May 6, 2005
Computational Biology
Microarrays Prove Reliable in Cross-platform Tests
Immunology
T Cell Misfits May Spell Autoimmunity
Pathology
Prostate Tumor Chemistry
Reveals Early Disease
Medical Education
Dienstag Named Medical Education Dean
Student Research Takes Stage at Soma Weiss Day
Minorities Appear to Use CAM Less Than Whites
Blueprint Drawn for Ebola Infection
Director Appointed for Research Compliance at HMS
Abelardo Morell Photograph Donated
Stem Cell Institute Awards 12 Seed Grants
Connors Gift Renames MGH Building After Thiers
Zelen Award and Talk Announced
Rabkin Fellows Chosen for ’05–’06
Honors and Advances
In Memoriam
Surgery Center Joins Push for Quality Improvement
Student Research Takes Stage at Soma Weiss Day
Bjornstad syndrome is a rare disease with a confounding set of symptoms—hearing loss and hair so kinky and brittle that people with the disease rarely visit a hairdresser. “They never need a hair-cut because their hair breaks off,” said Travis Hinson, HMS ’07, at the 65th Annual Soma Weiss Student Research Day, which drew well over a hundred students to display their work. Scientists have wondered what causes such an unusual pair of symptoms. Hinson and his colleagues have pinpointed a set of Bjornstad-associated defects in a gene that is involved in mitochondrial function.
Photo by Liza Green, HMS Media Services Johannes Kratz (right) explains his research on blood flow to professor Michael Gimbrone. |
Pancreatic cancer is a better known disease than Bjornstad syndrome, and yet it too baffles researchers. For example, the sonic hedgehog (SHH) gene is upregulated in many pancreatic tumors, yet it is not clear how many tumors overexpress SHH and to what extent. David Rosow, HMS ’05, working in the lab of assistant professor Sarah Thayer, studied 27 tumors and found that SHH was upregulated in all of them, often at very high levels. Some tumors displayed as much as 3,000 times the usual level of SHH. Clearly such tumors are deadly—only four percent of people with pancreatic cancer live five years beyond diagnosis. Rosow found that by blocking SHH he was able to slow the growth and even cause the regression of human pancreatic tumors that had been transplanted into mice.
Photo by Liza Green, HMS Media Services Viviany Taqueti (right) shares a laugh with her mentor, associate professor Andrew Lichtman, during the poster session on Soma Weiss Day. |
The power of movement—in this case blood flow—was the theme of a presentation by Johannes Kratz, HMS ’06. Arteries and veins are exposed to very different blood flow gradients. Kratz, working with assistant professor Guillermo Garcia-Cardena, exposed venous endothelial cells in both in vitro and in vivo settings to arterial flow. The cells upregulated arterial genetic markers. “This is one of the first demonstrations that extrinsic factors can act to determine cell fate,” said Kratz.
Minorities Appear to Use CAM Less Than Whites
Robert Graham and his colleagues have addressed a gap in published information about complementary and alternative medicine (CAM) use by issuing a study comparing alternative therapy use by Hispanic, black, and white adults across the country. Graham, a research fellow at the Division for Research and Education in Complementary and Integrative Medical Therapies at HMS’s Osher Institute, published his results in the April issue of the Journal of the National Medical Association.
Graham and his team, led by senior author Russell Phillips, HMS professor of medicine at Beth Israel Deaconess, analyzed data from the Alternative Health Supplement to the 2002 National Health Interview Survey (NHIS). Of the 29,990 respondents, more than 10,000 reported using CAM during the past year. Graham found that Hispanics and non-Hispanic blacks trailed non-Hispanic whites in CAM use, excluding prayer.
| “It’s particularly important to know about a patient’s CAM use as we see more potential herb–drug interactions appearing in the literature.” |
Problems with definitions and examples caused the survey results to run counter to decades of anthropological research in placing the rate of Hispanic folk medicine use as low as 0.2 percent. “Herbs commonly used by Hispanics, like cat’s claw and aloe, did not appear on the multiple-choice survey,” Graham said. The NHIS survey emphasized herbal medicine that was commercially available, while minority communities may favor herbs they can grow themselves.
Graham also points out that the survey asks about a traditional Latin-American healing system called curanderismo, but omits espiritismo, Santería (the “way of the saints”), and the practice of sobadores, a manual massage discipline. Graham hopes his analysis will provide guidance for future surveys: “NIH is sincerely trying to understand how different populations use CAM, but if you really want to know, you need a cross-disciplinary and multicultural approach.”
Blueprint Drawn for Ebola Infection
Most viruses have a springlike protein to punch into the host cell, allowing fusion with the membrane, and a molecular clamp to restrain the spring until the virus is positioned correctly. HMS research fellow Kartik Chandran, working at Brigham and Women’s Hospital, suspected Ebola’s clamp might recruit the host’s own protease enzymes to loosen its grip at the right time and place. Research confirmed Chandran’s idea and also suggested a drug therapy for the virus. His work with collaborators at HMS, the National Institutes of Health, and the Institute for Human Genetics in Germany appeared in the online edition of Science on April 14.
In many viruses, such as HIV, interaction with a cellular receptor protein loosens the clamp; other viruses require the acidic environment inside an endosome to perform this action. Ebola’s glycoprotein 1 (GP1) serves as this clamp, restraining and then releasing the membrane fusion machinery, glycoprotein 2 (GP2). The study’s senior author, James Cunningham, an HMS associate professor of medicine at BWH, points out there were several clues that Ebola was different from HIV, relying on an acid-dependent host factor in endosomes. Chandran previously worked on reoviruses, which require specific endosomal proteases to loosen the restraints on their membrane-puncturing spring.
Chandran and colleagues found that Ebola’s cellular invasion has two stages. In the first step, host proteases CatL or CatB (short for cathepsins L and B) digest a part of GP1 that protects the virus from immune recognition. This primes the virus for the second stage, in which the clamp is cleaved, releasing the spring-loaded membrane fusion machinery. In kidney epithelial cell cultures infected with Ebola Zaire, this second step relies entirely on the proteolytic enzyme CatB.
The researchers found that several inhibitors of the cathepsin enzymes markedly reduced viral growth. These small molecules may be pursued as antiviral drugs. Chandran thinks it is reasonable to hope that Ebola patients may tolerate the inhibitors for a short course of treatment, pointing out that “there are knockout mice missing CatB, and they are OK.” The protease enzymes and inhibitors have been characterized in detail by biochemists unaware of their role in Ebola. Currently, there are no drugs or vaccines approved for human use against the virus, which kills more than half of those it infects.
Ebola’s victims are ravaged by a “cytokine storm” produced by infected macrophages, creating a shock response and blood vessel leakage. “We don’t know if CatB and CatL are the enzymes that are working in macrophages,” Cunningham said, so he and Chandran are expanding their research to determine which Ebola strains subvert which endosomal proteases and in which tissues. They plan to do similar work on Marburg virus, which recently has killed hundreds of people in Angola.