BOSTON—His tall figure bent over a computer screen in his laboratory at the Massachusetts General Hospital, Dr. Gary Ruvkun rummages through a distant genetic data base for matches to a gene he believes is involved in diabetes. "You learn how to read these as they are ratcheting by," he says, while lines of data streak up his screen. "I think MTV is good training."
Living creatures were once the only repositories of genes. Now biologists can ferret through a Noah's ark of genes whose DNA sequences have been worked out and deposited in computer data banks. "It just makes things go incredibly fast," Ruvkun said.
DNA data banks have helped him open up a surprising new window onto the nature of diabetes, a disease that affects 5 percent of the population. He has found two families of genes that are involved in relaying messages about sugar metabolism to the information center in the nucleus of living cells. Defects in any of these genes could be contributory causes of the disease, he believes, and if so, biologists trying to trace the pedigrees of diabetic genes have a whole new range of targets to consider.
The genetic data banks are far from complete because the project to sequence the human genome, or determine the order of all of the chemical letters in its DNA, has barely begun and complete genomes are available for only a handful of bacteria and yeast. Still, partial or full sequences of most human genes have already been deposited.
The other source of Ruvkun's research is a microscopic roundworm called Caenorhabditis elegans, a standard laboratory organism surprisingly similar to humans, at least in terms of its cells' basic housekeeping functions. Though C. elegans and H. sapiens last shared an ancestor about 800 million years ago, many genes that perform the same function in both organisms still possess DNA sequences of recognizable similarity.
It was that kind of a match that unexpectedly drew Ruvkun into diabetes. He was studying a gene that helps switch the worm into a long-lived hibernation state called a dauer. The gene, known to worm experts as daf-2 (for dauer formation), directs the cell to produce a receptor protein that straddles the cell wall. The outside part of the protein responds to a hormone, and the inside part triggers a signaling pathway, relaying the hormone's message to its intended address in the cell's nucleus.
Hoping to learn more about how the gene might work, Ruvkun analyzed the order of the chemical letters in its DNA. With the sequence in hand, he analyzed it with a widely used computer program, known as Blast, that compares the sequence of a given gene to all others in a data bank and ranks the matching genes in order of their similarity. Genes of similar DNA sequence in two organisms usually perform the same or similar tasks.
When Ruvkun ran the daf-2 gene through the gene bank at the National Library of Medicine, he scored a hit on a most surprising target—the human gene that makes the receptor for insulin. The finding implied that the worm makes insulin, too, a fact unknown hitherto, and that it uses insulin to control both its fat metabolism and its hibernation program. Such an arrangement would make biological sense: The worms about to hibernate stop burning glucose and put on fat.
The discovery also raised hopes that the genes contributing to diabetes can be studied in worms, which are far easier to work with than humans. C. elegans does not in fact live long enough to develop diabetes, its usual life span being a mere 10 days or so. But it seems to have the same genetic pathways—systems of linked genes—as those that go awry in human diabetes.
Worms with defective daf-2 genes, for example, correspond to insulin resistance and Type 2 diabetes, the disease of people who make insulin but whose bodies do not respond to it correctly. These worms build up fat deposits instead of metabolizing glucose, as if it were time to hibernate.
Recently Ruvkun discovered how to cure his "diabetic" patients, by disabling a second gene called daf-16, which works in the same signaling pathway but further down from daf-2. The product of daf-16 operates in the nucleus of the cell and exerts a negative influence: It switches off the genes responsible for glucose metabolism.
Single-celled organisms like bacteria have it easy; each cell need worry only about its own survival. In multicellular organisms like plants and animals, each cell must respond correctly to messages from other cells. Hence elaborate signaling systems have evolved in which a receptor embedded in the cell's surface will convey a message to the cell's nucleus, switching on or off the genes that reside there.
The pathway between the receptor and the switching protein may contain several intermediates, and each component in the pathway is specified by its own gene. Working out the details of these complex signaling systems is a major preoccupation of molecular biology because defects in the signaling systems are a cause of cancer, diabetes and many other diseases.
In the normal sequence of events, the worm's version of insulin activates the daf-2 receptor, and the receptor sends a signal inside the cell to shut down the activity of daf-16's product. With that off-switch removed, glucose metabolism can proceed. When the receptor is inactive, daf-16 resumes its activity and halts the worm's glucose metabolism. But when daf-16 too is knocked out, the "diabetic" worm is cured.
When Ruvkun ran daf-16's DNA sequence through the genetic data banks, he found to his delight that this gene, too, had a set of three human counterparts.
"When this came back, we were jumping up and down," he said. Because of the growing comprehensiveness of the genetic data bases, the Blast program had enabled him to reach across eons of evolution. "We were working on this arcane problem of metabolic control in the worm and the data base allows us to jump into human metabolic control," Ruvkun said.
So important is glucose metabolism to animals that its regulation is likely to be a complex matter. Another worm expert, Donald L. Riddle at the University of Missouri, has identified several of the worm genes that make the components of a second pathway that is parallel to the insulin pathway and converges on the same target, the region of DNA that controls the glucose metabolism genes. Worms get fat when the second pathway is inactivated, just as they do when the insulin pathway is ineffective; both pathways must be active for glucose metabolism to proceed.
In worms the second pathway is triggered by a hormone that differs from insulin. The human counterpart to this hormone has yet to be discovered, but Ruvkun believes a version of the second pathway exists in human cells, too, and that the second pathway is somehow inactivated by obesity. That would explain why obese people tend to develop diabetes, he said.
Ruvkun, a molecular biologist, is not bashful in asserting the importance of his work on diabetes. "I think this is the most novel lead in terms of diabetes in a very long time," he said in August after identifying the worm insulin receptor. Though it is too early to assess the claim, diabetes experts are watching his work with interest.
"I'm fascinated by his work," said Dr. Graeme I. Bell, who studies the genetics of diabetes at the University of Chicago. "Whether I can actually incorporate it into my own view of things, time will tell."
Leaving the computer screen, Ruvkun shows a visitor an experiment on a worm. To find out how C. elegans uses insulin, one of his colleagues, Sarah Pierce, has fused a jellyfish gene onto the worm's insulin gene. The jellyfish gene is one that makes a beautiful green fluorescing protein. In every cell of the worm where the insulin gene is switched on, the jellyfish gene is switched on, too, making the cell glow green when bathed with fluorescent light.
Under the microscope lies an anesthetized worm, with lines of green light traversing its delicate, transparent body like a highway at night. The insulin-secreting cells seem mostly to belong to the worm's nervous system. Ruvkun is pleased with the result because the human pancreas, he notes, is derived in the embryo from nervous tissue.
The control of sugar metabolism by insulin is so fundamental to life that its basic elements have barely changed in 600 million years. "A lot of what we do was developed in Precambrian seas," Ruvkun said. Publication Date : 1997-12-30
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