Twenty-four years ago on September 17th, a young volunteer in a clinical trial tragically died due to a severe immune response against a novel treatment in the then-nascent field of gene therapy. Contributing factors were unethical informed consent practices, lax inclusion criteria, and failure to disclose the full scope of known adverse side effects. We must not forget his tragic death as we develop new innovative treatments or we would risk losing decades of scientific progress.
When it comes to medicine and pharmaceuticals, we rightly take a highly cautionary and heavily regulated approach with many checks and balances. Because of this, we live in a time when medicines are the safest and most effective they have ever been in human history.
Arthur C. Clark's 3rd law of Science Fiction states: “Any sufficiently advanced technology is indistinguishable from magic.” This is certainly true for gene therapy and other advances in genetic medicine, such as CAR-T treatments, RNA-based technologies, including mRNA-based vaccines, or still experimental gene editing approaches.
The Pharmaceutical Community remembers Jesse Gelsinger; his death was where pushing the envelope of exploration blurs into unethical medical experimentation. Jesse was born with OTCD (ornithine transcarbamylase deficiency syndrome). With the help of a restricted diet and medication, he managed to live with the disease. But Jesse didn't want to have to take 50 pills a day for the rest of his life and was eager for a cure. When he turned 18, he enrolled in an experimental treatment that promised just that.
Gene therapy requires infecting a patient with a neutralized virus that carries a piece of DNA missing from the patient’s genetic code. It is like installing a "software patch" for a computer’s operating system - in this case, it would be a healthy copy of the OTC gene. Once the code is inserted, the patient’s body can produce its own OTC, which helps the patient to metabolize ammonia correctly.
It was a treatment ahead of its time. One that would save the lives of babies born with this rare condition for generations to come. It was a genetic medicine moonshot. In Jesse's case, it could have been a completely new lease on life.
Tragically, Jesse began suffering severe side effects shortly after being injected with the highest possible amount of the experimental drug allowed under FDA rules. He became dizzy and confused – it was clear his body had launched a massive immune response to combat the viral vector contained in the experimental drug. The result was a cytokine storm - a cascading series of failures in which immune cells attack healthy living tissue. Jesse succumbed to multiple organ failure and brain death. He was taken off life support 24 years ago yesterday – September 17, 1999. He was just 18 years old.
"The death is the latest in a series of setbacks for a promising approach that has so far failed to deliver its first cure, and that has been criticized as moving too quickly from the laboratory bench to the bedside," the Washington Post reported at the time.
In the aftermath, it was clear that unethical corners had been cut. The experimental drug that ended Jesse's life was known to cause significant negative side effects in other patients and had killed test animals used in its development. However, this vital information was not fully disclosed when Jesse enrolled in the trial. Had he known that the virus had killed monkeys and caused serious harm to other test subjects, he might have dropped out, too.
When the case made national headlines, the Federal Government began an investigation that revealed how "691 volunteers in gene-therapy experiments had either died or fallen ill in the seven years before Jesse's death; only 39 of these incidents had been reported promptly as required" according to a joint report by the FDA and NIH.
In 1999, the human genome had only been partially decoded; the first cloned mammal, Dolly the Sheep, had just given birth to two healthy lambs. Genetic Medicine was touted as a potential cure for cancer.
The ambitious experiment designed to cure Jesse was like the researchers were trying to reach the moon using the original Wright Brothers airplane. In addition to negligence, the technology just wasn't there yet.
"With what I know now, I wouldn't have proceeded with the study. We were drawn into the simplicity of the concept. You just put the gene in," scientist James Wilson, who led the experiment, said in an interview with Scientific American on the 10th anniversary of Jesse’s death.
Today, several gene therapies have been approved, and patients have received them safely. The technology that the scientists were trying to develop to cure Jesse has evolved and can work safely.
With the modern capabilities we have today, we are again on the cusp of a genetic revolution breakthrough. Nevertheless, we must not fall prey to scientific hubris. Papers discussing failures are far more valuable in coming up with a solution than papers outlining successes.
Keeping patients in the dark about potential negative consequences in a study goes beyond oversight and past negligence and into the realm of deceit. Had genetic medicine researchers disclosed vital information to Jesse, he would have known the risks, but he didn't. As a result, genetic medicine research was set back by at least a decade.
We must not repeat the mistakes of the past if we are to continue developing genetic therapies. What we must remember when thinking of Jesse Gelsinger is that Pharma is and should always be a force for good. Deaths in clinical trials, unfortunately, do happen, but if the well-being of the patient is in any way knowingly or negligently compromised, we have not just failed them, but we have also failed every other person who lives each day with the disease we aimed to cure.