Genetic knowledge is increasing exponentially -- as headlines scream "They've found the gene for" everything from fatal disorders to personality traits -- but our sense of disease risks doesn't necessarily keep pace

Is biology destiny?

Janice Hopkins Tanne

Isidore Edelman's father had no formal education. "He was an immigrant. All his life he regretted the education he wanted and never got. Education at that time was a luxury. He had to make a living," says Dr. Edelman, now director of Columbia University's genome project.

How much do genetic discoveries really matter? Do genes tell our future any better than the astrologer in the storefront down the street? What difference did they make for Edelman's father?

Every day people read that another gene has been discovered, leading to a veritable ABC of genes for Alzheimer's disease, baldness, colon cancer, ad infinitum. (The notion of a single gene for any given condition has spread so far into the popular culture that a recent Hollywood film looked to the genetic code for its title--"GATTACA"--and was promoted with the slogan "There is no gene for the human spirit.") Many assume that a single gene causes each disease and that soon after discovery will come a test and a treatment. If only science were so simple.

Mapping ourselves and our fellow mongrels

At Columbia, scientists and ethicists are deeply involved in the national Human Genome Project, a vast endeavor to map and sequence the approximately 100,000 genes making up the human 2005! So far, researchers have identified about 10,000 genes but few links between genes and common diseases, perhaps because the diseases involve many genes and the environment. The pace of gene identification picked up dramatically earlier this year when Dr. Craig Venter, head of the Institute for Genomic Research, and the scientific instruments company Perkin-Elmer set up a new enterprise. It aims to sequence the entire human genome in only three years, using a technique developed at the institute and new, fast DNA sequencing devices developed by the company.

The human genome is not exactly exclusive. "We share more than 90 percent of our genome with rats. We share much more with non-human primates. In fact, we're closer to chimpanzees than chimps are to gorillas," Edelman says. At the structural and functional level, genes are so similar that a researcher described flies as "little people with wings." Human beings are very close to each other, sharing about 99.9 percent of their genome. The other 0.1 percent contains differences (polymorphisms) that help explain inherited traits and diseases.

"If you find a gene, chances are nobody knows where it goes on the genome and nobody knows what it does," Edelman says. Genes make up less than 5 percent of the human genome. Most of the DNA lies between the genes like a vast desert between strip malls. It's called junk DNA because nobody knows why it's there or what it's doing.

Genes tell cells what proteins to produce, and proteins are the basis of all biological processes. Several techniques exist to locate genes on a chromosome to create a physical map. A different map, called a genetic linkage map, finds genes that are inherited together (linked) and so must be close together on the same chromosome. The technique has helped researchers find mutations that cause hereditary diseases, such as the gene for Huntington's disease. Dr. Nancy Wexler, Higgins Professor of Neuropsychology at Columbia, won the prestigious Albert Lasker Award for that discovery, made with colleagues at other institutions.

Huntington's disease, a fatal neurologic disorder, is genetically determined. If a child inherits the gene for Huntington's disease, he or she will get the disease sooner or later. There are about 5,000 diseases with such straightforward genetic causes, but most are rare. Much more common is an interaction with the environment, in which a gene makes a person susceptible to disease but an additional factor is needed to cause the disease. (Even in women with a breast cancer gene, for example, 10 percent do not get the disease.) A third causal mechanism is an environmental event that produces a mutation in a gene. If the mutation is in a body (somatic) cell, it is repeated each time the cell divides, perhaps leading to a tumor or other disorder. If the mutation occurs in a sperm or egg cell (a germ cell), it may be passed on to a child.

The most controversial area of genetic research, Edelman adds, is the role of genes in behavior, the ancient nature/nurture question. "Do genes cause violence, homosexuality, drug addiction?" he asks. "Are males genetically superior in math? The information base is soft, and researchers have emotional commitments to their positions." Though behavioral genetics elicits vehement opinions, causality in this area is at least as complex as in biological disease.

Understanding a gene's function offers possibilities for treatment--though dramatic claims for gene replacement therapies, experts caution, are probably premature. "It would be very difficult to replace a gene in a tumor, but maybe you could repair the function of the gene with a drug," explains Dr. Ramon Parsons of Columbia's pathology and medicine departments. "With oncogenes [genes contributing to cancers], you might be able to block their function with a drug."

Dr. Claudio Stern, chairman of Columbia's Department of Genetics and Development, says scientists won't be able to give the public useful, comprehensive information about their disease risk until basic questions are answered: "We don't know how genes are regulated. How they express their messages. How the genome works during fetal development. How they guide normal cell behavior." Lack of funding for basic, non-targeted research hinders development of treatments such as introducing new genes into a cell without damaging them. Nevertheless, companies are rushing headlong to use existing knowledge to make genetic diagnoses.

The chip will see you now

Soon many genetic tests will be done by a microchip. "We can ramp up diagnostic screening to do 64,000 tests on a 12-cm microchip," says Dr. Conrad Gilliam, professor of genetics and development at Columbia. "If there are 20 genes involved in retinitis pigmentosa and several hundred variations of each one, you could screen for all of them at once, using DNA from a drop of blood. Prototype chips are already being tested for diagnosing AIDS and cystic fibrosis," he says, predicting that diagnostic chips will be in doctors' offices within two years. President Clinton even mentioned the chips in his 1998 State of the Union address.

Unfortunately, in genetic diagnosis, knowledge is often not power. Genetic testing can reveal genes linked to disease long before methods exist to treat or cure the disease. In some cases, the genetic susceptibility may only slightly increase a person's risk; in others, genetic susceptibility means a death sentence or inescapable bad news. Knowledge of susceptibility may destroy precious personal relationships, cast clouds on a person's future, and leave a person open to discrimination in insurance and employment.

More than most people, Nancy Wexler understands the meaning of genetic diagnosis. When she was only 22, she learned that her mother had Huntington's disease. She and her sister had a 50-50 chance of inheriting the disease. She began a hunt for the Huntington's gene among a cluster of affected families in Venezuela, chronicling the family tree of the 13,000 individuals and collecting blood for studies. Working with colleagues in the Huntington's Disease Collaborative Research Group, Dr. Wexler found the gene in 1993.1 A test was soon developed.

The key question has always been: Who should take this test? If positive, a test for Huntington's disease means the person will become affected in mid-life and die after years of mental and physical degeneration. Should a person at risk take the test before marrying and having children? If the test is negative, the individual can look forward to a normal future. If the person has already married and had children, will it help to know whether the future is bleak? And, in such a case, what about the children? Should youngsters be tested to see if they are fated for mid-life disaster? Caught in these dilemmas, many choose not to know, just as many who take the AIDS test never come back for the results.

Wexler says, "Many people at risk of a genetically influenced disease are better off with psychotherapy than with testing." When she asks people what they would do if they knew they would get the disease, they often say that they would do something now that they had planned on doing later--travel, for example. Then, she asks, why not do it now? She recommends doing whatever makes life meaningful, regardless of genetic verdicts.

With genetic testing, says Dr. Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, "The main issue is who needs the test. If you think there's high risk in your family, maybe yes. The test is usually a comparison with others in your family. General testing doesn't make much sense, because the tests aren't good enough for testing everybody. Who will help you interpret the results? It's rare that the test will tell you whether you'll get the disease. There may be a range of outcomes."

Sometimes knowledge is power

"Who will know about the test?" Caplan asks. "Health insurance companies? The police, employers, the military? There are no federal laws protecting privacy of genetic information. It may be more risky to take the test and to wind up uninsured. Testing should be voluntary. Unless there is a cure or a treatment, children should not be tested," he says.

Harold Edgar, professor of law at Columbia, argues that there are pressures to reveal genetic information once it is known. A company will not want to sell insurance to an individual who knows he is at serious risk while the company remains ignorant of that fact. Another concern is that information about genes that increase risk for a disorder will come only from huge studies. Anonymous entry of patient records protects the patient from discrimination, but if a study indicates that a gene increases risk, anonymous information means individuals cannot be warned.

Two current proposals show the opposite sides of the privacy issue. The proposed national health identifier number, similar to the Social Security number, would give doctors instant access to a person's medical history and allow researchers to study large population groups easily and economically to determine the best treatments for many diseases. However, such an identifier would compromise the privacy of medical information, including genetic information, and might give rise to discrimination. On the other side of the issue are several bills introduced into Congress protecting privacy of medical records and protecting individuals from discrimination based on their medical histories.

The public has heard but not fully comprehended the news of genetic susceptibility to disease. The few exceptions are women who know they have the "breast cancer genes" and others who have the "colon cancer genes." Unless they have had excellent genetic counseling, however, even these individuals may not truly understand their real risk of disease. What we need to recognize is that every one of us carries several pieces of bad news in our genes; the realization that none of us is perfect may help advance the idea that everyone deserves equal treatment in society and in health care.

1. Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72 (1993): 971-983.

Related links...

  • Human Genome Program

  • The Genome Database, HGP

  • Joint Genome Institute

  • Hereditary Disease Foundation

  • National Human Genome Research Institute

  • Steve Jones, "In the Genetic Toyshop," review of books by Gina Kolata, Jeremy Rifkin, and Edward O. Wilson, New York Review of Books

  • Jeffrey Obser, "Gene Blues" (on caveats about genetic testing), Salon

  • Reed Edwin Pyeritz, "Family History and Genetic Risk Factors" (editorial), JAMA 278 (1997):1284-1285

  • Bernadine Healy, "BRCA Genes--Bookmaking, Fortunetelling, and Medical Care" (editorial), NEJM 336 (1997):1448

  • Huntington's Disease Information, Renette Davis, U. of Chicago

  • Collection of Huntington's disease resources, Michael McCarren, Western Pennsylvania HDSA

  • JANICE HOPKINS TANNE has won nine awards for excellence in medical journalism. Her articles appear in the British Medical Journal, American Health for Women, New York, Parade, Physician's Weekly, and other publications.

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