Baby’s first gene edit
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It's a big week for baby KJ. After spending nearly his entire first year of life in the Children's Hospital of Philadelphia, he is going home.

Baby KJ is not like your average baby. He was diagnosed with a rare genetic disease shortly after birth, something that roughly one in a million babies have. But baby KJ got a genetic treatment for it that no baby has ever had. And it worked. He's had quite a nice little growth spurt. I like to think it's really helped him grow some nice children.

Chubby cheeks. Man, the day he walks into, like, school with a book bag on and we, like, let him go at the door, like, you're going to have to, I might have to take the day off that day. The miracle of baby KJ coming up on Today Explained. KJ, buddy, what you doing down there? What are you doing? KJ! Support for this show comes from Monday.com.

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This is Today Explained. Jason Mast writes about science, medicine, and biotech over at Stat News. Lately, he's been writing about baby KJ. Who is adorable. We asked him to tell us about the baby. So baby KJ was born last summer. He was the Muldoon's fourth child. Five weeks before KJ was supposed to be born, Nicole called me and said...

They're told that he's quite healthy and we're going to put him in the NICU for now, but, you know, he'll be back with you very soon. And then basically within 48 hours, a nurse pulls Kyle aside, the father, and pulls up KJ's arm and drops it down.

And instead of flopping, as you would expect a baby's arm or anyone's arm really to do, it kind of shudders down. And what they find is that his ammonia levels are in the thousands, when it should be, you know, like 10 or 20. And this is...

Very dangerous. This toxin, ammonia, builds up in your blood and then eventually will build up in your brain. If that went on unchecked for a day to two days, the patient would be at very high risk of death. One of the doctors came to us and said, "We think we know what's wrong. Your son is very sick."

But the best place in the world for your child to be when he's very sick is next door. So they rush KJ across the street, basically, to the Children's Hospital of Philadelphia from UPenn Hospital. And they immediately put him on medicines to bring down that ammonia, put him on a strict diet. And they sequence his genome. And they say, OK, what exactly is the issue here? And they find that he has a mutation in this one gene. CPS1. But what they realize is that this is actually a mutation that might be

editable that we might be able to make a gene editing treatment for. We either have to get a liver transplant or give him this medicine that's never been given to anybody before, right? I mean, what an impossible decision to make. I just think that we felt like this was the best possible scenario for a life that at one point we didn't know if he would be able to have.

For the last couple of years, they had been basically preparing for a baby like KJ because there had been all these advancements in gene editing over the last decade. Many of your listeners probably have heard vaguely of CRISPR. There's one drug already approved for sickle cell. There's more in the works. But the advancements had come to the point where you could make these really fine-tuned changes in DNA. And that both creates some opportunities and some challenges. And the opportunity is there you can, like,

treat as, you know, happened with KJ ultimately. You can treat an individual patient's mutation, but you can only treat maybe that patient or this small handful of patients with this one very precise mutation. In cases like KJ, you're going to need to actually make that treatment and

really quickly. In these really severe metabolic diseases of infancy, we know that we have to act quickly if we're going to make a difference in the lives of these babies. And so they were like, can we do this in time ourselves? Can we go from an infant and make a treatment in time to help them? Because this is like a first-time deal. This is like an experiment. Yes. And they had been running what they called sort of time trials where they would pick

variant that's in the literature or that Becca would encounter, and they would see how fast can we do this, not with any intention of we're going to put this in a patient, but we're just going to see how fast can we do this. And initially it takes over a year, and that was a couple years ago, but they get faster and faster until they can do it in what seems like a number of months. And what that starts is basically a six-month sprint to can we build this therapy in time? And it brings in researchers and companies in California, in California,

Boston, in Vancouver, in Iowa, all sprinting, working overtime to see can we build this treatment before KJ either needs a liver transplant or has an ammonia attack that's going to really cause some long-term damage. We had learned everything we needed to learn to actually get it all done.

in six months in time to actually help them. They managed to get it tested in mice and monkeys. They managed to, you know, do some testing on it to make sure that it doesn't accidentally edit the wrong portion of the genome. They get companies who basically are willing to, like, manufacture this at relatively low cost or for free. It's not clear exactly how

but they were able to sort of cut a deal with these manufacturers. And at six months, baby KJ is treated with the first dose. This is in February. It's not...

amazingly effective, the first one, because it's a very small dose. They want to be very careful. But then they go for a second dose a few weeks later. And then the third dose, not yet clear how the third dose has gone. But after the second dose, they were able to really lower the medications he had been on to control ammonia. And they were able to loosen his diet so he could start eating protein for the first time, really, and like growing.

And they no longer expect to give him a liver transplant. And they're hoping he has a, you know, not cured, but a much more mild form of his condition. And for people who are wondering, like, how you edit a living baby's DNA exactly or a monkey or a mouse, how do you do it?

There's basically a delivery vehicle that's required to get your gene editing machinery into the liver. And they use what's called a lipid nanoparticle, which is basically a tiny little...

Soap bubble that's very, very, very, very, very small. That's sort of the delivery vehicle. And then inside of that, you put basically two components. There's a gene editing protein that's sort of a two-part protein. It nicks DNA, and it has a part that changes a single letter from one to the other, which

And then there's what's called a guide RNA, which is basically GPS coordinates. And in this case, we programmed it to go to the site of the genetic variant that is actually causing the disease in KJ. So you have a GPS coordinate within the genome for which letter to switch. You have a protein that switches the letter. And then you have this sort of FedEx envelope of a soap bubble that gets it into the liver. It sounds very technical, but like,

Is another word you could use for this miracle? I feel like in general, in science journalism, we avoid words like miracle and like cure quite often. But it is like, it is amazing. This is not a thing that could have been done for most of, until like basically very, very, very recently. This is a thing that like,

Researchers have been trying to do this being sort of like broadly treat these kinds of conditions for a very long time. You can look back at like publications and how people talked in the 80s or 90s when they kind of thought they were on the threshold of being able to, you know, replace genes and do things like this. And

And they weren't. And it didn't work. And now you hear you have a baby like KJ. And we don't yet know what his life will hold. We don't yet know exactly how well this works. But, like, the early signs are very promising. And that is, it is incredible. And it comes out of, like, all of this gritty, biochemical, unsexy work and all this funding over all these years that have now produced this.

Are other people getting in line? I mean, so this is the big question, and it's sort of the more pessimistic, like the easy thing to do, sort of like if you're skeptical, is to look at this and be like,

Amazing, exciting. Love that this happened for KJ. Researchers pulled off something incredible. Not repeatable. You can't do it again. It's not going to work. And they have a really valid point. The researchers involved here won't say how much it cost. It definitely cost them millions of dollars. There's no one pulling off that money to make that at scale for thousands of infants or even hundreds of infants or even dozens of infants.

This was supported in part by the NIH, who helped do some of the manufacturing for the monkey studies, if I recall correctly. And the NIH is currently facing massive funding cuts. And so where is the money, where is the process going to come to do this at scale? Also, I should add, like, you can only kind of—you can only do this—

basically with a couple different types of conditions. You can do it with conditions that affect the liver. You can do it, it's more complicated, but you can do it with conditions that affect the blood. Pretty much anything else, researchers are not yet at a place where they can reliably do this kind of gene editing work. And so for now, this won't be a one-off, but there won't be that many patients who benefit from it in the next few years, probably not.

Is there anyone who's saying, hold the line? Maybe this isn't the best idea? Is there anyone pushing back? There's someone who's like, no, they should not have treated KJ. But there are, there will be, and there have to be discussions around KJ.

what is the best use of our resources? Should we be doing these N of 1 cases versus trying to find ways of treating large swaths of diseases if it's going to be so resource-intensive for one patient? There's going to have to be considerations about, you know, the less testing you require, the more patients you can treat. So there's going to have to be discussions around how—

much testing you do and what is safe and what is a good bar for efficacy and who pays for this, which diseases require this versus you're going to have to demand a lot more testing, as I was saying. And those will be a bunch of ethical questions that the field will have to figure out and will not be easy.

I think people are in favor of this overall, but like the question is when and for who and who pays and a lot of naughty issues on the horizon. Read Jason Mast at statnews.com.

People don't seem to have too many issues with using CRISPR to edit the genes and save the life of a living, already born baby KJ, but do not get people started on the embryos. We're actually going to get someone started on the embryos when we're back on Today Explained.

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Scientists used CRISPR technology to edit the genes of baby KJ to save his life. But let us not forget that we have also, as a human race, used CRISPR to edit the genes of an embryo. A scientist in China in 2018 manipulated embryos that were then taken from the lab, put into a woman in the hope of establishing a pregnancy. And it turns out that at least two pregnancies were established.

Two beautiful little Chinese girls named Lulu and Nana came crying into the world as healthy as any other babies a few weeks ago. One couple gave birth to twins in 2018 and then a third child was born in 2019. Those children are born of genetically modified embryos, which means that they are in fact the

the first genome-edited children, and they get referred to as the CRISPR babies. During IVF, a technology called CRISPR was used on embryos, disabling a particular gene that allows HIV to enter a cell. CRISPR is the technology, just an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats, and you can appreciate why nobody would want to say that out loud, and so they are our CRISPR babies.

Their genes were reportedly manipulated to see if we could create humans who could be resistant to HIV, smallpox, and cholera. That seems good, right? But there was a lot of debate. We invited bioethicist Francoise Baylis to tell us why.

In a way, to tell the story accurately, one needs to appreciate and know that the initial response, which was largely on social media in China following this announcement, was really quite positive.

It's not morality, it's cowardice to seek permission from 30 governing bodies before taking every step. Nice work! If you can help parents with a genetic disorder have a healthy baby, I don't understand why people are so upset. I mean, Nazi scientists went to hell in a handbasket, but produced some of the most influential research of the 20th century.

Very shortly thereafter, however, it shifted and changed because as people were basically responding online around the world, you were really hearing a different kind of tone. I would say that no babies should be born

at this point in time following the use of this technology. There has been consensus that to take an embryo with altered genes and put it in a woman to create a child is just beyond the pale in terms of what's morally acceptable. And very quickly you see this shift happen to the point that a lot of the social media in China disappears. So what it looks like now is that you have, from the beginning,

a consistent, coherent perspective that this is deeply problematic science. And the only context in which it's seen differently is a couple of individual scientists who either are amongst those who just believe science should be free, we should endorse blue sky science,

and others who actually wanted to do the work themselves. And so you have a small pocket of people who are saying, no, this is actually tremendous. This is in fact important progress. We need to do this. Some will add, we need to do this responsibly. How long have we as a species been trying to alter our DNA or thinking about it?

Oh, probably been thinking about it for a very long time. If you include people that do science fiction writing, right? And I think it's always in the context typically of an enhancement. So it's actually not limited to the idea that we would be able to offer therapeutic interventions to people, but rather that we'd be able to make new humans, super humans. The imagination really kind of moves in a particular direction once we actually have the human embryo outside of the body.

And that's happening in the 1970s. So once we get the human embryo outside of the body, we have the ability to manipulate this thing. We begin to study this thing, right? What happens when we take this and put it back into a uterus? And then once it is in a woman's body and is continuing to develop, we have all kinds of other technologies we use to scrutinize the development and to see whether or not we think we're going to have a healthy birth. And so it's in this context that we now start imagining

Well, if this isn't on the right track, what do we do? Well, could we identify embryos that have a problem before we actually transfer them? And then you'd only transfer the healthy embryos. And we make that transition in the 1990s. So we go from being able to look at the embryo, thinking about transferring the embryo in a healthy context, to getting to a point where we can take the embryo and look at it and make a judgment about its quality and then decide to transfer or not.

And now getting to the stage where we're thinking, well, while we're looking at this thing in the lab, why don't we just tinker with it? And there's some risks to doing that tinkering.

Well, there's always risks to doing tinkering because the important thing about research is it's a step into the unknown. We don't actually know what we're going to do, what we're going to find. And that's true whether we're talking about patients enrolled in a clinical trial or whether we're talking about biological material in a laboratory. So I think we need to appreciate that when we don't know, we don't know the good things or the potentially harmful things.

And I think that's the context in which many people are worried about manipulating the human embryo. Because if you've made a mistake, that mistake will be visited upon generation after generation after generation. You're going in, you're cutting the DNA and you could just mess things up. Is anyone regulating this process? I mean, thinking about what's going on with the, I don't know, scientific community in the United States right now.

funding is being pulled, regulations are being revoked. What's going on in the rest of the world when it comes especially to gene editing? If you were to look at it globally, I would say to you about half of the world's countries explicitly prohibit this kind of research.

No country explicitly permits this kind of research. And there are a number of countries where they haven't bothered to write anything about this research. And just to put that in perspective, I mean, you can think about small islands. My family comes from Barbados. It's a very small island in the Caribbean. Why would they take up any of their policy effort to try to regulate in this space? It's not research they're likely to pursue.

Does baby KJ get us closer to both more treatments like his and also maybe more people wanting to edit genes?

I think it does, and I think it's going to make for some very interesting and difficult conversations, conversations we need to have. So it's absolutely true that there's a lot of enthusiasm for what looks like a successful treatment for a person who otherwise would have had a number of complicated health challenges. As we continue to develop that, you will have people say,

Why are we doing this? Like shouldn't we just do one and done? Like shouldn't we just fix this in the embryo such that when that person is born they don't have the condition and none of their children will be at risk of having the condition because depending on where you go right now you will be treating people who will go on to live and may choose to reproduce and may have offspring with the very same condition that they had for which they were genetically modified.

I understand that, but I also think that it's a mistake to go down that path. With that project, you are trying to take over the human evolutionary story. And I think that's a really, really significant move.

For some, it'll be about awe, and for others, it'll be about hubris. And the reality of it is, we can't know what the future will bring, and it's a space in which people will say, should we invest time, talent, and treasure? And I'm going to say back in that context that I think if you're looking at therapeutic interventions, the number of persons that you would create is infinitesimally small.

So I want you to think about that. What else could you do that might have a more important impact over time? Francoise Baylis is a distinguished research professor emerata at Dalhousie University in Halifax, Nova Scotia, Canada. Our episode was produced by Victoria Chamberlain, edited by Miranda Kennedy, fact-checked by Abishai Artsy, and mixed by Patrick Boyd.

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