After an uproar, price of AIDS drug falls in Africa

A drug discovered in a Yale laboratory made headlines this spring in the ongoing debate about the provision of AIDS medications in the Third World. The physicians’ group Doctors Without Borders called on the University, which holds the patent for d4T, and Bristol-Myers Squibb (BMS), which has a license to market it, to allow cheaper or generic versions to be sold in Africa. At a cost of between $10,000 and $15,000 a year, antiretroviral therapy is out of the reach of most of the 25 million people in sub-Saharan Africa who have AIDS and the 3.8 million who are infected with HIV.

BMS said in mid-March, after discussions with the University, that it would make its two AIDS drugs, d4T and ddI, available throughout Africa for $1 per day and allow generic versions to be sold as well.

The issue surfaced when an Indian pharmaceutical company, Cipla, made an offer to provide triple-therapy AIDS cocktails at $350 per year per patient in developing countries. That package included d4T at 5 cents a tablet. Doctors Without Borders, however, was unwilling to distribute the generic drug because of concerns over infringement of patent rights in South Africa. The humanitarian group pressed both the University and BMS for a solution, and Yale students later joined in calls for price relief. The discussions reached senior levels of the University and BMS, which modified the license agreement in order to make the drug more affordable and widely available. Although BMS was free to set the price of the drug, the company also sought permission from the University to offer patent relief in Africa. In recent years the drug, known generically as stavudine and marketed as Zerit, has brought Yale about $40 million a year in royalty income.

Joining the voices clamoring for low-cost drugs was William Prusoff, Ph.D., emeritus professor of pharmacology, who with his collaborator, the late Tai-Shun Lin, Ph.D., discovered the drug’s value as an antiviral in 1986. “We weren’t doing this to make money. We were interested in developing a compound that would be a benefit to society,” Prusoff said.

No time to lose

A high-profile panel criticizes efforts to fight AIDS/HIV.

Last year, a committee of 16 scientists and academics began evaluating the nation’s efforts to prevent the spread of AIDS and HIV. What it found was unsettling: a lack of coordination among federal agencies, funding of interventions that showed no evidence of success, reliance on political rather than scientific criteria for funding and, perhaps most startling, no clear goal for prevention.

“Despite the fact that we know so much about how to prevent HIV,” said Michael H. Merson, M.D., dean of public health and one of two Yale faculty members on the panel, “we can’t get the job done.”

The Committee on HIV Prevention Strategies in the United States concluded that the nation’s public health system needs to set the obvious yet previously unstated goal of averting as many new HIV infections as possible with the resources available. Under current funding, the committee estimated that a reallocation of resources could reduce new infections by 30 percent. And interventions currently denied federal funding, such as needle exchange programs and comprehensive sex education, could prevent even more infections. “That is probably the most important thing to realize,” said the other Yale faculty member on the committee, Edward H. Kaplan, Ph.D., a professor of both management sciences and public health. “You can get better results not only by increasing the budget, but also by changing the allocation.”

The committee was established by the Institute of Medicine at the request of the Centers for Disease Control and Prevention, which wanted to have a prevention framework in place before the 2000 presidential election, Merson said.

One of the national effort’s main failures, the report said, is in the allocation of HIV prevention resources. Money for prevention follows reports of AIDS cases, but because HIV incubates for 10 years, this approach yields old data. “It rewards people for counting cases of AIDS instead of preventing HIV infections,” Kaplan said.

The report proposed a six-pronged prevention strategy. Allocation of resources should target not reported AIDS cases, but estimates of new HIV infections through anonymous testing of “sentinel groups,” such as drug users in treatment. Evaluations of existing programs should determine whether interventions work. HIV prevention counseling should reinforce prevention messages among those already infected. Research and interventions should strengthen local capacity to implement effective programs. Federal agencies should continue to invest in HIV prevention. Finally, the committee recommended overcoming social barriers to HIV prevention, such as opposition to syringe exchanges, comprehensive sex education and condom availability in schools, and facilitation of prevention efforts in prisons.

“This is the greatest public health crisis the world has faced since the bubonic plague pandemic of the Middle Ages,” Merson said, adding that years from now people will ask a simple question: “How did a country that had all the knowledge it needed about the virus and the resources required to prevent its spread allow such a tragedy to occur, killing so many people?”

Pioneer in tobacco research receives first Winslow Medal

Last fall when the World Health Organization began negotiating a new global treaty aimed at curbing tobacco use, particularly among young people, Sir Richard Doll, M.D., D.Sci., looked on with a great deal of satisfaction.

In 1950, Doll published the first convincing evidence that smoking was the cause of lung cancer. This was during an era when a physician might try to calm a patient’s nerves by offering a cigarette. Doll, a smoker at the time, had speculated that rising lung cancer rates might have to do with the increase in the number of cars on the road. Through painstaking epidemiological work, however, he and his colleague Sir Austin Bradford Hill found and documented the link to tobacco.

This and Doll’s lifelong contributions to epidemiology and public health—including the understanding of peptic ulcer disease, the health effects of oral contraceptives and the role ionizing radiation plays in causing leukemia—prompted the Yale University School of Public Health to make Doll the first recipient of the C-E.A. Winslow Medal in mid-October.

The medal is given in honor of Charles-Edward Amory Winslow, who established Yale’s Department of Public Health, as it was known when it was founded in 1915, and is regarded by many in the United States as the founder of the modern discipline of public health. During his tenure at Yale, Winslow expanded the definition of public health from the narrow confines of public hygiene to include the prevention and control of heart disease, cancer, stroke, mental illness and diseases associated with poverty. According to Dean Michael H. Merson, M.D., many important changes occurred during Winslow’s tenure. Bacteriology evolved into microbiology to include parasitology and virology, and public health experts began to recognize the social aspects of sickness.

Merson said Doll was selected as the first recipient of the medal because he is the “foremost epidemiologist of the second half of the 20th century.” Doll’s papers, which are “classics because of the rigor in their study design, the elegance of their analysis, and the clarity of their reporting,” established his reputation as the “epidemiologist’s epidemiologist,” Merson said.

During the course of his career, Doll refrained from speaking out against tobacco companies because, as he said in an interview, “my job was to do the research and make evidence. ... The active research worker has to disassociate himself from the steps that are taken as a result of his research.” But now that he is no longer actively researching the tobacco issue, he is happy to give his opinion on the continued efforts of those in the tobacco industry who market their products to youth.

“It’s like selling heroin,” he said. “One happens to be legal and the other isn’t, but they are both equally morally evil. I don’t object to the manufacture of it. We’re not going to stop that overnight. What I object to is its promotion, encouraging people to use it.”

Doll, who received his medical degree in 1937 and his doctor of science in 1958 from the University of London, considers his work on tobacco to be his greatest professional accomplishment. Formerly the director of the United Kingdom Medical Research Council’s Statistical Unit, Doll was appointed the Regius Professor of Medicine at the University of Oxford in 1969. At Oxford he also directed the Cancer Epidemiology and Clinical Trials Unit, and has continued to work with the unit since his retirement as a professor in 1983.

Managing complex data about the brain

In recent years, the state of knowledge about the human brain—whether at the level of molecules, cells, or entire signaling pathways—has increased so much that it has given rise to a whole new field of study. The science of neuroinformatics looks for ways to sort and store these floods of data that will keep them widely accessible, open to interaction with other data and amenable to continual revisions and updates. A big step forward took place in October, when the NIH-supported Human Brain Project awarded a $4.6 million grant to the School of Medicine for the establishment of a multipurpose, neuronal database on the World Wide Web.

The four-year effort of developing the site, known as SenseLab (senselab.med.yale.edu), is headed by Gordon M. Shepherd, M.D., D.Phil., professor of neurobiology, along with colleagues Perry L. Miller, M.D., Ph.D., professor of anesthesiology and director of the Yale Center for Medical Informatics, and Michael Hines, Ph.D., research scientist in the departments of Neurology and Computer Science. “The purpose of the site is to support research on the integrative actions of neurons and circuits, in the same way that the Human Genome Project has so effectively supported research on genes and proteins,” said Shepherd.

Within this Web site, users can work with data from each of SenseLab’s five databases interactively. The databases focus on neuronal models (including models that can be manipulated onscreen), membrane properties of neurons, neurotransmitter receptors and ion channels, olfactory genes and their proteins, and odor molecules. In addition, users may search the databases by neuron or category of neuron, as well as by neurotransmitter, receptor or electrical current. Efforts are now under way to enhance the site with links to brain atlases on the Web and to other databases, such as archives of brain images and of the anatomy of different types of neurons. The Yale scientists are also developing more effective ways to add data from electronically published journal articles into the SenseLab databases by means of automatic search tools. In Shepherd’s view, “It’s an exciting time to be in on the creation of a new field that will be crucial to future research in neuroscience.”

New facility brings cell imaging down to the molecule

Until March of this year, whenever Frederick J. Sigworth, Ph.D., needed electron cryomicroscopy to view the membrane proteins he studies, he sent a graduate student on the train to New York with a thermos that maintained samples in liquid nitrogen at minus 200 degrees Celsius. Now Sigworth, a professor of cellular and molecular physiology, need go no further than the lower level of Sterling Hall of Medicine. There, in newly renovated space, is a cluster of core resources that allows scientists to apply the latest microimaging techniques to their work.

The Center for Cell and Molecular Imaging and the Core Computing Facility for Bioinformatics and Image Analysis offer electron microscopy, electron cryomicroscopy, confocal microscopy and core computing facilities for data analysis and interpretation. “These technologies are too complicated and too expensive for any one faculty member or laboratory to manage on their own,” said Carolyn W. Slayman, Ph.D., deputy dean for academic and scientific affairs. “Core facilities offer access to specialists and to equipment costing anything from hundreds of thousands to millions of dollars.”

The upgraded facilities are the result of three years of planning that began in 1998, when Dean David A. Kessler, M.D., convened a committee to review the medical school’s plans for structural biology. The committee came to the realization that, “more and more, state-of-the-art medicine is dependent on knowing the structure of these molecules,” said Sigworth, one of its members. The school has since recruited faculty members with expertise in the new imaging technologies, upgraded existing hardware and purchased new equipment, such as additional electron microscopes, confocal microscopes, electron cryomicroscopes and a two-photon microscope. The new microscopes provide a variety of imaging possibilities for a broad array of specimens at a range of different resolutions.

An open house in late January officially inaugurated the new facilities. Vinzenz M. Unger, Ph.D., assistant professor of molecular biophysics and biochemistry, coordinates the electron cryomicroscopy laboratory and provides training for new users. Marc Pypaert, Ph.D., associate research scientist in cell biology, provides training and use of electron microscopes. Michael H. Nathanson, M.D., Ph.D., associate professor of medicine, is in charge of confocal microscopy. The bioinformatics facility, managed by Anne Marie Quinn, M.P.H. ’00, is a place where scientists and students can take data for analysis and interpretation or search for genomics data on the Internet. The next phase of the facility is an expanded X-ray crystallography laboratory at the medical school.

To those who gave their bodies to medicine, a gesture of gratitude

As they begin to study medicine, students who aspire to be physicians or physician associates meet their first “patients” in the anatomy lab. “These patients had a wish,” said Lawrence Rizzolo, Ph.D., professor of anatomy, “that a hard-working, dedicated student would take their remains and use them to advantage.” The students know little about these patients at first—no more than their age, sex and race. Over the course of six months, however, the students become intimately familiar with them as they chart the geography of the human body. They learn from the calluses on their hands, the scars from prior surgeries, tattoos on their skin and the signs of disease and repair they may find inside.

On Feb. 28, students and faculty held a Service of Gratitude in the Historical Library to thank the donors for their gift to science. During most of the 15 years students have organized the service, it was styled, in the words of anatomy professor William Stewart, Ph.D., on a Quaker meeting. People gathered and offered their thoughts on their first patients. About five years ago students decided to present a more formal program, Stewart said. The 75-minute ceremony this winter included songs and poems as well as remarks by students. Medical student Kavita Mariwalla tried to imagine her patient’s personal life in two poems she wrote. “When I examine your heart as a structure,” she said, “I will remember that you kept secrets in it.”

The service, Rizzolo said, allows students to express the frustrations, angst and other emotions that come with the experience of exploring a cadaver. “It is really their first experience with a patient, even though the patient is dead,” he said. “It raises a lot of thoughts about their own mortality and their lives as clinicians.”

Each year, when the anatomy class ends, the bodies are cremated. About every five years, when ashes have accumulated, they are interred in a common grave at Evergreen Cemetery in New Haven. This year, medical students plan to inscribe headstones for each of the five common graves that hold the remains of the bodies.

“Topping off” the Congress Avenue Building

“It’s one thing as a parent to watch your own children grow,” Dean David Kessler told the crowd gathered outside the Congress Avenue Building on March 21, “but I must say, as dean, it is quite another to watch this baby grow.” The dean thanked city and community leaders and iron workers, who gathered with faculty members, students, alumni and project staff as the workers lifted the highest piece of structural steel in the 450,000-square-foot building’s massive frame into place. An American flag and an evergreen tree were welded to the 1,000-pound beam for good luck, and iron workers and others signed the beam, right, before it shot skyward at the end of a crane. All told, 7,000 pieces of steel weighing 3,500 tons went into the framing, which was completed during the course of several exceptionally snowy months. “It seemed like the winter didn’t want us to finish this job,” said Otto Del Medico, the superintendent of Iron Workers Local 424. “We fought the weather every day.” When completed in March 2003, the building will house disease-oriented research programs, greatly expanded teaching space, a magnetic resonance center and an animal care facility. Kessler’s remarks from the “topping off” ceremony and updates on the project may be accessed at http://info.med.yale.edu/cab.

Also in Chronicle:

Price of AIDS drug falls in Africa   |  No time to lose  |  Pioneer in tobacco research  | Managing complex data about the brain  |  New facility for cell imaging  |  A gesture of gratitude  |  “Topping off” the Congress Avenue Building

Rounds  |  Findings  |  Et cetera   

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Originally published in Yale Medicine, Spring 2001.
Copyright © 2001 Yale University School of Medicine. All rights reserved.