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Cancer Biology
Drugs that successfully carve away at cancers of the lung, brain, breast, and other organs could be acting as double-edged swords, according to a new study by Harvard Medical School researchers. As solid tumors shrink, so do the microscopic pores in the blood vessels surrounding the tumors--to such an extent that some tumor-killing agents may no longer be able to squeeze through vessel walls to reach their targets.
In addition, first-time therapies may fail because therapeutic agents are too bulky to pass through the blood vessel pores in the first place. The study, which appears in the April 14 Proceedings of the National Academy of Sciences, is the first to measure the size of the pores that line the blood vessels surrounding a variety of solid tumors. The findings suggest a fundamental change in approach to cancer therapy.
Rakesh Jain believes paying attention to the size of drug agents could lead to more effective cancer therapies.
Rakesh Jain, the A. Werk Cook professor of radiation oncology at Massachusetts General Hospital, and his colleagues grew six different cancers in immune-deficient mice and measured pore size of surrounding blood vessels. The one human and five mouse cancers were grown at various places inside the mouse's body to mimic metastasis. To see what happens as tumors shrink, the researchers cut off hormones to hormone-dependent tumors.
Not only did pore size vary among the six tumor types--for example, mouse breast tumors had much bigger openings than mouse liver cancers--it varied among sites within the same tumor. Solid tumors often contained a mixture of bigger and smaller openings.
Pore size also varied depending on where the cells grew. Breast tumors grown in the brain, for example, had blood vessels with much smaller pores than did tumors grown under the skin. Pore size was also greatly reduced in the shrunken hormone-dependent tumors. In fact, withdrawal of testosterone resulted in a reduction of pore size from 200 nanometers (nm) to less than 7 nm within 48 hours in a testosterone-dependent tumor.
"So that tells you that you just can't make a drug and expect it to work on all tumors," says Jain. Sue Hobbs and Wayne Monsky, an MD-PhD student and postdoctoral fellow in Jain's lab, are lead authors on the paper.
Therapy that Beats Itself
The findings cast new light on some old cancer puzzles. One of these has been to understand why anticancer agents that look so good in the petri dish fail when it comes to killing cancer cells in the body. The new findings suggest such promising drugs may never get a chance to prove their cancer-killing powers because they have been engineered too large for the microscopic doors they have to pass through.
Equally perplexing has been watching chemotherapies succeed only to fail after a few rounds. Many have chalked up these failures to the development of resistance--occurring when successive rounds of chemotherapy allow impervious mutants to gain a foothold. "You can't talk about multidrug resistance if you can't get the drugs into the tumor," says Jain. He believes there is another explanation for such disappointing results: chemotherapeutic agents may, by shrinking tumors, be shrinking blood vessel pores--in effect, closing the door behind them.
Even before they get to carry out their death-dealing
mission, anticancer agents (1) face enormous obstacles. First, they must
make their way into and through the thicket of blood vessels surrounding
tumor cells. Next, they must shimmy through the blood vessel walls (2) and
into the tumor itself, where they encounter enormous pressure gradients
that stymie movement (3). To complete their task, drugs must disperse in
concentrations high enough to kill every cancerous cell. Jain and his colleagues
have revealed blood vessel pores are highly variable in size, making it
difficult for some drugs to get into the tumor (black arrows). Those agents
that do get in and shrink tumors may thwart later drug assaults. When tumors
shrink, blood vessel pores also contract, making it impossible for subsequent
anticancer agents to get into the tumor.
What this means is that drug makers must not only design agents that get through a variety of microscopic doors, they must also think about aiming their drugs at a moving target--blood vessel pores that change in size over the course of treatment. Yet drug companies have been taking a one-size-fits-all approach. In the area of gene therapy, the trend has been to design bigger and more impressive molecules.
"The public, investors, the government are so enamored of the sophisticated new gene therapies. They're looking at these Mercedes and Lamborghinis. But they don't ask--can these new therapies get through the doorway?" says Jain.
Shimmying through shrinking blood vessel pores is just one of many challenges facing drug agents. Ten years ago, Jain showed that just getting into the blood supply surrounding the tumors is a difficult task. "Nobody had measured resistance to blood flow in tumor vessels before. It was like walking into a wide open field," he says. Rather than a neat and orderly array, Jain and his colleagues showed that the capillaries, arteries, and veins surrounding tumors are a jumbled mass--thick in some areas and pinched in others. And to make navigation even more difficult, the blood flowing through them is highly viscous--more like sludge than water.
Blood vessels surrounding tumors are also known to be very leaky in some areas though not in others. It was only recently with the development of his immune-deficient mouse model that Jain was able to grow enough kinds of tumors to tackle the question of blood vessel pores systematically. He and his colleagues injected fluorescently labeled particles of increasing size in the blood vessels of the six tumors at various locations and watched to see which ones got out. They used the same approach to see the effects of tumor shrinkage.
Even if drugs are designed that can get through pores, they will face an uphill battle once they get inside a tumor. The pressure exerted by the material surrounding tumor cells, called the interstitium, is enormous, as Jain and his colleagues have recently shown. Jain believes that there are ways around such obstacles. For example, it may be possible to lower pressure by draining the interstitium inside tumors. In fact, Jain and his colleagues are currently working on such a tumor drain. "We are trying to understand and modify the barriers more and more," he says.
--Misia Landau
With Combination Drug Therapy Failing for Some,
Scientists Move Experimental Gene Therapy into
the Clinic
In 1988, Wayne Marasco began to pursue the notion that a treatment for AIDS could be found by ambushing HIV in its hideaway inside immune cells.
Curiously, the HMS assistant professor of medicine at the Dana- Farber Cancer Institute wanted to do so with antibodies--proteins that the immune system dispatches into the bloodstream to fight HIV but that were commonly thought to be useless once HIV had infected and burrowed inside the system's T cells. Now, a decade later, Marasco is getting ready to test this idea in humans.
Over the past ten years, Wayne Marasco has conducted the basic research undergirding an upcoming gene therapy trial to be conducted jointly at two Harvard-affiliated hospitals.
This fall, he will codirect the first AIDS gene therapy trial of his "intrabody" approach, for which he engineered a T cell-generated antibody whose purpose is to cripple HIV inside the T cells.
Also heading the trial will be Martin Hirsch, HMS professor of medicine at Massachusetts General Hospital and an expert in HIV combination drug therapy.
The trial comes amid revived interest in gene therapy for AIDS. As research accumulates about the limitations of combination therapy, physicians are asking what tools research will hand them next to treat their patients. "We still need better therapies than we have today," says Hirsch. "Triple drug regimens are no cure for HIV infection."
For example, a trial Hirsch recently completed shows he cannot safely simplify the cumbersome drug regimen after six months of treatment, suggesting that patients permanently have to take the full drug combination. Moreover, triple-drug therapy works in only half the patients who start it long after infection, he says. Patients who took single drugs before switching to a triple-drug regimen also respond poorly.
To be sure, gene therapy for AIDS is still a long way off. Staggering technical and financial hurdles stand in the way of turning any gene therapy approach into standard treatment. But this trial is one of several approaches in early clinical stages across the country and, if promising, may become an adjuvant therapy that could benefit some patients.
The trial aims to achieve "intracellular immunization," a term coined by Nobel laureate David Baltimore, who now heads a national effort to create an HIV vaccine. The theory sounds simple: add genes to T cells to make them resistant to HIV and infuse them into patients periodically. The devil was in the details.
Marasco started by reengineering antibodies that specifically recognized gp120, an HIV coat protein and a focus of AIDS research at the time. He retained the gene encoding the recognition part of the antibody and combined it with other genes that would allow this new protein--the intrabody--to be expressed inside T cells. Normally, only B cells make antibodies, and they dump them into the bloodstream or display them on their surface.
In 1993, Marasco was the first to show that one could get a functional intrabody to block a protein inside a cell. By 1995, he knew that his intrabody could indeed inhibit HIV replication in human CD4 T cells, the primary target of HIV. But just as he received approval to conduct a clinical trial, he decided to forgo this first opportunity.
More Bang for the Buck
Why? Parallel work on another HIV protein hinted he should switch targets. His and other research showed that therapies directed against a small regulatory protein called tat might thwart HIV more effectively because it helps spread the infection in several key ways. Primarily, it boosts the transcription of HIV proteins in infected cells. But tat also leaves the cell and enters other infected cells, where it can jolt a dormant virus into replicating. Tat even makes uninfected cells more prone to infection, and it dampens the body's immune response. "I think tat is a great target," says Marasco.
Last month, Marasco, first author Mark Poznansky of Imperial College School of Medicine in London, and their colleagues published in Human Gene Therapy experiments that pave the way for the upcoming trial. The scientists inserted the gene for the anti-tat intrabody into CD4 cells taken from the blood of people at different stages of HIV infection. They found the intrabody was expressed in up to 30 percent of the cells, and it strongly inhibited HIV replication. It also protected lymphocytes from healthy volunteers against subsequent HIV assaults.
This paper shows the three-year detour paid off: the anti-tat intrabody blocked HIV replication better than did its anti-gp120 cousin. This may be because the intrabody hurts tat at several levels (see diagram.) It keeps tat out of the nucleus, where it would enhance transcription; it clogs tat's active site; and it feeds tat into the cell's protein-mincing degradation machinery.
T Cells Strike Back: HIV's tat protein spreads the infection by boosting viral replication. To do that, tat needs to move from the cytoplasm, where it is made, into the nucleus (see box.) With the intrabody approach--a kind of gene therapy soon to be tested in humans--scientists hope to keep tat out of the nucleus (1), to disable any tat molecules that do get in by gumming up their active site (2), and to destroy tat in the cell's protein degradation machine, the proteasome (3). The upcoming trial is one of several ongoing attempts at "immunizing" individual T cells so they can ward off HIV.
In another, still unpublished, study, Marasco addresses a potential complication that generally plagues protein therapies: the patient might mount an immune reaction against the intrabody, which was originally a mouse protein. Marasco's team clipped off the small region binding to tat, and replaced all remaining areas needed for a complete intrabody with highly conserved human genes, hoping this version will pass as a "self" protein. Still, a cytotoxic reaction remains a concern. "It would really limit the overall usefulness of this approach," Marasco says.
The Intrabody Trial
The phase I trial will enroll 10 AIDS patients whose triple-drug therapy is failing. At DFCI, scientists will remove some of patients' lymphocytes, insert the intrabody gene and a marker gene and multiply the cells. At MGH, they will then reinfuse them and track their fate over time.
The volunteers are unlikely to benefit from this trial, which is primarily designed to establish safety. But it will tell the researchers if the intrabody gene is expressed and if it helps the engineered cells survive and multiply--and it might just show a slight effect on viral load and CD4 counts.
Moreover, Marasco hopes that promising trials will revive the pharmaceutical industry's interest in tat as a drug target. Years ago, experimental drugs against tat outperformed, in vitro, experimental drugs against the HIV proteins reverse transcriptase and protease, which have since entered the market. But inexplicably, these anti-tat drugs proved useless in vivo, and the companies shelved the projects.
Meanwhile, his group is collaborating with David Scadden, associate professor of medicine at the MGH Cancer Center, to lay the groundwork for the next clinical step. They are experimenting with slipping the gene into immature lymphocyte precursors, which could, in theory, yield a lifelong supply of the resistant cells. Initial data with stem cells from human umbilical cord blood look promising, Marasco says.
Now that his idea has reached a critical juncture, Marasco often thinks about the seemingly glacial pace of science, especially during years spent eliminating all foreseeable bugs."Being so close is a rewarding feeling," he says. "This is something we took from theory through the basic science to an experimental therapeutic. This is how long it takes."
--Gabrielle Strobel
Phages To Flaunt 10 Billion Human
Antibodies at Dana-FarberThe first human gene therapy trial for the so-called "intrabody" approach (see main story) is but one fruit of the years of painstaking research Wayne Marasco has
invested into manipulating antibody genes. He is now spinning off his expertise into a project that will benefit researchers at DFCI and the wider Harvard community.
Scientists searching for specific human antibodies as future therapeutic agents or research tools will be able to screen their favorite protein--be it a target involved in infectious, autoimmune, or inflammatory disease, or a tumor antigen--against 10 billion human antibodies. These will be displayed by phages--viruses infecting bacteria--into which Marasco has cloned antibody genes isolated from 52 human volunteers.
Phage library technology is quickly finding use in biotech and pharmaceutical companies as a novel way of fingering the elusive one-in-a-million compound that binds strongly and specifically to a protein of interest. Called the DFCI Human Antibody Phage Display Core Facility, the service is expected to be operational by late summer.
In the Cardiovascular Research Center at MGH there lives a mutant zebrafish called Santa, named for its big heart. Mark Fishman, professor of medicine at MGH, also has mutant zebrafish strains called Bonnie and Clyde and Slow Mo, named for their twin hearts and slow-beating heart. He even has one line nicknamed the Harvard mutant, in which each heart cell beats independently and "no cell talks to anyone else."
These mutant fish are part of a multinational project aimed at using the zebrafish (Danio rerio), as a model for early vertebrate development. Fishman and Leonard Zon, associate professor of pediatrics at Children's Hospital, described their zebrafish work at a March 2627 meeting in Boston that showcased the role of developmental biology and model organisms in identifying new targets for human drug therapies. In the April issue of Nature Genetics they also report separate investigations into the zebrafish genome.
Fishman's MGH group and Zon's team at Children's constitute one of the world's leading centers in zebrafish research. Other major players include scientists at the University of Oregon, where zebrafish genetics was first explored, and researchers at the Max Planck Institute in Tübingen, Germany, led by Nobel laureate Christiane Nüsslein-Volhard, who created thousands of zebrafish mutants.
The fish men: Mark Fishman and Leonard Zon study
thousands
of zebrafish to learn about organ and blood
development
in vertebrates.
Fishman's specialty is the cardiovascular system. You can see every cell in the heart of a living zebrafish embryo, he says, which is essentially identical to that of a human three weeks after conception. Through analysis of defects in the heart and blood vessels of these small fish, he hopes to learn the source of similar abnormalities in human patients. The Slow Mo mutant, for instance, has a problem similar to people whose heart beats too slowly. When lab members studied the fish they found that a single ion current was missing. "That particular current, referred to as Ih, is one that we now believe is the real pacemaking current of the heart," says Fishman. Cardiac valve defects, in which blood trickles against the flow generated by the pumping heart, are also seen in both mutant zebrafish and human cardiology patients.
Over at Children's, Zon houses 40,000 zebrafish in his lab. "You can tell him I've got fish envy," he quips, referring to the 300,000 zebrafish swimming in Fishman's tanks at MGH. Members of Zon's lab study hematopoiesis--how blood cells form and develop. "We have mutants covering the entire spectrum, from the earliest stem cell all the way to the terminally differentiated red cell," says Zon. They even have one with the fish equivalent of thalassemia--a type of human red cell disorder caused by abnormal production of hemoglobin.
Zebrafish are a model for early embryonic development in vertebrates. In a normal or wild type (wt) two-day-old embryo, the heart and blood vessels stain darkly with the marker flk1. Lack of staining in the Cloche mutant (mut) indicates a defective gene essential for early formation of blood vessels and the inner lining of the heart.
But why are researchers so interested in the inner workings of this small fish--more familiar as a resident of home aquariums than a crusader for biomedical research? Though much has been learned about early animal development through study of mutant fruit flies, scientists need appropriate model organisms to learn about the organs and systems specific to humans and other vertebrates. A combination of attributes made the zebrafish a winning candidate.
In contrast to other vertebrate models such as frogs and chickens, zebrafish have short generation times and limited housing requirements. Unlike mice, the embryos develop in a completely transparent egg, not in the mother's uterus, and hundreds of eggs are produced from a single mating. Previous genetic studies in zebrafish gave it a head start over other small fishes that are also prolific breeders with transparent embryos.
In 1992, Fishman's group in Boston and Nüsslein-Volhard's group in Germany set up mutagenesis screens to produce thousands of zebrafish offspring, each carrying a different mutation. By analyzing the embryos produced by the mutants' grandchildren, they could see what ill-effects they had wrought.
Producing, isolating, and characterizing the mutant fish took three years, and the results of these first screens filled the entire December 1996 issue of the journal Development. Identifying and isolating the gene or genes responsible for each defect was the next problem. Studying the phenotype of a mutation--how the organism looks and behaves--advances understanding about the biological defect, but it will not lead to therapy for human abnormalities unless the gene is identified, says Fishman. This is where the two new publications in Nature Genetics fit in.
Fishman and a team of researchers at MGH constructed a complete map of the zebrafish genome using DNA markers that vary between different individuals. The map is "a fantastic service to the community," says Zon. He likens a genome map to a map of the United States. "In the zebrafish, without a map it's like walking from New York to L.A. and looking for that gene; somewhere in between is the mutation of interest that's causing a zebrafish disease," he says. The markers act like DNA reference points--small towns between New York and L.A.--from which a more intensive search for the candidate gene can begin.
The publication by Zon and his collaborators used a different genomic map to broadly compare the zebrafish and mammalian genomes, including that of humans. The genome comparison facilitates what Zon calls "genomic ping-ponging" where scientists go back and forth between different species, using the information from one to fill gaps in the other.
With a bevy of mutant zebrafish available and maps in hand, scientists are on their way toward finding the defective genes. The goal of reversing mutations and devising treatments for human defects and disorders can then begin in earnest.
--Kristin Weidenbach
Zinc is indispensable to life--essential to catalysis, growth, cell division, differentiation, expression of the genetic message, and signal transduction in all phyla and species. Neural and cerebral function critically depend on it.
Forty years ago, Bert L. Vallee, the Edgar M. Bronfman senior distinguished professor, discovered metallothionein (MT), a zinc protein that now has been revealed to be central to the function of zinc. Chemically inert, zinc is affected neither by oxidation nor reduction. MT seems to be the master switch that turns on zinc to make it metabolically active, as has now been demonstrated in a trio of papers that appear in the March 31 issue of Proceedings of the National Academy of Sciences, co-authored by Vallee, Wolfgang Maret, assistant professor of biochemistry, and coworkers at the Center for Biochemical and Biophysical Sciences and Medicine.
By all counts, MT is a most unconventional protein. It usually contains seven zinc atoms, each of which is bound to four cysteine sulfurs in a previously unknown cluster structure. This structure forms a network of zinc-sulfur interactions that have no precedent in the nonliving world. The protein envelops the zinc atoms in a manner that effectively shields them from the environment and arranges them in two clusters. It binds zinc very tightly yet leaves it mobile, so it can move in and out rapidly--another phenomenon not seen before. These PNAS reports show that the cluster unit works by a novel mechanism, which allows the cysteine sulfur ligands to zinc to be oxidized and reduced--allowing an oxidoreductive mechanism to modulate affinity of the otherwise inert zinc atom. It follows that zinc mobility in living cells is changed by the oxidation-reduction state of the cell. This mechanism of action is an entirely new concept for the structure-function relationships of a metalloprotein.
The findings have far reaching impact on pathogenic mechanisms, since genetic approaches have shown metallothionein to be metabolically essential.
Oxygen is a great energy source because it is a reactive molecule. But this reactivity makes it dangerous to the animals and plants that use it. Aerobic organisms have evolved a variety of mechanisms to protect their DNA from oxidative damage caused by reactive oxygen species, such as free radicals, that may be present in the environment or generated during metabolism. Dps is a novel histonelike protein in the bacterium E. coli that protects DNA from oxidative damage and causes compaction of the chromosomal DNA.
James Hogle, the Edward S. Harkness professor of biological chemistry and molecular pharmacology, and his colleagues report in the April Nature Structural Biology that they have now determined the structure of Dps. They discovered that Dps is very similar to the iron storage protein ferritin, found in the liver, spleen, and bone marrow. Twenty-four simple ferritin molecules associate to form a large spherical particle that can store up to 4,000 iron atoms.
Given the structural similarity of Dps and ferritin, the authors suggest Dps may protect DNA from oxidative damage by sequestering iron ions that could otherwise generate free radicals. By binding to the DNA, and specifically by condensing the chromosome into a compact structure, Dps may localize this iron sequestering activity to where it can provide maximum protection of the DNA.
Tantalizing anti-obesity treatments may be one step closer with the discovery of a protein that blocks leptin signaling in the brain. HMS researchers at Beth Israel Deaconess Medical Center report their findings in the March issue of Molecular Cell.
Leptin--a hormone produced in fat cells--acts on the hypothalamus to regulate food intake and body weight. Like the multifarious roles of insulin in the pathogenesis of diabetes, the role of leptin is prominent but somewhat mysterious in obesity. Overweight mice with mutations in leptin production or absorption have been studied intensely, but until now, the link between leptin resistance and leptin deficiency remained elusive.
Jeffrey Flier, professor of medicine at BID, and his colleagues at HMS and BID have now identified a protein, SOCS-3, that appears to orchestrate a negative-feedback circuit connecting production or administration of leptin in body tissues to inhibition of signaling via the leptin receptor in the brain.
Following peripheral leptin administration, SOCS-3 increased rapidly in regions of the hypothalamus known to be involved in body weight regulation. It then blocked transduction of the leptin-induced signal by interfering with tyrosine phosphorylation of the leptin receptor. Thus, detection of leptin in the body tissues leads to shut-down of leptin signaling machinery in the brain.
Overproduction of SOCS-3 may be the cause of leptin resistance seen in some forms of mouse and human obesity. "This is a very exciting discovery because if we can develop drugs to limit this leptin inhibitor, they might allow leptin to work better and one day be able to curb obesity," says Flier.
In the March 20 issue of Cell, scientists at the Dana-Farber Cancer Institute described a new molecule with key roles in the regulation of body temperature and defense against obesity. The protein, PGC-1, switches on transcription factors and other nuclear receptors that regulate adaptive thermogenesis--release of stored energy as heat.
Adaptive thermogenesis is a specialty of brown fat and skeletal muscle cells that release heat energy in response to cold or overfeeding. Energy is dissipated via changes in the number or function of mitochondria, the powerhouses of eukaryotic cells. Many of the genes at work in adaptive thermogenesis have been uncovered, but very little is known about how the process is regulated.
Bruce Spiegelman, professor of cell biology at DFCI, and his colleagues cloned PGC-1 from mouse brown fat. They found that it increased dramatically when mice were exposed to cold, or when cultured brown fat cells were treated with hormones known as ß-adrenergic agents that play a role in thermogenesis. Upregulation of PGC-1 subsequently stimulated expression of nuclear hormone receptors involved in the differentiation of brown fat cells, particularly thyroid hormone receptor and PPAR-y.
Based on the tissues where it is expressed and its ability to activate the thyroid hormone receptor, PGC-1 may be a useful therapeutic target to combat the abnormally low respiration rates characteristic of hypothyroidism. Regulation of PGC-1 may also provide new opportunities to manipulate energy expenditure in vivo and treat energy homeostasis disorders such as obesity and obesity-linked diabetes.
A new research computing facility, a clinical training grants program, and a shipment of computers are the first fruits of the School-wide IT Initiative, Dean Joseph B. Martin announced on March 31 at the initiative's first plenary meeting.
These near-term projects, which are now under way, complement the core of this faculty-driven initiative, which is to craft a long-term vision for information technology, linking its use to the needs and priorities of the School and affiliated institutions. (See Focus, February 20, 1998.)
The Research Computing Center will provide technical support and foster collaboration in using computers for scientific investigation. A result of joint planning by the basic science departments, the center will be a resource for faculty, staff, and students, complementing existing IT services in each department. The center, for example, will license widely used applications (such as DNA sequencing software), offer training, and provide access to electronic resources like protein databases and computer graphics. Services are due to expand in the near future from the Quad to the broader Longwood Medical Area, says Bob Freeman, director of research computing.
Martin announced the Dean's Clerkship Innovation Fund, an annual grant stream of $300,000 to back innovative uses of information technology in clinical clerkships. The purpose is to spawn Intranet-based resources available to students and faculty at every training site. The dean said he is looking to the Educational Computing Committee for recommendations on implementing this grants program.
Expanding student computing is the other early priority of the initiative. Computer facilities on the Quad are being upgraded and expanded for students in the MD, PhD, and DMD programs and for postdoctoral fellows. The project will increase the number of student workstations in the MEC from 62 to 108, and staff will be added. New workstations for graduate students and postdocs will be installed in the basic science departments. This project is due to be completed in the summer, says Richard Gillis, director of educational resources.
Faculty Council
At the March meeting of the Faculty Council, members and guests continued an ongoing discussion of ways to evaluate clinical teaching in the ambulatory and inpatient settings. Council guests Robert Fletcher, professor of ambulatory care and prevention at HPHC; Frederick Lovejoy Jr., the Berenberg professor of pediatrics at CH; Steven Weinberger, professor of medicine at BID; and council member George Thibault, professor of medicine at BWH, described different instruments for evaluating teaching, including the self-report on teaching, teacher assessments by students, peer assessments via ad hoc reviews, a careful look at nonpublished material (such as a candidate's syllabi, computer-based educational tools, and case studies), and review of published scholarship.
Other suggestions included site visits to doctors' offices outside the hospital where teaching is being done, quantitative evaluation of teaching (including specifics on number of students and amount of time spent teaching), and leadership contributions (e.g., clerkship direction). Additionally, note was made of the value of good documentation of teaching, the need for an organizational theme and focus for excellent clinical teaching and advising, and the benefit of innovations in teaching that reflect changes in practice.
Guests and members expressed interest in seeing HMS put greater value on the substantial teaching contributions made by many in the community and in seeking avenues to improve the assessment of teaching in a rapidly changing health care delivery environment. Many recommended that the quality of the candidate's teaching should carry a great deal of weight and suggested that an overemphasis on traditional publishing as a path for promotion diminishes the value of individuals who excel at training the next generation of doctors. Attendees felt strongly that the future of HMS depends on quality teaching and that showing teachers that they are valued in the promotion process is one way to reward their efforts. One member said the community should not be stopped from carefully assessing teaching just because it is difficult. The dean stated that one objective of assessing teaching closely is to reward teaching in the promotion process, but another is to improve the quality of teaching.
Comments from members included the opinion that, especially in the surgical realm, one-on-one teaching can be of more value than lectures. One member stated that an assessment of teaching quality has to look beyond whether students enjoyed a teacher due to his or her charisma and focus on how much the students have learned.
Standing Committee on Diversity
Council members then approved the recommendation that the Executive Council on Diversity become a standing committee of the Faculty of Medicine. William Silen, faculty dean for development and diversity and chair of the committee, explained that this committee will replace the Committee on Race and Diversity and will have a broad-based membership with wide representation from underrepresented minorities. He reported that the preamble for this committee in the book of standing committees will read: "Established by the Dean in 1998 to find strategies to enhance diversity, in its broadest sense, in the student, faculty, and staff bodies, and to facilitate collaboration among the ongoing efforts in diversity in the Harvard Medical institutions." Silen praised the work of those who served on the Committee on Race and Diversity and singled out former chairs, Isaac Schiff and Paula Pinkston, for their contributions.
A proposal to create the Harvard Medical School Division of Sleep Medicine was approved. The Division will provide a focus for sleep-related activities in the HMS community and will promote and facilitate teaching and research on basic and clinical aspects of sleep and circadian biology, with particular emphasis on development of curricular programs at the undergraduate, graduate, and postgraduate levels. Collaborations on sleep research among scientists throughout the Harvard system will be developed.
The council also approved the use of the Harvard name for two new centers: the MIT/Harvard Center for Magnetic Resonance and the Harvard School of Dental Medicine/Harvard Medical School Center for Craniofacial Tissue Engineering. These centers had been discussed at the February 11, 1998, meeting of the council, and like the Division of Sleep Medicine request, will be sent to HU's Office of the Provost for final approval.
On April 6, Donna Shalala (right), Secretary of the U.S. Department of
Health and Human 
Services, delivered a talk at HMS on "Quality and
Consumer Protection in Health Care." Addressing a largely student audience,
she outlined the Patients' Bill of Rights, founded on the need for information,
choice, emergency services, nondiscrimination, recourse, and confidentiality
in health care. The rights list was a product of the Health Care Quality
Commission created by President Clinton, which Shalala cochaired. The program
was presented by the HMS Student Health Policy Committee. Greeting Shalala
above are committee members Amy Hansen, HMS '00, and Arnold Seto, HMS '00.
* Suzanne Fletcher, professor of ambulatory care and prevention at Harvard Pilgrim Health Care, will receive the Robert Glaser Award from the Society of General Internal Medicine, the national society for research and teaching primary care internal medicine, at the SGIM national meeting in Chicago from April 2326. This award recognizes Fletcher's "distinguished lifetime achievement in generalism in medicine." Robert Glaser, an HMS alumnus, is former president of both the Markey Foundation and the HMS Alumni Council.
* Ron Walls, associate professor of medicine in the Division of Emergency Medicine at BWH, has been appointed top editor of the newly launched Journal Watch for Emergency Medicine. The journal, published by the Massachusetts Medical Society, abstracts literature relevant to emergency physicians to keep them up to date on a broad range of relevant medical subjects.
* John Potts Jr., the Jackson distinguished professor of clinical medicine at MGH, has received an honorary degree from the University of Leuven in Belgium. He is recognized for "his unique combination of leadership in basic research, which transformed the understanding of endocrinology; for his exemplary mentorship of many clinical and basic scientists; for his leadership as chief of internal medicine and as a physician in chief of a leading academic hospital; for his guidance in improving links between academia and industry while preserving academic freedom; and for his willingness to share expertise and knowledge with other institutions and minority groups."
* HSDM has established the Dr. A. Razzaque Ahmed Visiting Lectureship to allow a senior scholar with an international reputation in teaching and research in dental medicine an opportunity to share research or clinical expertise with students and faculty at HSDM and the Boston medical community. The successful candidate will be expected to spend three consecutive days at HSDM during the spring of 1999. To apply, or for further information, call the HSDM Office of Resource Development at 432-1534.
* The HMS Division of Medical Ethics invites submissions for the Henry K. Beecher Prize in Medical Ethics, a $1,000 annual prize for the best essay relating to contemporary medical ethics written by an HMS student. Essays that have been published or accepted for publication are not eligible. The Beecher Prize honors Henry K. Beecher, the first professor of anesthesia at Harvard. The deadline is May 1, 1998. Entries may be submitted to Edward Lowenstein at the HMS Division of Medical Ethics, 641 Huntington Avenue, Boston, MA 02115; fax: 432-3721; e-mail:elowenst@bidmc. harvard.edu.
The NIH-sponsored Program in Gene Transfer for Heart, Lung, and Blood Disease has created a Pilot and Feasibility Project Core grants program to facilitate novel approaches to vector development and gene transfer techniques. The consortium of investigators implementing the program are Victor Dzau, Richard Mulligan, Robert Rosenberg, Gary Gibbons, Michael Mann, and Richard Pratt. The program's pilot core has made available up to $30,000 per year (direct costs) for each of up to three one-year projects, which are potentially renewable for a second year. Those interested should send a one-page summary plus an NIH-formatted curriculum vitae to Eleni Schizas, Research Administrator, Thorn-13, BWH, 75 Francis St., Boston, MA 02115. The deadline is May 15, 1998. For further information, including additional deadlines, contact Victor Dzau at 732-6340.
Melvin L. Taymor, clinical professor emeritus of obstetrics and gynecology at BID, died on March 21, at age 79.
Taymor attended Johns Hopkins University and received his medical degree from Tufts Medical School. After a surgical internship at Beth Israel Hospital, he spent two years in the U.S. Navy in the Pacific during World War II. After the war he was an obstetrical intern at Margaret Hague Maternity Center in Jersey City, N.J. He did his residency in pathology and surgery at both the Free Hospital for Women and the Peter Bent Brigham Hospital. He also held a postdoctoral fellowship at MGH.
He was chief of gynecology at Peter Bent Brigham Hospital from 1970 to 1976, and chief of the Division of Infertility and Reproductive Endocrinology at Beth Israel from 1977 to 1987. He specialized in fertility problems until his retirement in 1997.
Taymor's early focus on the physiology of reproduction led to increased understanding of the ovulation cycle. He successfully induced ovulation and pregnancy with now-commonplace fertility injections. He and his colleagues also orchestrated the first baby born via in vitro fertilization in New England at Beth Israel in 1984.
He leaves his wife, Betsy (Bernstein); three children, Michael of Palo Alto, Calif., Laurie of Cambridge, and Julie of New York City; a sister, Susanne T. Wolozin of Needham; and four grandchildren.
In his memory, the OB/GYN Department of BWH has established the Melvin Taymor, MD, Memorial Fund to support reproductive infertility research. To make contributions, or for more information, contact Leslie Kolterman, at the BWH Development Office at 732-5500, ext. 5008.
As we look to the future of medical education in this country, I believe that it is critically important to begin considering international experiences as a vital part of the learning process. The U.S. is witnessing a transformation in its health care system, which has permeated all aspects of the field, including the very nature and structure of medical education. It has become clear that a world of interdependent economies, mass travel, and rapid exchange of ideas requires a more global perspective.
I believe that my own experience can attest to the importance and impact of international exposure on the education of a young physician. Between my third and fourth years, I had the opportunity to spend 10 months in Germany as a Fulbright Scholar at the University of Heidelberg. At the university, I did numerous hospital rotations as part of the final or "practical" year and also participated in lecture courses and seminars.
I have identified four areas that I feel highlight the most significant and interesting contrasts between the German and American systems, including didactic time, clinical time, schedule flexibility, and student interactions. The most obvious differences exist in the allocation of time between lectures and "hands-on" experience in the clinical setting. Although there is some variation, medical schools in the States generally allow less time for didactics and more time for rotations. During the first two years, classroom time focuses on providing a background in anatomy, physiology, and pathophysiology, which is built upon in the last two years. By contrast, in Germany there is an emphasis on greater depth and breadth in the presentation of clinical material in required lectures and elective seminars. Essentially all specialty fields are represented in lecture courses, which often include a direct patient observation and instruction on diagnostic techniques.
One advantage of the German approach is that it affords students the opportunity to gain greater exposure to specialty areas early in their education. Yet the increased classroom instruction corresponds to less time for clinical rotations and significantly reduces opportunities for hospital electives. "Practical year" students have clearly defined roles in the hospital and relatively limited involvement in clinical decision-making. American medical students tend to spend more time in conferences, giving them greater opportunity for problem-solving and discussion of pathophysiologic and therapeutic issues pertaining to their patients. While the Germans I spoke with generally felt that they had a strong theoretical background in basic science, anatomy, and pathophysiology, they expressed concern about their ability to apply conceptual knowledge to clinical practice.
Student Choice
Although less obvious than the differences in didactic and clinical time, the elements of schedule flexibility and student interactions are equally intriguing. In contrast to the fairly structured American medical school system, German universities allow for much greater flexibility and individualization in student schedules. All classes are offered every semester, and the order and timing of courses are largely undefined. In addition, the students have approximately five months of "lecture-free" time every year. During these months, they are able to pursue research, independent study, or clinical shadowing experiences and are strongly encouraged to explore opportunities abroad.
Unfortunately, the flexibility of the German medical school schedule comes at the cost of class camaraderie. Unlike most American medical students who progress through four years as a unified class, Germans generally have weaker ties with their classmates and fewer opportunities for cooperative learning or study groups.
Since my trip to Heidelberg, Harvard Medical School has become involved in an exchange program with the Ludwig Maximilians University in Munich. As part of this program, approximately 10 final-year students from Munich participate in clinical rotations at Harvard hospitals and are given an introduction to the fundamentals of the New Pathway. This year's students arrived at the beginning of April and will stay until mid-October. For the first time this spring, one of our fourth-year HMS students is also going to Munich to do a one-month rotation in internal medicine. These programs represent exciting new opportunities to enrich our educational system, promising a broader perspective and improved insight on classroom education and clinical training.
--Kirsten Greineder, HMS '98
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