It was just the kind of success that scientists had been promising for decades.
The boys had been born with faulty versions of a key immune-system gene, leaving them so vulnerable to everyday infections that a common cold could prove fatal. But when French researchers inserted normal copies of that gene into the boys' blood cells, the children were instantly cured -- able to play with their friends instead of living inside sterile bubbles, and ready to go down in history as the first humans to be cured of a disease by gene therapy.
Now scientists are scrambling to understand why, in some of the boys, the treatment has triggered a life-threatening form of leukemia, in which their renovated white blood cells are multiplying out of control and the boys are having to undergo chemotherapy to kill the very cells they had so desperately needed. The problem has brought dozens of gene therapy studies to a halt and has cast a pall over the struggling research field, which seeks to cure diseases by giving people new genes.
In an awkward coincidence, the unfolding debacle will be the highlight of a Food and Drug Administration meeting today, 50 years to the day after James Watson and Francis Crick launched the modern age of genetic medicine by deducing, with the help of a cardboard model, the three-dimensional structure of DNA.
Researchers say they have begun to figure out what went wrong in the French experiment. But more generally, experts said, the setback is representative of what is sure to be a difficult adolescence for gene-based medicine, and especially for gene therapy -- the archetypal clinical application of Watson and Crick's celebrated discovery.
To be sure, recent advances in genetics promise great improvements in the diagnosis and treatment of diseases. And genetics has already made big differences in forensics and criminal justice, and by giving birth to the burgeoning biotechnology industry. The entire field is to be feted at a series of events in New York, Washington and Cambridge, England -- where Watson and Crick did their seminal work -- between now and April 25, the 50th anniversary of the publication of their results in the journal Nature.
But genes, it is turning out, are not the simple, modular cassettes that scientists had envisioned in the early years. They not only act, but they also listen and react, and they misbehave in the absence of proper oversight and regulation.
Scientists, having figured out at last how to give people new genes and turn those genes on, now face the even more daunting challenge of learning how to turn them off -- or at least get them to respond as naturally as possible to the many biochemical signals that normally keep the body in balance.
"For the first eight or nine years of gene therapy, when gene delivery wasn't efficient enough to get an effect, we also didn't see side effects," said W. French Anderson, director of gene therapy at the University of Southern California, and the scientist who led the first U.S. gene therapy experiment in 1990.
"But every powerful technology has powerful side effects," Anderson said. "Now we're getting efficient enough to get therapeutic effects, so naturally there's going to be side effects."
The French experiment, under the direction of Alain Fischer at the Necker Hospital in Paris, involved children with X-linked severe combined immune deficiency (X-SCID). The disease is generally fatal within the first few years of life, and the only conventional treatment -- a well-matched bone marrow transplant -- is dangerous, results in an imperfect cure and is often unavailable.
Fischer's approach was to remove some of the boys' faulty white blood cells and mix them in laboratory dishes with viruses that had been genetically engineered to contain the gene the boys lacked. The viruses infected the boys' cells, delivering the new genes to the cells' DNA. Then doctors infused the repaired cells into the young patients, who ranged in age from 1 month to 12 months.
The results were spectacular: Nine of the 11 boys were apparently cured. But in September, about three years after treatment, rampant overgrowth of white blood cells was diagnosed in one of the boys. Molecular analyses showed that some of the viruses had dropped their therapeutic payloads in a bad location: atop another gene, called LMO2, which when disrupted can lead to untrammeled cell division and cancer.
At first, scientists hoped the incident was but a bit of bad luck. But in January the same problem was diagnosed in a second boy in the study. And earlier this month the French team announced that tests on a third boy's cells show the same molecular disruption, though the boy has not developed symptoms.
Now Fischer and others have come to believe that most of the boys treated with the gene-laden viruses will be found to have the same problem. The odds of a virus dumping its load on LMO2 are less than one in 100,000 per cell, but as many as 150 million cells are infected and infused into the young patients, said Christof von Kalle of Cincinnati Children's Hospital Research Foundation, who is conducting much of the analysis for the French team.
It is still uncertain whether LMO2 disruption by itself is enough to trigger leukemia, von Kalle and Fischer said in interviews, or whether additional disruptions are needed to start that process. Also unclear is whether such disruptions may pose a medical risk in only the youngest of patients, whose immune systems are still in a rapid stage of development. The two boys in which leukemia was diagnosed so far were the youngest treated, at 1 month and 3 months of age.
Nonetheless, several experts said, the incident indicates the kind of problems the field is sure to see more of now that scientists have finally begun to overcome what had been their main problems: an inability to get enough new genes into cells to make a difference, and an inability to get those new genes to work.
"Up until now, gene therapy was always looked at as an efficiency problem, with not enough cells expressing the gene," von Kalle said. "Now for the first time we've fallen off the horse on the other side."
For the FDA, the most pressing problem is to figure out the extent to which similar experiments might harbor the same risks. The agency has suspended 30 U.S. gene therapy experiments that were using or were about to use genes or viruses similar to those in the French study. Patients in those studies are now being told of the newly discovered risk, and researchers have been instructed to beef up their surveillance for untoward effects.
Today's meeting will focus largely on the question of which experiments should be allowed to move forward once added safety measures are put into place. It may be, for example, that the leukemia risk is significant only when the experiment involves the X-SCID gene -- whose biological purpose, after all, is to help white blood cells proliferate. In that case, similar experiments involving different genes to cure different diseases may get the go-ahead.
But, scientists said, gene therapy is going to have to do better at mimicking the body's own complicated means of regulating genes, in terms of when and where in the body they become active and just how active they ought to be.
One goal for the field is to wean itself from the retroviruses that were used in the French experiment. The viruses have been popular because they insert their genetic payloads directly into cells' DNA, giving the newly delivered genes a platform from which they can work indefinitely.
But retroviruses splice those genes at random locations in a cell's DNA, and as the French study shows, some locations are worse than others. Researchers have begun to experiment with other gene-delivery vehicles, including other kinds of viruses, synthetic fat bubbles, and even "naked DNA" that can sometimes find its way into cells without any help.
Researchers are also developing gene therapies that include so-called suicide genes, which would allow doctors to shut down the added gene by giving a patient a special drug. And they are developing genetic inserts that include not only the therapeutic gene itself, but also the flanking genetic sequences that help the gene respond to the body's own signals to turn on or off as needed.
"There are almost as many gene therapies as there are diseases to be cured," Fischer said. "The problems to be solved, efficacy and toxicity, are potentially extremely different for each."
The ultimate goal is "homologous recombination," a method by which unhealthy genes are removed from the body's cells and healthy replacements -- along with proper regulatory elements -- are inserted precisely in their places. Earlier this year, scientists at the University of Wisconsin reported the first successful homologous recombination in laboratory-grown human stem cells, a first step in the difficult process of making the technology work for patients.
"We are far from using that at the clinical level," Fischer said. "In the long term, we can all work on making that dream real."
More generally, scientists said, the lesson to be gleaned from the French experiment is that, practically speaking, even the best genetic therapies will be subject to the same frustrating truth that has long dogged conventional medicine: Biology is complicated, and any amount of tinkering is bound to bring surprises.
Despite all the promises of a perfect new medicine -- of treating diseases at their molecular cores and building healthy bodies from the inside out -- even the best genetic therapies will still force doctors and patients to balance benefits against risks.
Indeed, said Philip Noguchi of the FDA division that oversees gene therapy, it may even be that with minor modifications the French treatment for X-SCID will be deemed acceptable to regulators and parents, even with its risks.
"What we have here is a difficult disease for which you have extraordinarily promising results, kids leaving the hospital and leading relatively normal lives, and you also have adverse events which are serious but which so far appear to be treatable with chemotherapy," Noguchi said.
That is not the perfect future that Watson and Crick envisioned when, after making their historic discovery on Feb. 28, 1953, they repaired to the nearby Eagle pub and Crick made his now famous declaration: "We've discovered the secret of life!"
But it's a future that gives Fischer's boys some hope, which they wouldn't have had a few years ago.