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Cell Biology
Using proteins from the humble frog as a guide, researchers in the Department of Cell Biology have identified four human genes with critical roles in cell division--and implications for cancer therapy. In the February 20 Science, Hongtao Yu, Jan-Michael Peters, and Randall King in the laboratory of Marc Kirschner, the Carl W. Walter professor of cell biology, report the results of research in which they harnessed a Xenopus protein to identify the four human genes previously unidentified in the eight-unit anaphase-promoting complex.
For successful cell division--in which the cytoplasmic and genetic contents of a cell are faithfully reproduced in the daughter cells--two cycles must be synchronized. The DNA is replicated in one cycle, and the chromosomes divide during mitosis, the second cycle.
| Hongtao Yu and Marc Kirschner observe the frog tanks and discuss how they and colleagues harnessed Xenopus to discover new human genes. |
The AP complex is one of the mitotic ringleaders. "It is absolutely required for cell proliferation," says Yu. The protein complex drives a dividing cell from the metaphase stage of mitosis into anaphase--from the point at which the chromosomes find their partners and gather in pairs in the center of the cell, to the point at which each member of the chromosomal pair separates and migrates to the opposite cellular poles. A new cell membrane forms between the chromosomal clumps, and cell division concludes with cytokinesis--the formation of two identical daughter cells; each contains a copy of the parent cell's genetic information.
The AP complex is activated as cells progress through mitosis. During the transition between metaphase and anaphase, the AP complex acts as a kind of line inspector--identifying unneeded proteins and tagging them with ubiquitin molecules. Proteins with a ubiquitin "tail" are then destroyed by proteasomes. The AP complex recognizes proteins scheduled for deletion by the presence of a small section called the destruction box. This systematic culling of mitotic proteins drives the cell through the various stages of division.
What Matters
There is still much that the Kirschner group does not know about the regulation of the AP complex, but it is clear that in normal cells it is turned off if the spindle upon which the chromosomes gather during metaphase is damaged. The spindle draws each set of chromosomes towards the cellular poles, ensuring that the correct number of chromosomes end up in each daughter cell. The AP complex's ability to detect a malformed spindle and prevent cell division, and its seminal role in mitosis, make it an attractive candidate for the fight against cancer, in which cells escape regulation and divide uncontrollably.
"Proliferating cells go through mitosis rapidly, and also there's concern that tumor cells go through it with low fidelity," says Kirschner. He suggests that in cancer cells, the AP complex may not be receiving the correct checkpoint signals--the complex is activated too readily, driving the cell through division when the process should be aborted.
In the ongoing search for new anticancer therapies, the AP complex also provides "a whole new set of targets, which don't function at all in non-dividing cells," says Kirschner. Like the anticancer drug Taxol that also disrupts mitosis, the advantage with an AP complex inhibitor would be a preferential effect on rapidly dividing tumor cells. "A lot of normal cells are just not dividing at all," says Yu. These law-abiding noncancerous cells would be invisible to the AP complex inhibitor, avoiding dangerous side effects that limit the use of many anticancer drugs.
An essential step in the development of any new drug is an accurate detection system that will report whether the compound being tested is having the desired effect on the target cell. The Kirschner group has developed a biochemical method for analyzing inhibitors of AP complex activity. "The intention is to use the assay to screen for small molecule inhibitors, which might be very useful in anticancer and antiproliferation drugs," says Kirschner.
A Molecular Stage Director: The anaphase-promoting complex governs progression of the dividing cell from the metaphase stage of mitosis, in which the chromosomes align at the cell center, to anaphase, in which the chromosomes separate to the poles of the cell. The process concludes with the formation of two daughter cells (cytokinesis). Degradation of key regulator proteins such as the anaphase inhibitors PDS1 and CUT2, and the mitosis initiator cyclin B, drives the cell cycle forward. The AP complex recognizes the destruction box on proteins to be disposed of and "flags" them for degradation by adding small ubiquitin molecules (Ub) to each.
Randall King, the first fellow hired by the new Harvard Institute of Chemistry and Cell Biology, is responsible for further development and scale-up of the assay for high-throughput applications. Within the next month, he will begin screening a library of two million chemical compounds, looking for those that inhibit the AP complex or the ubiquitin-linking reactions. One compound with promise is a small protein fragment that mimics the destruction box. Yu and his colleagues have synthesized this tiny protein fragment, which inhibits the AP complex's activity in vitro by binding to the recognition site on the complex and preventing it from binding its normal targets. Similar protein fragments with superior stability and cell permeability are also being investigated.
Cloning of the final components of the AP complex improves the researchers' ability to take advantage of this new target. "This paper is important because it allows us to reconstitute the AP complex," says King. "It allows us to understand more about the mechanism of how the AP complex functions, and if we find an inhibitor, it gives us the ability to find out exactly how the inhibition is working."
The studies were funded by two grants from the National Institutes of Health.
--Kristin Weidenbach
A recently finished pilot study, based at Cambridge Hospital, organized lay members of the community to help teach primary care residents how to give care. Two of these community members were 101 years old. The others were 82 and 78. Together they composed a council of elders, who formally met not only with residents but with senior faculty, nurse practitioners, and medical students to explain the care that elders would like to receive.
The funding came as one of three mini-grants that were spun off the Medical School's Geriatrics in Primary Care Initiative supported by the John A. Hartford Foundation. The early evidence from the year-long pilot shows that the elder council has caused significant changes in the way the residents practice medicine.
The study is a blend of several streams of research in medical education. David Baron, an instructor in medicine at Cambridge Hospital, became the director of the geriatrics rotation of the Primary Care Internal Medicine Residency Program in 1994. He and David Bor, head of medicine at the hospital and the Charles S. Davidson associate professor of medicine, wanted their program to be the "ideal geriatrics residency rotation," Baron says. "I wanted to make it into something that would really flower."
Commitment to the Community
Bor says they wanted the residency to address four main issues: connection to the community; interdisciplinary care (training residents with nurse practitioners, for example); multicultural aspects of caring for the elderly; and prevention of frailty.
Bor and Arlene Katz, instructor in social medicine at HMS, had been developing a project on improving care to elders. When the mini-grant became available, the elder council project emerged, and the three faculty members became the coprincipal investigators.
David Baron, Arlene Katz, and David Bor (l to r) ran a study in which an elder council advised primary care residents on geriatric care.
To identify candidates for the board, Katz enlisted the help of Loring Conant, a clinical instructor in medicine at Cambridge Hospital and director of the Senior Center in Cambridge. Conant chose a convenience sample of elders who were relatively healthy, functional, and independent. All lived in their own homes. But as Katz explains, "A special kind of preparation is needed to have a dialogue among people from these very different worlds--old people, young doctors, and senior faculty." So Katz met with the elders several times before the large group meeting to ask for their advice about care, training, and policy. She also met with the residents and nurse practitioners.
The general session was held last spring. Residents and nurse-practitioner students presented cases that revolved around a dilemma in the life of one of their elder patients. Bor says this approach gave a powerful insight to the young professionals: "we are here to learn from our patients." He says connections between residents and geriatric patients are not automatic since the patients are two generations removed and, to the residents, the patient's role as teacher is unfamiliar.
One case that came before the board involved a woman suffering from increasing cognitive decline, including memory loss, who was trying to decide whether to move to a rest home or remain in her own house. To move would mean receiving competent care but severing ties with her husband of many years. Yet their marriage had been troubled, so she might not get the care she needed at home.
The elders gave diverse responses--no thundering consensus--involving what was most at stake for each of them. Still, the resident came away with a clearer direction: "I was given great suggestions of how to help give my patient purpose," she says.
Bor's assessment is that the resident felt empowered to say to her patient: "'I think it is appropriate for you to go to the rest home.'" And this is what the woman did. Katz says, "The board was a way to broaden the base of decision-making with the patient rather than for the patient." The investigators say the board has helped the residents understand the patient's model of care and to work within that model.
In reflecting on the general meeting, one resident said interacting with the elders led her away from the hopelessness she usually felt when dealing with elders in the hospital, who are often demented or otherwise unable to communicate. The experience persuaded another resident to do functional assessments on all of her patients, not just geriatric patients, which is the norm. The assessments involve observation and discussion of what the patients can do for themselves. Can they cook, drive, walk up stairs? Now she looks at the function--the lived experience--of all her patients. "It also helps them see that I'm interested in the whole life picture," she says.
Functional assessment was part of the core curriculum developed by the Geriatrics in Primary Care Initiative, Baron says. The elder council project built on the output of the larger program, which Cambridge Hospital was involved in, he explains. The three investigators are now looking for ways to continue the council, further document results, and expand the model to other populations with particular health risks.
--Robert Neal
As if crew members on the Russian space station Mir do not face enough problems during their workday, many probably struggle with another when they finally close their eyes: insomnia. A recent survey of 58 American astronauts found that most took longer to fall asleep and slept fewer hours and more fitfully in space. Many resorted to sleeping pills, which are known to affect alertness and performance the following day.
Some crew members aboard the next two space shuttles--Neurolab, to be launched next month, and the shuttle carrying John Glenn next fall--may have an easier time of it. Each night before going to bed, they will take a pill containing either 0.3 mg of melatonin or placebo. They will not know which they are taking. The regimen is part of a study, headed by Charles Czeisler, associate professor of medicine, and Derk-Jan Dijk, assistant professor of medicine, to test the sleep-promoting properties of melatonin. Both of the researchers are at Brigham and Women's Hospital.
According to Czeisler and Dijk, crew members should fall asleep faster, sleep longer and less fitfully on the nights they take melatonin, and they should suffer no decrease in alertness and performance the next day. Their hypothesis is based on 19 ground-based experiments conducted over the past four years. Healthy earthbound subjects were put on a daily schedule that induced the kind of sleeplessness experienced by astronauts. Before bedtime, they were given, in a randomized double-blind protocol, melatonin or placebo. "We have not finished the ground-based projects, but the results were encouraging enough that we did recommend they try melatonin on the flight," says Czeisler.
In addition to leading to a potential new space insomnia treatment, the researchers hope to come away with a better understanding of what regulates sleep. It is widely believed that sleep is governed by two opposing but interacting processes. The circadian system promotes sleep in a rhythmic way, through an internal "clock," which also drives a whole variety of physiological processes--in fact, sleep coincides with a progressive lowering of body temperature and a rise in melatonin, among other changes.
In contrast, the homeostatic drive for sleep works in an "appetitive" fashion--it builds the longer one is awake, just as hunger builds the longer one fasts. If the two drives worked in the same fashion, we might not stay alert throughout the day. In fact, the circadian drive for sleep only kicks in after 9 or 10 p.m. During the day, the circadian system pushes for wakefulness.
Yet it is not clear how the circadian system regulates sleep. For example, does the release of melatonin at night act directly to promote sleep or does it work by affecting other circadian processes, such as body temperature? Czeisler, Dijk, and their colleagues have been exploring this question. Astronauts will wear sleep monitors and other equipment that will enable the researchers to measure the effect of melatonin not just on sleep but also on a wide range of physiological processes.
Czeisler will be on hand for the Neurolab launch on April 16. "The space environment during Earth orbit will pose many challenges to sleep and to the entire circadian system," he says.
--Misia Landau
One of the more flamboyant explanations for what might cause autoimmune diseases involves viral subterfuge. Some viruses, the theory goes, evade immune detection by carrying protein segments that mimic human proteins, which the body's T cells recognize as self. Occasionally, the T cells blow the virus's cover but, in their attack, accidentally damage human cells as well. The trouble is, researchers have found only indirect evidence to support this idea.
Better evidence comes in the February 27 Science. Harvey Cantor, HMS professor of pathology at the DFCI, and his collaborators report that molecular mimicry indeed plays a role in herpes stromal keratitis (HSK), a leading cause of human blindness, in which T cells destroy the eye's cornea.
Cantor's team discovered that herpes simplex virus-type 1 (HSV-1) expresses a protein called UL6, which can stimulate the self-destructive T cells in mice with HSK. The researchers injected mice with UL6 and then transferred their T cells into other mice. The recipients promptly developed severe HSK.
The clincher came when the scientists removed UL6 from the virus. T cells exposed to the clipped virus no longer caused HSK, whereas T cells exposed to the native virus did.
While the authors prove that molecular mimicry plays a role in the development of this autoimmune disease in mice, they stop short of claiming that it always induces HSK; inflammation also seems to play a role. But for the first time, this study uncloaks most of the players at work in a specific mimicry operation: the virus, its offending peptide, and the self-reactive T cells of the host. Cantor's group does not yet know which peptide in the cornea draws the wrath of the T cells.
American physicians are not doing enough to help their patients quit smoking, Harvard researchers report in the February 25 Journal of the American Medical Association. Quitting smoking is one of the cheapest and most effective steps a patient can take to improve overall health.
Researchers found that few physicians follow the current treatment guidelines issued in 1996 by the federal Agency for Health Care Policy and Research, which recommend that physicians ask patients about smoking in every office visit, routinely advise them to quit, and help them do so.
The physicians surveyed reported that they urged smokers to quit in only 16 percent of office visits in 1991, the first year of the study. That rate increased to 29 percent in 1993, but fell to 21 percent by 1995, the last year studied. Nicotine replacement therapy followed a similar pattern. Physicians prescribed the nicotine patch or gum in 0.4 percent of visits in 1991, in 2.2 percent in 1993, and in 1.3 percent in 1995.
This temporary increase coincided with the introduction of the nicotine patch in the U.S. "We suspect that the increase in smoking treatment seen in 1993 is associated with the heavy marketing of the patch to both physicians and the general public," comments co-author Nancy Rigotti, assistant professor of ambulatory care and prevention at MGH. Anne Thorndike, research fellow in medicine at MGH, is first author.
Insulin-resistant diabetes is a disease of--well, insulin resistance. Less widely appreciated is that insulin resistance occurs in almost everyone who gains weight and becomes sedentary. Yet only people who fail to compensate for this resistance by cranking up insulin production become diabetic--currently up to 10 million people nationwide.
No single molecular explanation exists for these two hallmarks of type II diabetes--insulin resistance and insufficient insulin secretion. Now, researchers led by Morris White, a Howard Hughes Medical Institute investigator at Joslin Diabetes Center and associate professor of biological chemistry in the Department of Medicine, may have found one.
In the February 26 Nature, White and colleagues at Harvard and Yale report that mice lacking the gene IRS-2 develop progressive insulin resistance and reduced function of the pancreatic beta cells that make insulin. This double whammy causes excess blood sugar in the mice as well as other symptoms of human type II diabetes.
By combining these two effects, this model manages to bridge a long-standing gap between the two prevailing lines of diabetes research, one focusing on insulin's action in its target tissues, the other focusing on insulin secretion in the pancreas.
The IRS-2-deficient mice mimic human diabetes more closely than other mouse models. Morris adds that his team's mice will soon be used by the pharmaceutical industry to search for new diabetes drugs.
IRS-2 encodes a protein involved in signal transduction, which serves as an adapter protein linking the intracellular side of the insulin receptor to effector proteins. In muscle and the liver, the protein seems to mediate metabolic functions only, but in the pancreas, the IRS-2 protein probably promotes beta cell survival and proliferation as well, says Morris.
This study raises the question of whether correcting possible defects in human IRS-2 could treat diabetes, he adds. His team has not found IRS-2 mutations in patients, but he suspects that more subtle defects in the protein's function could lead to the disease.
People who take the anticoagulant drug warfarin increase their risk of internal bleeding by also taking large amounts of the pain reliever acetaminophen, Harvard researchers report in the March 4 Journal of the American Medical Association.
"While acetaminophen generally is a very safe drug for pain and fever, continuous use for seven days or more should prompt closer monitoring of anticoagulation levels to reduce the risk of hemorrhage," says the study's first author, Elaine Hylek, instructor in medicine at MGH.
Millions of people with atrial fibrillation and other conditions take the blood-thinner warfarin to prevent the development of blood clots. They often choose acetaminophen for pain relief because aspirin and non-steroidal anti-inflammatory drugs like ibuprofen can cause gastric bleeding.
The researchers surveyed 289 MGH patients on warfarin who had monthly blood tests to measure their anticoagulation levels. Of the 93 patients who had values indicating a high risk for hemorrhage, 30 percent took seven or more acetaminophen tablets per week.
Use of high doses of acetaminophen was the biggest risk factor for bleeding, followed by other drug interactions and by having cancer or a diarrheal disease. Conversely, eating plenty of green vegetables reduced the risk for bleeding while on warfarin.
The Vosges Mountains of northeastern France are a treacherous range, cut by deep ravines, and famous for their dense forests, persistent thick fog, and pitch black nights. They held other dangers for the soldiers--all Japanese-American--of the 442nd Regimental Combat Team. Their mission, one of the most famous of World War II, was to rescue the "lost battalion," which had been spearheading an attack against the Nazis. It was cut off from the rest of its unit, the 36th Texas Division, and surrounded on a wooded hilltop. The beleaguered battalion tried to escape, and the 36th made many rescue attempts, but the Nazis beat them back, inflicting heavy casualties. The lost battalion was in danger of being wiped out.
In a last ditch effort, the 442nd--known for its toughness--had been sent to tackle the Nazis. Despite heavy artillery barrages and hidden machine gun nests, the 442nd managed to carve through Nazi lines. But the four-day battle was so deadly that when the 442nd's I company finally broke through, 27 soldiers were left out of an initial 200. The 442nd lost a total of a thousand soldiers in rescuing the 175 Texan survivors. The 442nd received so many medals for valor that it became the most decorated unit for its size in American military history.
Although his main focus is the gastrointestinal tract, Susumu Ito has made significant contributions to our understanding of the reproductive tract and infectious disease.
Susumu Ito, the James Stillman professor emeritus of comparative anatomy, took part in the I company attack. He carried in his pocket a Bible and a piece of cloth with a thousand red stitches. The talisman had been given to him by his mother to keep bullets away, but Ito was prepared for a different outcome. "I believed that if the next shot or shell hit me, that's my fate. It's not correct to say I wasn't scared. But I accepted whatever would happen," says Ito.
Over the last fifty years, he has carried many of his soldierly qualities into his scientific career. While some researchers have a burning question that drives their work, Ito has accepted scientific challenges as they have appeared, which has led him into varied scientific terrain. He is best known for his work on the gastrointestinal tract--he helped discover what the mucosal cells lining the stomach look like, how they work, and how they repair themselves when injured. But he has also done extensive research on the reproductive system, which he continues to pursue, and has an abiding interest in infectious disease.
He has also engaged in his share of scientific battles, many of which he has won. Perhaps his most controversial discovery came in the early 1980s when he and William Silen, who is the Johnson and Johnson distinguished professor of surgery, showed that repair of the mucosal lining of the stomach is an astonishingly rapid process. This process, called restitution, is now widely accepted.
Becoming a scientist was an unlikely fate for Ito, who was born in 1919 in Stockton, California to Japanese immigrant sharecroppers. As a child, he accompanied his parents in the fields but preferred the activities of the older boys--hunting and trapping insects, birds, and other small animals. He would learn more about biology in the fields than in his one-room schoolhouses which, like the succession of shacks that the Itos inhabited, had no electricity or running water.
It was not just the humbleness of his origins but also the pervasive discrimination against Japanese-Americans that made Ito's career as a scientist so unlikely. In the 1920s, many schools in California were segregated by race. Indeed, Ito attended third grade at a school in which barbed wire separated Japanese-American students from their white classmates.
It was his mother who taught him a lesson that would help him deal with the discrimination. "She would say, 'You should behave in a way so that people are understanding of you, considerate of you, and kind to you. Get along, though do not necessarily ingratiate yourself. In any case, contribute more than you ever expect to receive,'" he says.
When it came to their son's future, his parents did not have high expectations. There were few doctors, lawyers, or scientists even among wealthier Japanese-Americans. As a child, Ito had an affinity for mechanical things and especially cars, so his parents--by now owners of a Japanese bathhouse--sent him to auto mechanic school. When he finished, he found that as a Japanese-American he could not get work in most shops and had to take a succession of menial jobs, which bored him.
Susumu Ito started out as an auto mechanic (shown with his car at right.) During WW II he served in the famous 442nd Regimental Combat Team (third from left above). After the war, he went to college and then to graduate school to study biology. He came to HMS in 1961, where he has been ever since.
By the time the draft came in 1940, Ito was ready. "I figured this will be more interesting," he says. When war was declared, Ito was placed in the all Japanese-American 442nd battalion and sent to Europe. "One of the reasons for creating our unit was to make us visible--to overcome discrimination," says Ito. Although most of the officers were Caucasian, Ito was informed one morning that he had been promoted to lieutenant. The very next mission was the lost battalion rescue.
Aiming at Science
After the war, Ito took advantage of the free tuition and stipend offered to veterans through the G.I. Bill, and attended college, first studying engineering--"I hated it"--and then biology. Against the advice of his biology teacher, who urged him to pursue a more practical career, he entered graduate school at Western Reserve.
His real scientific awakening came when he visited Woods Hole in the summer of 1951. Ito was astounded not just by its scientific wealth but also its openness--no locks on offices or labs, people coming and going at all hours of the day and night, students mixing with eminent scientists. "The Nobel laureate Otto Loewi would look over my shoulder and say, 'Son, vat haf you dere?'"
But it was his encounter with the Japanese scientist Katsuma Dahn that most impressed him. "His openness, generosity, sincerity--his real concern not only for knowledge but individuals--really had a lasting and permanent effect on me," says Ito.
After a postdoc in Germany, Ito was invited by Don Fawcett to join the Cornell Medical School anatomy department. The pair came to HMS in 1961. Ito began his research into the gastrointestinal system to fill a gap in his department's teaching schedule but quickly made a name for himself in the field. At the time, there was a widespread belief that the membranes of one class of cells, parietal cells, were vesicular. Ito, using a different microscopic technique, observed them to be tubular. "So we had a big battle. I think I've convinced most people they're mostly tubules, though tubules can be broken up into vesicles and turn into vacuoles by fixative," he says.
His next battle arose after he picked up a journal article saying the stomach could be protected against alcohol and other noxious agents by tiny amounts of the hormone prostaglandin. "I said this is nonsense," says Ito. Though he did not see any protection when he repeated the experiment, he did observe something surprising: injured stomach tissue repaired itself very quickly. With Silen, Ito showed the tissue did this by producing a gel layer under which undamaged mucosal cells could migrate and fill in for the damaged cells.
Ito, who still comes to work at 5 a.m., is currently working on a variety of projects, including a rather unusual rescue mission: "My daughter teaches in the Belmont school district where they have a big problem with lice in kids' hair," he says. He believes the lice's hard chitinous shell may become integrated with the hair shaft as lice mature. If so, it may be possible to devise a shampoo containing chitin-dissolving enzymes. "So that would be a morphological way of solving this," he says, adding, "Now, isn't this fun?"
--Misia Landau
At the February meeting of the Faculty Council, members discussed the use of the Harvard name for two new centers: the MIT/Harvard Center for Magnetic Resonance and the Harvard Center for Craniofacial Tissue Engineering. Requests for use of the Harvard name must be approved by the council.
Gerhard Wagner, the Elkan R. Blout professor of biological chemistry and molecular pharmacology, and Robert Griffin, professor of chemistry at MIT and director of the Francis Bitter Magnet Laboratory, explained that the proposed MIT/Harvard Center for Magnetic Resonance would be a joint effort between the two institutions building on existing bonds and creating new ones in this highly visible field. The center would be expected to attract major funding from federal agencies. Harvard and MIT have long conducted research involving nuclear magnetic resonance (NMR) and its application to biologic systems, frequently collaborating and sharing instrumentation and space. Harvard Medical School also purchased a spectrometer, which is housed at MIT. There has been a great increase locally and nationally in NMR research, but while interest has increased, the cost and the space required for cutting-edge equipment have also increased. Consequently, it is now difficult for individual researchers to have the highest power NMR magnets in their laboratories. The center would acquire these magnets and house them at the Francis Bitter Magnet Laboratory at MIT. The center would also develop initiatives to soon seek the renewal of its NIH CMR proposal, purchase two 900 Mhz NMR systems, and establish an NIH-sponsored training program in magnetic resonance.
The proposal for the Harvard Center for Craniofacial Tissue Engineering was presented by Harvard School of Dental Medicine Dean R. Bruce Donoff; Joseph Vacanti, professor of surgery, and Hans Peter Weber, the Raymond and Elva Pomfret Nagle associate professor of restorative dentistry. The center would facilitate interdisciplinary faculty collaboration for the purpose of teaching, research, and training. Membership and participation would involve the faculties of HSDM, HMS, MIT, and Harvard-affiliated hospitals. The center would seek to further research in biomimetic tissue engineering and biomaterials designed to enhance the development of natural and synthetic materials used for the repair, regeneration, and reconstruction of oral and craniofacial tissues and organs. Biomimetic research involves understanding, expansion, and modification of existing materials and development of new materials.
Council members also heard from Executive Dean Dennis Kasper regarding discussions from Eugene Braunwald's review committee surrounding the process by which senior appointments are recommended. While final recommendations regarding changes in the process to make the duration shorter and to increase the critical nature of the evaluation have not been made yet, Kasper presented several suggestions to the council.
During a recent education retreat sponsored by the HMS Beth Israel Deaconess Mt. Auburn Institute for Education and Research, junior faculty members expressed both concern and confusion about the various ladders for promotion, what was expected, and where to go for answers to promotion issues, echoing comments from the past two council meetings. They spoke of their need for more and effective mentoring; for regular, comprehensive meetings with department heads to assess career progress; and for help in becoming proactive in tallying their own accomplishments. It was also noted that non-quantifiable aspects for promotion need to be valued in promotion considerations, and that internal peer review of teaching was one way to quantify a candidate's efforts.
A report from the Standing Committee on conflicts of interest and commitment will be rescheduled for an upcoming council meeting.
Appointments To Full Professor
These faculty members were appointed to a full professorship in February.
* Robert H. Cleveland, Professor of Radiology, Children's Hospital
Cleveland, a pediatric radiologist, uses information derived from imaging procedures to create databases on large patient populations. Data from cystic fibrosis patients was used to predict the rate of deterioration and to determine variables associated with the increased rate of decline. Similarly derived data on infants with maternally acquired HIV is being used to assess the clinical course of these patients. Cleveland has recently been appointed director of health professional education at Children's.
* M. Amin Arnaout, Professor of Medicine, Mass. General Hospital
Arnaout, director of the Inflammation Program and Structural Biology Facility at MGH, is a nephrologist interested in leukocyte biology and cell adhesion. His observations established the role of cell adhesion in the immune system. His research focuses on the biology and structure of leukocyte integrins. He also studies the role of adhesion-dependent pathways in kidney development.
* Blaise F.D. Bourgeois, Professor of Neurology, Children's Hospital
Bourgeois is a pediatric epileptologist involved in clinical trials of antiepileptic drugs. He also studies the clinical pharmacology of the drugs, such as the pharmacokinetic and pharmacodynamic significance of drug metabolites, the clinical significance of induction and deinduction of carbamazepine biotransformation, the use of pharmacokinetic parameters for rapid drug changes in patients, pharmacodynamic interactions, and cross-tolerance between antiepileptic drugs.
HMS Rated No. 1In a ranking of the 125 accredited medical schools in the country, Harvard Medical School has been named number one by U.S. News & World Report. The ranking is based on a school's reputation, research activity, the percentage of students who enter primary-care residencies, student selectivity, and faculty resources. In the specialty categories, Harvard ranked first in internal medicine, pediatrics, and women's health; third in AIDS; fourth in drugs and alcohol; and fourth in geriatrics. |
* Robert McCarley, head of the department of psychiatry at the Brockton VA Medical Center, is one of two recipients of the 1998 American Psychiatric Association Award for Research in Psychiatry. The award includes a $2,500 grant and will be presented on June 1. McCarley's research focuses on the neurobiology of behavior, specifically the neurophysiology and neuropharmacology of control of the states of sleep and wakefulness.
* Thomas A. Keating and Aaron F. Straight, both postdocs at HMS, have been awarded Damon RunyonWalter Winchell Foundation fellowships. Recipients are outstanding young scientists who conduct theoretical and experimental research relevant to the study of cancer and the search for its causes, mechanisms, therapies, and prevention at major research centers. The three-year fellowships will be carried out in the labs of each fellow's sponsor. Keating's sponsor is Christopher T. Walsh, the Hamilton Kuhn professor of biological chemistry and molecular pharmacology. Straight's sponsor is Timothy J. Mitchison, professor of cell biology.
* The Judge Baker Children's Center has been granted $550,000 by the Corporation for Public Broadcasting for its children's TV program, Willoughby's Wonders. Alvin Pouissant, director of the JBCC Media Center and clinical professor of psychiatry at HMS, said the money will help develop 13 new episodes, and will help raise additional funding for the show. Susan Linn, instructor in psychiatry at HMS and the show's creator, said the show is a live-action comedy-drama centering around a diverse group of children and focusing on developmental issues such as coping skills, cooperation, empathy, and persistence. The filming of Willoughby's Wonders established JBCC as the first mental health center in the U.S. to produce a national television pilot.
* The Second International Harvard Conference on Internet and Society will be held May 2629 at Harvard University. Registration spaces are available through a lottery to current faculty, students, and staff with a valid picture ID. Those selected will have full access to the entire conference, including meals and materials, for a fee of $25. The regular registration fee is $1,295. To enter the lottery, e-mail cybercon@sph.harvard.edu by March 23. Include your name, ID number, and school. The e-mail's subject should be "I & S Lottery." You may only enter once. Winners will be notified via e-mail on March 30, and have until April 24 to register. For more information on the conference, visit http://cybercon98.harvard.edu.
"Dilemma of the Helixes," a painting by Rong Li, assistant professor of cell biology, was reproduced on the cover of the February 6 Cell. The journal's editors commissioned the painting for its review issue on macromolecular machines. "The painting is an abstract interpretation of protein function and movement and was inspired by the idea of protein machines," Li explains. She studies the role of actin on cell polarity and has been painting for more than 10 years.
A few months ago I received an alarming e-mail message from a colleague in my field about some results I had previously published. Even though he was following my protocol, his results differed significantly from mine. What caused this discrepancy? Had he done something differently? Had I been unclear in the description of my methods? Could my results be flawed?
Since researchers build on the work of their peers, they must first establish the validity of their colleagues' findings by reenacting their experiments and replicating reported results. Irreproducible results are deemed unreliable, so progress is impeded. For this reason, it is important to determine why inconsistencies occur and to reconcile conflicting data.
While human error accounts for some irreproducible results, other discrepancies are due to incomplete or inaccurate accounts of methodology in the literature. Even in prominent journals such as Science or Nature, space constraints force scientists to condense explanations of complicated protocols into simplified synopses of their methods. Consequently, important details may be omitted, making it difficult for the reader to duplicate the experiments. In other situations, results are published months or even years after the original experiments were performed, increasing the likelihood that researchers will forget seemingly trivial components of their procedures. Ultimately, these problems can contribute to inconsistencies in data from different investigators.
Why aren't discrepancies immediately addressed? In some cases, inconsistencies are left unresolved due to the isolating effects of unchecked rivalry. Competitors sometimes choose to ignore one another's work without attempting to reconcile differences in data. In other cases, it is a matter of economy. Unless the conclusions are crucial to a researcher's goals, there is little incentive for him or her to spend time and resources reconciling discordant results.
Old Trails
Often, experiments yielding incongruous data are abandoned in favor of more straightforward investigations. In my own research, I have performed experiments whose results did not agree with past findings, but I assumed that I had neglected to follow the protocol precisely or that I wasn't aware of all of the conditions necessary to obtain the published results. Since these experiments were peripheral to my main interests, I never bothered to figure out why I got data inconsistent with those previously reported. I simply moved on to the long list of experiments more pertinent to my thesis, leaving the unexplained discrepancies buried in my lab notebook.
Even when scientists communicate their difficulties in reproducing data, the investigator who initially reported the results in question is not obligated to address the discrepancy. It is much easier to dismiss such problems as anomalies or mistakes by other experimenters. While the principal investigator is usually the contact point for questions, the experiments are often performed by graduate students or postdocs who might have left long ago. Understandably, when conflicts surface, the principal investigator may be reluctant to dig through old lab notebooks in order to revisit experiments of former lab workers.
In my own situation, I was surprised when my colleague thanked me for helping him with "his problem." I felt that it was my responsibility to set the record straight, and I considered resolving our differences to be a top priority. After weeks of troubleshooting, I found part of the reason for the conflict: I had misreported the concentration of a chemical I had used in my experiments. This detail seemed minor at the time, but to my surprise, I found that a slight deviation resulted in a radically altered outcome.
Over a year has passed since I published those experiments. Have any other scientists experienced similar difficulties? If so, I was never informed. I am grateful that my colleague took the time to advise me of the discrepancies. Without this knowledge, I would never have questioned my initial results, nor would I have realized my mistake. While this does not account for all of the inconsistencies, it is a first step. I hope that ongoing investigation and communication will point to the other reasons for our differences.
--Robin Lucas
Robin Lucas is an HMS graduate student in the BBS microbiology program.
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