Published online 7 May 2009 | Nature | doi:10.1038/news.2009.455

News: Q&A

James Wilson

Gene therapy researcher warns stem-cell scientists not to repeat his field's mistakes.

James M. WilsonJames M. Wilson

Gene therapy researcher James Wilson, of the University of Pennsylvania in Philadelphia, directed a clinical trial involving gene therapy that led to the death of 18-year-old Jesse Gelsinger in 1999. Now he has published an essay warning researchers working on human embryonic and induced pluripotent stem cells not to repeat gene therapy's mistakes1. He spoke to Nature about his concerns.

Why are you speaking up now?

The morning I saw all the hype around the announcement regarding Geron's approval to proceed with clinical trials (see Nature 457, 516; 2009), I was very concerned that stem cells might be headed along the same path as gene therapy. I wanted to do what I could to avoid the rise-and-fall phenomenon that we saw in gene therapy with stem-cell research.

What do you mean by gene therapy's "rise and fall"?

The sky was the limit for gene therapy in the 1990s. Almost every conceivable disease was considered a potential beneficiary of gene therapy, and it was tested in many of them in the clinic. Then in 1999 to 2000, stakeholders became concerned that gene therapy wasn't realizing its potential as quickly as people had said or had hoped it would. And then, in 1999, a young man, Jesse Gelsinger, died in a clinical trial that I directed here at the University of Pennsylvania. That led to a lot of questioning and concerns and an unravelling of support for the field.

What similarities do you see between gene therapy and stem-cell research?

The concept seems very simple — put a gene in or put a cell in and it will morph into something else — but is untested and has obvious potential applications in a wide variety of diseases. There is an almost exaggerated expectation of results, in terms of scope and timing, and then entering into clinical trials. I'm concerned that we're going to get a rush to the clinic. If we do that, we may see the same unravelling that we saw in gene therapy in 1999 and 2000, which would be very regrettable. Major setbacks are hard to overcome.

Who is responsible for the hype?

I'm more knowledgeable about who was responsible for the overselling of gene therapy. It was all the stakeholders: the investigators, because there's funding, press coverage and recognition; the press, because it's exciting and sellable; and institutions, because if there is recognition and grants, they sure don't discourage publicity. And disease-specific groups and foundations respond with tremendous hope. The need of those groups and the desire to move forward is very compelling to anyone involved in the research, and leads to the investigator pushing too hard or overstating the potential of the therapy.

“There is an almost exaggerated expectation of results. I'm concerned that we're going to get a rush to the clinic. If we do that, we may see the same unravelling of support that we saw in gene therapy.”

James Wilson
University of Pennsylvania

What should be done to address that?

The International Society for Stem Cell Research was founded early in the clinical development of stem cells and has issued guidelines. It could play a pivotal role in managing expectations. I also think that the National Institutes of Health can play an important role. The funding priorities that have come out this year as part of the stimulus package are focusing on basic research, and that is a very important checkpoint because it controls investigator behaviour and priorities. If we can get dollars to do research in some of the basic areas rather than clinical trials, then that's where we'll go.

The other point that concerns me about the current state of stem-cell clinical trials is that there isn't a mechanism for public disclosure of what's being approved and conducted in the United States.

You mean this doesn't occur through the Food and Drug Administration's approval process?

Food and Drug Administration deliberations are by law confidential, so they can't be disclosed. So some other mechanism for requiring public disclosure of clinical trials and adverse events in stem-cell research is all that's necessary. My recommendation is that something like the National Institutes of Health's Recombinant DNA Advisory Committee be established.

Isn't there anything that would require public reporting of adverse events in stem-cell research?

Nothing exists.

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What basic research should be done in stem cells?

Many of the issues that have caused problems in the clinic for gene therapy are relevant to stem cells. One is delivery of the cells. Another is immunogenicity — if you're using cells donated from another individual, they'll be viewed as foreign and cause very complicated immune responses. The third is that embryonic stem cells may transform into tumour cells, and there's already some evidence of that from one study2. The field needs to pay attention to those areas.

Is the translational focus of the National Institutes of Health and the California Institute of Medicine misguided?

Not necessarily. It's important to focus your basic questions around translation. That is different [from] moving prematurely into the clinic.

Does your personal involvement in the rise and fall of gene therapy make you particularly sensitive to these issues?

I think I am in a good and somewhat unique position to reflect on the evolution of the field of gene therapy, because I was involved from the beginning. Directing this study where there was a very unfortunate and tragic death, and all the fallout from that, forced me to become a little more reflective about what I do and what I've done. 

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