A partnership that aids cancer's migration

For mosquito, the scent of a human is a molecular event

Et cetera

Gene mutation linked to OCD

Honors for immunologist

A partnership that aids cancer’s migration

When Ras teams up with cell polarity genes, mutations are found to produce metastatic tumors.

In the world of cancer-causing genes, Ras is a celebrity. Mutated versions of this gene appear in more than half of all human cancers, including metastatic cancers, in which cells from a primary tumor disperse to other organs or systems of the body and there give rise to new tumors. Clearly, Ras is a culprit in many terminal cases. But since a large number of Ras-based tumors are benign and never spread beyond their original site, it was thought that the oncogenic Ras triggers only tumorigenesis. Now, research demonstrates that Ras also contributes to metastasis and it collaborates with a partner to do so. Tian Xu, Ph.D. ’90, professor and vice chair of the Department of Genetics and an associate investigator for the Howard Hughes Medical Institute (HHMI), has identified five genes that interact with Ras to cause metastasis.

Each of these “cell polarity genes” normally fills an important role in maintaining the orientation of the cell with regard to the inside or the outer surface of the body. The normal version of Ras, meanwhile, transmits signals that aid in development by controlling the rate at which various cells reproduce and differentiate. Although neither a mutation in a cell polarity gene nor a mutation in Ras leads to malignancy on its own, Xu and graduate student Raymond Pagliarini have shown in an animal model that when tumor cells have both mutations, they invariably produce metastatic tumors.

The scientists arrived at these findings by creating a genetic screen in Drosophila melanogaster, the fruit fly. If Drosophila seems at first to be an unsuitable model for humans, it is only because our outer forms look so different. Inside we have a great deal in common: for instance, 70 percent of the disease-causing genes in humans also appear in the fruit fly. Xu and Pagliarini first used fruit flies with mutant Ras genes to create noninvasive tumors in developing larvae, then added other mutations to see whether the tumors become metastatic. Although only a handful of these combinations produced the results they were looking for, Xu and Pagliarini’s observations are likely to spur the development of new drugs for cancer treatment, targeting genes that collaborate with Ras to deadly effect.

As for Ras itself, this gene has been in the sights of pharmaceutical companies for some time now, and Xu points out that it still represents a good target for anti-cancer drugs. “Inactivating the tumor-producing effect of mutant Ras genes,” he says, “will likely be simpler than re-creating the tumor-suppressing effect of genes that are no longer normal, but mutated.”

As Xu sees it, “cancer is generally a late-stage disease—but in most of human history, longevity was much lower than it is now. People didn’t live long enough to get cancer.” What then was the original function of these genes? “We believe they are normally involved in regulating development, especially the size of cells and tissues, and ultimately the size of whole animals,” Xu says.

The most exciting aspect of Xu’s work on the metastatic partners of Ras is undoubtedly its clinical potential, but in Xu’s eyes this series of experiments offers another far-reaching benefit as well. “This work really showed the power of model organisms like fruit flies, because we can use them to do a lot of experiments that would not be possible in humans,” he says. It was this painstaking, gene-by-gene screening that allowed researchers to find the specific gene interactions that lead to metastasis, and thus to identify the drug targets that look so promising today.

—Sandra Ackerman

Divining the scent of a human: for mosquito, it’s a molecular event

To most people perspiration ranks low on lists of attractive features, but one creature finds the smell of human sweat irresistible: the female of Anopheles gambiae, commonly known as the mosquito. Just what makes our perspiration so alluring to this ruthless predator is a question that intrigues not only the companies that make insect repellents and the people who use them, but most of all the epidemiologists trying to reduce the toll of mosquito-borne diseases.

Now scientific research is beginning to reveal an answer. John R. Carlson, Ph.D., professor of molecular, cellular and developmental biology, Elissa Hallem, a graduate student in the Interdepartmental Neuroscience Program, and colleagues have developed a transgenic technique that allows them to identify the functions of specific odor receptors in the mosquito antenna. Their paper, published in the January 15 issue of Nature, describes how the researchers pinpointed the receptor gene, AgOr1, and the compound to which this receptor responds, the odorous molecule 4-methylphenol.

The scientists used a “knockout” fruit fly lacking one if its odor-receptor genes. They substituted the mosquito gene AgOr1 and then measured the animal’s response to various odors; the only molecule to produce a strong response was 4-methylphenol. A similar gene, AgOr2, used as a control, showed no such response. This observation, together with previous findings that AgOr1 is present only in female mosquitoes and that the expression of this gene tends to diminish after the mosquito has had a blood meal, suggests that the AgOr1 receptor plays an important role in the mosquito’s hunting and feeding behavior.

According to Carlson, this work puts researchers “on the right track” toward developing a truly effective mosquito repellent. “If we can find each of the odor receptors and identify the specific compounds they’re responding to, the next step would be to come up with inhibitor or blocker compounds, which would bind to the receptors but not activate them,” he explains. The mosquito would thus be unable to perceive the odors that normally lead it to a human banquet. Large numbers of people might be protected from bites, or from life-threatening infections. (The mosquito-borne disease malaria kills an estimated one million people each year, most of them children.)

The research on odor receptors may also have a direct application in insect control: the odors most attractive to mosquitoes could be used to lure the insects away from human populations and into traps where they could be destroyed. In principle, says Carlson, the same techniques might even be used against crop pests. But he cautions that “the system we have created, a system that can identify odor-receptor genes, has not yet been applied in other insects.” With the work on mosquitoes yielding such promising results, progress on dealing with other insects is probably not far behind.

—S.J.A.

Et Cetera

Gene mutation linked to OCD

A mutated gene’s link to a rare form of obsessive compulsive disorder (OCD) is the strongest proof yet that neuropsychiatric disease can result from a malformed neuronal protein.

In studies published last October and August in Molecular Psychiatry and Molecular Pharmacology, researchers at Yale and the National Institute of Mental Health found that a rare form of OCD is associated with a mutation in the serotonin transporter gene that disrupts the normal regulation of transport.

“There are not a lot of established connections between genes and behavior,” said Gary Rudnick, Ph.D., professor of pharmacology, who conducted the research with Fusun Kilic, Ph.D., of the University of Arkansas for Medical Sciences. “Our finding focuses on the role of the serotonin transporter in mood and behavior and ties it to a specific behavioral disorder.”

The researchers found in two unrelated families a gene mutation that increases up-take of serotonin by the transporter. Further study could lead to a better understanding of how OCD develops and how medications might affect the serotonin transporter.

—John Curtis

Honors for immunologist

Scientists from around the world gathered in November to honor the late Richard K. Gershon, M.D. ’59, 20 years after his death and 30 years after his discovery of suppressor T cells.

Gershon started his career as a pathologist and switched his focus to immunology when he began working on a tumor model in hamsters. His discovery was initially greeted with skepticism, but suppressor T cells, which reduce the immune response of other cells to antigens, are now seen as vitally important in a variety of diseases. In recognition of his work, Gershon was elected to the National Academy of Sciences in 1980.

A lecture has been held in his honor each year since his untimely death in 1983, but this year the Section of Immunobiology and his family noted his passing with a symposium that featured leaders in suppressor T cell research.

—J.C.