Much of the excitement in genetics today comes from its lively offspring, "genomics." This newcomer specializes in large-scale analyses of all the genetic material in the genomes of organisms ranging from bacteria to mammals. Genomics is expected to provide the functional meaning of newly revealed DNA sequences: What do these genes really do? And that precise knowledge, in turn, heralds a revolution in the diagnosis, monitoring, and treatment of diseases.

Meanwhile, new DNA-sequencing techniques using high-speed robots are flourishing. So are ingenious combinations of YACs (yeast artificial chromosomes), BACs (bacterial artificial chromosomes), PACS (fragments of DNA in a vector derived from a bacteriophage known as P1), and MACs (mammalian artificial chromosomes), which supply genetic fodder for the machines that do the sequencing.

A Gifted Young Patient Battles Cystic Fibrosis
Jeff Pinard, the young man with cystic fibrosis who was seeking his own genetic flaw as a college student, is now 31 and hanging in there. After going home to his parents in Grand Rapids, Michigan, he was hospitalized again because of pancreatic problems that produced excruciating pain. These problems remain unsolved, despite a variety of treatments. Until recently, he did computer work for an electric company, mostly from home. But he has had to stop because of repeated crises that landed him in the hospital. He remains optimistic, however, and according to his mother, "he's had some periods of time when he has been without pain." How long? "Oh, a couple of weeks at a time ...."

Lap-Chee Tsui of the University of Toronto finally identified and sequenced Pinard's second, milder CF mutation, adding it to the list of more than 850 known mutations in the CF gene. But it is difficult to count CF mutations these days, Tsui says, because "many mutations are now found in atypical diseases, such as male infertility and pancreatitis."

A major study of pancreatitis led by Jonathan Cohn of Duke University Medical Center and published in the New England Journal of Medicine recently concluded that many adults who suffer from so-called "idiopathic" pancreatitis (pancreatitis of unknown cause) actually have cystic fibrosis. The authors add that these findings "will change how physicians treat patients with this condition."

A Natural Antibiotic
The major symptom of CF is lung infection. In 1996, Michael Welsh, an HHMI investigator who teaches medicine and physiology at the University of Iowa, discovered why these infections occur—and offered a new approach to treatment that is still being developed. Welsh had a longtime interest in epithelia, the sheets of cells that line the internal and external surfaces of the body, including those lining the airway. When the CFTR gene was identified, he was among the first to examine the role of the protein made by this gene.

"We found out that it's actually a chloride channel, through which salt moves across the membrane," Welsh says. "That was very satisfying, because then you could begin to tie together the physiology—defective epithelia—and the gene product, the chloride channel." Then his team made an intriguing discovery: Normal epithelial tissue can kill a large number of bacteria, while similar tissue from people with CF fails to do so, or even allows the bacteria to multiply.

Welsh guessed that the fluid covering the airway normally contains factors such as defensins, molecules that are part of our innate, nonspecific defense system. He wondered whether these were also present in people with CF. To his surprise, he found natural antibiotic substances both in healthy people and in those with CF. In CF patients, however, the substances' activity was greatly reduced by the abnormally high salt concentration resulting from the defective CFTR channel. When Welsh lowered the salt concentration, even the epithelia of CF patients became able to kill bacteria.

The team's conclusion: Drugs that reduce the salt concentration in airway fluid may help treat or prevent the sometimes fatal lung infections of CF patients. Other antibiotic drugs that resemble defensins may also be developed for this purpose.

As for his experiments with gene transfer, "they remain just that—experiments," says Welsh. "We can deliver the normal CFTR gene, but we cannot deliver it efficiently enough," he explains. "The problem is the delivery. We need to go back to the lab and try to make it work better."

Genetic Screening
"We are slowly moving closer and closer to implementation of genetic screening for CF," says Arthur Beaudet of the Baylor College of Medicine. Several labs around the country now provide such tests. "And we can get 50 different mutations on a single test for as little effort as one," Beaudet says. He adds that the tests have become so sensitive that "somewhat over 90 percent of CF carriers would be correctly identified." Therefore the tests would detect more than 81 percent of the couples at risk. Beaudet believes that newly married couples should be given a set of prepared mouth swabs to take home, so that they can test themselves at their leisure. Further tests would then be necessary only if both members of the pair are carriers of CF.

About 40 specialized centers worldwide offer in vitro fertilization to avoid genetic diseases. At the Illinois Masonic Hospital in Chicago, for example, Charles Strom and Yuri Verlinsky screen the eggs of mothers who are carriers of CF before fertilizing them with the husband's sperm. In this analysis they use only the eggs' polar bodies, which would be cast off anyway, Strom explains. If the test indicates the egg is free of the CF mutation, the doctors proceed with fertilization. "More than 16 healthy children have been born to CF carriers with this method," Strom reports. The method has now been extended to a variety of genetic diseases, including hemophilia, thalassemia, and sickle cell anemia.

New Findings About Brain Disorders
There was great rejoicing when Nancy Wexler's quest for the cause of Huntington's disease finally succeeded in 1993, after nearly eight years of effort described as "a nightmare of false leads, confounding data, and backbreaking work." The faulty gene was named huntingtin. The guilty mutation turned out to code for an extra-long, repeated stretch of glutamine, an amino acid in huntingtin, the protein made by this gene. But no one knew how the expanded glutamine repeats cause brain neurons to sicken and die.

Several other "triplet-repeat" diseases are known. They all attack some part of the nervous system, and all of them are still mysterious. Scientists have begun to search for clues to the function of huntingtin in the proteins that interact with it. "The beauty of having the Huntington's disease gene in hand is that we are now able to place it in animals and learn its effects," says Wexler. In 1996, Gillian Bates and her team at Guy's Hospital, London, put fragments of the human HD gene into mice for the first time. The mice developed HD-like symptoms two months after birth and died soon afterward.

Researchers then discovered that the abnormal form of huntingtin produces misfolded proteins, which stick together in toxic clumps inside patients' brain cells. Next, working with mouse models of HD, Columbia University scientists Ai Yamamoto and Rene Hen found that shutting off the production of the abnormal protein not only halted the progression of the disease, but actually cleared some of the toxic clumps.

Fruit flies were also enlisted in the fight. In 1998, George Jackson of UCLA's Department of Neurology inserted fragments of the HD gene into the large nerve cells in the eye of a fruit fly. He found that, just as in human beings, the cells' fate depended on the number of glutamine repeats in the HD gene's DNA. The eyes of flies whose gene had only two repeats remained normal. Those with 75 repeats were normal for a month, but then began to degenerate slowly. When the flies had 120 repeats, their eyes suffered massive cell destruction. Wexler is greatly encouraged by these findings. She points out that "the fly eye is a perfect laboratory to test the effects of drugs that will protect the eye and prevent degeneration." And because of many similarities between HD and other neurodegenerative conditions, including Alzheimer's, and Parkinson's diseases, scientists hope that the findings from one of these areas will advance research in the others.

The Viking Genes
Other gene defects uncovered in recent years include mutations predisposing people to such widespread ailments as breast cancer, familial polyposis of the colon, Alzheimer's, and Parkinson's.

Many family groups have helped in these searches. Scientists now look forward to working with the biggest genetic trove of all--the Viking gene pool, which can be found in very pure form among the 170,000 people of Iceland. Some of these families can be traced back for hundreds of years, and their records will soon be available to researchers. As DNA-based biology expands, so does the need for large groups of people with detailed and accurate family trees.

— Maya Pines

The Dolan DNA Learning Center at Cold Spring Harbor Laboratory,
an interactive primer on genetics and molecular biology.

National Human Genome Research Institute (NHGRI),
a description of the Human Genome Project and status report.

Ethical, Legal and Social Issues(ELSI) and the Human Genome Project,
information from the Department of Energy about the ethical, legal and social issues surrounding the Human Genome Project. Information also available from NHGRI.

National Organization for Rare Disorders (NORD),
a federation of voluntary health organizations dedicated to assisting those with rare disorders.

The Genetic Alliance,
a consortium of support groups for individuals with genetic conditions and their families as well as advocacy and public education.

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