TCS Daily


A Revolution, Almost

By Sydney Smith - February 6, 2003 12:00 AM

Recently, the New England Journal of Medicine formally recognized that medicine is on the threshold of a revolution. The recognition was a subtle but important one. Tucked away among the headline-grabbing latest research papers for the past couple of months has been a series of review articles designed to educate the practicing physician on the basics of molecular genetics. It isn't the first time that recent advances in genetics and their implication for medicine have been discussed on the journal's pages. It's a subject that's been dealt with extensively not only by it and other journals over the past several years, but by the popular media, too. It is, however, the first time that any journal of such stature has mounted an effort to bridge the gap between research and practice. With this series the journal, with its global readership, has taken the lead in bringing practicing physicians into the new frontier of genomic medicine.

And we do need the help. Most of the latest advances in gene-based medicine have happened only recently - in the past five to ten years - thanks largely to the success of the Human Genome Project. Most practicing physicians completed their basic science training long before the ambitious project was conceived. As a result, the majority of us tend to think of genetics in terms of straightforward Mendelian patterns rather than complex interactions of three-dimensional molecules. As a profession, we simply aren't prepared to give the current explosion of genetic advances the scrutiny they deserve before applying them to practice, let alone to counsel patients on their many nuances. As a result, genomic medicine has been slow to gain acceptance and widespread use in the day-to-day practice of medicine. You may read of genetic tests for breast cancer and Alzheimer's disease, but chances are your doctor doesn't offer them to you the same way he offers cholesterol screening.

There's more at work here than our collective ignorance, however. The science itself has serious limitations that impede its application to daily life. Take, for example, the case of cystic fibrosis. It's a common disease, as genetic diseases go, and its gene, discovered in 1989, was one of the earliest identified. It has all the earmarks of a disease that should lend itself perfectly to genetic screening. It exists in a silent carrier state. Its inheritance follows simple, straightforward, Mendelian rules. If two carriers have a child, that child has a twenty-five percent chance of having cystic fibrosis. Presumably we could prevent it altogether if we screened people for the silent carrier state. In fact, last year the American College of Obstetrics and Gynecology recommended we do just that, but the test has yet to see widespread use.

A good portion of the blame for its tepid reception rests with the nature of the gene itself. For, although the inheritance of cystic fibrosis is straightforward, the gene isn't. Any one of several hundred different mutations can result in the disease. Accurately testing for every mutation isn't possible, so the screening test focuses on the most common few (anywhere from 25 to 87, depending on the lab). As a result, screening only identifies about 90% of carriers. A negative test doesn't eliminate the risk of having a child with cystic fibrosis.

Then there's the matter of what to do with positive test results. Two parents who test positive for the gene mutations still have a seventy-five percent chance of having a normal child. Once they've conceived, they can elect to have amniocentesis to test the fetus for the mutated gene and abort it if positive, but having the disease doesn't preclude having a happy and fulfilling life. As recently as twenty years ago, the majority of cystic fibrosis patients died in their teens from pulmonary complications. Today, the majority live into their late twenties and early thirties, have families of their own, and generally function as productive members of society. Some argue that early identification of the disease would facilitate early treatment and improve survival, but we don't know that for sure. It's no wonder, then, that few elect to have the $300 test, or that few doctors choose to navigate its messy waters.

The issues involved with other genetic tests are even less straightforward. Some mutations, like those in the BRCA 1 and BRCA 2 breast cancer genes, translate only into an increased risk of disease rather than the disease itself. To complicate matters further, the disease has no cure and no reliable method of prevention. Others, such as the mutation responsible for hemochromatosis, a disorder of iron metabolism, don't necessarily translate into disease at all. Only a small proportion of mutation carriers go on to develop iron overload. Gene mutations associated with more common diseases, such as heart disease, diabetes, and Alzheimer's are on even less solid footing - their expression more variable, their association more tenuous. When it comes to translating genes into meaningful indicators of disease, the track record so far is abysmal.

That's not to say that genomic medicine is worthless. It isn't. It's just that it's still in its infancy, and genetic screening is just the first, and easiest, of its potential applications to be explored. The field's greatest hope lies not in the predictive power of genes, but in their therapeutic potential. Leukemia patients are routinely tested now for a genetic mutation that inhibits their ability to handle mercaptopurine, a drug used in the treatment for acute lymphoblastic leukemia. If they have the mutation, they're given a lower dose of the drug, and experience far fewer side effects. Someday, the same may be done for other, more commonly used drugs. Although far from ready for prime time, gene therapy is beginning to show promise, especially in cases of hereditary immunodeficiencies. Someday, we may be able to use gene therapy to cure cystic fibrosis or to target cancer cells, rending many of the controversies over genetic screening moot. These are the dreams that fuel the revolution, and in the end it will be their successes that define medicine's new frontier. In the meantime all we can do is wait, and hope, and prepare.
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