are a little bit more like visual learners. I want to be able to visualize, like literally what is happening here? So don't make this like the 90-minute introduction to base-headed-crisper, but like could you in a few minutes explain to me, like at the concrete, like molecular or atomic level, Like, what is happening here when you are providing a therapy that's changing a C to a T? So the therapy itself is a bunch of particles. And when I say a bunch, I actually mean billions of particles that are, you know, effectively, like, you know, made in, by a manufacturer in this case, through a chemical process, right? So it's combining chemicals.

And so you make these particles, these billions of particles. Each of those particles has a couple of components. And when you take these billions apart, and I'll talk about what those components are in a moment, when you take these particles and then you put them into the bloodstream through basically an IV, it hits the bloodstream and starts circulating around. The liver's job is to clean things out of the blood. So as these billions of particles are going around the bloodstream, the liver is taking it out of circulation.

It's picking up these particles. And as that happens, the particles are getting into the liver cells and delivering the cargo. Right? and that cargo ends up being, as I mentioned, two components. One of the components that comes about from that cargo is a protein. The other component is a small molecule that effectively acts like a GPS. And the protein and the RNA, those two components come together, and they form a little molecular machine.

And the GPS tells the protein where to go in those billions of bases in the genome. And so what happens is that this little molecular, molecular machine, and this is what we call CRISPR, it gets into the cell, it's made in the cell, it all assembles into this molecular machine, the molecular machine goes into the central part of the cell, the nucleus as it's called, that's where all the DNA content is, that's where the billions of billions of letters are in the genetic code. And this machine can quickly scan across all of it. And that GPS tells it exactly where to go. It scans across until it finds an address that matches what's in the GPS.

then it then does what it's supposed to do. And as I mentioned, in this protein, this CRISPR protein, it has an enzyme that will actually find the misspelling, because it's been told where to go. And if it sees that misspelling, it will actually make a chemical change on that base, that letter, and switch it to the normal letter. And then once that's done, it's done.

And now everything should go back to normal. least in that one cell where that correction has been made. If every cell in KJ's body has this mutation, why was it enough to fix this mutation only in the liver? Yeah, so the gene, the actual code, is in all the cells of the body, but what happens in the body is that certain genes are on, they actually make proteins only in the cells where they need to be on. So even though there's like billions of bases across and all the genes are in all of the genes. the cells, only certain ones are on, say, in the liver, the ones that need to be on, the ones that don't need to be on, they're off.

And so it doesn't really make a difference. In the heart, other genes are on, the genes that need to be on in the heart to make the proteins that are important for heart function. And the brain, same thing, like different parts of the brain, different genes are on and some genes are off. And so in this case, this particular enzyme, the gene is on in lots of places, but the place where it has the most important role by far is the liver. And if you can fix it in the liver, you can fix the disease.

So that's why it was important to get into the liver, to get into the liver cells, because we knew that if we could fix it in enough liver cells, we'd be able to at least improve the disease. And, you know, by the same reflection, as I said earlier, you know, the standard of care right now is just to replace the liver. The misspelling would still be in the other parts of the body. Just replacing the liver would be enough to actually fix the disease. It's my understanding that what made this breakthrough remarkable

was not just the technology, but also the speed at which it was developed. I mean, the quotes in the New York Times story are really remarkable. One scientist said that, quote, scientists burned a vat of midnight oil on this, the size of San Francisco Bay. Such speed to producing a clinic-grade crisper for genetic disease has no precedent in our field, not even close. Another called the speed, quote, astounding. Give us a sense of how you were able to work this fast. Obviously, if this is the fastest it's ever moved, then something happened here that's abnormal, that's unusual. So why was this case unusual?

Yeah, so really we had the need for speed here. That's what drove us to do this as, to try to do it as quickly as we could, right? So this disease is devastating, as I explained. He's sick a couple of days after birth. He's at high risk for bad things happening. Anytime his ammonia level goes up because he has like a little bit of an illness or this or that. It could cause irreversible injury to his brain that function he'll never get back. So the clock is ticking.

Quick as something like this has ever been done before is on the order of years. So we knew that that wasn't going to fly. He didn't have years, right? We wanted to get this done in months. We had to basically get KJ's genetic testing results, which took several days after he was born and realized there was a problem and sent off for the genetic testing and whatnot. It takes a few days to get the results.

And then see what misspelling he has. And then once you know what the misspelling is, that's exactly what happened on August 8th. My colleague Becca got the report with the misspellings and then told me that's when the clock starts. We could not have possibly started the drug development process until we had that information because we needed to make it for that misspelling, for him, personalized, bespoke, customize, whatever word do you want to use. I mean, it's really for KJ. And the flip side is that this drug will only work for KJ. It won't work for anyone else with this disease or any other disease. It is KJ's drug.

In fact, that's why it's named after him. If you dig into the details of why it's named the name it is, which is KJ Garan Abing Samaran or K.A. It's named for KJ because he is the one patient who will benefit from this. And so the reason we were able to do it is that Becca and I had been working together for a number of years, anticipating that we would need to be able to do this quickly if we actually wanted to help these patients. And these are among the sickest patients that my colleague Becca has. She's a metabolic specialist.

She's a pediatrician. And so she has a group of patients with metabolic disorders like CPS1 deficiency. And these are some of the most severest cases she has, the ones with the most unmet need, the ones that have the worst outcomes. And so we were preparing for this day. And so we were doing, as I said, these time trials, almost like practice runs, where she would give me a variant, you know, a misspelling that she had seen before or that she thought would be a good one to work and then sort of challenge me, all right, go to your laboratory.

How quickly can you come up with the solution? And the first time we did it, I thought, okay, this will be fun and this would be great. And let's see how, you know, what we do it. And we did not do well the first time. It took us like a year and a half. Ordinarily, like not a big deal. And drug development tends to have longer timelines. But, you know, if we're actually doing this for real, for a real patient and that was

the variance, like, wow, we flunked. Like, we needed to make it in months. That didn't happen. Then the second one she gave me, it was like, okay, we got a little bit better, you know, like, you know, got it a little more quickly. And so we went, you know, the third one, the fourth one, each one got better and better. And we learned where the pain points were and figured out how to workarounds. We figured out how to streamline it.

And we got to the point where we got it down to like several months, a few months even. And then this was in the summer of 2024. And then KJ was born. And it was like, okay, we think we can come up with a solution. We won't know until we try, but, you know, at least looking at the same. the misspelling and the sequence around the misspelling. It's like, I think we have a good shot at this. And so I immediately started sending emails out to my colleagues.

The next morning, I recruited a graduate student in my lab, Sarah Grandinetti, who ended up doing a lot of the work in the laboratory to actually make this all happen. So she deserves a huge amount of the credit. She immediately agreed to do it. She dropped what she was doing. She said, I'm going to work on this. I'm going to try to help this kid. She didn't know anything more about the kid than I did, didn't know the name, didn't know any of the details.

I actually didn't even know if it was a female or a male until like, many months later. It was truly anonymized to us. But we had the misspelling. We knew the change. We knew the variant we had to try to fix. And so she did most of the work, but we planted it out very carefully. We started working immediately. And within several weeks, we had the answer, much faster than we had ever had it, even in any of our time trials. It's like, wow, was not expecting that. I want to ask some technical questions about the implications of this breakthrough for the future of science. But first, on the emotional side, how are you feeling? How are you and Becca feeling being a piece of medical science history right now with, it seems like the world of science

talking about you, big splashy treatment in the New York Times? Is it surreal? Is it overwhelming? Yeah, surreal, overwhelming, unreal. I mean, a lot of, I mean, I'm feeling a lot of that, even through the development process, right? Once the parents had agreed, then it really became a sprint. Like, can we get this drug made? You know, you're working so hard. You don't have time to think about it. And every so often it occurs to, wow, we're trying to do this really unprecedented, almost crazy thing. What really made it real, to the extent that I'm still able to process it, is we approached the FDA. We'd approach them early on, and they had been on board and very supportive. And, like, you know, I can't put myself in their shoes, but,

you know, hopefully excited that this effort was being made. But they were, you know, very willing to work with us and expedite things. And the message we got from them is we understand this is an unusual situation. You don't have much time. You can't check all the boxes we normally would want you to check. Do what you can. Give us what you can. We'll go from there. And they honored that. And so we're now talking, you know, mid-February. We submit an application. We've made this drug. Can we give it to KJ? Can you give us an answer in a week? Which is like, you know, ridiculously short amount of time to be expecting, you know, like the FDA to do it. But they did it. And then the day they approved it, which was exactly a week later, just as we'd asked them, I remember getting the phone call from Becca,

found out first. And it's hard to look at yourself if you don't have a mirror, but what everyone around me, because I was at actually, funnily enough, one of my graduate students had just defended her thesis, and so we're at a celebration in her honor. And then I get the phone call. And what everyone else around me told me is like, biggest grin on your face that like we've ever seen. Oh my gosh. Like, this is real. Like it's felt like, you know, just a research project up to those now, but now we actually have permission from the FDA to give this therapy to KJ, and we're going to do it in a few days. Like, nothing's going to stop us.

You know, several days later, we actually gave KJ the first dose. And so everyone was, you know, very, very, you know, anxious and nervous. Like, it will go well, no kid this age has ever gotten this type of drug before. It went smoothly. We were cognizant, I think, that this was, in a way, a little bit of history in the making. And certainly, like, everyone around us was making it clear that they thought this was history in the making because it was like a crowd of people kind of peeking in the room, you know, like checking in and whatnot. And we're just trying to do business as usual, even though we appreciate that it wasn't business as usual. But, you know, we were there, started the infusion and took place over two hours.

He slept through the whole thing. KJ was like, whatever. Parents are anxious. So we're chatting with the parents and trying to keep them, but also ourselves calm. And, you know, again, try to do business as usual as possible. And he sailed through it and it was fine. And we felt very good after that that everything was fine because our priority first and foremost was safety. Nothing bad happened.

Everything was great. He tolerated. Now, whether it worked or not, well, that's a different question. So you've delivered this historic, personalized gene editing therapy to an adorable sleeping baby. How do you know the therapy is working? What's the question you're trying to answer to know if this treatment is succeeding? The real question is what happens if we start giving them more protein in his diet? Because that's the key thing.

If we can't give them more protein, then we haven't really done much good. And so we started just stepping up, day by day, how much protein we're giving. And then watching the ammonia level like a hawk. Because if it hadn't worked and we gave more protein, ammonia levels would rise. And then we'd have to stop and take care of that. But day by day, by day, ammonia levels remain normal. So we kept going up, up, and eventually we got to a normal amount of protein. amended dietary allowance that every kid at that age should be getting.

And he was still tolerating it fine. And it's like really seems like we helped him. So now we're just kind of like blown away. And each day it was like, is it still the same? Is it still the same? What's going on with the ammonia? And like our day becomes organized around when that lab test comes back. And then I wasn't even in country at the time.

I was in Ireland at a scientific conference. So I'm sort of getting things like secondhand remotely from Becca. And like each day we're, you know, like cheering inside. Like, okay, another day, another day. Okay. So then now he's getting full protein. So then the other thing, as I told you earlier, we do is we reduce the scavenger medication that you take three times a day and that helps to clear the ammonia.

So we started weaning that down and then things started to like, you know, like it really looked like we get the ceiling and things started to rise again. Okay. So we helped him, but it wasn't complete, right? But so good progress. And we had given him a very, very low dose because of safety, safety first. So we weren't necessarily expecting much to happen. But we had set things up so that we could give him more dose. because of safety, safety first. So we weren't necessarily expecting much to happen, but we had to set things up so that we could give him more doses. We can give them up to three doses. And that's something that's unprecedented as well. No person has ever received three doses of this.

And here we're proposing to do it in an infant for the first time getting this therapy at all, getting a personalized therapy, getting a corrective therapy that corrects them is spelling. There are all sorts of unprecedented things here. And then just to top it off, oh, yeah, we're just going to give three doses, or up to three doses. That's never been done before, but we think it's the safest way to do it. Instead of giving a very high dose to start with

and hope for the best, do it stepwise, give him a very, very low dose. And if things look good, give him the next dose up and the next dose up. And so over the next several weeks, we ended up giving him dose number two and then very recently, just in the last few weeks,

dose number three. And what I can say is at least from toast number two, it looked like things improved even more because we were actually able to bring down the scavenger medication. we were able to cut in in half, which is actually, you know, a pretty, pretty large amount. And things still look very good. So you've used base editing technology to target the liver.

It's almost like rather than a liver transplant, this is a liver transformation. You're using gene editing to transform KJ's liver cells so they can process protein without this deathly ammonia spike. I think folks familiar with organ replacement surgery know that even after a successful operation, there can still be complications. So today, can we say that personalized gene editing therapy has cured KJ, or would that be premature? Can we say we've fully corrected him? Absolutely not. I wouldn't, you know, I wouldn't even come close to saying that, but have we improved him? I really think we do. How durable this is? I don't know. That's something we're just

kind of have to track for, you know, months and years to come. He's been in the hospital since he was born, you know, more than nine months to go now, but he's on the verge of going home for the first time in his life. He's tolerating even like these infections, his ammonia's not going up. He's safe to go home. And, you know, if he gets sick again, they'll probably bring him back to the emergency room. They'll check in ammonia and make sure everything's okay. But I think we've done good by him. Whenever there's a first ever breakthrough in science, my reaction is always a combination of excited and curious about, wait, why isn't this more common, right? So the promise here is so exciting. The fact that we could use CRISPR-based gene editing to treat individual

rare diseases, which is a little bit of an ironic term, because there are, what, tens of millions of people who suffer from rare diseases. So rare diseases aren't rare. They're just the individual disease itself is rare. Why was this the first? first time, something like this has happened. Like, what are the kind of barriers to this sort of science in other cases? Are they on the scientific side of actually understanding, like, what is genetic error? Is it, like, the process itself, like, other teams haven't gone through the kind of dress rehearsals that you and Becca have gone through? Like, you guys are, like, the Philadelphia Phillies who, like, practice had to turn this incredible triple play 10,000 times.

And then in the bottom of the ninth in some, like, playoff game, it turns out you have to practice, execute that exact same chip of play, and so you do it successfully? Is it regulatory barriers? Is there a category that we can say, this is a bottleneck that we should pay more attention to, to make these kind of breakthroughs more common? I think it's all of the above, so, you know, to take them one by one, the technology, right? CRISPR technology is very new. It really didn't come on the scene until 2013. That's only 12 years ago. And the newer versions, like the base editing that we're using here to actually correct them spellings, that's even more recent. That's like 2016, 2017.

And so it takes a little bit of time, you know, give us a few years to actually, like, take it from the laboratory where these technologies were invented to actual patients, right? It's going to take at least a few years. Like, doing it in just, you know, seven, eight years, I think it's actually really quick as drug development goes. So, you know, part of it is that,

just us being able to catch up and actually, you know, translate these technologies to patients. Regulatory, for sure, right? So, you know, you have to work with the FDA if you're in the United States. Other countries have, you know, more flexible arrangements or, you know, maybe the bar is not quite as high. But the FDA is like, you know, very, very rigorous. And so if this were not a desperately sick child, we wouldn't be able to do this in six months because the FDA would demand a lot more and it would take years. And so that's, you know, standard for drug development.

It was because this was a very devastatingly ill child where the clock was ticking. And the FDA understood that the clock was ticking, that we were able to use what's known as the expanded access pathway. Compassionate use, I think, is the way that most people know about it. Where it's understood that this is experimental, we have no idea if it's going to work, but it's worth taking the shot. So I think that was part of it, you know, being able to present a case. And I think it helps that, you know, we're academics, we're, we're physicians, you know, we're doing this for a child. There's no intrinsic profit motive as there would be with a company, which is fine. That's totally fine.

That's the purpose of company. All right. But, you know, the incentives are a little different. And so I think because of that, the FDA regards it a little bit differently. And then I think, you know, part of it is, you know, again, speaking of companies, like, you know, they're responsible to their investors, their boards. And so they're looking to make drugs that will help as many patients as possible. And the easiest way to do that is to focus on a common disease or if it's a rare disease. disease, one of the more common rare diseases where they have a large market and then they can

make the perfect drug. They can spend a lot of time optimizing it. And then once it looks really good, you go through clinical trials and it gets approved, then you can hopefully give it to tens of thousands, hundreds of thousands, millions of patients. The flip side is that no company is really going, at least in the current model, no company will ever try to help a kid like KJ. And so it was really left to us on the academic side. And I guess the last factor there is just audacity. maybe like this is worth doing. Let's try like heck to make it happen. We started doing those time trials,

and so that put us in a good position that when KJ was born, we actually were able to help them. You keep talking about the importance of speed in this breakthrough. What are the ingredients of speed? Is speed about the personality of the scientists? Is it about removing procedural or regulatory bottlenecks that exist? Is it about the nature of the emergency? Because KJ could have died in days, weeks without this intervention?

Like, when you, I love the idea of speed, but because I love it, I want to understand it. What are its ingredients? Yeah, I mean, I think motivation, passion is a big part of it, right? If you're not passionate about it, then you're just not going to go the extra mile to actually try to get things done quickly. You know, just, you know, think, okay, I've done my day's work. It's 5 p.m. I'm checking out. Come back in at 9 a.m., like, that's not going to fly, right? You've got to be willing to put in the hours.

And when the need is there, not to give you the sense that we're working like around the clock for nine months in a row. Like, that's not sustainable. But when the need was there, the FDA needed a rapid response for us or when we needed to get something together, get an experiment done very quickly. We were ready to do it. We were happy to do it. That's a big part of it. Beyond that, I would say, you know, to go back to the sports metaphors, practice, practice, practice being from Philly, right? That should resonate.

The reason we were able to get it done as effectively and as quickly as we did is because we had been practicing. A lot of things need to go right. but because we had practiced so intensively, pretty much everything did go right because we were already familiar with most of the ways in which things were go wrong and it sort of developed proactively workarounds to make sure that things went smoothly.

I really do think that's the reason that we put up. If we hadn't done all those time trials, Becca and I, you know, beforehand, it would have been like that first attempt we made where it took a year and a half and just it wouldn't have been able to help them. But because we had done all those time trials, all those practice runs,

we were in good position to get it right on the first try when we were doing it for real. I asked some my friends in the CRISPR space to come up with some hard questions I could ask you at the end of our interview. So let's do that in a rapid fire. You recently did an interview with Fyodor Urnav, which was just published in CRISPR Journal, and he made this point. I found really interesting. As of May 2025, my concern bordering on fear is that the for-profit pipeline of CRISPR cures is narrow. It seems that biotech companies are all attempting to work on the same diseases simultaneously. It's like you're walking into the world's greatest food supermarket with an ever-increasing array of

ingredients, but everyone's making a hot dog, end quote. And to just be specific about this reference, he points out that there's a handful of gene targets, notably sickle cell, PCSK9, a protein associated with high cholesterol, and AAT, that a ton of different companies are focused on and therefore a small number of targets is dominating the field. How important or how worried are you about this kind of market concentration

that's happening in the field of CRISPR? Well, I mean, this is the concern that drove Becca and me and, you know, Fodor has his own efforts at the Innovated Genomics Institute at UC Berkeley. And there are a few others who are intently motivated by this problem to try to change the model, right?

very worried about it. Yeah. I mean, this is, you know, this is what I was talking about earlier. Like, you know, companies with, you know, that owe something to their investors and their boards and, you know, they have a, they have a mission to generate revenue and profit. They're going to gravitate to the same diseases because there are only so many, like, really attractive commercial opportunities and exactly the diseases you named. And that means you're ignoring, you know, the hundreds, the thousands of rare, ultra rare, end of one type scenarios. The companies just are not going to go there. For me, for Becca, for Fyodor, for others, that has been an enormously motivating factor to show that there is another way to do it,

that at least for the most severely affected cases, we can relatively quickly and relatively inexpensively orders of magnitude less expense actually pull off, making a drug, and actually help a kid. And I think what I hope is that that will just inspire a lot more people to try to do the same things, other scientists, other physicians, you know, show that there is a path to doing this. It can be done, and I expect there will be a lot of fast followers.

And I think it might motivate either existing companies to come into this space and actually say, hey, you know, maybe there is a model here that can work or inspire the creation of new commercial entities that will pick up the slack here. Turning to implications here, there are thousands of rare diseases like KJs that are caused by the unlucky inheritance of a few bad alleles. and with genome sequencing being so cheap, and with IVF being relatively easy, one question that I got was, are we too focused on cures for, I suppose, babies who are born, when the bigger bang for buck might be the prevention by parental screening and, I suppose, in vitro intervention,

essentially, I suppose, doing base editing on embryos or fetuses. I don't know whether embryo or fetuses. right stage of intervention. But is it too creepy or impossible to think about these kind of interventions before the baby is born? Yeah. So, you know, to unpack your question, there are several layers there, and there's some subtleties here that we don't simply, I mean, we could talk for hours about it, so I'll just keep it very brief. I think at the embryo stage, I'd be very, very wary of doing embryo editing to try to prevent disease, because in almost every situation, you can simply screen embryos. If you're worried about mom and dad, like, passing on a devastating disease

to their child, you can almost always screen embryos and identify the ones that don't have the disease causing changes and ensure that the kid is healthy. So the use cases for actually editing embryos proactively is very, very, very small, very small. And there are technical reasons and reasons why it's simply like a bad idea from a safety perspective. You can actually make things worse, at least with existing technology. So I'd be very wary of going there. But you bring a, what to me is a much more interesting question. What about, you know, a fetus, right? So, you know, there's already a pregnancy. And then you discover early on, wow, there's something wrong there. And either it's picked up by ultrasound or maybe eventually we get to the point where we're doing

whole genome sequencing on, you know, like at the fetal stage and trying to pick up things very early and you realize something's going on, and it's the type of disease that's very devastating and damage is already happening before birth. Like, in general disease, think something along those lines. And if you wait until after birth, it's too late. Like a lot of irreversible damage is done. I think there are some very compelling use cases to actually, exactly as you suggest, like do gene editing before birth.

And this is something my laboratory in collaboration with other laboratories is actively exploring. Not for, you know, garden variety diseases that you could easily treat after birth, to be very, very clear. those use cases, those scenarios where there's a devastating genetic disorder that was picked up before birth is already causing irreversible damage. And so we've shown, at least as proof of concept in the laboratory and animal models, large animal models, that it works, that you can actually do gene editing at the fetal stage productively and actually correct disease-causing variants and things of that sort.

So I think a big part of the future will lie there. and I think it'll greatly open up the possibilities for a lot of diseases where the earlier you can treat the better, some of these very severe metabolic diseases, neurodevelopmental disorders, and so forth. So in this case, with KJ, there was a clear mutation that had to be fixed. But how do you feel about the possibility that we could one day have a base editor that mimicked a more complex therapy like OZempic? What is the barrier between where we are today in science and essentially using CRISPR, to achieve outcomes that we're getting today from something like GLP ones.

I think it's just simply understanding the genetics, right? So it's not, it's more than anything else. Like, if there is a disease-causing change, a variant, and you're very convinced that that is what's causing the disease, and is that one single factor more than anything else that's causing the disease, and that if you correct that, you should address the disease, I mean, that's easy for us to understand.

That's pretty straightforward. And so we're already in a good position to do that. when you get to polygenic type diseases, the poly meaning many, and there are actually multiple genes involved, that's where it gets tricky because even now, even though we've been studying the human genome since it was sequenced around your 2000,

we've had a generation of time, you know, 25 years to really work on it. We still don't fully understand which genes you would need to modify in order to get a desired outcome, right, for something complex. like weight control, you suggest to the ozepic, or diabetes, which is also ozepic. Or, you know, like heart disease, what I work, I'm actually a cardiologist. It's the leading

cause of death worldwide. It's a very, very complex disease. There are lots of factors that go into it. Part of it is genetics. Part of it is not. But even the part that is genetics, it's many genes contributing. And we simply don't have a good enough understanding yet. I'll say yet, because eventually we will. But we don't have an understanding yet. What genes would you need to modify in where to most productively tackle those diseases. So it's not even a question of the technology. I think the technology to do so-called multiplex editing, where you do multiple genes simultaneously,

I think we're already getting to be able to do that. We just don't know what the right combination of genes is for most of these diseases. When it's one gene, great, simple. We know. For more complex diseases, we just don't know yet. This breakthrough is barely a week old, but I wonder what you hope, scientists understand to be possible today, that they didn't believe it to be possible one week ago?

What's the example that you hope this breakthrough sets for the field? That it is possible. It is possible with great speed, relatively modest expenses to actually make a bespoke therapy for a single patient in real time. Like from the moment they're born and actually be able to intervene in their disease course early enough to make a significant difference. No precedent for that in our field, in our corner of the world in gene editing. So I hope people understand scientists and clinicians understand. The door is open. Does that mean that it's going to be easy to do?

No. Does it mean that all diseases, all rare genetic diseases, are going to be a mental to this approach right away? No. I mean, this is going to be most useful for diseases in the liver. If you want to get to the brain, if you want to get to the heart, if you want to get other organs, we're not there yet. In the fullness of time, I have no doubt we will eventually get there. but it might take five years, 10 years. So we can't tackle all diseases, but the door is open to take the first steps and start

treating some patients and eventually expand, expand, expand, as we get better at delivering to other organs, other parts of the body, as our editing technologies get more and more refined. It just means that there will be a growing opportunity to help many, many more patients who could not be helped up until this point. Karen Musunuru, many thanks to you. Many thanks to Becca, who we try to get her on the show, but you guys are running around so much. I'm just so grateful I got 60 minutes of one of your time. Thank you so much for doing this show, and obviously thank you even more for this extraordinary breakthrough.

My great pleasure. Many thanks to Dr. Musanuru. I want to draw two things from this interview. The first is the virtue of speed. This medicine was created because doctors rushed and scientists rushed and researchers rushed and research. rushed and companies rushed and regulators rushed. I think sometimes in some cultures, and especially in some bureaucracies, speed is thought of as something that's negative. But here we can so clearly see that the reason KHA is alive, the reason that personalized

gene editing exists in the world is because a set of careful doctors valued speed. saw the essential nature of speed in order to save this baby's life. And I just think in many systems, both in government and science across bureaucracies, speed is not prioritized enough. And therefore, I so appreciated Kieran telling me about how this breakthrough was made possible because they knew that time was of the essence. The second point to make is strange to the opposite. Science takes a long time to get ready for a moment like this. You know, CRISPR was a originally discovered, depending on when you want to start the clock, either in the late 1980s in Japan or the early 1990s in Spain by several scientists working with bacteria, where they saw

the first evidence of bacteria's ability to sort of encode in the genome of resistance to viral disease. And this was the discovery that inspired scientists to see the possibility of gene editing for humans. But you know, you just look at the dates. Late 1980s, early 1990s, this is a technology that at the very least is decades old. And the reason that I point out that, you know, this is a decades-old technology

is to bring us back to the episode that we did on the cuts to American science that are happening right now. We might not feel them in six months. We might not feel them in a year. But it's what, we're going to lose out in 10 years and 20 years and 30 years? What crisper's are hiding in the world, in the cosmos, that we're not going to uncover

because we've slashed NIH and academic scientific funding by 30, 40, 50 percent? That's my great fear. It's not that science will suddenly be worse in 2025. it's all the discoveries, all of the life-saving and baby-saving discoveries that we'll be missing in the 2050s if we go through with this plan to decimate science today. Thanks very much, and we'll talk to you next week.