Gene therapy is based on a simple-sounding, yet deceptively complicated premise: adding or replacing faulty genes to fix medical problems. A compelling idea that came out of breakthroughs in DNA research, the field grew lightning fast. But the death of teenager Jesse Gelsinger after a gene therapy clinical trial left the public and scientists questioning the field’s promise.
How did the field grow so quickly? Why did ethical blunders leave it in the dark ages for so many years? And what does this tell us about the role of regulation?
Why did researchers push ahead with clinical trials despite gene therapy still being in its infancy? What does the Jesse Gelsinger story tell us about the personal risk behind medical breakthroughs?
Credits
Host: Alexis Pedrick
Executive Producer: Mariel Carr
Producer: Rigoberto Hernandez
Associate Producer: Sarah Kaplan
Audio Engineer: Samia Bouzid
Music by Blue Dot Sessions
Resource List
American Experience: The Boy in the Bubble. PBS.
Begley, Sharon. “Out of Prison, the ‘Father of Gene Therapy’ Faces a Harsh Reality: a Tarnished Legacy and an Ankle Monitor.” STAT News, July 23, 2018.
Cobb, Matthew. As Gods: A Moral History of the Genetic Age. New York: Basic Books, 2022.
“C‑SPAN: Paul Gelsinger.” C‑SPAN.
Gelsinger, Paul L. “Jesse’s Intent.” Circare.
ABC Evening News. Vanderbilt Television News Archive, December 8, 1999.
CBS Evening News. Vanderbilt Television News Archive, May 28, 1999.
NBC Nightly News Broadcast. Vanderbilt Television News Archive, December 8, 1999.
“Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy.” Georgetown University Library.
Rinde, Meir. “The Death of Jesse Gelsinger, 20 Years Later.” Science History Institute, June 4, 2019.
Stolberg, Sheryl Gay. “The Biotech Death of Jesse Gelsinger.” New York Times Magazine, November 28, 1999.
“Teen Dies Undergoing Experimental Gene Therapy.” Washington Post, September 29, 1999.
“The Glimmering Promise of Gene Therapy.” MIT Technology Review, November 1, 2006.
The NewsHour with Jim Lehrer, 1999-12-08. NewsHour Productions. American Archive of Public Broadcasting (GBH and the Library of Congress), Boston, MA and Washington, DC.
Wilson, James . “Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency.”
Transcript
Alexis Pedrick: From the Science History Institute, I’m Alexis Pedrick, and this is Distillations.
The history of genetic engineering has been defined by hypothetical dreams and hypothetical nightmares. But this story is about one family’s very real nightmare.
When Jesse Gelsinger was born in 1981, he seemed healthy. But by age three, something didn’t seem right. His family doctor diagnosed him with anemia and said he should be on a high-protein diet.
Paul Gelsinger: That was probably the worst thing for Jesse.
Alexis Pedrick: This is Paul Gelsinger, Jesse’s dad. He says that just a few days of this diet were nearly catastrophic.
Paul Gelsinger: Saturday morning, he woke up, parked himself in front of the television to watch cartoons, and immediately fell asleep; and we could not arouse him.
Alexis Pedrick: Jesse went into a stage one coma. In the hospital, he was diagnosed with a rare genetic disorder called ornithine transcarbamylase deficiency, or OTCD. It’s a metabolic disorder.
Usually when we eat protein, it produces ammonia in our blood, which we then urinate away. But in Jesse’s case, the gene that turns that ammonia into urine was faulty, so ammonia was building up inside of him, and it’s toxic to the nervous system. The treatment for OTCD is a combination of a low-protein diet and medication. When Jesse woke up from the coma, he started this treatment. And as the years went on, he did pretty well.
Paul Gelsinger: He was advancing normally. He was underweight and short, but he did well. He did well in school, well enough. He wasn’t the best of students, but I think that was more because of his condition than his actual mental acuity.
Alexis Pedrick: Jesse had other health scares, but his OTCD was manageable. He had a mild version of the disorder, and by the time he was a teenager, he was living a mostly normal adolescent life, despite the fact that he had to take more than 30 pills a day.
Paul Gelsinger: He was always the life of the party. He was the center of attention. He was a crack-up kid. He could make everybody laugh. He was so good at the pro-wrestling thing. And I’d sit there and watch pro-wrestling with him, and he was calling the moves that these guys were making before the announcers were. So, that’s how much he was into it. It was the thing he really liked the most.
Rocky was one of his heroes. Rambo. And Adam Sandler, of all people, was a role model for him. And I go, “Oh my God, what do I got here? I got a real doozy.”
Alexis Pedrick: Jesse’s family moved from New Jersey to Tucson, Arizona, in 1987, and they spent a lot of time on Mount Wrightson, the highest mountain in the area.
Paul Gelsinger: Jesse had a dirt bike and used to love to ride over in that area. And we had hiked it three times together, to the top of this 9300 foot mountain. In fact, the first time I hiked him up there, he was eight years old.
Alexis Pedrick: But Jesse’s OTCD was always lurking in the background.
Paul Gelsinger: It wasn’t until high school, his senior year, that he had another very severe hyperammonenic episode. He was not very good at taking his medication. He was slack on his diet. He got into a metabolic crisis, and it was like a catch-22. His body was feeding on his own protein, producing ammonia in his blood.
He ended up in a hospital, and they couldn’t get it under control. He was in there for days, and we thought we were going to lose him.
Alexis Pedrick: After that, Jesse went on a new medication that was twice as effective in getting the ammonia out of his blood.
Paul Gelsinger: Within a day, he popped up out of the coma. His ammonia levels dropped to normal levels, the same as a regular person: something he had never realized his entire life. Over the next couple of months, Jesse was able to tolerate a lot more protein, eat a lot more foods.
Everything about him improved tremendously. He put on 40 pounds in four months. In fact, I was teasing him: He was getting “a little pudgy.” That he needed to “take it easy. Okay, kid? So, he was doing great.
Alexis Pedrick: Around this time, Jesse and his family were approached about taking part in a clinical trial at the University of Pennsylvania. It was a trial for a new thing called “gene therapy.”
Since early on in our ability to tinker with DNA, there’s been a very compelling idea. If a disease is caused by a defective or missing gene, if we could just insert a corrective gene in its place, then we should be able to treat or even cure the disease. But you need a way to get that gene into someone’s body.
Now, viruses are great at infecting human cells. And if you can modify one with a new gene, theoretically, it can deliver that gene into the cells, too. And gene therapy is based on this simple-sounding yet deceptively complicated premise.
Paul Gelsinger: They described it as like a taxicab for carrying this corrective gene directly into the liver.
Alexis Pedrick: In this trial, investigators were using an adenovirus. Think flu or cold. So, yes, you’re intentionally giving someone a virus that might make them sick, but after they recover, they’d have a working gene. So, seemingly low risk for very high reward.
Paul Gelsinger: I read the literature on it. The safety they indicated was that there were side effects of flu-like symptoms. Jesse had had the flu in February following his metabolic crisis, and he did very well with that. He did not get sick from his disorder, so it didn’t raise alarms for me. I mean, the way they described it, everything was under control.
Alexis Pedrick: The investigators told Paul and Jesse that it was a study to prove that the therapy was safe, and that it was to help newborns, not Jesse himself.
Paul Gelsinger: Got a letter in the mail and then a phone call from Mark Batshaw, one of the principal investigators in the study. He was the expert on ornithine transcarbamylase deficiency. He’s one of the guys that helped develop the medication Jesse was currently on, the one that had saved his life just a few months prior.
And he made a very convincing argument that doing this would be beneficial. Okay? In advancing the technology and possibly saving these babies.
Alexis Pedrick: Paul had worked as a technician at DuPont, so he had a science background. He understood that gene therapy was an emerging field, but it seemed very promising.
Paul Gelsinger: I was drawn into the hype. I saw it as a door opening. Okay? Looking back, that’s where I was. It looked like they were actually about to achieve something and that it looked safe, that there weren’t any real pitfalls to this.
Alexis Pedrick: No pitfalls and a chance to help future generations of kids with this disorder. Jesse was sold, even if he didn’t get any direct benefit from this trial.
Paul Gelsinger: He’s doing it to save the babies. He said that out loud: “I’m doing this to save the babies.” He told a friend that. I… That is wow. Very impressed with my kid.
Alexis Pedrick: Paul was so confident that he decided to let Jesse, who was now 18, go to Philly on his own.
Paul Gelsinger: I had my own business. I was a licensed handyman in Tucson. You know, I’m a hustler, and I needed to work. You know, I was providing for my family. So, I put Jesse on this plane. Everything looks safe and secure. Gave him a hug. Last thing I said to him is, “I’m so proud of you, son. You’re my hero for doing this.”
Alexis Pedrick: Jesse died eight days later, just four days after receiving the gene therapy.
ABC News, December 8, 1999: At the National Institutes of Health in Maryland today, a group of scientists has gathered to discuss the death of a teenager who was part of a gene therapy experiment.
Alexis Pedrick: While his family mourned, his death set off alarm bells.
ABC News, December 8, 1999: There’s a serious question about whether he died because appropriate guidelines were not followed by the researchers.
Alexis Pedrick: How did a trial that seemed so low risk end up going so wrong? To understand how we got to Jesse Gelsinger’s story, we need to go back to the beginning of gene therapy itself.
Chapter One. Move Fast and Break Things.
Alexis Pedrick: Gene therapy doesn’t have a long history. We’re going back to just 12 years before Jesse was born. Remember the hype Paul Gelsinger described? It was there from the beginning.
In 1969, before a single gene had been “therapied,” a molecular biologist named Vasken Aposhian coined the term “gene therapy” to describe a field that didn’t exist yet. Just a year later, a physician named Stanfield Rogers imagined using a virus to deliver new genetic information into a human cell.
Matthew Cobb, the author of As Gods: A Moral History of the Genetic Age, tells us how this happened.
Matthew Cobb: Stanfield Rogers was very interested in a rabbit virus called “Shope virus.”
Alexis Pedrick: And he noticed that when lab workers were accidentally infected with it, they had low levels of an amino acid called “arginine.”
Matthew Cobb: And he suspected that this virus produced something called “arginase,” which is an enzyme that breaks down this amino acid. So, this was quite interesting.
Alexis Pedrick: Rogers did a thought experiment. What if he found someone whose body didn’t produce enough arginase? He could inject them with the Shope virus as a treatment.
Matthew Cobb: And then he discovered that in Germany there were two very young girls who had very high levels of arginine. They couldn’t produce arginase.
Alexis Pedrick: It built up in their bodies, causing seizures, cerebral palsy, and severe intellectual disabilities.
Matthew Cobb: And so he decided that he would inject these girls with this Shope virus. This was the first example of somebody trying to alter the genes by introducing some foreign piece of nucleic acid. In this case, it was through a virus.
Alexis Pedrick: He had found an actual disease for his hypothetical cure. But there was a problem.
Matthew Cobb: Whilst it was quite groundbreaking, it was also extremely unethical and unprincipled.
Alexis Pedrick: It was groundbreaking because no one had attempted to alter a human’s genes with foreign nucleic acid before, but it was far from sound science.
Matthew Cobb: There were huge headlines in the papers, right? All over the world, everybody was very, very excited about this. But there was no record kept of what happened. All we know: there was kind of a very bland statement that he later made saying that it didn’t affect the course of the disease. And so, almost certainly the two little girls would have died.
Alexis Pedrick: Not only did the experiment not work, but Stanfield Rogers didn’t publish in a scientific journal for peer review.
Matthew Cobb: It was very flaky science. So that, I think, shows this excitement of a physician to move quickly and break things. You know, “I’ve got to do this.” And also, dare I say it—-as a non-physician—sometimes quite a lot of pride and arrogance from the medical community about what should be possible and simply wanting to move forward very quickly.
Alexis Pedrick: A few years later, Rogers and his colleagues published a three-page article on the experiment, admitting that it did not influence the disease at all. And not only that, but no useful information was obtained.
All around, it was a scientific failure, but Rogers defended his experiment by saying that the disease was so terrible that even a long-shot experiment was worth trying. And in another sense, the experiment was wildly successful. It captured the public’s imagination.
Matthew Cobb: After the Stanfield Rogers experiment, Science magazine in 1972 had a big, long article, think piece, about this field, which didn’t actually exist. You know, “How can we move forward?”
Alexis Pedrick: Even though Stanfield Rogers’ experiment didn’t work, people were sold on the promise of gene therapy, and that translated into a lot of funding.
Matthew Cobb: Here’s a load of money. And as we’ll see, this is exactly what happened. Huge amounts of money were poured into this field in the 1980s—and the first half of 1990s—because people were very confident that there would be eventually financial support, even if the treatment was incredibly expensive.
Alexis Pedrick: Despite the shoddy science and lack of results, the attention and the money made gene therapy very enticing.
In 1980, a geneticist named Martin Cline was intrigued. He was the head of hematology at UCLA and wanted to try using gene therapy to cure a blood disease called “beta-thalassemia,” which is similar to sickle cell disease.
CBS News, May 28, 1981: He and his UCLA colleagues successfully transferred new genes into the blood-producing marrow cells of living mice. That raised the possibility of genetically altering defective marrow cells to make them work. Doctor Cline said, at the time, human trials were three years away.
Alexis Pedrick: But Cline didn’t wait three years. Remember? Move fast and break things.
CBS News, May 28, 1981: But three months later, he treated two patients who had fatal blood disorders. A young woman in Jerusalem and a 16-year-old girl in Italy.
Alexis Pedrick: The patients were unharmed, but the experiment was also unsuccessful.
Matthew Cobb: But that’s partly because the right controls weren’t taken. He wasn’t measuring things properly. He didn’t have the support of his…his local ethics committee. In fact, the local ethics committee said, “Don’t do this.” And he ignored them, saying, you know, “These people aren’t qualified. I’m the medic. I know how to do this.” That’s literally what he said.
Alexis Pedrick: Then, just like Rogers, there were big announcements in the press, not scientific journals. And there was that excitement again. But Cline didn’t get away unscathed.
Matthew Cobb: Martin Cline is another example of a medic, you know, behaving badly. So, Stanfield Rogers did a lot of, you know, not very good ethical things. It wasn’t a very good experiment, and so on. But he didn’t get punished for it.
Martin Cline, however, most definitely did. This was a massive event in 1980 when it turned out that it hadn’t worked and that he had, you know, disregarded the ethical guidelines. Both NIH and his university came down on him like a ton of bricks.
CBS News, May 28, 1981: Today, the National Institutes of Health charged that Doctor Cline committed the most serious violation yet of federal guidelines on genetic engineering and called for an unprecedented review of his research grants to see if he should continue receiving federal funds for his work.
Matthew Cobb: He was not allowed to get money for years and so on, and he became persona non grata. But I think the key point here is that, you know, this is a physician feeling very confident of himself. And this is, you know, “what else can I do?” That’s basically what he said. You know, “there are people in need.” And this is often a rhetorical argument which is used by physicians. “We need to move quickly because there are people in need.”
Well, yes, there are people in need for all sorts of things all over the world. And yet it happens to be your particular sexy technology that you think we’ve got to move fast on.
Chapter Two. The Captain Kirk of Gene Therapy.
Alexis Pedrick: Another impatient man would enter the fold right around the same time as Cline. He was a research physician and professor of biochemistry and pediatrics at the University of Southern California. And he was about to make quite a name for himself.
Matthew Cobb: At the same time as Cline’s doing this, there’s a very significant article published in the New England Journal of Medicine by a man who came to represent gene therapy: French Anderson. Saying, you know, “How can we wait any longer? Why should we wait? We’ve got to go forward.”
French Anderson – The NewsHour with Jim Lehrer, December 8, 1992: It’s really less the competition with other people as it is with…with nature. How can you get around nature’s defense mechanisms and cure an incurable disease? It’s very exciting.
Alexis Pedrick: But why was he in such a hurry?
Matthew Cobb: Because he wanted to be the first. I mean, he described himself as “the Captain Kirk of gene therapy.” So, he was hoping to be the man who would enable gene therapy to become a reality. I mean, and he was the big face of gene therapy. He was incredibly influential.
Alexis Pedrick: Anderson had set his sights on a rare disease called “severe combined immunodeficiency disorder,” or SCID, which is often called “bubble boy disease.”
News Archival: His real name was David Phillip Vetter, but the public knew him only as David, the boy in the bubble. Born without a working immune system, he lived his entire life isolated in a sterile plastic chamber.
Alexis Pedrick: French Anderson was intrigued by this case and the press that swirled around it, and he hoped the publicity would attract attention to his own work on SCID.
One reason Anderson chose SCID was because he believed it was a simple genetic disease to treat. SCID is caused by just one faulty gene, so the enzyme critical for a functioning immune system doesn’t get produced.
Anderson wanted to give a patient a corrective gene and cure them; but before he could begin any trials, he had to get approval from an oversight board called the “Recombinant DNA Advisory Committee,” or RAC. The group came out of the recombinant DNA controversies we covered earlier this season. So, Anderson presented his bubble-boy-cure idea to the committee.
Matthew Cobb: And his idea was pretty hopeless and was thrown out. And he later said, “Well, I would have voted against it as well.” So he then went a slightly different route and decided to just try and show that the technique could work, that he could actually change a human’s cells—the DNA in a human’s cells—by using a vector virus.
Alexis Pedrick: This was a “proof-of-concept” trial. There was nothing getting treated here. He was just putting a genetic marker in the virus, inserting it into a patient and hopefully seeing that same marker in the patient later.
Matthew Cobb: He did this experiment—because it is an “experiment.” This is not therapy. This is an experiment. A human experiment, right? He did it on volunteers who were at end of life. They had terrible cancers. They were going to die anyway. And this was not a cure.
So, they were incredibly, generously giving their bodies and what little time they had left to medical science to see whether it could…could work. And he was able to show that, in principle, the technique could work.
And this is really what kick-started all the great excitement because now we’ve got a technique—it seems as though we can work—and everybody begins to get incredibly excited about it because of the work of French Anderson.
Alexis Pedrick: Now, just to be clear, nothing and no one had been treated yet. No genes had been “therapied,” but French Anderson was emboldened by the results and the reaction, and he went back to the drawing board with his SCID cure.
Meanwhile, SCID got a different breakthrough that had nothing to do with gene therapy. It was an injection that temporarily gave patients the enzyme they were missing. Now, this wasn’t a cure, but it did help manage the disease.
Nevertheless, Anderson was still forging ahead, and he sent his new proposal to the RAC. And it was approved, with the caveat that the trial participants would continue getting those injections throughout the trial. On the day it was approved, the committee chair was elated.
Matthew Cobb: One physician said, “Doctors have been waiting for this for centuries.” “Doctors,” not patients. I think it’s very clear that research physicians, at least back then, most of them are men. They’re very driven, very ambitious, keen about fame and wealth, which were both very real.
Alexis Pedrick: And Anderson was about to get his biggest victory.
ABC News, December 8, 1999: Her name is Ashanthi DeSilva. She was born with a defective gene that crippled her immune system. She became the first patient ever to undergo gene therapy. Rarely in medicine has one experiment generated so much excitement.
Alexis Pedrick: By all accounts, the procedure went well. Ashanthi was able to go home, and she was producing the enzyme that her genetic illness prevented her from developing. Ashanthi became a symbol of gene therapy success.
This is French Anderson.
French Anderson – ABC News, December 8, 1999: Ashi is now a delightful young lady. She lives a totally normal life, and she’s uh 13 years old and delightful.
ABC News, December 8, 1999: Based on DeSilva’s case, newspapers and magazines hailed gene therapy as a breakthrough.
Alexis Pedrick: Anderson had accomplished his dream. He became the first person to successfully perform gene therapy on a human. And it propelled him to superstar status. He won awards.
Matthew Cobb: He said, “Oh, you know, of course, if I get a Nobel, I’ll be very pleased, but I’m not actually thinking about that.” Oh, yeah.
Alexis Pedrick: And then there was the attention from the media.
Matthew Cobb: He was runner-up for the TIME “Man of the Year” award.
Alexis Pedrick: A 1995 book called Altered Fates glorified Anderson.
Matthew Cobb: They described Anderson as “a visionary to the bone,” and they were—he and his colleagues—were modern-day Magellans, who are charting the vast molecular unknown of the human body. “They are the polar and African explorers of our time. And their field is wide open and ripe for magnificent findings.”
Oh, the media then bigs that up, and it just keeps on going until eventually the wheels come off.
Chapter Three. Embryonic.
Alexis Pedrick: French Anderson and the field of gene therapy were riding high. By 1995, 106 different gene therapy procedures had been approved nationwide. A total of 597 patients had undergone genetic therapy of some kind, but there had always been scientists who questioned whether it was all hype.
This is Stuart Orkin, a doctor who specializes in genetic blood disorders.
Stuart Orkin: They looked at this kind of work and said, “This is just not rigorous. It’s not controlled. It’s not quality work, and it’s damaging the field.”
Alexis Pedrick: One person who was skeptical was the director of the National Institutes of Health: Harold Varmus. He said at the time that the field had created, quote, “the mistaken and widespread perception of success.”
And one of the reasons he was worried was that the NIH was spending $200 million a year on it.
Stuart Orkin: Research money is always too short. There’s always competition in the review process as to whether you fund this grant or that grant. I think there was a lot of questions as to whether this should even be done at all, whether it was so premature that the NIH should not give research money.
Alexis Pedrick: Varmus wanted the NIH to survey the field at large and find out whether the agency was getting its money’s worth, so he tapped Orkin to lead the investigation.
Stuart Orkin: I think I was chosen because I was thought to be impartial. I wasn’t conflicted. I wasn’t involved in those studies. I was also seen as someone who had medical training; but I was also probably selected because I wasn’t known as someone who is particularly in the public eye.
Alexis Pedrick: He heard wildly diverging testimony.
Stuart Orkin: We had a couple of investigators who came in and said, “This work is so flawed that we should not fund any of it.” And we had other individuals who said, “Well, we have to do this because this is the future of medicine.” So, we had sort of two extremes.
Alexis Pedrick: Orkin was alarmed by one thing in particular. Gene therapy proponents were acting like it was a mature field, but it wasn’t.
Stuart Orkin: It was embryonic.
Alexis Pedrick: Yet people like French Anderson were moving on to the experimental phase before covering all of the basics.
Stuart Orkin: They were trying to do things that really were beyond our capabilities, frankly, at the time. You need to discover the fundamentals in order to make progress. We needed to understand the biology was complicated, and if we really wanted to have efficacy, in terms of therapy, we needed to understand the basic biology of the disease and the cells involved in the disease; what cells you needed to fix; how many cells? Lots of biological questions.
There’s no question. I think that’s where the tension was at the time. There was—the basic investigators were saying, “Well, we’re doing basic work. It may not be, you know, newsworthy for TIME magazine, but we think it’s really important.”
And on the other hand, we have a lot of resources being siphoned off to this work that makes it into TIME magazine and, you know, TV programs, things like that.
Alexis Pedrick: Orkin took issue with the fact that some investigators were putting their work out in the public press before publishing in scientific journals.
The NIH report also found that many trials were not well designed. They weren’t learning the mistakes from the trials they had done. The report was brutal on this front, quote, “Only a minority of clinical studies have been designed to yield useful basic information.”
Stuart Orkin: If you do a clinical trial, it’s not terrible if it’s not efficacious. But you have to learn from that trial to know what to do the next time. And the way the trials had been performed, it was failure but no insight into what to do next.
And so that was another message: that if you’re going to make a clinical trial, you owe it to both the patients and the science to make sure that you learn something that would make the next trial better.
Alexis Pedrick: And then there was this ethical issue. Some investigators, not all of them, were not always explaining to patients that their work was experimental, not therapeutic. They were giving patients false hope.
Stuart Orkin: And I think the question is always: “What’s hope, and what’s hype?” What I say is that hope is balanced with a dose of realism. Hype tends to reduce the realism part.
Alexis Pedrick: Now, maybe you’re thinking, “Well, French Anderson had that big success with Ashanthi DeSilva? Didn’t Orkin at least give him credit for that?”
And the answer is no; he didn’t. In fact, Orkin highlighted a huge problem with this case. He says she wasn’t cured by the gene therapy. She was taking medication that was already helping her disease when they did the procedure.
Stuart Orkin: What we were trying to say at the time was that the patients had other alternatives. And one could have argued, at the time, that those may not have been the best patients to enter into those initial trials, that perhaps patients without any alternative therapy would have been better choices.
Alexis Pedrick: When Orkin’s report came out, it raised some eyebrows. The NIH decided to divert its money to more basic research. Nature ran an editorial that warned, quote, “This is what happens when an entire field believes its own press.”
The report was a warning shot for the entire field: don’t oversell the results of gene therapy. Slow down, or there will be blowback.
Stuart Orkin: And the blowback is two ways. One is, I think, the public is going to be saying, “Why did you do this?” They’re going to be questioning the science and the motivations.
And secondly, I think the funders are obviously going to cut the funding off. And I think that’s sort of where we were in the 1995 era.
Alexis Pedrick: Orkin and the NIH didn’t want to kill gene therapy. They just wanted it done right.
Stuart Orkin: I think the concern was if it went on longer, that kind of, sort of what we called almost “cowboy kind of trials,” that it would set the field back many, many years or might actually set the field back forever.
Chapter Four. Jesse Gelsinger’s Final Days.
Alexis Pedrick: On September 8th, 1999, Jesse Gelsinger stepped off the plane in Philadelphia. He was scheduled to have the gene therapy injected into his liver five days later.
The trial had three main investigators: Mark Batshaw, an expert on Jesse’s disease; James Wilson, a researcher who ran a gene therapy lab at the University of Pennsylvania; and Steve Raper, a general surgeon with experience in clinical gene therapy. Raper was the one who would end up overseeing the procedure on Jesse.
The day before the infusion, Jesse had tests done at the hospital, and they showed his ammonia levels were higher than normal. This is Jesse’s dad, Paul.
Paul Gelsinger: I figured it was the stress of travel. You know, the change in diet, maybe. And I advised him. I said, “Listen, you’re with people that know this disorder better than anybody. You should trust them.”
They decided to go ahead and proceed with the experiment the following morning and infused Jesse. The next day I got a call. They were asking if Jesse had had any experience with jaundice because he was starting to get jaundice. And I said, “Yeah, when he was first born, he had jaundice.” And I said, “That’s a liver function. What’s going on, doc?”
His ammonia was starting to rise precipitously. He was becoming incoherent. I said, “Do I need to get on a plane?” He said, “Hold on, we’ll get back to you. We’re running some more tests.” I got a call a few hours later that he was going into hyperammonemic crisis. He was going deeper into a coma.
So I said, “Well, I’m getting on a plane, and I’m coming there. I’ll be there in the morning.” So, I took a red-eye flight that night out, and I arrived at about 8:00 in the morning. And I announced who I was at the nurses’ station, and the doctors came out to me and pulled me aside and told me what was going on, that Jesse was in real trouble.
Alexis Pedrick: Jesse’s blood oxygen was dropping. They had to put him on a machine that did the job his heart and lungs couldn’t do anymore.
Paul Gelsinger: And I walked from the hotel they had put us up in and back to the hospital to go see Jesse at about 11:30 at night. And he had a urine bag on the end of his bed, and it had blood in it. And I go, “Oh my God, this isn’t good. This is not-“
And overnight, Thursday night, essentially Jesse died. We shut off life support for Jesse at 2:30 in the afternoon Friday, September 17th, 1999: four days after they put this stuff in his body. It was obvious to me that’s what had killed him.
Alexis Pedrick: Four days earlier, when Jesse was still conscious, Paul had one last chance to speak to his son.
Paul Gelsinger: And my last words with my boy were, “Jesse, I love you.” And I got it right back from him: “I love you, too, Dad.” And my wife was on the phone: Mickey. She was on the phone, too. And she got the same thing from him. And those were actually my last words with my son.
Alexis Pedrick: Jesse’s death made national news and sent shockwaves through the field.
Anchor – NBC News, 1999: Gene therapy. It’s offered new hope to those battling diseases. But now, one of those patients, a young man, has died.
Newscaster – NBC News, 1999: The unexpected death in September of 18-year-old Jesse Gelsinger killed the enthusiasm, causing many to ask, “Is gene therapy dangerous? Should it be restricted?”
Alexis Pedrick: At first, Paul didn’t blame his son’s doctors or the hospital or the field of gene therapy. Here he is speaking about it in 1999, shortly after Jesse’s death.
Paul Gelsinger Archive: He was treated fine at UPenn. They did everything they could to help Jesse. What happened was totally unforeseen. They had no indication that anything would happen, like what happened to Jesse.
Alexis Pedrick: In fact, when Paul and his family spread Jesse’s ashes at Mount Wrightson, the place where Jesse liked to go dirt biking, he invited the doctor who administered the gene therapy, Dr. Steven Raper.
Paul Gelsinger: He was pretty upset by what had happened. These were good men. The two doctors that were directly involved in Jesse’s care.
Alexis Pedrick: But in the aftermath of Jesse’s death, Paul started to learn more about what went wrong. The first warning sign came from one of the members of the RAC, which had reviewed and approved the procedure.
Paul Gelsinger: He had misgivings that, you know, animals had died in the pre-clinical work, and that was my first knowledge of that. And I go, “Oh, wow.”
Alexis Pedrick: No one mentioned to Paul or Jesse that when monkeys had been given higher doses of the same gene therapy, they developed severe liver damage and blood clotting and then died or required euthanasia within days.
But they should have been told. Had they learned about this, they might have dropped out, and Jesse might still be alive today.
Several weeks after Jesse died, Paul was contacted by James Wilson.
Paul Gelsinger: He was the principal investigator. The guy in charge of the Wistar Institute at the University of Pennsylvania. He was the number one gene therapy researcher in the world at the time.
And he said, “I’m going to be there in Tucson. I’d like to meet with you.” And I hadn’t met this guy before, but he was the head honcho of all of this, and he actually came to my house. And my first question to him sitting on my back porch was, “what’s your financial interest in this?” And he explained to me, “I’m an unpaid consultant every Friday for the biotech company behind the research.”
Alexis Pedrick: The company was called Genovo. They were financing Wilson’s institute at Penn.
Paul Gelsinger: Actually took him out on a hike in the mountains to the east because I was, you know, I was doing a lot of hiking at that time, trying to resolve all of this, you know, running through my mind. And I took him out there, and we had a conversation. And he was really starting to worry because he was losing people at his institute. They were losing faith in him. And I actually stopped him on the trail out there.
And I said, I looked around and looked at him and I said, “Can you- you know, Jim, I think there’s something more important than that. Can you imagine losing one of your children?” And he goes, “Oh, yeah.” I said, “Yeah, well, that’s where I am.”
Alexis Pedrick: Paul’s discomfort was growing, but he didn’t have all the facts yet.
Paul Gelsinger: And I still didn’t know the real truth. I didn’t find out the real truth until that meeting in Bethesda.
Chapter Five. When You Do Bad Science, Bad Things Happen.
Alexis Pedrick: The RAC was set to meet in early December 1999 to discuss Jesse’s case, and Paul was going to fly in on his own dime to find out what happened. But first, James Wilson asked him to come to Philadelphia to visit his institute.
Paul Gelsinger: And he was sitting at his desk crying that the FDA had issued a press release that they were going to charge the University of Pennsylvania and his institute for Jesse’s death.
Alexis Pedrick: The next day, Paul learned about what the FDA had found. It was pretty damning.
This is a representative from the FDA.
FDA Representative – News Archive: Right now, we have preliminary evidence that there have been these protocol violations.
Alexis Pedrick: Before Jesse’s death, two other patients in the trial had experienced serious side-effects. According to the protocol, the UPenn scientists should have immediately informed the FDA or put the trial on hold. That did not happen.
The FDA also found that they violated protocol by not telling Paul and Jesse about the monkeys.
And then there was this. According to the FDA, Jesse shouldn’t have even been eligible for the trial. Remember the pre-trial test he got that showed high levels of ammonia? That suggested his liver was too weak to handle the injection.
Paul Gelsinger: I got up and challenged the FDA for their responsibility in this. I said, “How come you guys didn’t stop this from happening?” You know, they had a press conference after that first day of their meeting. And when they announced that, and it was just very upsetting for me.
Alexis Pedrick: Yet, at this point, James Wilson and the University of Pennsylvania were still defending their experimental trial. This is Wilson.
James Wilson – News Archive: At no time during or prior to this trial, did we, in any way, expect to see what we saw in Jesse Gelsinger.
Paul Gelsinger: I left that meeting, cried for an hour because I came to the realization we had been duped, that we had been not given the information we needed. There was no need for Jesse to be there. This clinical trial should have been shut down. This was a mess that should never have happened.
Alexis Pedrick: And the FDA agreed.
News Archive – February 2000: Late last month, the agency shut the Penn program down, charging that patients like Jesse weren’t being protected or properly informed of the risk.
Alexis Pedrick: In February 2000, the U.S. Senate held a committee hearing on gene therapy, and Paul testified. He was no longer defending Wilson or the University of Pennsylvania.
Paul Gelsinger – Senate Committee Hearing: It was an avoidable tragedy from which I will never fully recover. When lives are at stake—and my son’s life was at stake—the concern should not be on getting to the finish line first, but making sure no unnecessary risks are taken. No lives filled with potential and promise are lost forever. No more fathers lose their sons.
Alexis Pedrick: Later that summer, the company that funded James Wilson’s institute was bought, and he got $13.5 million in stock. Because, as it turns out, James Wilson had a 30% stake in the company.
Paul Gelsinger: Boom. Tell me it wasn’t about money then, you know? It’s like, “Wow, you people are unbelievable.”
It hit me as hard as it did. I said, “Oh my God, this has to be fixed. This is not right that they killed an innocent human being because of their blindness.” And they were really blind. They put blinders on. They didn’t want to see the truth, and they certainly didn’t want us to see it.
Alexis Pedrick: Paul filed a wrongful death lawsuit.
Paul Gelsinger: And they asked to resolve it out of court, which we did six weeks after filing it. They were dead in the water. They had no defense for what happened.
So essentially, since I discovered the truth, I’d seen this as medical manslaughter. That these guys were negligent in what they were doing, and they killed my child. Okay? And that’s wrong. That’s criminal. Okay?
Alexis Pedrick: A US Justice Department investigation ordered UPenn to pay $500,000 in fines. Although as part of the settlement, UPenn did not admit culpability in its treatment of Jesse.
The principal investigators had to go through retraining and research ethics and informed consent, and Wilson was supposed to write a “lessons learned” paper. In addition, he was also not allowed to sponsor research for five years.
Paul Gelsinger: I think he learned how to avoid responsibility in the future. That’s what I really think the man learned.
Alexis Pedrick: Jesse’s death had severe consequences for gene therapy at large. This is Matthew Cobb.
Matthew Cobb: This led to a huge drop in excitement and support for the…the whole field.
Alexis Pedrick: Guidelines tightened, and there was a chill in approving experiments. “Gene therapy” had become a dirty word.
We asked Paul Gelsinger what he thought of the words Stuart Orkin used to describe gene therapy in 1995: “embryonic.”
Paul Gelsinger: It was embryonic in 1995. And I think it was about to give birth in 1999, and it was a stillbirth. They killed it by pushing too far, too fast, by not even obeying their own protocol. That’s the violation right there.
It’s bad science doing that. When you do bad science, bad things happen.
Alexis Pedrick: Even the father of gene therapy, French Anderson, was not feeling hopeful. Here he is speaking to ABC News in 1999.
French Anderson – ABC News, 1999: We were too confident. We were too optimistic. Our problem now is not getting too depressed.
Alexis Pedrick: In a completely unrelated, but nonetheless deplorable situation, Anderson inflicted more harm on the entire field’s reputation in 2004 when he was convicted of sexually abusing a ten-year-old child.
Matthew Cobb: He’s the guy who’s going to win the Nobel Prize. He’s the first person who has ever carried out any kind of human gene therapy. Even though it wasn’t really therapy, you know, he’s “the Captain Kirk” of gene therapy. And then he is arrested and convicted and sent to jail.
So this again, I mean, it had nothing to do with science, but the community lost its figurehead and, you know, somebody who was the poster boy for the media.And this, again, had a terrible kind of cooling effect on enthusiasm and interest for the whole approach.
Alexis Pedrick: The field was in the dark-ages for more than a decade. However, it did re-emerge with a few success cases in rare diseases like childhood blindness, a cancer treatment known as CAR-T cell therapy, and therapies for some blood disorders, including one that was developed thanks to Stuart Orkin’s research.
He’s been working on this since the 1970s. He was patient and is now seeing the fruits of his labor.
Stuart Orkin: I think it’s important for the public to recognize that developing new therapies takes a long time. It takes much, much longer than any of us predict at the time we think of initiating it.
Alexis Pedrick: And James Wilson went through a redemptive arc. He raised millions of dollars for his research and had success that even Paul took notice of.
Paul Gelsinger: It’s important work they’re doing, and Jim Wilson has done important work since he switched away from antiviral gene therapy to adeno-associated viruses, which are much safer in human beings.
Alexis Pedrick: Paul Gelsinger still lives in Tucson, Arizona, where he keeps busy building houses. In 2021, for what would have been Jesse’s 40th birthday, he got a tattoo on his right shoulder in his honor.
Paul Gelsinger: He wanted to create his own wrestling federation when he grew up. Okay? And he called it “BLWF”: Bunch of Losers Wrestling Federation. Okay, so it was about the little guys. And his moniker was the flying squirrel.
So, I have a tattoo of a flying squirrel on my shoulder with Jesse’s name and “BLWF” under it. So if we learned anything, it’s about enjoying life because you never know when it’s going to end.
Alexis Pedrick: Gene therapy got off to a rocky start. That’s for sure.
In our next episode, we’ll talk about how the field has evolved and how different problems have come to the fore, like the impossibility of funding therapies for ultra-rare genetic diseases, which is a crisis for those patients because gene therapy is their only hope.
Distillations podcast is produced by the Science History Institute and recorded in the Laurie J. Landeau Digital Production Studios.
Our executive producer is Mariel Carr. Our producer is Rigoberto Hernandez. Our associate producer is Sarah Kaplan, and our sound designer is Samia Bouzid. This episode was reported by Rigoberto Hernandez.
Support for Distillations has been provided by the Middleton Foundation and the Wyncote Foundation. You can find all of our podcasts, as well as our videos and articles on our website at sciencehistory.org. And you can follow us on social media @scihistoryorg for news about our podcast and everything else going on in our free museum and library.
For Distillations, I’m Alexis Pedrick. Thanks for listening.
