It was a startling leap forward when scientists James Watson and Francis Crick discovered 37 years ago how the basic life-chemical deoxyribonucleic acid (DNA) is constructed. The achievement electrified medical researchers who had long been convinced that most human diseases are caused by malfunctions within the body’s 100,000 genes, which are made of DNA. In laboratories around the world, doctors excitedly organized elaborate and prolonged investigations which, in the past 10 years, have begun to yield dividends.
Scientists have identified the genes implicated in muscular dystrophy, cystic fibrosis and a rare form of colon cancer. And last week, the campaign to unlock genetic secrets and put them to work for human health took a dramatic tum: a review committee at the U.S. government’s National Institutes of -
Health (NIH) in Bethesda, Md., authorized two experiments in which, for the first time, genes will be the weapon and not the target.
In one experiment, doctors will try to reverse a rare immune-deficiency disease in children. In the other, they will attempt to intensify the body’s ability to fight cancer. Said Dr. Gerard J. McGarrity of the Coriell Institute for Medical Research in Camden, NJ.: “Medicine
has been waiting for this kind of thera_
py for thousands of years.”
Although both ventures still need the approval of acting NIH director Dr.
William Raub and the U.S. Food and Drug Administration (FDA), scientists in the United States and Canada were clearly jubilant at the prospect of the world’s first known human gene therapy, the long-heralded science of using genes to treat disease, and what it might lead to. Even Raub, who insisted that he would not be a “rubber stamp” for the NIH committee, acknowledged that he was “intrigued and excited.”
Dr. Michael Dosch, a 44-year-old German-bom professor of pediatrics and immunology at the University of Toronto, said that the NIH announcement “is one of the most exciting things to
Lung and Blood Institute and Dr. R. Michael Blaese and Dr.Kenneth Culver of the National Cancer Institute, part of NIH. It revolves around a rare disease that leaves children defenceless against infection because they have a defective gene that fails to make adenosine deaminase (ADA), an enzyme necessary for a healthy immune system. The three scientists plan to take blood from ADA-deficient patients, insert manufactured copies of the normal gene into the blood cells and put the blood back into the patients. Experiments
have happened in medicine in the last 100 years.” Other specialists speculated that gene therapy might one day lead to advances against other diseases largely resistant to treatment, including hemophilia and AIDS.
But, for the moment, international scientific attention focused on the two forthcoming projects. The first was designed by Dr. W. French Anderson of the U.S. National Heart,
on mice indicate that the normal gene will begin making the enzyme.
The second experiment, proposed by the cancer institute’s Dr. Steven Rosenberg, will be tried on consenting patients with advanced melanoma, a rapidly spreading and usually fatal form of skin cancer. For some time, scientists have known that blood has two natural but usually inadequate weapons against malignan_ cies—white cells called tumor-infiltrating lymphocytes, which seek out and weakly attack tumors, and tumor necrosis factor (TNF), a substance that does the same thing. Rosenberg has designed a gene that can make 100 times the amount of TNF normally produced in humans. He said that he plans to take tumor-infiltrating lymphocytes from the patients, insert the high-powered TNF gene and return the lymphocytes to the patients. Rosenberg added that he is counting on the super-gene to make enough TNF to destroy tumors without harming the surrounding tissue. If it works, scientists will be a step closer to the longheld search for the so-called magic bullet against cancer.
Both programs may be under way
before the end of the year. Officials at NIH and the FDA said that they expected to give clearances within the next few weeks. The Anderson-Blaese team said that it hoped to begin trials this fall on as many as 10 ADA-deficient children who have not responded well to conventional treatments, which include simply injecting the missing enzyme. The doctors said that all the patients would probably need monthly injections of genetically altered cells, which should bring about improvement within a year and, eventually, produce normal immune systems. As for the trials on cancer patients, the review committee told Rosenberg that he would first have to redesign his patient consent form, which should take only a few weeks.
Although ADA deficiency is one of the least common diseases—only about 20 children in the world have it—one of its victims achieved worldwide prominence about 15 years ago.
In Houston, a child identified only as David became known as “the boy in the bubble” because he lived inside a plastic envelope to shield him from contagion. As he grew, the bubble had to be made progressively larger. But in 1984, doctors took him out of it long enough to administer a bonemarrow transplant that they hoped would restore his immune system.
Before the transplant could take effect, David died of infection at the age of 12.
However, increasing numbers of scientists, searching for ways to introduce gene therapy as a weapon against disease, began concentrating on ADA deficiency as a test model because of its relative simplicity. First, it is a disorder of the blood, which is much easier to work with genetically than solid tissue. Second, it is caused by the absence of an enzyme that has been identified. And third, that enzyme is produced by a gene that has also been identified. Said Dr. John Dick, a geneticist at Toron-
to’s Hospital for Sick Children: “It was a standing joke in the research community that there were far more people working on ADA deficiency than had it.”
Meanwhile, several scientists said that the assault on the secrets of other diseases could become better designed and more effective if the expe riments are successful. “The larger implications for this procedure,” said Dick,
“probably involve AIDS and different forms of cancer therapy.” Dr. Robert A. Phillips, head of the hospital’s division of immunology and cancer research, said that there are “probably a lot of applications in the blood-forming system beyond ADA.” Those, he added, might include conditions affecting hemoglobin, the protein needed to carry oxygen to the cells. Louis Siminovitch, director of the Samuel Lunenfeld Research Institute at Toronto’s Mount Sinai Hospital, said that “the first successes, if there are successes, will be done
on blood cells.” Added Siminovitch: “Anything where there is a single-gene defect in a cell is open to this kind of therapy— theoretically.”
For his part, the University of Toronto’s Dosch said that the challenge facing the U.S. projects is huge. He added that the long-term issue is “not to cure ADA deficiency. The issue is whether gene transplantation can cure hu-
man disease.” Limiting the undertaking to ADA, said Dosch, would be “like saying, ‘Let’s go to the moon and when we get there let’s plant a flag.’ But surely the flag isn’t the point of the trip. It merely marks a milestone. The real point of the trip is what lies beyond.” For the Washington scientists about to embark on one of medicine’s most ambitious explorations, the immediate task is simply to launch the rocket.
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