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RESEARCH BRIEFS
Water Pore Structure Reveals Junction FunctionResearchers studying eye development have long debated the function of the abundant membrane protein aquaporin-0. By amino acid sequence, the molecule looks like a water pore, a specialized protein channel that conducts water molecules in and out of cells. But unlike other water pores, aquaporin-0 is located mostly at cell-cell contact points, suggesting that it functions as part of the molecular glue that holds lens cells together.
The molecular structure of aquaporin-0 shows how the water pore builds bridges between lens cells. Tetramers of aquaporin molecules on opposing cells make contact at multiple points in the intercellular space (right, with cell membrane in yellow). A close-up (left) shows the center of the junction, where proline residues from all eight junction members form a rosette. (Image courtesy of Nature) A look at the crystal structure of aquaporin-0, solved by HMS researchers, reveals for the first time how this unique structure forms lens cell junctions and gives researchers new clues about how water flow could be regulated in cells. From the beginning, aquaporin-0 crystals looked different from those of other water pores. They are large, double-layered sheets of protein that measure the exact thickness of the cell junctions in the lens. The channels in each layer face each other, just as they would be expected to do when two cells meet. "The crystals are junctional crystals," explained Tamir Gonen, a research fellow in the lab of Thomas Walz, HMS assistant professor of cell biology. Gonen and his colleagues used the crystals to solve the atomic structure of aquaporin-0 by electron crystallography, and their results appear in the May 13 issue of Nature. In the solved structure, four molecules of the protein in one crystal layer join up with a similar cluster in the opposite layer to form a junction. The molecular interactions occur mainly between proline residues that are found in aquaporin-0, but not in other aquaporins. Prolines from all eight of the aquaporin-0 molecules meet in the middle of the complex to form an elegantly symmetric rosette structure (see image above). When the researchers peered into the water channel, they found the pore was much narrower than the opening in other aquaporins and is probably not wide enough for water molecules to squeeze through. Since uncomplexed aquaporin-0 is known to function as a water channel, they hypothesized that when junctions form, a conformational change occurs that closes the channel. The answer to the question of whether aquaporin-0 is a channel or a junction may be that it is a bit of both, explained Gonen. In the developing eye lens, aquaporin-0 works as a water channel that facilitates circulation of nutrients and removal of waste from the lens cells. As the lens matures, the cells begin to pack more tightly together, condensing into a lens structure that will have the proper refractive index to allow vision. As this structure forms, aquaporin molecules on opposing cells come together, junctions form, and the water pore closes. The solution of the aquaporin-0 structure got a boost from a new structural biology computer grid, put together by co-author Piotr Sliz, a bioinformatician working with Walz and Steve Harrison, HMS professor of biological chemistry and molecular pharmacology. The Linux grid for structural biology links more than 100 HMS computers, including 50 64-bit machines at HCNR center for bioinformatics. The grid speeds up the calculations needed to solve complex protein structures. In the case of aquaporin-0, calculations that would have taken weeks to do sequentially on one computer were done in a half day by using 50 processors simultaneously, said Sliz. --Pat McCaffrey
A Fast Track to Patient ConfidenceFor a doctor, establishing a bond of trust with a patient smooths the way to successful medical care. To understand what inspires patient confidence, HMS researchers asked more than 400 patients to report on their feelings of care and trust after a first visit to a new specialist.The good news is that nearly 80 percent of the patients overall reported having complete confidence in their cardiologist, neurologist, or other specialist. But black and Hispanic patients were less trusting than white patients, with less than two thirds of blacks saying they trusted their doctor. Patients with poor health were less trusting than those with excellent health. The study was the first to look at trust among specialists, who account for half of patient visits. By questioning patients about specific details of their office visit, researchers pinpointed physician behaviors that seemed to foster trust. Doctors who elicited complete trust listened to patients' stories and dispensed the right amount of information. Trustworthy doctors also involved the patient in decision-making as much as the patient wanted, told patients what to do if their symptoms got worse, and spent as much time on the visit as the patient wanted. "These are actionable items," said Nancy Keating, HMS assistant professor of health care policy and of medicine and lead author on the paper, which appears in the May 10 Archives of Internal Medicine. The study suggests that doctors can improve trust by working on their communication skills and focusing on giving patients the information they want. "The 80 percent number seems high, but we'd like it to be even higher," Keating said. --Pat McCaffrey
China Steps Forward Against AIDSSuccessful treatment of AIDS in developing countries, long seen as prohibitively expensive, is now on the horizon. China, for one, with its population of 1.3 billion, appears to be effectively confronting its nascent epidemic. The forum for these revelations was the Third Asia Public Policy Workshop and Fourth W.H.R. Rivers Symposium on Social Policy and HIV/AIDS in China at Harvard's Kennedy School of Government in early May.Jim Yong Kim, HMS associate professor of social medicine and of medicine at Brigham and Women's Hospital, who is currently on leave serving as adviser to the director-general of the World Health Organization (WHO), explained the rationale for taking on treatment. First, the money is becoming available: $20 billion, including $15 billion promised by President Bush, and funds from the World Bank, the Clinton Foundation, and the Global Fund. Moreover, the WHO's core missions are prevention and health systems development. Since treating AIDS is a lifetime project, the delivery systems established should work for health care generally. "We are trying to bring the best thinkers in health systems who have been working on chronic care for diabetes so we can design something that will last and have an impact far beyond HIV," said Kim. As for China, while prevalence is still less than 0.1 percent, China needed to act immediately, Kim said. "And they are doing it. The central government's commitment ... is astounding." The Chinese Centers for Disease Control estimates that 840,000 Chinese carry the virus and that 80,000 are being treated for AIDS, said Shen Jie, director of the National Center for AIDS Prevention and Control of the Peoples' Republic of China. But only 7,000 are on antiretroviral drugs (ARV). According to official surveillance data, IV drug users account for 61 percent of the epidemic. Sexual transmission accounts for 8.4 percent of cases, blood collection for 9.4 percent, and blood products for 1.6 percent, said Joan Kaufman, codirector of the China AIDS Public Policy Program at the Kennedy School. The epidemic entered China in the late 1980s among IV drug users along the Myanmar border. The sexual epidemic is just beginning, as measured in monitored sex workers. "There is prostitution in every corner of the country, even in rural towns," said Kaufman. And there is a "very hidden population of gay men." Big risk factors include poverty, female gender, and minority status. Poverty and female gender go together: due to the cultural preference for boys, women are more often illiterate and more likely than men to be school dropouts, Kaufman said. "Many families fall into poverty because of the high cost of ... treating AIDS," she said. Health care is largely uninsured fee for service. The leadership has responded aggressively. On World AIDS Day, Dec. 1, 2003, Premier Wen Jiabao became the first Chinese leader to publicly address the AIDS epidemic, appearing on national television to shake hands with AIDS patients at Beijing's Ditan Hospital and announcing the "four frees." These are free antiretroviral drugs, testing for those who cannot afford it, prevention of mother-to-child transmission, and schooling of orphans. Other policies in a five-year action plan include improved surveillance and standardized case reporting and ensuring the supply of medicine. A national AIDS conference held in early April this year included ministers of all relevant ministries and directors of provincial health, finance, policy, and civil affairs bureaus, said Shen. Nonetheless, China faces many challenges, Kaufman said, including "insufficient social science research on risk determinants, behaviors, social networks, stigma, etc., that have a huge impact on vulnerability, use of services, and access to services." "What is known about AIDS globally is not being applied to research in China," Kaufman said. "Studies don't look much at household poverty.... Surveillance focuses mostly on high-risk populations and inadequately on the general population. As a result, there is poor understanding of how the epidemic is unfolding." That could prove fatal to millions. In post-reform China, top-down policy initiatives lack clout with local government, said Anthony Saich, director and faculty chair of the China Public Policy Program. Financially, local governments are largely self-supporting, and AIDS initiatives are mostly unfunded mandates. Moreover, the political will to vanquish SARS--cited as grounds for optimism on HIV--was based on a "severe" economic threat, said Lincoln Chen, director of the Global Equity Center at the Kennedy School. "I'm not convinced that either health or human rights generates [the necessary] political will." One member of the audience said that China lacked "pressure groups, civic associations, to keep this at the forefront of the minds of local officials." The point was dramatized by Thomas Cai, an HIV-positive activist from Guangdong province. People with AIDS "are victimized by the general public," and activists who try to work at the local level are told by officials to "stay in your home," he said. Even doctors discriminate against people with AIDS, Cai said, describing how he was told he needed surgery for a condition unrelated to his HIV. After he informed the doctors he had HIV, they told him he did not need the surgery. Many with AIDS have died for want of surgery, Cai said. Nonetheless, said Kaufman, one extraordinarily sophisticated resource, family planning, "reaches down to every village, and is a fantastic infrastructure for doing the necessary health education work." --David Holzman |
