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RESEARCH BRIEFSWinners and Losers Exhibit Model Fighting BehaviorA male fruit fly that picks a fight is likely to win the battle. A losing fruit fly does not give up easily, even if it takes him longer to re-engage his foe after a particularly intense encounter. Most fruit fly fights are resolved before they escalate to intense physical contact.
The hundreds of flyweight bouts in the HMS neurobiology lab of Edward Kravitz rarely make it to the intense limb-to-limb combat pictured above, but a statistical analysis of the fighting patterns has provided the basis for detailed studies of the neurobiology of aggression. (Image courtesy of Ed Kravitz) These are some of the results from a study of 75 fruit fly fights involving 9,000 individually scored moves in 2,000 skirmishes. The findings were reported in the April 16 Proceedings of the National Academy of Sciences. Undergraduate researchers in the lab of Edward Kravitz, the George Packer Berry professor of neurobiology at HMS, staged the fights to establish a model of normal fighting behavior (see Focus, November 30, 2001). As it turned out, fly fights were less predictable than lobster fights, which the Kravitz lab has been studying for 20 years. Trapped in a tank in a research lab, two lobsters follow a choreography so strict it can be set to classical music. Lobster fights usually begin with harmless tough-guy posturing and slowly escalate to fierce claw-to-claw combat before the loser retreats for good. Fruit fly fights are less ordered affairs and seem less bruising. The decision to retreat can come at any time, after any maneuver, at any level of fighting intensity. Yet patterns have emerged. Fruit flies have a favorite tactic--fencing--but they can also surprise their opponents with wing threats, charging, holding, or retreating. High-intensity encounters last four to five times longer than low-level encounters. And it takes more than twice as long for fruit flies to re-engage after a high-intensity encounter. Losing lobsters remember their defeat for up to a week and grovel in the presence of the winner. The loser may not eat and will not engage winners or losers of other fights for days. In fly fights, however, the loser keeps coming back for more. This may be because flies face few dangerous weapons, such as claws or teeth, that could threaten their survival if they try again, Kravitz said. Now that normal fighting behavior has been statistically quantified, the researchers are using a technique developed by Andrea Brand and Norbert Perrimon at HMS nine years ago to direct the expression of genes in fruit flies wherever and whenever an investigator desires. The Kravitz lab is using this method to block the release of the amine neurotransmitters serotonin and dopamine by a small shift in temperature. At 75 degrees the flies are normal, but at 85 degrees they lose the function of the dopamine and serotonin neurons. Dopamine and serotonin have been implicated in aggression studies in lobsters, other animal models, and rare human genetic mutations. Fly videos, the complete repertoire of fighting fly manuevers, and interviews with the researchers are on the Web.
Milking the Most From Your DietA report by HMS researchers could give those milk-mustached celebrities in TV and magazine ads a new reason to proclaim the benefits of dairy foods. In a study of 3,000 young adults, Mark Pereira, David Ludwig, and their colleagues found that subjects who consumed the highest amounts of dairy had a lower risk of developing insulin-resistance syndrome, a precursor to heart disease and diabetes. The effect was most marked in overweight subjects who, by virtue of their extra poundage, are already most vulnerable to the syndrome and its sequelae. "Insulin-resistance syndrome is the soil in which two main killers of Americans grow--type 2 diabetes and heart disease," said Ludwig, HMS assistant professor of pediatrics at Children's Hospital and senior author of the April 24 Journal of the American Medical Association study. Pereira, also an HMS assistant professor of pediatrics at Children's, is lead author. Insulin-resistance syndrome--a combination of obesity, hypertension, abnormal glucose metabolism, and dyslipidemia (low serum HDL-cholesterol levels)--is on the rise in young Americans. At the same time, young people are drinking less milk and more soft drinks, eating less dairy and more refined carbohydrates. To explore the relationship between insulin-resistance syndrome and dairy consumption, the researchers analyzed the intake of dairy--milk, milk drinks, butter, cream, cheese, yogurt, dips, ice cream--by young adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among overweight subjects, those eating the least amount of dairy were at least three times more likely to develop insulin-resistance syndrome after 10 years than those eating the most. The effect was less evident in lean subjects, who may be protected against obesity and insulin resistance for genetic or other reasons. How are those glasses of milk and cheese wedges conferring their benefit? One possibility is that dairy foods contain a health-promoting factor. Yet when the researchers accounted for factors found in dairy, such as calcium, the correlation with reduced risk of insulin resistance remained unchanged. Another possibility is that dairy drinks and foods are more satiating than equivalent numbers of calories in refined carbohydrates. Previous work by Ludwig, director of the obesity program at Children's Hospital, and colleagues has shown that refined starchy foods and concentrated sugars, which have a high glycemic index, promote hunger and food intake among obese teenagers (see Focus, March 19, 1999). More research is needed before dietary recommendations about dairy can be made, said Ludwig. Based on his and other people's research, he believes that current nutritional recommendations promoting low-fat, high-carbohydrate diets may need reevaluating. "When people are focusing on cutting back on fat, they are not eating more fruits and vegetables," he said. "They are consuming bagels, fat-free Twinkies, and soda pop."
Lymphatic Path to Cancer Spread May Start at Tumor MarginLike blood vessels, lymphatic vessels are a convenient route for metastasizing cancer cells to migrate through the body. But much less is known about the lymphatic system's role in metastasis than the vascular system's role. A new study by HMS researchers at Massachusetts General Hospital redirects attention away from the lymphatics inside the tumor--which are revealed as collapsed, nonfunctioning vessels--and toward the working vessels in the tumor margin and the normal surrounding tissue. The results will appear in Science and were published April 25 on the Science Express website. The MGH team led by Rakesh Jain, the A. Werk Cook professor of radiation oncology, implanted cultured mouse fibrosarcoma and melanoma cells into the limbs of living mice. Some mice received tumor cells engineered to overexpress vascular endothelial growth factor-C (VEGF-C), a protein that stimulates the formation of lymphatic vessels. Compared with control mice whose tumors expressed normal VEGF-C levels, the mice whose tumors overexpressed VEGF-C showed increases in lymphatic metastasis, but not in lung metastases via blood vessels. Next, Jain and colleagues probed the tumors using a variety of assays. Levels of the lymphatic marker protein LYVE-1 suggested that mice with VEGF-C-overexpressing tumors had more lymphatic vessels than controls, both within the tumor and in the margin. But three microlymphangiography assays--designed to reveal lymphatic structure and function--showed that lymphatics inside the tumor were collapsed and unable to transport labeled molecules or connect with the lymphatic network outside the tumor. Only in the margin did the lymphatic vessels look and function normally. The researchers also examined lung tumors from 22 patients. Although 10 patients had lymph node metastases, LYVE-1 was not detected inside any of their tumors. The results corroborate the mouse studies and point to an absence of functional lymphatics in human lung tumors. "These findings suggest new strategies for cancer treatment," said Jain. "Lymphatics at the tumor periphery are sufficient to carry cancer cells to other parts of the body, so these structures should be the targets of therapy. "By neutralizing VEGF-C at the tumor margins, we can potentially have a double effect," he added, because VEGF-C is also implicated in angiogenesis. "Hindering both blood vessel and lymphatic vessel formation may block tumor metastasis." The researchers suggest that while not implicated in metastasis, collapsed vessels may contribute to the high pressure within tumors, which can impair blood flow and drug delivery. --Tom Reynolds |
