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hairman of the Department of Molecular and Experimental Medicine and Professor in The Skaggs Institute, Ernest Beutler, M.D., has spent a major part of his career studying the mechanisms that underlie many genetic diseases and searching for treatments based on a fundamental understanding of the disorder. Among these are hereditary anemias, storage diseases such as Tay-Sachs, Gaucher, and galactosemia (the inability to use milk sugar). One of his current interests is hemochromatosis, a common disease characterized by excess iron storage. This easily treatable genetic disease is likely to become a test case in the broad-based discussions currently underway regarding the use of genetic tests to screen the population for susceptibility to disease. And projects underway in the Beutler lab will be at the center of, and possibly help resolve, the debate about the benefits and risks of genetic screening.

Hemochromatosis is the most common genetic disease in people of European origin. It is a disease in which the body retains more iron than it needs and the excess iron can lead to cirrhosis of the liver, diabetes, arthritis, and damage to the heart. It is also one of the most easily treatable of all genetic diseases. The treatment is simple, drawing a unit of blood at appropriate intervals in the blood bank. Through blood donation the excess iron is removed from the body, thereby allowing patients to avoid the symptoms and to enjoy a normal life expectancy.

GENETIC MUTATION FOR HEMOCHROMATOSIS

The key discovery came in mid-1996. A biotechnology company, Mercator Genetics, discovered a mutation in a gene called HFE that predisposes people to hemochromatosis. The Beutler laboratory, along with many others, had been searching for this important gene. In confirming that the mutation was indeed the cause of the disease, Beutler says, "the really important thing is that the cause of most cases of this disease is now known. This has made it possible for us to move ahead rapidly with studies of how best to detect this very treatable disease and when to treat it." Beutler points out that hereditary hemochromatosis is an interesting disorder in which to study the interaction of mutations with each other and the environment in causing or exacerbating the symptoms of disease. At the same time, it is likely to become a testing ground for probing or even modifying society's attitude toward widespread genetic testing.

GENETIC TESTING FOR HEMOCHROMATOSIS

By the end of 1996, two of the premier medical research and public health organizations in the United States, the Centers for Disease Control (CDC) and the National Human Genome Research Institute (NHGRI), considered it important to have experts address the issue of genetic screening. In March 1997 they convened a panel, which included Beutler and a number of other prominent physicians and research scientists, to discuss what course of action should be taken. The questions posed were: "Should there be widespread testing for hemochromatosis? And, if so, should it be based on measuring blood iron levels or should it be based on analysis of DNA?" The report, which has recently been published in the Journal of the American Medical Association, recommended against widespread genetic testing for hemochromatosis until more research had been conducted.

Working together with Dr. Vincent Felitti at Kaiser-Permanente in San Diego, Beutler has organized a study that should help answer these questions. Over the course of the next three years, the Kaiser-TSRI team will screen 60,000 patients for hemochromatosis. Each patient will, after giving appropriate informed consent, be given both a genetic test for the disease as well as the conventional blood tests. "In a population of this size, we expect to find about 200 patients with hemochromatosis. We will be able to establish comparative value of the new genetic test, on the one hand, and standard biochemical testing on the other." It will be the largest such screening study ever undertaken. The NIH and the CDC have provided funding of more than $4,000,000 for these clinical studies and the basic studies of iron metabolism that will be performed in the Beutler laboratory.

EXPLORING THE ORIGINS OF THE DISEASE

Beutler hopes that the screening project will also address some of the remaining mysteries surrounding the origin and course of the disease and the mechanisms by which the body normally absorbs iron. "We will evaluate iron intake, iron supplements, and the effect of infection with hepatitis viruses as well as other non-genetic factors," he says, "in order to examine the interactions between genetics and environment in this disease." Beutler and his colleagues have already shown that a second mutation in the HFE gene also increases the risk of developing hemochromatosis. When a person inherits one copy of the major mutation, called 845A, and a single copy of the other mutation, called 187G, neither of which is itself enough to cause disease, that person seems to have an increased risk, about 1.5 percent, of developing hemochromatosis. "What is different about these 1.5 percent of people from the 98.5 percent who do not develop hemochromatosis?" asks Beutler. The answer may lie in further mutations elsewhere in the iron transport pathway, or in various environmental causes. Between the Kaiser-TSRI study and the work in his own laboratory, Beutler intends to find out. In related work in his laboratory,

MORE EFFECTIVE SCREENING METHODS

The answer will be welcome, particularly to those who, like the CDC-NHGRI panel, want to determine the usefulness of screening. "By knowing more about auxiliary factors influencing whether someone actually develops hemochromatosis," says Beutler, "we may ultimately be able to make screening more effective." Beutler has high hopes that the upcoming screening study may provide information beyond that dealing with hemochromatosis. If the study results show that genetic testing is helpful, this may help dispel public distrust in this important technology, distrust that Beutler sees as misplaced because it is based on a misunderstanding. It is important to provide many safeguards for genetic information in the case of late-onset, difficult, or impossible- to-treat diseases, such as cancer or Huntington's disease. "But in the case of hemochromatosis, the benefits outweigh the risks. It is about as clear cut an example as one can find, because the disease is so easy to treat," he says. "It would be throwing out the baby with the bath water to conclude that testing for hemochromatosis should not be carried out because screening for Huntington's causes unnecessary pain to those who receive the information. This issue needs to be considered one disease at a time."

Genetic diseases, Beutler points out, are "experiments of nature" that have taught scientists much of what they know about how the body functions normally. In the early 1960's a study of a red blood defect that causes anemia led him to propose, and then to demonstrate, that only one of the two X-chromosomes in the cells of women was active. In the 1980's the study of an inherited defect in immunity led Dennis Carson, M.D., working with Beutler at TSRI, to design a new drug, 2-CdA, that is now the standard treatment for some forms of leukemia and has proved very useful for the treatment of multiple sclerosis. Beutler points out that "the discovery of the HFE gene mutation in patients with hemochromatosis is a vital piece of the puzzle that we will try to put together to understand how the amount of iron in our bodies is normally controlled."