Jason Mast
Appearances
Today, Explained
Baby’s first gene edit
So baby KJ was born last summer. He was the Muldoon's fourth child.
Today, Explained
Baby’s first gene edit
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, it's to do, it kind of shutters down.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
So they rushed 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 sequenced his genome. And they say, okay, what exactly is the issue here? And they find that he has a mutation in this one gene.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
For the last couple 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.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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 really quickly.
Today, Explained
Baby’s first gene edit
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?
Today, Explained
Baby’s first gene edit
Yes. And they had been running what they called sort of time trials where they like would pick a 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 can see how fast can we do this?
Today, Explained
Baby’s first gene edit
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 he brings in researchers and companies.
Today, Explained
Baby’s first gene edit
in California, in 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.
Today, Explained
Baby’s first gene edit
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... But they were able to sort of cut a deal with these manufacturers.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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. And then there's what's called a guide RNA, which is basically GPS coordinates that
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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 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.
Today, Explained
Baby’s first gene edit
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 all of this gritty, biochemical, unsexy work and all this funding over all these years that have now produced this.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
The researchers involved here won't say how much it costs. It definitely costs in the millions of dollars. There's no one pulling up 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.
Today, Explained
Baby’s first gene edit
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.
Today, Explained
Baby’s first gene edit
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. Yeah.
Today, Explained
Baby’s first gene edit
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 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 KJ?
Today, Explained
Baby’s first gene edit
diseases, if it's going to be so resource intensive for one patient, there's going to have to be considerations about, you know, you can, 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 are
Today, Explained
Baby’s first gene edit
require this versus that 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. A few people are in favor of this overall, but the question is when and for who and who pays and a lot of naughty issues on the horizon.