Hosts
Derek Thompson
Derek ThompsonAbout the episode
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.
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Summary
In the following excerpt, Derek and Dr. Kiran Musunuru introduce the medical case of KJ Muldoon, and Musunuru explains how he came to work on the novel treatment for Muldoon.
Derek Thompson: Tell me about KJ Muldoon. When did doctors first realize that something was wrong?
Dr. Kiran Musunuru: 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, 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, “OK, I need to check for all these various things,” and found that the ammonia level was very, very high, over 1,000. 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. 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 of Philadelphia, and there’s an underground tunnel. So they quickly took them underground through the tunnel to CHOP, the children’s hospital; got him into the intensive care unit; and started dialysis because that’s the only way you can deal with this on an emergency basis.
Thompson: So the doctors run tests, and they realize that KJ has a rare disorder called CPS1 deficiency. What is that?
Musunuru: 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 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 ammonia is normally cleared from the body by a series of enzymes that turn 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, and at least in the United States, are eating vastly more protein than we really need probably. But it’s OK. 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 he was 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 a common cold or 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. You can’t get nutrition, and then when you grow older, you’re not hitting developmental milestones. And then that obviously has a lot of downstream consequences.
Thompson: On August 8, 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 baby with a rare genetic disease, and is there something you can do to save this baby’s life?” What happened next?
Musunuru: To be very clear, the person who called me, or really actually emailed me, Dr. Rebecca Ahrens-Nicklas, my colleague at CHOP, at the Children’s Hospital of Philadelphia, we’ve actually been working together for years, so this wasn’t random doctor 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 of years. So that one email that has gotten a lot of attention, it’s actually one of probably dozens and dozens of emails we exchange on a daily basis. And we’ve been working toward 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 8. But exactly as you said, I get the email from my dear colleague, Becca, as she goes by, saying, “We have this patient. Here are the genetic testing results.” But she gave me the information, and I took a look at the variants, and she was looking at the variants 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, if you want to talk about the actual letters in the DNA code, it was a C to T change, a cytosine to thymine change, for what that’s worth. Out of the billions and billions and billions of letters in the DNA code and 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, “Hm, 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.
This excerpt has been edited and condensed.
Host: Derek Thompson
Guest: Dr. Kiran Musunuru
Producer: Devon Baroldi