Genetic Researchers Close In on Answers

Ever since it became clear that the United States would launch a massive project to identify every one of the estimated 100,000 genes in the human body, scientists from laboratories throughout the country and around the world have vied to get in on the ground floor.

Even though a formal plan for the $3-billion project will not be assembled until later this summer, two recent meetings--one here at the Cold Spring Harbor Laboratory and a conference in Washington--quickly demonstrated that scientists have already begun several key experiments.

The discovery, for example, of special genetic structures on the ends of chromosomes promises to speed up the mapping process and has already brought scientists closer to identifying the gene that causes Huntington’s disease, a rare, inherited neurological disorder.

The so-called genome project is an effort to map the location of every human gene along the 46 chromosomes (23 in sperm and eggs) within every cell. Each chromosome contains a fibrous molecule of deoxyribonucleic acid, or DNA, the chemical essence of the heredity.

A gene contains four DNA sub-units frequently known by their first letters, A, T, G and C. The sequence or order of these genetic letters specifies the shape and function of the body’s proteins--from enzymes to antibodies to muscle fibers. The total length of the genetic alphabet is estimated to be about 3 billion letters. The genome project’s leaders hope, ultimately, to learn the sequence of every genetic letter.

Enormous Benefit

The benefit for the treatment of human diseases is expected to be enormous if scientists are able to design therapies and prevention strategies that address the genetic causes of disease. Research projects to identify the location of various genes--especially those related to human disease--are already under way.

Last year, a team of Department of Energy researchers scored a significant advance when they found the ends of the chromosomes--structures of specialized DNA called telomeres. Until last year, biologists had no idea where or how chromosomes ended. The telomere work led the Cold Spring conference.

Without knowledge of these chromosome boundaries, the genome project would have been like assembling a 100,000-piece puzzle without knowing where the edges were, said Robert Mayzis, head of genetics at the Los Alamos National Laboratory in Los Alamos, N.M., where the discovery was made.

The advance, first published last autumn, appears to be speeding up mapping work, especially for important genetic defects associated with diseases.

‘Look in One Direction’

At the Cold Spring Harbor conference, scientists described how having the telomeres is helping them close in on the gene for Huntington’s disease. Previous studies suggested that it was near the tip of Chromosome 4, but no one knew how near, or where the tip was located.

“When you have the chromosome ends,” said Charles Cantor, chief of genetics at Columbia University College of Physicians and Surgeons, “you only have to look in one direction” to locate a gene.

Using the telomeres as a starting place, Cantor’s group has begun closing in on the Huntington’s gene. At the Cold Spring meeting, they reported being within 200,000 letters of the gene. Before the chromosome ends were identified, scientists only had genetic probes within an estimated 1 million to 5 million letter DNA region that they believed held the Huntington’s gene.

Actually finding the Huntington’s gene may still be difficult because physicians do not know which protein in the body is affected by the gene defect and how having the altered or missing protein damages the brains of these patients. This makes it more difficult to identify the actual sequence of genetic letters that carry the information.

Hot on the Trail

Cantor said his group is exploring some tricks to get around the problem. Other groups, too, are hot on the trail. David R. Cox from UC San Francisco reported a different approach using radiation-caused mutations in the human cells to also close in on the Huntington’s gene.

Scientists are also closer to finding the gene responsible for cystic fibrosis, a commonly inherited disease that damages the individual’s lungs and makes digestion more difficult.

Francis F. Collins, a member of the Howard Hughes Medical Institute at the University of Michigan in Ann Arbor, has narrowed the search for the cystic fibrosis gene on Chromosome 7 to within 280,000 letters of DNA, instead of within 900,000.

In addition to defining genetic boundaries, the telomeres play two critical functions: They prevent the chromosomes from merging and they allow the chromosomes to reproduce.

The cellular machinery that copies the long middle stretches of DNA fiber does not work at the ends and scientists were not sure how the ends of the chromosomes were reproduced.

Unique Protein

It turns out that a unique protein recognizes the special DNA sequences in the telomere and allows reproduction to occur, Mayzis said. If that were not the case, DNA would be lost with each round of replication, eliminating vital genes and, he said, “we would shorten ourselves out of existence.”

Telomeres also appear to be living, molecular fossils, Mayzis said, a link between human beings and prehistoric species. His group tested 93 living species of vertebrates--from rattlesnakes to humans--and found no difference. Since vertebrates evolved about 400 million years ago, “we now know at least one sequence (of DNA) that we shared with the dinosaurs.”