Sometimes it takes a disaster to remind scientists and the public just how far out on a limb they have ventured together, as happened with the Challenger explosion and the accident at Chernobyl.
Now gene therapy, the bold effort to revolutionize medicine by reshaping people's genes, finds itself in the midst of a similarly wrenching and contemplative reassessment in the aftermath of the death of Jesse Gelsinger -- the first person to be killed by having his genetic code rewritten.
Ever since researchers at the National Institutes of Health (NIH) dripped new genes into a 4-year-old Ohio girl's vein in 1990 in an effort to cure her inherited immune system disorder, gene therapy has stood out as one of medicine's brightest hopes. But the conceptually simple approach, which promised a new era in which diseases would be cured at their molecular roots, has suffered repeated failures.
Getting new genes into people, and especially to the organs where they are most needed, has proven unexpectedly difficult. And getting those genes to work for more than a few weeks or months has been almost impossible.
"It's fair to say that in 300 clinical trials and 6,000 patients or so, if I had to show you a ringing endorsement that it works, there are none. That is the truth," said Inder Verma, a gene researcher at the Salk Institute in La Jolla, Calif., and one of the field's founders. "We all know now it was overblown and overhyped."
If anything gave scientists solace during their years of frustration, it was that gene therapy at least seemed safe. But that presumption was shattered in September with Gelsinger's death at the University of Pennsylvania.
Now gene therapy stands at a scientific, ethical and financial crossroads.
It is a crossroads still filled with promise, represented most poignantly earlier this month by a little-noted report that two French newborns with deadly inherited diseases appear to have had their fates reversed by infusions of new genes. Those preliminary results could turn out to be the field's long-awaited first cures.
But it is also a crossroads laden with risk. Medical risk, as became clear with Gelsinger's death. And equally important, the risk that gene therapy -- which still faces major technical hurdles but is under pressure from corporate sponsors to produce a return on their investment -- will speed ahead too quickly, gloss over its problems, and lose the support of a public that is already uncertain about the wisdom of tinkering with people's genes.
"Scientists call gene therapy `elegant,' " said Thomas Murray, president of the Hastings Center, a bioethics institute in Garrison, N.Y. "But obviously it is not elegant at this point. It is damn messy, and in fact we now see it can be dangerous. Patients and research subjects need to be told about the risks, and protocols need to be approved or denied in full knowledge of those risks."
Conflicts of Interest
As with so many areas of genetic research, including cloning and human embryo research, the concept of gene therapy has long rattled society with a mix of excitement and fear.
Protesters attended many of the NIH meetings at which the first gene therapy proposal was reviewed. Some considered the experiment the ultimate act of hubris, a profound meddling in God's handiwork. Others predicted ominously that the well-intentioned goal of curing genetic diseases would grow into a high-tech quest for genetic perfection and open a new era of racist eugenics.
In part because of those social concerns, and also because of the many scientific uncertainties raised by human genetic engineering, federal officials created a higher and more public standard of review for gene therapy experiments than exists for conventional new therapies. And in September 1990, a team of NIH researchers finally got the satisfaction of overseeing the first approved infusion of new genes into a patient.
Today that patient, Ashanthi DeSilva, is a mostly healthy 13-year-old girl who "gets an occasional cold," said her father, Raj. But scientists still don't know how much of her health is due to her new genes, and how much of it is due to the immune system-boosting drug that she has continued to take since before she was given that new DNA. And since then, despite a plethora of efforts against cystic fibrosis, inherited high cholesterol, muscular dystrophy, heart disease, cancer, AIDS and other ailments, not a single patient has been cured by gene therapy.
As the field foundered, however, it also began to undergo a subtle transformation that is at the heart of gene therapy's predicament today. One of the first clues that something was changing was that researchers started to focus on cancer more than the rare genetic diseases that the field had first aimed to treat. The economics of developing a cure for cancer were much more attractive than those for a disease with just a few hundred victims. And more than ever, gene therapy was becoming dominated by profit-seeking companies rather than by academic and federally funded researchers.
In a related development, scientists who once shared their results openly at scientific meetings grew more secretive under the competitive pressures to develop the first blockbuster therapy. Increasingly, talk was of patents rather than patients. By the time Gelsinger died in September, some corporate researchers were already battling the NIH in bids to keep serious injuries or deaths in their studies from becoming public.
The University of Pennsylvania, where Gelsinger died, is in many ways representative of the new world of gene therapy. It has allied itself with several financially interlinked biotechnology companies. These firms stood to gain financially if the Gelsinger study had proved successful, including one founded by the leading geneticist in that study.
The Penn team has said that financial considerations had no impact on patient care decisions in the study and had nothing to do with the multiple violations of patient protection rules that federal investigators have uncovered -- including the team's failure to properly inform the Food and Drug Administration about the side effects in volunteers that, if reported, would have forced a halt of the experiment. But some experts believe that the Penn violations are evidence that the field of gene therapy has strayed from its initial promise of public accountability.
"What happened in the Penn study should not be brushed off lightly," said LeRoy Walters, a Georgetown University ethicist and former chairman of the Recombinant DNA Advisory Committee (RAC), the NIH committee that oversees gene therapy. "It's one of the top research groups in the country, certainly one of the largest. They were in a position to know the rules better than most people. I think they betrayed the trusts of the patients participating in that trial and betrayed the trust of FDA . . . and the RAC in what they did."
The FDA and the NIH are jointly investigating whether the Penn team's lapses were exceptional or representative of the gene therapy field. But even as they try to answer that question, those agencies are under pressure from the biotechnology industry to scale back their special reporting requirements so fewer gene therapy results would end up in the public domain.
In essence, the emerging debate about gene therapy oversight comes down to a single question: Has the field of gene therapy reached a stage of scientific rigor, and has a sensitive public grown comfortable enough with the concept of human genetic manipulation, for gene researchers to be regulated as conventional drug developers? A special NIH advisory panel is focusing on that question, and a congressional hearing on the topic is planned for January.
But behind that question is a much more difficult one: How can patients and volunteers be protected, and conflicts of interest among researchers minimized, as academic medical researchers and corporate sponsors become increasingly interdependent? It's a question not unique to gene therapy, but one that has come into special focus with gene therapy because of the field's tradition of public review.
"We're dealing with a clash of cultures and values," said Murray of the Hastings Center. "The culture and values of science and the culture and values of industry, one embracing openness and the other embracing secrecy."
Glimmers of Hope
Ironically, the intense attention given to the Penn debacle throughout December overshadowed what might otherwise have been gene therapy's best news in years: A report at the annual meeting of the American Society of Hematology on what may be the field's first cures.
The experiment involved two unrelated infants born with an ailment similar to Ashanthi's. The disease leaves the immune system lacking two kinds of cells that are central to the body's ability to fight infections.
Most infants born with the disease do not live to their second birthday. But the two French boys, whose identities are being kept confidential at their parents' request, were infused with healthy versions of their faulty genes nine months ago, when they were about nine months old, and both now have the missing immune cells circulating in their blood. And in contrast to the constant infections they suffered after birth, neither boy has been sick since getting the new genes, said lead researcher Alain Fischer of the Necker Hospital in Paris.
It may be many years before scientists know if the two boys are truly cured. The new genes may have taken up residence in short-lived cells that will disappear within a few years, or the genes may simply stop working after a while.
But the French boys are not the only glimmers of hope on the horizon. Researchers from Philadelphia reported earlier this month that two patients with hemophilia, the bleeding disorder, are getting by with half the usual number of coagulation shots since they were given the blood clotting genes they had lacked since birth.
At the same time, the field is inching closer to some more controversial endeavors, including "germline" gene therapy, in which genetic changes would be made in a patient's sperm or eggs to be passed down to future generations. Until recently, that has been considered taboo because, tempting as it may be to free a family of an age-old inherited affliction, the therapy could end up causing genetic problems of its own, which would then become part of that family's line forever.
Despite those concerns, NIH officials have talked openly this year about allowing some germline efforts. And already, the NIH and the FDA have begun to review a preliminary proposal to conduct gene therapy on a fetus. That would be the world's first effort to change someone's genetic inheritance before birth.
Gelsinger's death, and all the questions about science and ethics it has raised, may postpone some of these ventures. But probably not for long, several experts agreed.
"As with the [space shuttle] Challenger, we had perhaps grown a tad bit complacent in some areas, and after the accident, we had to retrench," said RAC member C. Estuardo Aguilar-Cordova of Texas Children's Hospital. "But that doesn't mean we had to stop all space exploration. On the contrary, the fact that there has been such a punctuated sacrifice by the death of an individual can really strengthen our resolve and makes a heavier burden on us to do better and put 100 percent effort into this."
If the two French boys continue to thrive, that would produce a lot of inspiration for researchers trying to do better, Aguilar-Cordova said. He called the boys "the first sentence of gene therapy's Chapter Two."
"Chapter One was characterized by a tremendous naivete," he said. Chapter Two, he said, will be about cures.
One Treatment Method
Genetically engineered viruses inject potentially curative genes into a patient's liver cells.
A metabolic pathway is blocked in patients with a genetic disorder called OTC deficiency. Dangerous ammonia levels build up.
Genetically engineered adenovirus (with some toxic genes removed) infects liver, injecting normal OTC genes into liver cell DNA.
Altered liver cells engage in normal OTC metabolism, breaking down ammonia.