Contents:
Microbiology
With their knack for insinuating their own genes into a cell's DNA, retroviruses seem the perfect vehicle for getting therapeutic genes into sick cells. But harnessing these nimble microbes has not been easy. Finding a way to steer them to needy cells--and only those cells--has been one of the major challenges facing gene therapy. A pair of HMS researchers may have found a solution to this critical problem. They have created a novel molecular device that enables genetically modified retroviruses not only to seek out but enter specific cells in culture.
Whereas previous attempts have focused on modifying the retrovirus to give it better aim, the new method leaves the virus vehicle untouched. Instead, it links the virus and target cells by means of a molecular bridge consisting of two proteins--epidermal growth factor (EGF) and the avian leukosis virus (ALV) receptor. These, in turn, bind proteins found on specific human cells and viruses, respectively. The specificity of the binding--between EGF and its human cell surface receptor and between the ALV receptor and the viral protein--is what allows the virus to hook up with particular cell targets.
| John Young and Sophie Snitkovsky (not shown) have discovered a way to help viruses deliver therapeutic genes to specific cell targets and only those targets. |
When applied to cultured cells, the protein hybrid allowed the virus not only to bind but also enter its designated cell targets, the researchers report in the June 9 Proceedings of the National Academy of Sciences. This is the first time this kind of gene therapy delivery system has been shown to enable successful targeting and infecting of selected cells in vitro.
"The novel thing here is that this device works efficiently. It allows for the first time the possibility that we can use this approach to target any cell type we want," says John Young, associate professor of microbiology and molecular genetics at HMS. He developed the method in collaboration with graduate student Sophie Snitkovsky. If it is successful in vivo, the method could be used in gene therapy protocols to deliver particular genes to selected groups of cells, including tumors and diseased tissues such as the defective lungs of cystic fibrosis patients.
Until recently, many gene therapy trials have employed ex vivo strategies--genetically modifying target cells outside the body and reimplanting them in the body--to achieve this goal. But this is an invasive and generally impractical procedure with variable results. Efforts to design in vivo delivery systems have focused on modifying the virus, for example, by building into the envelope a structure that directs the virus to a specific cell type. But the tinkering appears to interfere with the ability of the virus to enter the cells.
"We wanted to find an approach where we could preserve as much as possible the normal virus-envelope receptor interaction," says Young. Supported in part by an HMS Funds for Discovery Award, he and Snitkovsky created the EGF-ALV receptor protein hybrid and applied it to a series of cell types, including one with the normal EGF receptor and one without. Only those cells with the EGF receptor bound the molecular device.
Normally, viruses get their genes into cells by attaching
to a compatible receptor found on certain cells (left). Cells lacking this
viral receptor but having others, such as the EGF receptor, are immune to
infection (center). To infect these cells, the researchers took a viral
receptor and fused it to the EGF ligand, giving the virus and cell each
something to bind to. The resulting protein bridge allowed the virus not
only to attach but also enter its cell target.
To see if the virus, once linked, could actually enter cells, the researchers introduced a gene conferring resistance to the antibiotic neomycin into the viruses. They added the gene-carrying viruses to the cells, and then exposed the cells to neomycin. To their surprise, the researchers saw cell colonies--demonstrating that cells had been infected by the viruses carrying the resistance gene. In fact, a much higher percentage of the cells were infected than expected. "It was really quite remarkable. I think jumping up and down is the way you'd describe our reaction," says Young.
The success may be due in part to the simplicity of the ALV system. Unlike HIV, which requires multiple protein receptors to enter a cell, ALV seems to use a single protein receptor. While the ALV receptor thus appears to be uniquely suited to the protein bridge approach, EGF is only one of many possible protein partners. Young and Snitkovsky speculate the method could be used on a variety of cell surface markers, including those found on cancer cells. They are currently exploring other possibilities in conjunction with graduate student Adrienne Boerger and other colleagues at HMS. They are also working on ways to deliver the protein hybrid in vivo.
"The way I look upon this experiment is that it has opened the door to the possibility of targeting by this mechanism," says Young. "It solves that problem in tissue culture. Translating that to the in vivo situation is the focus of our current work."
--Misia Landau
A five-state study by Harvard researchers suggests that in certain cases, medical practice guidelines and the treatment recommended by practicing physicians may be two different things.
The researchers say that in other cases, for which clinical research is more complete, the practicing physicians closely agreed with clinical experts, who develop the majority of these guidelines.
The study found that practicing physicians and clinical experts (who may be more familiar with published research) disagreed on how to treat the most elderly heart attack patients. The inconsistency suggests a potential conflict between the treatments practicing physicians recommend for this patient population and the practice guidelines that insurance companies use to determine which treatments will be covered.
To remedy the situation, the researchers say that evaluations of "best" medical practices should be founded on the beliefs not only of expert panels but also of physicians practicing in the community. Including the practitioners' perspective would increase the breadth of clinical experience the guidelines represent. The researchers also recommend that more clinical research be done on the most elderly patients--those 75 and older--so medical literature can reflect more complete clinical results.
| John Ayanian suggests that community physicians contribute to practice guidelines. |
"This is one of the first large-scale studies on practice patterns to take into account the beliefs of practicing physicians," says lead author John Ayanian, assistant professor of medicine and health care policy at HMS and Brigham and Women's Hospital. "It is important for policymakers to understand practicing physicians beliefs if they want to improve care by altering physician behavior and decision-making," he says.
The study appears in the June 25 New England Journal of Medicine along with a second article and an editorial on quality of care. The second article, co-authored by Lucian Leape of the Harvard School of Public Health, compares the beliefs of different expert panels.
The Physician Raters
The Medical School researchers presented a mix of cases to 1,058 practicing physicians and a panel of nine clinical experts. The physicians rated the appropriateness of coronary angiography for 20 categories of patients who had recently had an acute myocardial infarction. This procedure, x-ray imaging of the coronary arteries after injection of a contrast material, helps in diagnosing the cause of the heart attack and in planning further treatment. The practicing physicians included internists, family practitioners, and cardiologists in California, Florida, New York, Pennsylvania, and Texas. The nine experts also represented a range of specialties.
Though there was general agreement between the practicing physicians and expert panel for most case categories, those in which the patient was 75 or older and had no complications resulted in significant variation between the two groups.
Ratings of the Appropriateness of Coronary
Angiography After Acute Myocardial Infarction
by
Surveyed Physicians and an Expert Panel
| Clinical Indication | Patient's Age (Yr) | Onset of Symptoms (Hr) | Thrombolytic Therapy | Complications | Rating by Surveyed Physicians | Rating by Expert Panel |
| Median (interquartile range) | Median (interquartile range) | |||||
| K | >=75 | <6 | Contraindicated | None | 6 (3-8) | 3 (3-5) |
| L | >=75 | <6 | Contraindicated | Persistent Chest Pain | 8 (7-9) | 7 (7-8) |
| M | >=75 | <6 | Not Contraindicated or Administered | None | 5 (3-7) | 2 (2-4) |
| N | >=75 | <6 | Not Contraindicated or Administered | Persistent Chest Pain | 7 (5-9) | 7 (6-8) |
| O | >=75 | <6 | Administered | None | 2 (1-4) | 1 (1-3) |
| P | >=75 | <6 | Administered | Persistent Chest Pain | 8 (7-9) | 7 (4-8) |
| Q | >=75 | >12 | Not Administered | None | 4 (2-6) | 4 (2-5) |
| R | >=75 | >12 | Not Administered | Persistent Chest Pain | 8 (7-9) | 8 (7-8) |
| S | >=75 | >12 | Not Administered | Persistent Pulmonary Edema | 8 (6-9) | 8 (5-9) |
| T | >=75 | >12 | Not Administered | Stress-induced Ischemia | 8 (7-9) | 6 (6-7) |
The chart shows only that half of the hypothetical cases studied in which the patient was 75 or older.
"One potential explanation is that practicing physicians have more experience in seeing positive benefits of angiography for older patients, while the expert panel may be following the medical literature more closely. We don't have an abundant set of data to guide us for older patients," Ayanian says. "We need to improve the evidence available through clinical research to guide us in the care of these patients."
New Tool for Health Services
One of the noteworthy aspects of the study was the use of hierarchical regression modeling, a statistical technique that was developed more than a decade ago but only recently applied to health services research. It identifies the source of variation in treatment recommendations by establishing a "hierarchy," or nested set of effects associated with physician characteristics. The method enabled the researchers first to identify which patient characteristics (such as the presence or absence of complications) influenced physicians' recommendations. Then the researchers could look across physicians to determine how the relationship between physician beliefs about the procedure's benefit and patient characteristics varied by physician specialty, state, age, and sex. "The effects were estimated using a computer simulation technique that cycles through all of the ratings and determines whether there is a propensity for a particular physician to rate high, for example," says co-author Sharon-Lise Normand, associate professor of biostatistics in the HMS Department of Health Care Policy. This propensity could be correlated to the physician's characteristics.
The technique showed that disagreement also existed within the group of practicing physicians. Their varying expertise and practice environment seemed to influence their beliefs. For complicated cases, cardiologists rated coronary angiography as more appropriate than did primary care physicians. Even among cardiologists, marked variation existed for uncomplicated cases: those who performed invasive procedures gave higher ratings for the appropriateness of angiography than did cardiologists who did not. Furthermore, physicians from hospitals providing invasive treatments like coronary angioplasty and bypass surgery rated angiography as more appropriate in uncomplicated cases than did physicians from other hospitals. Physicians working in health maintenance organizations rated angiography as less appropriate than did other physicians.
The 20 case categories in the study are defined by sets of clinical indications: patient age, time of heart attack, status of thrombolytic therapy, and presence of complications such as chest pain. The physicians rated the appropriateness of coronary angiography for patients in each category using a nine-unit scale with 1 being very inappropriate; 5, uncertain; and 9, very appropriate.
Other study co-authors, all from HMS, were Mary Beth Landrum, assistant professor of biostatistics; Edward Guadagnoli, associate professor of health care policy; and Barbara McNeil, chair of the Department of Health Care Policy. The study was supported by a grant from the federal Agency for Health Care Policy and Research.
--Robert Neal
HMS Alum Will Lead Harvard-wide Clinical Trials Program
Raphael (Ray) Dolin will
begin
at HMS in September.
Raphael Dolin, a leading expert on viral infections, has been appointed
faculty dean for clinical programs by HMS Dean Joseph B. Martin. Currently
the chair of medicine at the University of Rochester and physician in chief
at Strong Memorial Hospital, Dolin will begin his new role in mid-September.
Richard Kitz, the current faculty dean for clinical affairs had previously announced his desire to step down by September from the position that he had held half-time since 1994. Dolin will be stepping into the position with a new title, expanded time commitment, and a portfolio broadened in large part by the effort of HMS and its major affiliates to launch an extensive clinical trials program.
The clinical trials effort has been under discussion for nearly a year and was given broad support to begin a business planning phase at a retreat July 7 by the administrative and medical leadership of Partners, CareGroup, Dana-Farber, Children's Hospital, and Harvard Pilgrim. The program, however, must pass several additional hurdles to prove its feasibility and determine its scope. If given a go, it is expected to be up and running within a year.
"Ray Dolin's outstanding background as a clinical leader and as a leader of clinical investigation make him an ideal choice for our new dean for clinical programs and to spearhead our clinical trials initiative," said Dennis Kasper, executive dean for academic programs.
Dolin has extensive research and clinical experience working with gastrointestinal, influenza, and herpes viruses. Most recently he has focused on the development and clinical evaluation of HIV vaccines, and he hopes to continue the latter work here. His clinical appointment will be at Brigham and Women's, where he expects to have one clinic a week and will serve as professor of medicine pending his academic appointment.
A graduate of Harvard College and HMS '67, Dolin did his residency on the Harvard Service at Boston City Hospital and a fellowship at the Channing Laboratory. After serving in various positions at the National Institute of Allergy and Infectious Diseases, he began his academic career as a professor of medicine and head of the Infectious Disease Unit at the University of Vermont College of Medicine in 1978. He moved to the University of Rochester in 1982 as head of the Infectious Disease Unit and professor of medicine and of microbiology and immunology. He was appointed Charles A. Dewey Professor of Medicine and chair of the department in 1991.
"This is a great age for clinical research, with exciting opportunities to better understand the fundamental nature of disease and then translate these advances into genuine benefits for our patients," said Dolin. "And Harvard is a great place to make this happen.
"It has unparalleled breadth and depth with outstanding basic and clinical investigators and facilities at both the School and its affiliates. The opportunity to facilitate these collaborations is an exciting prospect," he added.
A co-editor of Principles and Practice of Infectious Diseases, Dolin also co-edited the soon to be published textbook AIDS Therapy. He is a member of the NIAID AIDS Research Advisory Committee and the NIH AIDS Vaccine Research Committee, having previously served on the Board of Scientific Counselors of NIAID and the Anti-Infective Drugs Advisory Committee of the FDA.
--Don Gibbons
Clotrimazole, a drug marketed to fight fungal infections, stops cell growth and proliferation through a chain of reactions that inhibits the start of protein translation. The drug's mechanism for blocking the creation of some proteins underscores its potential for cancer therapy, report José Halperin, associate professor of medicine at HMS, and his colleagues in the July 7 Proceedings of the National Academy of Sciences.
Following up on earlier research, Halperin found that clotrimazole arrests cellular growth by flushing calcium ions from intracellular stores. The release of these ions activates an enzyme, protein kinase R, which phosphorylates the protein eIF2-alpha. That, in turn, interferes with an energy exchange necessary to initiate a new round of protein translation. Stopping protein synthesis reduces the expression of growth-promoting cyclins A, E, and D1. Without the cyclins, cyclin dependent kinases cannot activate, and the cell is stopped from dividing.
Inhibiting the first step of translation and reducing the expression of cyclins, prevents the cell from progressing from the phase just before DNA synthesis begins, to the next step of the cell's growth and division cycle. Uncovering clotrimazole's mechanism as an anticancer drug demonstrates the potential of translation initiation as a target for cancer therapy, says first author Hussein Aktas, research associate in the Laboratory for Membrane Transport at HMS, where the research was conducted.
The surgical procedure pallidotomy has proven its ability to reduce the side effects of treating Parkinson's disease with dopamine, calming tremors and dyskinesias. About 70 percent of patients showed improvement following the surgery, announced G. Rees Cosgrove at a press seminar on "Brain and Psyche 1998." Cosgrove is an associate professor of clinical surgery (neurosurgery) at HMS and the Movement Disorders Center of Massachusetts General Hospital.
Over five years, Cosgrove treated 85 patients with pallidotomy, creating a tiny lesion in a brain structure called the globus pallidus. It is thought that the operation works by partially restoring the balance between competing neurochemical control systems in the brain. The average improvement in motor skills, according to the Clinical Global Improvement Scale, was 30 percent, with the dyskinesias almost abolished on the side of the body opposite where the lesion was created.
The ideal candidates for the treatment, says Cosgrove, develop Parkinson's in their 30s and 40s and have since developed severe drug-induced dyskinesias. Pallidotomy was originally used to treat Parkinson's in the 1940s and '50s but fell into disuse with the introduction of drug therapies. The procedure made a comeback in Europe in the 1980s as a treatment for the side effects of those therapies.
Fibrous clumps of amyloid-beta protein have long been associated with Alzheimer's disease, and now researchers have shown that the protein can directly cause brain degeneration. In the July issue of Nature Medicine, Bruce Yankner, associate professor of neurology at HMS and Children's Hospital, along with Changiz Geula, an assistant professor of medicine at HMS and Beth Israel Deaconess, report that injecting the protein into rhesus monkeys killed brain cells. The technique represents a new primate model for Alzheimer's.
In 1990 Yankner found that amyloid-beta can kill brain cells in vitro, but still had to discover whether the protein had the same effects in vivo. When studies of mice turned out inconclusive, he started looking for a new model. In the current study, he injected amyloid-beta into the brains of aged monkeys, which resulted in Alzheimer's-like brain degeneration, including neuronal loss, tau phosphorylation, and microglial proliferation. In a second part of the study, the researchers found that amyloid-beta causes more damage in old brains than young brains.
Along with providing some insight into the degenerative mechanisms of Alzheimer's, the research has created a much-needed model for studying the disease. "If we can learn why the aging brain, but not the young brain, is susceptible to the toxic effects of amyloid-beta, we may be able to target the susceptibility factor with drugs," says Yankner.
Stopping the AIDS epidemic will require the development of an effective HIV vaccine, but the approaches taken so far have had little success, says Norman Letvin, professor of medicine at HMS and Beth Israel Deaconess. In a review of progress on an HIV-1 vaccine in the June 19 Science, he suggests that researchers need to find out more about the virus and the immune response to it before they can improve their vaccination strategies.
The prospect of a live HIV vaccine similar to the one used against smallpox appears unlikely. Although such a vaccine has protected macaques from simian immunodeficiency virus (SIV) in some experiments, the long-term results have been controversial. "There is accumulating evidence in macaques that the genetic strategies that have been used to date cannot create a safe live, attenuated AIDS virus vaccine," writes Letvin. His view was echoed by the results of an experiment by Ruth Ruprecht, associate professor of medicine at HMS and Dana-Farber, presented at the recent 12th World AIDS Conference in Geneva. She found that an SIV vaccine can be deadly, with the weakened virus mutating into a disease-causing form in a significant number of vaccinated animals.
Inactivated viruses with adjuvant, a recipe similar to the vaccines that protect people against influenza and polio, have elicited a nonvirus specific response in monkeys. However, that response was to attack the cells in which the virus was cultivated, rather than the virus.
Subunit vaccines made of highly purified viral proteins hold some promise, writes Letvin. Although the National Institutes of Health canceled large-scale trials using this type of vaccine, other U.S. government agencies and private vaccine manufacturers are proceeding with trials in Thailand. The vaccine does not elicit HIV-1 specific cytotoxic T lymphocytes or generate an antibody response that can neutralize the virus. Still, he writes, this type of vaccine may be useful in conjunction with other vaccination strategies.
Inserting genes from HIV into other viruses to create a live vector-based vaccine has the potential to elicit a strong immune response. The limitation of this approach, Letvin says, is that the genes have to be small, genetically stable, and safe. Another drawback is that the viruses used to carry the gene, such as vaccinia, can create life-threatening infections in immunosuppressed people. Tinkering with the virus used to carry the genes, or even using bacteria, might be the solution, he writes.
--Cassie Ferguson
It took 26 years of consistent funding by the National Cancer Institute to take the field of angiogenesis from theory to agents capable of dramatically shrinking tumors, Judah Folkman, professor of pediatric surgery at HMS and Children's Hospital, told a Senate forum on the economic impact of biomedical science on June 23.
Financial expert Peter Lynch, a member of the board of the Fidelity Group of Funds, told the senators that the nation is in danger of eating its technological seed corn if it does not increase its investment in basic science. Noting that 73 percent of all patents come from publicly funded research, Lynch said technology-dependent industries are thriving now because of public investments in the 1960s, '70s, and '80s. However, he warned that with the share of the gross domestic product devoted to federal R&D dropping from 1.8 percent in 1960 to less than 0.6 percent today, tomorrow's jobs are in jeopardy.
Senator Kennedy (left) opened the forum saying, "Biomedical
is one of the most 
important federal investments."
Judah Folkman (right) gave a dramatic reason why.
Folkman noted that it's not just the jobs created by the biotechnology and pharmaceutical industry that are at risk, but also the careers of the vast pool of top young scientists whom we have trained. "They are frustrated by the low success rates for grants and many are considering leaving the field."
Basic science funding's double benefit of cures and jobs was echoed at the forum by Henri Termeer, president and CEO of Boston-based Genzyme Corp.
The forum, hosted by HMS alumnus Bill Frist (R-TN) and fellow senators Connie Mack (R-FL), Edward Kennedy (D-MA), and Tom Harkin (D-IA), was organized by two groups pushing for a doubling of the NIH budget in five years, America's Campaign for Medical Breakthroughs and the Task Force on Science, Health and the Economy. The latter is chaired by Boston businessman Arthur Ullian, who serves on an HMS advisory committee, as do Frist, Lynch, and Termeer.
Neurons may be the principal actors of the brain but, like many prima donnas, they depend on a retinue of helpers to enhance their function of sending messages. These attendants, called glial cells, perform a variety of tasks--supporting neurons, mopping up excess chemicals from the extracellular space, guiding immature neurons as they migrate through the brain, blanketing their long processes with the communication-enhancing substance called myelin.
This beneficial arrangement is subverted in people suffering from malignant brain tumors. Glia divide uncontrollably, forming masses called glioblastomas that are difficult to treat. Some send out tentacles that cannot be surgically removed. In addition, individual tumor cells may break off and cross the corpus callosum, the band of tissue bridging the two halves of the brain, setting up new centers of disease. Because these migrant cells do not divide during their journey, and may even remain dormant in their new lairs, they elude chemotherapeutic agents designed to track down and kill dividing cancer cells.
"Our aim was to make a model
that allows greater control
of lesions and also dissection
of genetic events that in the
future might allow for better
diagnosis and treatment."
--Harold Varmus
"The enemy here is monstrous," said Xandra Breakefield, professor of neurology at HMS and MGH. She was speaking on June 24 at the Second Annual Symposium of the Giovanni Armenise-Harvard Foundation, in a program titled "The Genetics of Human Brain Cancer." (See p. 7 for coverage of the preceding Armenise program.) After years of frustrated attempts, scientists are beginning to understand how brain tumors form--and how they might be stopped. Speakers at the symposium, attended by over 200 people, pinpointed some of the mutant genes that cause glial cells to relentlessly divide and outlined strategies to arrest the process.
An All-out Attack
Breakefield and her colleagues have been testing a gene-therapy strategy in rats that tackles brain tumors on all fronts--the main mass, migrant tumor cells, and new foci. After removing the tumor surgically, the researchers inject viruses carrying a variety of anticancer genes. Some, hefting toxin genes, kill tumor cells directly. Others carry the gene for an enzyme that converts nonpoisonous substances into toxins and cause the cells to produce toxins that spread to other tumor cells. "We are able to save 50 percent of rats this way," she said.
To target migrant tumor cells, they are taking an equally ingenious approach. Rather than deliver gene-carrying viruses directly, the researchers are packaging them into a line of migratory brain cells, called neural progenitor cells, developed by Evan Snyder, assistant professor of neurology at HMS and Children's Hospital, and his colleagues. In preliminary experiments, the virus-carrying cells migrated and even killed cells at the tumor edge, Breakefield said. Eventually, she hopes to use the virus-carrying cells to "sensitize" migrant tumor cells, that is, to render them susceptible to conventional treatments. She described a plan in which neural progenitors would be used to deliver "activating" genes that prod migrant tumor cells into dividing, thereby making them visible to chemotherapeutic agents.
Finally, to target new foci, she and her colleagues are testing ways of delivering gene-carrying vectors through the new blood supply surrounding tumors. "Unfortunately, you don't get neovascularization until the tumor is a certain size," Breakefield said.
Tumor Formation
A novel answer to the question of how glioblastomas form--and specifically the role played by the well-known tumor-suppressor gene p53--was presented by HMS professor of cell biology Frank McKeon. Researchers have suspected that in addition to monitoring DNA damage, p53 plays a role in maintaining the proper number of chromosomes in the glial cell--perhaps by overseeing their attachment to spindles during cell division--but it was not clear what that role actually was. McKeon and his colleagues have recently conducted an experiment suggesting that rather than monitor the situation directly, p53 may receive distress signals from another protein.
Normally, if a chromosome fails to attach to a spindle, a signal is sent out to halt mitosis. If the problem is not remedied within a period of time, the cell commits suicide. The researchers found that when they blocked the normal action of this protein, Bub1, glial cells would clump rather than die. They did so even if the cell had a normal p53 gene. "So p53 is probably responding to signals from spindle assembly checkpoints," said McKeon.
Other recent findings from his lab suggest p53 is interacting with a whole host of proteins. For example, graduate student Annie Yang has recently discovered a protein, p63, that when truncated prevents the p53 gene from being expressed. "We think we're stumbling and bumbling into a whole network of interactions," said McKeon.
Echoing the theme of multiple interactions, Harold Varmus, director of the National Institutes of Health, described how he and his colleagues transfected two mutant genes--EGFR and cdk4--into mice developed by NIH colleague Eric Holland. Only when both mutants were introduced--and only when they were transfected into mice lacking both copies of the INK4 gene--did they produce tumors. Adding mutant p53 to the mix significantly increased the number of tumors.
Although preliminary, such investigations into the genetic events underlying glioblastomas could point the way toward better diagnosis and treatment, said Varmus. He and his colleagues have designed their mouse model with this aim. The NIH mice develop hydrocephaly when they have brain tumors, making the tumors visible and eliminating the need to sacrifice the animals for diagnosis. Varmus and his colleagues plan to use nuclear magnetic resonance imaging to scan the brains of the hydrocephalic mice and possibly rescue them. "We want to see tumors earlier while the animal is still alive and perhaps select them for therapy," he said.
--Misia Landau
Armenise-Harvard Researchers Speak International Language
While the Italian soccer team was competing for the World Cup in Paris, a meeting room on Cape Cod was crowded with 130 basic researchers, one third of them from Italy. In the front row sat Count Giovanni Auletta Armenise, flanked by Dean Joseph Martin and former dean Daniel Tosteson. Like everyone else, they watched mesmerized as a culture of epithelial cells, prodded by a dose of extracellular "scatter factors," sprouted branched processes as elaborate as deer antlers. The video was grainy, black and white, and only three minutes long. Yet for this group, it spoke an international language more compelling than sport.
The Second Annual Symposium of the Giovanni Armenise-Harvard Foundation, whose first program was held in Chatham on June 22 and 23, brought together foundation-sponsored investigators for two intense days of lectures, poster presentations, and networking. Sessions centered on neurobiology, cell membrane traffic, gene transcription, cell signaling and cycling, and plant defense and pathogenesis. Although each presentation was tightly focused and highly specialized, the underlying goal was always the same: to find patterns that hold true for different types of cells, tissues, and organisms.
Italian plant biologists Guilia De Lorenzo (left) and Felice Cervone are studying a family of proteins that seem to be involved in plant immune function.
For example, the scatter factors described by Paolo Comoglio, of the Institute for Cancer Research in Turin, are needed for development of many types of tissue. In mammalian embryos, they control branched morphogenesis--in which cells break away, migrate, become polarized, and form tubules--in normal tissues including nerve, muscle, blood vessels, and bone. Additionally, Comoglio's lab has demonstrated that certain point mutations in these specialized factors can transform healthy growth into malignancy, showing that they play a role in pathogenesis, as well.
In a presentation that helped explain the workings of whole organisms rather than tissues, Charles Weitz, assistant professor of neurobiology at HMS, described the molecular mechanisms of endogenous, self-sustaining clocks that have been found in everything from bacteria and fungi to plants, invertebrates, and humans. Only a year ago, researchers at Northwestern University identified the first mammalian circadian gene. Weitz and his HMS colleagues have since found that this gene's protein, CLOCK, forms a heterodimer with a second protein, BMAL1, to turn on a well-known circadian gene called per.
Further experiments indicate that teamwork is the key. Together, CLOCK and BMAL1 have 10 to 15 times the transcription activity of either protein acting alone. Now that it is clear that these two proteins turn on per, Weitz said, the next challenge is to figure out what turns the gene off during normal circadian rhythms.
Speakers at a session on plant defense and pathogenesis took an even broader view, blurring traditional boundaries by demonstrating that the animal and plant kingdoms are more alike, in at least some regards, than previously thought. Frederick Ausubel, professor of genetics at HMS and MGH, described how novel pathogens made in his lab can cause disease in certain model plants, flies, nematodes, and mice. Strains that are especially virulent in plants, Ausubel said, are often even more pathogenic in animals. Felice Cervone and Giulia De Lorenzo, plant biologists from the University of Rome, made the case that plants, like animals, readily identify nonself molecules that may pose a threat to them. The scientists are investigating a family of proteins that appear to have immunologic functions in plants.
At HMS, the Armenise-Harvard science centers are in cell signal transduction, directed by Marc Kirschner; structural biology, directed by Stephen Harrison; neurobiology, directed by Gerald Fischbach; and human cancer viruses, directed by Peter Howley. Programs in plant biology are directed by Frederick Ausubel at MGH.
--Patricia Thomas
Children's Hospital has announced that Stephen Laverty will become its next president and chief operating officer, succeeding David Weiner, who will step down from these positions but continue as chief executive officer. Laverty will assume his new role in the fall.
Weiner said that the completion of the search "is a crucial element in our plan to advance Children's mission into the future. Steve's arrival will enable me to provide more focused leadership for the broad-based child health care system we are building."
For the past six years, Laverty has been the president and chief executive officer of Winchester Hospital, which he joined in 1985. Previously, he directed financial services and budget planning at Milton Hospital, St. Elizabeth's Hospital, and Brigham and Women's.
Weiner pointed to the affiliation between Children's and Winchester Hospital as a chance to have gotten to know Laverty personally. "He has clearly demonstrated his deep commitment to excellence in care delivery and to the health and well-being of children and families," Weiner said.
These faculty members were appointed to a full professorship in June.
Graham Colditz
Professor of Medicine
Brigham and Women's Hospital
Colditz, director of chronic disease epidemiology at the Channing Laboratory, studies lifestyle and prevention of chronic diseases. He has studied hormone therapy and risk of breast cancer in postmenopausal women, physical activity and its relation to cancer risk, and adult weight change in relation to diabetes and hypertension. He also studies diet and activity in relation to weight gain among adolescents.
Tucker Collins
Professor of Pathology
Brigham and Women's Hospital
Collins is a pathologist interested in the role of specific types of transcription factors in vascular disease. His research has focused on nuclear factor-kappa B and its role in the inflammatory cytokine-induced expression of the endothelial-leukocyte adhesion molecules. His group also studies the transcription factors regulating expression of platelet-derived growth factor in the vessel wall.
Patricia D'Amore
Professor of Ophthalmology
Schepens Eye Research Institute
D'Amore's laboratory focuses on understanding the mechanisms that regulate vascular development and growth control. D'Amore uses tissue culture models and mouse genetics to investigate the role and regulation of polypeptide growth factors and intercellular interactions in the processes of vasculogenesis and angiogenesis.
George Taylor
Professor of Radiology
Children's Hospital
Taylor is director of the Kresge Laboratory for Pediatric Imaging Research and chief of the Division of Body Imaging at Children's Hospital. His clinical research interests include the role of imaging in intermediate outcomes and initial decision-making in blunt abdominal trauma. His current laboratory work focuses on developing ultrasound contrast agents for potential quantification of blood flow in various tissues.
These full professors were appointed to an endowed or distinguished chair.
Richard Kitz
Henry Isaiah Dorr Distinguished
Professor of Research and Teaching in Anaesthetics and Anaesthesia
Massachusetts General Hospital
Kitz's major research interests include the design, synthesis, and testing of novel compounds used as molecular probes and drugs, such as anticholinesterases and short-acting, nondepolarizing neuromuscular blocking agents. He also is interested in patient safety, standards of anesthetic care, and the economics of medical care in the United States.
Edward Lowenstein
Henry Isaiah Dorr Professor
of Research and Teaching in Anaesthetics and Anaesthesia
Massachusetts
General Hospital
Lowenstein, provost in the MGH Department of Anesthesia and Critical Care and former BID anesthetist in chief, is a cardiac anesthesiologist who is particularly recognized for pioneering opioid anesthesia and developing principles for safely anesthetizing patients with coronary artery disease for surgery. His recent research is in coronary and pulmonary microvascular reactivity. From 1997 to '98, he served as the first senior fellow in the HMS Division of Medical Ethics, conducting activities to gain additional insight into the moral issues surrounding end-of-life care.
Stephen H. Robinson, the George C. Reisman professor of medicine
at BID, died on May 27 at age 65.
Robinson was born and raised in Brooklyn, N.Y. He graduated from Harvard College in 1954 and Harvard Medical School in 1958. He did his internship and residency at the Harvard Medical Service of Boston City Hospital, where he worked under William B. Castle. After appointments at the National Institutes of Health and the University of Chicago, he returned to the Harvard community in 1965. Over the course of 30 years, he was chief of hematology, clinical director of the Department of Internal Medicine, and codirector of the oncology and hematology training program for postdoctoral studies at BID.
Robinson was the first master of the William B. Castle Society at HMS, which was formed in 1987. He was a proponent of the New Pathway method of education, stressing small-group, self-directed learning and medical societies as a means of establishing long-term relationships among students and faculty.
As a researcher, Robinson investigated how bile and blood cells form in the human body and how normal blood cells can recover from toxic side effects of leukemic-cell targeted chemotherapy.
He leaves his wife, Carole (Latter); two daughters, Lisa Swanson of Mill Valley, Calif., and Susan Robinson Scheer of Arlington, Va.; a son, Michael, of New York City; a sister, Sheila Scher of Cedarhurst, N. Y.; and three grandchildren.
* R. Heather Palmer, lecturer on health services at HSPH, received a grant of $2,449,037 for a study on how to better diagnose jaundice in newborns. Jeffrey N. Katz, associate professor of medicine at BWH, received a two-year $472,306 grant for a study on the quality of hip replacements. Both grants are from the Agency for Health Care Policy and Research of the U.S. Department of Health and Human Services.
* Judah Folkman, the Julia Dyckman Andrus professor of pediatric surgery at Children's and professor of anatomy and cell biology, will be awarded the Charles A. Dana Foundation's Distinguished Achievement Award in October for his "innovative lifetime work in cancer research." The award carries an honorarium of $50,000 which may be donated to any nonprofit organization Folkman chooses.
* Theo Manschreck, clinical professor of psychiatry at the Brockton Veterans Administration Hospital and medical director of the Dr. John C. Corrigan Mental Health Center in Fall River, received the Third Annual Rothstein Award from the Alliance for the Mentally Ill of Massachusetts in May. The award is presented to a psychiatrist "whose compassion and dedication advances clinical psychiatry and the treatment and care of persons with serious mental illness." Manschreck's major research involves schizophrenic disorders and psychosis, including genetic markers, neurology, memory mechanisms and cognition, speech disturbance, and imaging.
* Alan M. Harvey, instructor in anesthesia at BWH, was reelected to a second term as Speaker of the House of Delegates of the Massachusetts Medical Society on May 7. The House of Delegates is the legislative and policy-making body of the society. Harvey has been a member of the society's executive board since 1994, and also serves as an alternate delegate to the AMA.
* Yashika Dooley, '00, Erica Marsh, '00, and Alfredo Hinojosa Quiñones, '99, have been selected as 1998 Academic Medicine Fellows by Bristol-Myers Squibb Company and the National Medical Fellowships Inc. Each fellowship award is $6,000. Fellowships will take place over an eight- to twelve-week period this summer, or as an elective rotation of equal length in the 1998-99 academic year, and include a three-day research symposium in Princeton, New Jersey.
* Dan Calac, '99, is one of eight fellows selected for the 1998 Arthur Ashe Program in AIDS Care, sponsored by the National Medical Fellowships Inc. He is recognized for "his potential for a responsible role in HIV related care and research." The fellowship award is $6,000, which he will use for a one month rotation at the Harvard AIDS Institute in October 1998. Calac also received a $10,000 fellowship from the Massachusetts Medical Society for his academic achievement and his commitment to public service. He is active in the Four Directions Summer Program, a student-run project that brings Native American undergraduates to Harvard for eight weeks to perform research, shadow physicians, and meet Native American medical students.
* Constance Cepko, HMS professor of genetics, is one of 147 new members elected to the American Academy of Arts and Sciences in April. The only new member from the HMS community, Cepko joins approximately 4,000 fellows nationwide who have been recognized for their contributions to sciences, scholarship, public affairs, and the arts.
* Tucker Collins, professor of pathology at Brigham and Women's Hospital, received an honorary Doctor of Science degree from Amherst College at its commencement ceremony on May 24. The award recognized him as "a pioneer in the field of vascular biology," who has contributed to the treatment of atherosclerosis, thrombosis, and hypertension. Collins graduated from Amherst in 1975.
Other Administrative Appointments Are Moving Forward
inda Thomas, a cell biologist, began as the new assistant dean for academic programs on July 6. Working with Dennis Kasper, executive dean for academic programs, she will facilitate academic projects across the entire HMS faculty.
Thomas came to HMS from NIH where she served as director of the inherited diseases and disorders program at the National Institute of Dental Research. She began work at NIH as a postdoctoral researcher after receiving her PhD from UCSF in 1990.
"Dr. Thomas combines outstanding training and experience in bench science with extensive administrative skills," wrote Kasper in a letter announcing her arrival.
"I see my role as expanding access to the office of the academic dean and helping to make sure projects move forward smoothly and as rapidly as is appropriate," said Thomas.
In other administrative recruitments, Dean Joseph B. Martin has begun
a national search for a new executive dean for administration, a position
that will combine some of the duties previously held by David Bray and John
Deeley, both of whom have announced plans to take new positions this year.
Deeley will become the vice dean for administration at NYU Medical School
in September and Bray is expanding his academic medicine consulting work.
Martin also announced that candidates have been identified and are being
interviewed for the new dean for research, who will foster collaboration,
industry partnerships, and other aspects of the research enterprise.
--Don Gibbons
Genetics is the key to understanding the role that coat proteins play in sorting and packaging protein cargo for transport, said Randy Schekman, chair of the Department of Molecular and Cell Biology at the University of California, Berkeley, during the biennial Fawcett Lecture at HMS on May 28.
Following an introduction by Marc Kirschner, head of the HMS Department of Cell Biology, Schekman reviewed the research leading up to his recent work with COPII, a protein that drives vesicle formation.
Schekman studies protein secretion in test tubes, reconstituting the elements of the budding reaction in the yeast Saccharomyces cerevisiae to see how vesicles dock, fuse, and deliver their proteins.
"I figured one way to really solve the problem would be a cell-free system," he said. "My conviction is that biochemistry is an important follow through to cell biology and that it is possible to combine yeast genetics and biochemistry to study membrane traffic."
Along with his colleagues at Berkeley, Schekman was the first to recognize that the secretory process could be dissected using S. cerevisiae as a model. He developed yeast that were defective for a set of genes called sec, which are required for protein transport. These genes could be turned on and off by altering the temperature, thereby stopping at will the transport of proteins from the cytosol into the endoplasmic reticulum, the sorting of proteins within the Golgi, and the transport of secretory vesicles to the plasma membrane.
Understanding the role of coat proteins may provide insight into some human diseases, Schekman said. For example, he is interested in proteins associated with Alzheimer's disease, because the amyloid plaques that accumulate outside nerve cells may be secreted unnecessarily, causing brain degeneration.
--Cassie Ferguson
So what do you plan to do after you graduate? I must have been asked this question by friends and family nearly as many times as the old reliable, When will you be done with school? and the ubiquitous, What exactly is it that you do? At one time, I had a quick and easy response. Like most other students in my program, I planned to teach and do research in academia. Over the past four years, however, my interests and goals have gradually changed, and I find myself exploring other options.
For many, an alternate career may seem more attractive once they realize just how long it takes to get a permanent academic position. After four years of college and five years or more of graduate school, students are expected to complete at least one post-doc for three years or more. After finishing this educational marathon, there is certainly no guarantee of finding a tenure-track academic position. Even those who do get jobs at colleges and universities may face years of scrounging for funds and racing to publish in hopes of getting tenure.
My fellow students and I began graduate school well aware of the monumental task before us. Many have put off attaining financial security and starting a family in favor of pursuing their careers. I have watched my college friends get married, have children, buy cars and homes, and even save for the future while I struggle just to pay the rent. After eight years of higher education, I may well be 10 years away from any real job security in academia. Like a growing number of my classmates, I have started to question whether the long and difficult years ahead will be worth reaching that pinnacle of academe, a tenured professorship.
A few years ago, such musings would be considered heresy. It was taboo for PhDs in science to abandon the hallowed halls of colleges and universities to pursue a nontraditional occupation. Today, nearly everyone I talk to from my class has at least considered doing just that. The BBS program has even sponsored forums for graduate students to make contacts in a variety of other fields including business and industry, journalism, law, education, and public policy. The American Association for the Advancement of Science (AAAS) has a new Web site (http://www.nextwave.org) devoted in part to promoting alternate careers for scientists. AAAS also sponsors several fellowships designed to give graduate students in science experiences in other fields.
We Need Choices
For students to successfully colonize new niches, major changes should be made in faculty attitudes and graduate school training. Advisers should accept that not everyone wants to follow in their footsteps and that students need experiences outside of the lab if they are to embark on an alternate path. The curriculum should change to reflect the interests of graduate students, including courses to introduce basic concepts in business, science writing, education, and law. If Harvard wishes for its graduate programs to remain competitive in the future, there must be a greater focus on ensuring that students will be adequately prepared for the job market in the real world.
When I asked my adviser about the nine years she spent doing two post-doctoral fellowships, she simply remarked, "I loved it!" It occurred to me that in all likelihood, I would never be able to say that about academic research. While I appreciate the education I have received--and I certainly don't regret coming to graduate school--I realize that my future has to be quite different from the path my adviser chose if I am to be happy. I can only hope that someday I will be as satisfied with my career as she is with hers.
--Robin Lucas
Robin Lucas is an HMS graduate student in the BBS microbiology program.
Calendar Deadlines: Focus normally appears every other Friday, with some variation for holidays and summer. The calendar in each standard issue includes events in the two-week period beginning the Wednesday after the Friday issue date. The deadline for calendar submissions is Wednesday of the week before the issue date. This means that the deadline for submission is two to four weeks before the event. Sorry, we cannot accept any submissions that come in after the deadline. If you would like to receive submission information, leave your request and fax number at 432-1592. The next Focus deadline is July 8.
Key to Institutions:
BBRI-Boston Biomed. Rsrch. Inst.
BIDE-Beth Israel Deaconess/East
Campus
BIDW-Beth Israel Deaconess/West Campus
BWH-Brigham
& Women's Hosp.
BVA-Brockton Veterans Administration
CBR-Center for Blood Research
CAM-Cambridge Hosp.
CH-Children's Hosp.
DFCI-Dana-Farber Cancer Inst.
FDC-Forsyth Dental Ctr.
HMS-Harvard Medical School
HIM-Harvard Insts. of Medicine
HSDM-Harvard School
of Dental Medicine
HSPH-Harvard School of Public Health
HU-Harvard University
JBCC-Judge Baker Children's
Ctr.
JDC-Joslin Diabetes Ctr.
MTA-Mt. Auburn
Hosp.
MEEI-Mass. Eye & Ear Infirmary
MGH-Mass.
General Hosp.
MGHE-Mass. General Hosp. East
MH-McLean
Hosp.
MMHC-Mass. Mental Health Ctr.
SBI-Shriners
Burns Inst.
SERI-Schepens Eye Research Inst.
SRH-Spaulding
Rehab. Hosp.
WRVA-West Roxbury VA
The Office of Admissions will be giving tours of the Medical School on
these dates (registration is required): Mon. July 27 and Mon. Aug. 10
To obtain reg. info., visit the admissions Web site at: http://www.hms.harvard.edu/admissions/tours/schedule/index.html
Wednesday, July 22
Anesthesiology Grand Rounds
Reginald Weissglas, Mack Griffith,
Stephen Houser, Vimal Akhouri, Stephanie Kaplan, Matthew Vo, BID
Medical Jeopardy
7:00-8:45 am, Sherman Aud., BIDE
Surgery Grand Rounds Michael Stone, BID Role of Axillary Dissection in Breast Cancer 8:15 am, Kennedy Bldg, Rm. G2A, BIDW
Medicine Grand Rounds Ellen Elias, CH Mira Irons, CH Smith-Lemli-Opitz Syndrome: A Disorder of Cholesterol Metabolism 12:00 pm, Enders Aud., CH
Thursday, July 23
Anesthesiology Grand Rounds Thomas Stossel, BWH Can Research on How Cells Crawl Be Helpful in ARDS 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Anesthesiology Lecture Series David Sutcliffe, BID ASA Legislative Activities 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Tuesday, July 28
Gastroenterology Research Seminar Richard Blumberg, BWH Lymphocyte-Epithelial Cell Interactions in the Intestine: An Update 4:30-5:15 pm, Jackson 7, G.I. Unit Lib., MGH
Gastroenterology Grand Rounds Mark Ott, MGH Management of Retroperitoneal Sarcomas 11:00 am-12:00 pm, Blake 4, Isselbacher Lib., MGH
Wednesday, July 29
Anesthesiology Grand Rounds
Jennifer Elliott, Andy Bucholz,
John Makrides, Chris Quartararo, BID
DEBATE: Continuous Bispectral
Analysis Should Become a Standard Monitoring Technique
7:00-8:45
am, Sherman Aud., BIDESurgery Grand Rounds David Rattner, MGH Acute Pancreatitis
8:15 am, Kennedy Bldg., Rm. G2A, BIDW
Medicine Grand Rounds Robert C. Moellering, Jr., BID Antibiotic Resistance: A Modern Plague 12:00 pm, Enders Aud., CH
Thursday, July 30
Anesthesiology Grand Rounds Thomas Gutheil, MMHC The Physician-Patient Alliance 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Anesthesiology Lecture Series Mary Ann Vann, BID Ambulatory Anesthesia 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Wednesday, August 5
Anesthesiology Grand Rounds Frances McGowan, CH Inflammatory Reactions to Cardiopulmonary Bypass 7:00-8:45 am, Sherman Aud., BIDE
Thursday, August 6
Anesthesiology Lecture Series Charles Nargozian, CH Pediatric Airway Problems in Adult Patients 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Thursday, August 13
Anesthesiology Grand Rounds Eugene Orringer, U.N.C. Preoperative Assessment of the Sickle Cell Patient 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Anesthesiology Lecture Series David Calcagni, BID Fiberoptic Intubations 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Focus
A Publication
of HMS Office of Public Affairs
Harvard Medical School, Office of Public Affairs
25 Shattuck Street, Room 001, Boston, MA 02115
Tel: 617/432-1589, Fax: 617/432-0089
E-mail: Focus@hms.harvard.edu
Editor
Robert Neal
Senior Science Writer
Misia Landau
Science Writer
Gabrielle Strobel
Production Manager
Suzanne Clifford
Assistant Editor
Tiffany Doyle
Copy Editor
Tom Reynolds
Photography:
Graham Ramsay (Young and Lucas photos)