In the 1990s, a new treatment was getting a lot of hype as a "cure-all" for devastating diseases: Human gene therapy.
"It was the next big thing," recalled Art Caplan, then the new medical ethicist at the University of Pennsylvania, one of the main research hubs for this approach.
Human gene therapy involves replacing or correcting mutated genes that are causing illnesses by engineering viruses to carry specially designed DNA to "fix" what's wrong.
Caplan says James Wilson, who ran Penn's Institute for Human Gene Therapy, and his research team honed in on OTC, a rare metabolic disorder affecting the body's ability to get rid of ammonia. It can be deadly, especially for babies.
After conducting animal studies, the team decided to test the gene therapy in adults with a mild form of OTC.
"That's how they got to Jesse Gelsinger, one of the most famous names in clinical trials," Caplan said.
The trial was not intended to cure the 18-year-old volunteer; it was meant to save babies with OTC, to allow them to survive long enough to get on a special diet.
But Gelsinger died, and huge backlash followed.
The impact on clinical trials
Caplan well remembers that turbulent time.
Some things came out, he said, including that Wilson had an economic interest in a company that was commercializing the production of these gene therapy viruses. Conflict of interest then became a big issue in clinical trials.
Despite signals that there were problems with the virus in the trials with animals, Wilson and his group had thought they'd adjusted for that, Caplan said. "Others said, 'Boy, you should not have gone so fast.'
"Even today when somebody says, 'Let's try out a new treatment ... we want to get into human trials,' I hear all the time the echo of the death of Jesse Gelsinger," Caplan said
Maiken Scott: What changed in terms of informed consent?
Art Caplan: A lot of people said the informed consent wasn't good enough. It hadn't mentioned in the animal signals that there might be problems with gene therapy. Did it really layout clearly the risks? And I think people redoubled their efforts to make sure, clearly on the first trials in humans that it says about as loudly as you can, 'No benefit expected, this is a safety study.'
Scott: Many things have changed since this trial. Are we better off?
Caplan: We've done better on conflict of interest. Researchers know they should not own stock or equity or stand to profit directly from what they study.
The disclosures that people get on informed consent, I am not sure how effective they are. I am not sure they read that consent form.
There are a lot more regulations, a lot more paperwork, a lot more oversight. And I do worry that it's raised the cost of doing clinical trials. While I am not against all of that, we have to come up with ways to streamline it and make it more efficient.
I think we are too risk averse. I think we are kidding ourselves, that we can regulate and have enough oversight to take whole risk out of research.
I do worry that some people aren't getting benefits as fast as they might because the paperwork is slow or people decide not to go into clinical trial work because of the bureaucracy.
A major renaissance
And for gene therapy, the trials continued. In another nightmare scenario, children in France developed leukemia as a side effect of the treatment.
In 2008, there was a major victory for human gene therapy at the Children's Hospital of Philadelphia, where scientists treated a boy with a genetic disease causing blindness. Science writer Ricki Lewis describes that case in her new book, The Forever Fix: Gene Therapy and the Boy Who Saved It.
The boy visited the Philadelphia Zoo just four days after receiving the therapy, Lewis writes. When he heard other kids talking about the zoo balloon, he lifted his face to the sky, and started to scream -- it was the first time he had seen the sun.
A major renaissance for human gene therapy followed. And the European Union recently approved sale of a gene-therapy drug to treat a rare metabolic disease. It's a huge milestone, said Lewis, adding that gene therapy's time has finally arrived.
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