The first apparently successful gene therapy was carried out by French Anderson, Michael Blaese, and Ken Culver at the National Institutes of Health in 1990. They chose a very rare disorder called adenosine deaminase deficiency (ADA), in which the lack of an enzyme disables the immune system, leaving one as defenseless as David Vetter, the boy in the plastic bubble. The experimental subjects were two young girls, four-year-old Ashanti DeSilva and nine-year-old Cindy Cutshall.
How do you shoot a new gene into a patient? At that time, retroviruses suggested themselves as the logical weapon of choice. In general, viruses are efficient genetic vectors; they make their living by injecting DNA into other cells. Retroviruses, a special group, have RNA, rather than DNA, as their genetic material. But while most viruses infect a cell, reproduce, and then kill the host cell as the "daughter" viruses escape to infect others, retroviruses are typically kinder and gentler, at least to the host cell: new viral copies are dispatched without destroying it. This does not necessarily mean that a retrovirus is any easier on the host organism; sometimes it is quite the contrary, as demonstrated by the effects of HIV, perhaps the best-known retrovirus. But it does mean that the viral genes – and any extra gene the virus may be induced to ferry – will become a permanent part of the undestroyed cell's genome. Genetic engineering has produced retroviruses that are as safe as possible for gene therapy; stripped of all the viral genes that aren't essential for invading the host cell's genome – and their means for accomplishing this purpose are formidable – retroviruses become the ideal gene vector.
But we are still left with the problem of how to target only the cells affected by the mutation, the ones that need the replacement gene. Today this remains the greatest challenge facing gene therapy: how do you get the good gene into muscle cells to treat DMD, lung cells to treat cystic fibrosis, or brain cells to treat Huntington disease? The choice of the obscure disease ADA was therefore a very sensible one for the first gene therapy trial: the target cells for ADA are readily available – immune-system cells circulating in the blood. Anderson's team was able to extract millions and millions of immune cells from the girls' blood and grow them in petri dishes, where they could be infected with a retrovirus carrying a functional copy of the gene. Once the cell's natural DNA had incorporated the viral genome carrying the replacement gene, the cells were ready to be fed back into the patients' blood.
In September 1990, Ashanti DeSilva was the first to undergo the procedure; Cindy Cutshall's therapy followed four months later. Each received infusions of genetically doctored immune cells every few months. At the same time, each was continued on the non-gene therapy of enzyme replacement, the same manner in which Gaucher disease patients are treated, but in lower doses. This precaution was required by the NIH's Human Gene Therapy Subcommittee, which argued reasonably that it was too dangerous to expose the girls to a new therapy without a safety net. The experiment, though not a perfectly controlled one, did seem to work: the immune systems of both girls improved, and they were better able to fight off minor infections. I personally can attest that Cutshall seemed a very healthy eleven-year-old when she and her family visited Cold Spring Harbor in 1992. Eleven years later, however, the results are not entirely conclusive. DeSilva's immune system is now approaching normal function, but only about one-quarter of her T cells are derived from the gene therapy. Cutshall's blood contains an even smaller proportion of gene-therapy T cells, though her immune system is working well. It is, however, difficult to say exactly how much of the girls' improvement is due to the gene therapy and how much to the continuing enzyme treatment. The result is therefore too ambiguous to be understood without reservation as a clear gene-therapy success.
The Cutshall/DeSilva trials were not the first time the NIH had thrown its weight around in the world of gene therapy. In fact, the Human Gene Therapy Subcommittee was formed at the NIH in 1980 in response to the first gene-therapy experiment ever performed. The trial was a failure and stirred up such a controversy that the government almost moved to strangle the newborn enterprise in its cradle. By all accounts, the man at the center of the storm, Martin Cline, was a clever, ambitious clinician, devoted to the relief of his patients' woes. His special interest was beta-thalassemia, the hemoglobinopathy Bernadette Modell had screened for among London's Cypriot community. After successful animal experiments, Cline applied to the review board of the University of California Los Angeles, where he worked, for permission to try the gene therapy on humans using nonrecombinant DNA. While the application was still being reviewed, an overzealous Cline had arranged to treat two women outside the United States, one in Israel and one in Italy, but he used recombinant genes, whose use was still prohibited under NIH guidelines. On returning to Los Angeles, Cline found that his application had been rejected; the review board ruled that more animal data would have to be presented before an attempt with humans could be sanctioned. Cline had broken just about every rule in the book: not only had he proceeded to treat human subjects without authorization, but he had also used an unequivocally prohibited method. Cline suffered the consequences: he lost his federal funding and was forced to resign as chairman of his department. Gene therapy had lost its first practitioner.
The Cline episode was by no means the last time that scientists attempting gene therapy found themselves in hot water with regulators. Tragically, it took the death of a patient in a gene-therapy trial to bring home the sobering message: gene therapy – that complicated cocktail of viruses, growth factors, and patients – is dangerous. But the message was more than that: because there are so many unknowns in the gene-therapy equation, strict oversight of all procedures involving humans is absolutely necessary. Jesse Gelsinger died both because we do not know enough to predict with complete confidence an individual's response to gene therapy and because scientists took inexcusable shortcuts.
In 1999, Gelsinger, an Arizona teenager, heard about an experiment being conducted by James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania. Gelsinger was suffering from ornithine trans-carbamylase deficiency (OTC), a hereditary impairment of the liver's ability to process urea, a natural product of protein metabolism. Untreated, the disease can be lethal, and though, like PKU, it can be managed with simple medication and an appropriate diet, OTC does leave its victims particularly vulnerable to other ailments. The eighteen-year-old Gelsinger had only a mild case, but a childhood brush with death precipitated by his condition emboldened him to volunteer in the hope of helping to find a cure for himself and others like him. The Pennsylvania therapy aimed to use an adenovirus (a member of the group that causes the common cold) as the vector of the corrected gene. But a few hours after the viruses carrying a normal version of the OTC gene had been injected into his liver, Gelsinger developed a fever. A rampant infection followed, accompanied by blood clots and liver hemorrhaging. Three days after the injection, Jesse Gelsinger was dead.
The teenager's death was a shock not only to his family but to the research community as well. A detailed investigation revealed serious procedural lapses. Most glaring perhaps was this: although two patients had shown signs of liver toxicity earlier in the same study, the cases had gone unreported to any regulatory authority and were never disclosed to the volunteers in the study. Had the Gelsingers been informed, Jesse would likely not have been so quick to volunteer, and he might well be alive today. The tragedy dealt a serious blow to the progress of gene therapy. For a time, the FDA halted all such experiments at the university and at several other programs across the country. Bill Frist of Tennessee, the Senate's sole physician, conducted an investigation into reporting procedures in human trials; President Clinton called for improvement in standards of "informed consent," championing the right of experimental subjects to be apprised of all potential risks. If any good has come from Jesse Gelsinger's death, it is that federal oversight of human trials has been tightened.
The gene-therapy community was still reeling from the shock wave caused by Ge
lsinger's death when heartening news of a success story came from France. The disorder targeted was SCID, the immune deficiency that condemned David Vetter to life in a bubble. Though bone marrow transplants can effect a cure – the recipient of the first transplant, done in 1968, is still healthy today – the success rate is only about 40 percent and even successful transplants frequently lead to grim complications, as in Vetter's sad case. In 2000 a team under Alain Fischer at the Necker Hospital in Paris carried out gene therapy on two infants who, like David, had been kept in sterile isolation since birth. As with the treatment for ADA, a retrovirus was used to ferry the needed gene into cells extracted from the babies; the cells were then reintroduced. But, in a notable innovation, the French group harvested the cells to be modified from the infants' bone marrow. By using the marrow's immune stem cells rather than ordinary T cells found in the blood, the method, if successful, promised to furnish a self-perpetuating genetic fix. When stem cells reproduce, they increase not only their own numbers but also the numbers of the specialized somatic cells into which they naturally differentiate. Therefore any T cells produced from altered stem cells would also carry the inserted gene, making the repeated infusions of modified cells unnecessary.
And that is exactly what happened: ten months later, T cells containing a working copy of the missing gene were found in both patients, and their immune systems were performing as well as those of any normal children. Fischer's method has since been applied to other SCID children. After a long and not altogether auspicious start, gene therapy had finally notched an unequivocal success. But the champagne celebration did not last long. In October 2002, doctors found that one of the two original patients was suffering from leukemia, a cancer of the bone marrow in which certain types of cell are overproduced. Though it has not been established for sure that the genetic procedure was responsible, the circumstantial evidence is mighty strong. Gene therapy seems to have cured the baby's SCID but caused leukemia as a side effect.
Side effects have always dogged medicine. Drugs may affect more than just their intended target, or surgical procedures may end up causing complications. Though in many ways a departure from conventional medicine, genetic medicine, we now know, is also subject to the same law of unintended consequences. Fischer's SCID treatment probably inadvertently created new problems in the process of fixing the original one. After all, any treatment requiring the insertion of viral DNA into the DNA of patients' cells is inherently risky because the foreign DNA may by chance disrupt the functioning of a critical gene. Because typically the cell in which this has occurred will die, such events usually have no impact. But it is possible that the disrupted gene is one whose elimination does not kill the cell, but rather unlocks its capacity to multiply unchecked: the viral insertion can cause cancer. This seems to be what happened to the SCID baby.
Gene therapy may yet be a long way from delivering the miracles foreseen at the dawn of the genetic revolution. Jesse Gelsinger's death was a severe setback. The leukemia side effect of the SCID treatment, however, is even more damaging. In Gelsinger's case, it seems that unpardonable mismanagement was largely responsible – a problem that has hopefully been fixed by tighter regulation. But there is no ready solution to the side-effect problem. Probably we will have to rely on the depressing calculus that applies in this case: that gene therapy has at least cured a condition, SCID, worse than the one it has caused, leukemia. The good news is that the baby boy in question is apparently responding well to the chemotherapy used to treat the leukemia. However, between them the Gelsinger and leukemia incidents have crystallized many of the difficult issues that need yet to be resolved if somatic gene therapy is to enter the medical mainstream. And I am not so naive as to deny that future trials will likely uncover yet more difficulties. It may be some time before we can claim beyond doubt to have neutralized every conceivable danger, but I nevertheless believe that the potential of this technology to lift the curse of genetic disease is simply too great for medicine to turn away from it.
Your DNA can tell someone a lot about you. As we've seen, if Huntington runs in your family, your DNA can literally reveal your future; soon, depending on whether you possess a particular variant of a gene (or combination of genes), DNA may also speak to your relative risk of succumbing to common killers like heart disease. What version you have of the APOE gene can already serve as a predictor of Alzheimer. But should you worry that this profoundly personal information might be used against you? Not surprisingly, for many Americans the greatest concern is that genetic profiling may one day lead to their being denied health-care insurance.
In 2000 the American Journal of Human Genetics published the results of a survey that had asked health insurers whether they would adjust rates to take account of genetic information if it were available to them. Would they, in principle, be prepared to charge more for a customer in perfect health who carried a mutation predisposing him or her to a disorder? About two-thirds admitted they would. The other third were in all likelihood lying. Insurance companies are not philanthropies, but businesses, with shareholders to please. There is no reason to suppose that, left to their own devices, they wouldn't do what they have always done: maximize the premiums of those at risk, and where possible avoid altogether those customers most likely to collect. The same report described a case where an insurance company raised an individual's rates based on a suspicion of a genetic disorder, merely because this individual had requested a diagnostic test for Huntington disease.
As we come to know ourselves at the molecular level, is it inevitable that those of us who have drawn the short straws in the genetic lottery will be made to pay a price, in this way and others? And why presume such abuse would begin and end with insurers? My DNA profile might show that I am likely to have a heart attack or stroke, become an alcoholic, or suffer clinical depression. Might such information cause a prospective employer to think twice about hiring me?
Such questions suggest that Brave New World may be upon us well before the twenty-fifth century of Huxley's imagination. DNA is a potent fact of twenty-first-century life – a genie that will never be put back in the bottle. What we allow to be done with it, however, is something we must decide as a democratic society. Unfortunately, in such societies, laws tend to lag behind the need for them: a traffic light isn't typically installed at a dangerous intersection until after a few accidents have occurred. It may require a few horror stories of gross injustice, of individuals made the victims of their own genomes, to motivate the passage of appropriate legislation. What should it look like? Genetic privacy should be a touchstone, but not necessarily the ultimate objective. Balances will need to be struck with society's other priorities, not least the fight against disease, an effort whose progress will more and more depend upon giving medical researchers access to as much genetic data as can be collected from the general population.
While legislation ought not defeat our ambition to exploit the full potential of DNA to alleviate human suffering, or to tell us about ourselves and our origins, or to identify those among us guilty of crimes, it must minimally ensure that no citizen be deprived of civil or human rights on the basis of what might be inscribed in his or her genes.
Meanwhile, it may be a comfort to know that despite a wealth of genetic information already at the industry's disposal and regardless of what they tell pollsters, insurance companies have, on the whole, shown little impulse toward factoring genetic considerations into their calculations for setting rates. The wretched pale skin I inherited has already proved its susceptibility to cancer, but the last time I looked, I still wasn't being charged a higher premium for it. Again, the rationale is business, not charity. Insurers have traditionally set rates using actuarial tables that estimate overall health and longevity mainly on the basis of how we live. I suspect that even if genetic data were universally available, insurers would still find such lifestyle factors – whether one smokes or not, whether one works in a coal mine as opposed to a flower shop – vastly more p
redictive of one's health risk than the overwhelming majority of relatively subtle differences determined by genetic variation from one person to another. It's indisputable that those whose DNA reveals an unavoidable destiny of debilitation need special protection under the law, but the propensity toward ailments like heart disease and cancer are certain to prove so widespread and complicated as to make them an impractical basis for cost-cutting discriminations. The essential premise of insurance, that payments of the happy many who never have cause to collect will underwrite the relief of the unfortunate few, is not likely to be abolished owing to the accumulation of any amount of genetic information.
Dna: The Secret of Life Page 40