Blazing a Genetic Trail in Medicine

The miraculous substance that contains all of our genetic instructions, DNA, is rapidly becoming a key to modern medicine. By focusing on the diaphanous and extraordinarily long filaments of DNA that we inherit from our parents, scientists are finding the root causes of dozens of previously mysterious diseases: abnormal genes. These discoveries are allowing researchers to make precise diagnoses and predictions, to design more effective drugs, and to prevent many painful disorders. The new findings also pave the way for the development of the ultimate therapy - substituting a normal gene for a malfunctioning one so as to correct a patient's genetic defect permanently.

Recently, scientists have made spectacular progress against two fatal genetic diseases of children, cystic fibrosis and Duchenne muscular dystrophy. In addition, they have identified the genetic flaws that predispose people to more widespread, though still poorly understood ailments - various forms of heart disease, breast and colon cancer, diabetes, arthritis - which are not usually thought of as genetic in origin.

While many of the researchers who are exploring our genetic wilderness want to find the sources of the nearly 4,000 disorders caused by defects in single genes, others have an even broader goal: They hope to locate and map all of the 50,000 to 100,000 genes on our chromosomes. This map of our complete biological inheritance "the marvelous message, evolved for 3 billion years or more, which gives rise to each one of us," as Robert Sinsheimer of the University of California, Santa Barbara, calls it - will guide biological research for years to come. And it will radically simplify the search for the genetic flaws that cause disease.

Once scientists have identified such a flaw, they need to understand just how it produces a particular illness. They must determine the normal gene's function in human cells: What kind of protein does it instruct the cells to make, in what quantities, at what times, and in what specific places? Then the researchers can ask whether the genetic flaw results in too little protein, the wrong kind of protein, or no protein at all - and how best to counteract the effects of this failure.

For most genetic disorders, researchers are still at the very beginning of the trail. They have no clues to the DNA error that causes a disease, and they are still trying to find large families whose DNA patterns can help them track it down.

By contrast, scientists who work on cystic fibrosis and a few other diseases have covered much of the trail. They have already succeeded in correcting the gene defect inside living human cells by inserting healthy genes into these cells in a laboratory dish - an achievement that may lead to gene therapy.

The farther scientists go along the trail, the broader the implications of their findings. For example, the discovery of the gene defect that causes Duchenne muscular dystrophy, a muscle-wasting disease, led scientists to identify a previously unknown protein that plays an important role in all muscle function. This gives them a clearer view of how muscle cells work and allows them to diagnose other muscle disorders with exceptional precision, as well as devise new approaches to treatment.

Any new treatment will need to be tested on animals. In fact, the next explosion of information in medical genetics is expected to come from the study of animals - particularly with defects that mimic human disorders. The techniques for producing animal models of disease are improving rapidly. Even today, "designer mice" are playing an increasingly important role in research.

The growth of powerful computerized databases is bringing further insights. Only a month after the discovery of the genetic error involved in neurofibromatosis, a disfiguring and sometimes disabling hereditary disease, a computer search revealed a match between the protein made by normal copies of the newly uncovered gene and a protein that acts to suppress the development of cancers of the lung, liver, and brain - a key finding for cancer researchers.

Such revelations are becoming increasingly frequent. "If a new sequence has no match in the databases as they are, a week later a still newer sequence will match it," observes Walter Gilbert of Harvard University.

Brain disorders such as schizophrenia or Alzheimer's disease may be next to yield to the genetic approach. "We won't know what went wrong in most cases of mental disease until we can find the gene that sets it off," says James Watson, co-discoverer of the structure of DNA.

Progress in medical genetics is picking up speed. Every day, more pieces of the puzzle fall into place. As a harried but exultant geneticist declared at a scientific meeting recently, "This is a very exciting time. . . I encourage you to stay tuned."

Go to next story: Case Studies - Hereditary Colon Cancer

Go to The American Academy of Neurology's Duchenne/Becker Muscular Dystrophy Page and The Hereditary Hearing Impairment Resource Registry