May 20, 2005
Cell Biology
Broken Hearts May
Mend After All
Neuroscience
Breathing Restored After Severe Spinal-cord Injury
Immunology
Insulin Prods Development of Type 1 Diabetes
Publishing
Publishing Partnership Issues First Six Consumer Health Books
Overweight Undermines Health
Gene Network Discovered Supporting Cell Migration
Voracious Kudzu Drains Thirst for Alcohol
Proceedings of the HMS
Faculty Council
HMS and Children’s Announce New Endowed Chairs
Three HMS Professors Elected to NAS
New Appointments to Full Professor
New Members Join Academy of Arts and Sciences
Gawande to Speak on Class Day
In Memoriam
Unexpected Tragedy in a Little
Girl’s Expected Death
Overweight Undermines Health
A well-publicized April study reporting that overweight but not obese people were likely to live longer than people of normal weight threatens to unravel public health prevention efforts showing the health risks of extra pounds, say researchers at HSPH and HMS.
“We have not seen evidence of a dramatic weakening of obesity’s impact on mortality,” said JoAnn Manson, the Elizabeth F. Brigham professor of women’s health at HMS and Brigham and Women’s Hospital and professor in the Department of Epidemiology at HSPH. “The findings of the new report should not lead to complacency about the epidemic of obesity.”
| “The findings of the new report should not lead to complacency about the epidemic of obesity.” |
Hu and Manson base their concern in part on a paper they co-authored with HSPH colleagues in the Dec. 23 New England Journal of Medicine. The study explored the idea that exercise might counter the unhealthy effects of extra fat and that being overweight or obese might be less important than being fit.
Instead, they found that excessive weight and limited exercise are strong and independent predictors of early death. Compared to fit, lean women, the risk of early death increased by 55 percent for sedentary, lean women, by 91 percent for fit, obese women, and by 140 percent for sedentary, obese women.
“Physical activity doesn’t cancel out obesity, and being lean doesn’t cancel out a sedentary lifestyle,” Manson said. “You need to be both physically active and maintain a healthy weight in order to have optimal health.”
These health issues have a powerful effect on mortality. The combination of sedentary lifestyle and obesity could account for 31 percent of all premature deaths, including 59 percent of deaths from cardiovascular disease and 21 percent of deaths from cancer among nonsmoking women, the researchers estimated.
Worried about the potential public health damage of the April study by government researchers, Manson, Hu, and their colleagues have organized a May 26 symposium at HSPH to examine the methodological factors underlying the contradictory findings. The government study, for example, may have failed to account adequately for the adverse affects of smoking, which is more common among lean people, and low body weight caused by chronic disease, which is highly prevalent among the elderly. These miscalculations may have inflated the mortality rates among lean people and also diminished the harmful impact of being overweight or obese.
Gene Network Discovered Supporting Cell Migration
HMS professor of pathology Yang Shi and colleagues have made a leap forward in understanding the regulation of a network of genes that may be crucial to both normal tissue development and tumor growth and metastasis. Using gene chip technology that allows researchers to look at expression levels for every gene in an organism, Shi and first author Johnathan Whetstine, an HMS research fellow in pathology, found that hundreds of genes in the roundworm Caenorhabditis elegans were regulated by the action of a single key enzyme, which is targeted by chemotherapy drugs currently in clinical trials. Their work was reported in Molecular Cell on May 13.
Histone deacetylase enzymes, or HDACs, remove acetyl groups from the histone proteins that package DNA, regulating gene expression. A ubiquitous (class 1) deacetylase, HDAC-1 had been investigated in yeast and cell culture, but little is known about the enzymes’ physiological role in intact organisms. Yeast studies had suggested that HDAC could be connected to cell migration, a key process in both normal embryonic development and tumor metastasis. Shi challenged Whetstine to learn more by studying the enzyme in the roundworm.
| Cell invasion was regulated by overexpression or knockdown of human HDAC-1. |
Although HDA-1 is ubiquitous, an expression database showed that its target genes are concentrated in gut and hypodermal tissues and extracellular matrix functions, which are responsible for the way cells create connective tissue, attach to it, and travel through it. The team used chromatin immunoprecipitation to ob-serve the enzyme physically associated with many of these genes, indicating they are direct targets of HDA-1.
In experiments to determine how relevant their roundworm results are to human tumors, Whetstine ran invasion assays with human melanoma cells. Cell invasion was regulated by overexpression or knockdown of human HDAC-1 and also by a cystatin gene that HDA-1 strongly upregulates.
This basic research into regulatory mechanisms common to people and roundworms may provide a basis for understanding anticancer HDAC-inhibitor drugs and provide a rationale for combining them with lines of attack on tumors. “We’re hoping that with a deeper understanding of how HDAC-1 works in an organism, clinicians will be able to create better combinations of drugs to inhibit metastasis,” Shi said. In his lab, research will continue toward understanding the specificities and redundancies of the different classes of HDACs and their roles in development.
Voracious Kudzu Drains Thirst for Alcohol
Kudzu, the invasive “vine that ate the South,” may get a chance to earn a more positive reputation, according to research by HMS professor of psychiatry and McLean Hospital researcher Scott Lukas. In a study published in May in Alcoholism: Clinical and Experimental Research, Lukas and colleagues found that compounds from kudzu slowed alcohol consumption by heavy drinkers. The researchers did not observe any side effects and the 11 volunteers did not report a lowered desire to drink—but they did drink significantly less.
The climbing vine is viewed in Chinese traditional medicine as an herbal remedy against drunkenness. The single clinical study of kudzu in humans had shown no effect, while several animal models supported the herb’s usefulness. Lukas realized that the isoflavone chemicals thought to be responsible for kudzu’s effect were too diluted in available preparations, so HMS associate professor of psychiatry Yue-Wei David Lee, a co-author of the study, developed a method to purify the isoflavones to about 20 times the typical concentration in commercial products.
Selecting nonaddicted heavy drinkers with no family history of alcoholism, Lukas’s team observed drinking behavior in a lab similar to a studio apartment. Subjects could watch TV or listen to a stereo while drinking their favorite beer. The room was equipped with a hidden scale in the only convenient table, relaying the weight of the beer bottle to a computer elsewhere in the lab, so the team was able to analyze a “sip-by-sip” record of each drinking session.
Lukas compared the timing and volume of drinking on the part of volunteers taking a kudzu extract with these behaviors by the same volunteers after a course of placebo. The weeklong kudzu treatment did not cause any detected changes in blood chemistry or liver function, yet the treated group drank less in total, and their sips of alcohol were smaller and less frequent. These volunteers reported feeling intoxicated earlier and apparently slowed their consumption accordingly. The researchers cannot yet say exactly how kudzu caused these effects, but they expect to learn more by monitoring alcohol levels in the brain in an upcoming study.
Lukas sees a potential for a kudzu-based drug to reduce the harm that alcohol does to binge drinkers and to society, pointing out that “the lack of side effects opens the door for teenagers or pregnant women to benefit from these compounds.” To reach that potential, the kudzu extract must now undergo larger clinical trials to identify effective dosages and courses of treatment.