John has always lived with the specter of death, for like all cystic-fibrosis patients, he knows that his next lung infection may be his last. Because of a genetic defect, the cells lining his lungs cannot shuttle water and salts across their membranes; mucus builds up, inviting a lethal infection. But in 1989, when scientists discovered the defective gene that causes cystic fibrosis, John allowed himself feeling that CF patients seldom indulge in: hope. And when he heard that researchers at the University of North Carolina were launching an experiment in which 12 patients would be given healthy CF genes, John, 26, volunteered. Now it's harder to sustain the hope. As scientists reported last week in The New England Journal of Medicine, the healthy genes infiltrated very few of the patients' cells. Five patients developed lung inflammation. And in no patient did enough genes slip into enough cells to make any difference in their condition.
In theory, at least, it all seemed straightforward. Riding the revolution in genetics, scientists have identified more than 3,200 genetic defects linked to diseases including colon cancer, Huntington's and cystic fibrosis. Only last week researchers at the National Cancer Institute announced the discovery of a mutation in a gene linked to inherited breast cancer; the mutation arises in 1 percent of Jews of Eastern European descent, making it their most common genetic disorder. Of all the possibilities that these discoveries offer-from developing new drugs to screening fetuses for lethal genetic defects-the most tantalizing has been the prospect of substituting a good gene for a bad one. In such "gene therapy," healthy versions of missing or defective genes would be slipped into a patient as easily as a computer jock installs a software patch to correct a bug-ridden program.
But it hasn't worked out that way. The National Institutes of Health has approved 125 human-gene-therapy experiments since 1990, almost all to measure whether the techniques are safe. Fewer than a dozen were actually aimed at helping patients. Not a single one has yet shown that gene therapy can cure anything. "When there's no proof that something works," says geneticist Robert Erickson of the University of Arizona, "it's not much different than snake off."
The latest blow fell last week, with reports in The New England Journal that two more gene-therapy experiments had not worked. In one study, led by Dr. Jerry Men-dell of Ohio State University, 12 little boys with Duchenne's muscular dystrophy received six monthly injections of immature muscle cells. The hope was that the genes in the healthy cells would fuse with the boys' wasted muscle cells, which lack the dystrophin gene that gives muscles their strength. In eight boys the repair gene did not even get into the muscle cells. In the other four the gene did sneak in, but to little avail: there was no improvement in the boys' strength. The other sobering news came from the North Carolina experiment. Dr. Richard Boucher and colleagues hope to cure CF with a sort of viral Trojan horse. The idea is to splice into a common cold virus, or adenovirus, a healthy version of the CF gene. The team sprayed adenovirus-es containing healthy genes into volunteers' noses; the virus, and hence the gene, was supposed to infiltrate respiratory cells just as cold viruses do normally. But in seven of the patients virtually no genes even got into the cells. In the other five, a few genes got in. But they did not work well enough to have any effect on the disease.
The surprising part of all this is that gene therapies had shown promise in treating lab animals with hemophilia, muscular dystrophy, cancer, immune deficiency and other ills. But as immunologist Christopher Wilson and geneticist Mark Kay of the University of Washington wrote in the journal Nature Medicine last month, "mice are not human beings . . . Major impediments remain to be overcome if gene therapy is to become a reality." Some of the obstacles:
Natural defenses. In several experiments a patient's immune system has killed the Trojan horse--the virus carrying the healthy gene. As a result, too few genes enter the defective cells to cure disease. "This probably shouldn't have come as a surprise," says Wilson. "Humans have evolved an immune system that keeps foreign invaders at bay"-even if the invader is a virus carrying a gene that might cure a fatal illness.
Leaks. The repair gene sometimes escapes the target tissue. In the cystic-fibrosis trial at UNC, viruses wound up in some patients' pharynx (above the esophagus) and stool. In another trial, a gene that was supposed to treat brain cancer infected the lining of the brain in one patient. He got meningitis (but survived). The Food and Drug Administration shut down the experiment.
Impermanence. Some genetic diseases involve cells that rarely divide. So even if repair genes slip into, say, lots of liver cells, it will not be a permanent fix: the cells carrying the new, healthy gene do not pass it on to any progeny. Any improvement in a patient's condition is thus short-lived.
It is not difficult to see why the public might think gene therapy is farther along than it is. In the first such experiment ever done, in 1990, an NIH team led by W. French Anderson and Michael Blaese treated two little girls suffering from severe combined immunodeficiency (SCID). Because SCID children lack a gene called ADA, they cannot produce the white blood cells necessary to fight off viruses and disease bacteria; untreated children die, often by age 1. NIH researchers injected the girls with blood cells contain in a healthy ADA gene. Both girls are doing fine. But they remain on a $250,000-per-year drug that does exactly what the new gene is intended to do -- so it is impossible to know wether they owe their lives to the old medicine or the new gene. The ambiguity didn't stop scientists from using the girls as examples of successful gene therapy when they tried to wangle more money out of Congress a year ago, however. In fact, the outcome is probably less clear, judging by a similar experiment on three SCID newborns at Children's Hospital in los Angeles led by Drs. Donald Kohn and Robertson Parkman. Between 1 percent and 10 percent of their little patient's blood cells now contains the ADA gene. Apparently, the gene got into some cells. But did it get into enough to help? Because the toddlers remain on the drug, Kohn remains humble: "It's still unclear whether we have cured them or not."
NIH director Harold Varmus is concerned enough about gene therapy that in February he appointed a panel of 10 researchers to scrutinize it. He asked in particular whether biotech companies had pushed ahead with clinical trial no to advance the science but to inflate the value of their stock. The panel report should be made public by the end of the year. Academics have been in just as much of a hurry as private companies. Establishing a gene-therapy center raises the profile and prestige of a hospital or university increasing its attractiveness to deep-pocketed donors, says Parkman: "It's advertising for money." The rush to grab some of the cachet surrounding gene therapy affects funding agencies journals, too, contends Richard Mulligan, the founder of Somatix Therapy Corp. of Alameda, Calif., and also the soon-to-be director of gene therapy at Harvard University. Agencies have approved clinical trials without examining underlying and unanswered questions of basic science, Mulligan says: "The standard of the science being done have set inappropriately low. And unlike any other discipline, more bad science gets publicized. There are journals that will print any sort of gene-therapy report because of the excitement."
There is nothing wrong with impatience in the name of curing the sick and dying.But the lack of scientific spadework -- in virology, genetics and cell biology -- may have cost he field of gene therapy several years. Fr. Ronald Crystal of Cornell University Medical College argues, however, that "the logic behind gene therapy is so compelling, the science is so deep, there is no question it is going to work. "James Wilson of the University of Pennsylvania does not even regard the cystic-fibrosis results as a setback but rather as "normal evolution. We'll go back to the lab and fix it." To cure gene therapy of what ails it, he and others have proposed various schemes to foil the immune system's attack on the Trojan-horse adenovirus. Even the unsuccessful gene trials reported last week have taught researchers what is nd isn't likely to work. UNC's Boucher is already several steps beyond the CF trial reported last week, working on delivery systems that might get more healthy genes into more sick cells.
One or another of the new approaches may be the breakthrough the field needs. Champions of gene therapy hope ir comes soon. If we are unable to demonstrate [success] in the next three or four years," warns Thomas Okarma, chairman of Applied Immune Sciences Inc. in Snata Clara, Calif., "the pendulum is going to swing from flaming to smoldering to smoking to out." The 80,000 human genes offer the promise of 80,000 disease treatment: after the field's troubled infancy, the gene doctors would be grateful or a single one. And so would John, 26, the CF patient who would very much like to become 27.
Scientists announced last week that they've located about half of the genes in the human body. They don't know what they all do--or how they work-but the atlas published in the journal Nature is a milestone in the Human Genome Project.
1 Just about every cell in the body contains two copies of every gene. they're made of a long, twisty molecule called DAN.
2 DNA gets packaged into 23 pairs of chromosomes in the nucleus of the cell. Scientists think these chromosomes contain about 80,000 genes.
3 Genes are made up of sequences of smaller molecules called bases that sit on the spiraling DNA backbone. Designated A,C,T, or G, they encode the information the body needs to build proteins.
4 If those bases get out of order or the sequence gets "misspelled," a mutaion can occur.
Scientists have found 3,200 mutations in human genes that cause disease. They hope that by substituting healthy genes for these defective ones they can cure illnesses from cancer to cystic fibrosis. But the reality has not lived up to the promise.