News From Harvard Medical, Dental, & Public Health Schools --August 15, 1997
CONTENTS
Ancient Greeks told the story of Narcissus, the hunter who fell in love with his reflection and died of unrequited love, to warn about the dangers of self-obsession. Little could they have known that millennia later, mortals would be able to peer beyond the human face to the seat of obsession itself, the human brain.
New methods of brain imaging are providing researchers not
only with snapshots of brain structure but with images of brain activity
as clear and dynamic as Narcissus' reflection. Functional brain imaging,
as the field is called, began in the early '70s with the development of
positron emission tomography (PET). These early images, captured from infused
radioactive agents, tended to be fuzzy and required costly equipment as
well as radiation exposure for the subject. Several years ago, HMS researchers
discovered that a widely used clinical tool, magnetic resonance imaging
(MRI), also could "visualize" active areas of the brain--at a
lower cost and with greater clarity than PET scans.
Bruce Rosen (left) and Scott Rauch are
looking at
how brain circuits
break down in psychiatric disease.
Since then, HMS researchers, and researchers around the world, have been using functional magnetic resonance imaging (fMRI) to study the brain as it performs tasks involved in vision, memory, and learning. Functional MRI is being used to investigate and diagnose a wide range of psychiatric diseases, as well. Currently, HMS researchers are finding ways to improve the power of fMRI by honing the technique and combining it with other functional imaging methods.
Catching a Wave
"The pace of activity in the field is more like riding a wave than a horse. You're not really in control of it," says Bruce Rosen, associate professor of radiology and codirector of the NMR center at Massachusetts General Hospital East. Established in 1989, the center has grown from a pioneering band of 4 researchers to its current staff of more than 40. Rosen's codirector is Tom Brady, the Laurence Lamson Robbins professor of radiology.
The wave of MRI research began when Jack Belliveau, a graduate student working with Rosen, began experimenting with gadolinium, a chemical known to produce strong changes in MR signals in the brain. Rosen and others suspected gadolinium was reflecting increases in blood volume. Belliveau showed this was, in fact, the case.
Knowing that blood volume increases in active areas of the brain, Belliveau, now an assistant professor of radiology, injected human MR subjects with the chemical and exposed them to flashing lights. Sure enough, the gadolinium produced clear and stunning MR signals in the visual areas of the brain, the first demonstration that MR could monitor brain activity. Within months, Ken Kwong, instructor in radiology, showed that changes in blood flow and oxygenation produced their own magnetic signals, and that these could be picked up by MR. Human subjects no longer had to be injected with the potentially toxic gadolinium.
A Case of Less Being More: Sometimes apparently complex problems have simple solutions. The problem of how to tease apart fMRI activity signals--which correlate with experimental trials--is a case in point, says Randy Buckner. "What Anders [Dale] and I did was an amazingly mundane thing," he says. The two researchers found that individual fMRI signals could be pulled apart by subtracting one from another. Their findings will be published in an upcoming issue of Human Brain Mapping and were spotlighted in the June 27 Science.
Their research now makes it possible to detect responses as close as 2 seconds apart. But many cognitive processes, such as distinguishing a novel word, occur in milliseconds--too fast for fMRI to detect. Anders Dale has devised a way to detect these instantaneous processes by teaming fMRI with other methods of brain imaging, such as magnetic encephalography (MEG). Using this method, he and Buckner have been able to detect responses to trials that are less than 150 milliseconds apart (see figure). In addition, the new method has allowed the researchers to produce images of brain activity that are much sharper than those produced by MEG alone (top vs. bottom images).
Better Tool, New Use
"So you could test the same subjects over and over--expose them to this visual stimulus, that visual stimulus--over and over," says Roger Tootell, assistant professor of radiology. Tootell, then a Quad-based researcher, was tracking down an area in the human brain called the mediotemporal visual cortex (MT), which in macaques helps detect motion. He read about the work of Kwong and Belliveau, made contact, and, working weekends with Kwong, found the human MT.
Over the past five years, Tootell and his colleague Anders Dale and others have used fMRI to identify other human visual areas--V1, V2, V3, VP, V3A, and V4V. They are piecing together a picture of the human visual cortex that is both familiar and surprising.
While many of the newly identified human visual areas function as they do in macaques, Tootell and his colleagues have recently uncovered an unexpected difference. Primates identify moving objects by detecting motion at the objects' edges. There is evidence that in macaques MT plays a critical role in detecting these motion boundaries. Yet as Tootell and graduate student in neurobiology John Reppas report in the July 10 issue of Nature, when human MRI subjects were exposed to motion boundaries, it was not MT but other visual areas, such as V1, that were activated. "So we don't just have a larger version of a macaque brain," says Tootell.
This high-tech peering into the visual system provides a window on what makes the human brain unique. "We're just trying to do this with humans so later on you can do higher order tasks of more interesting things like reading or language," says Tootell.
Pushing the MRI Envelope
In fact, Tootell's work on the visual cortex attracted memory
and language researcher Randy Buckner to the MGH center. As a graduate student
at Washington University in St. Louis, Buckner had discovered that a region
of the brain associated with word retrieval consisted of several subdivisions,
each performing a slightly different function. Buckner, who is currently
instructor of radiology at the center, wanted to tease apart the functional
subdivisions of this brain region, the left anterior cortex, when he came
across Tootell's work. Buckner was so impressed with the technical savoir-faire
of the MGH crew that he decided to join Dale on a different kind of project--one
designed to enhance the effectiveness of fMRI.
Anders
Dale, Randy Buckner, and Roger Tootell
(l to r) are explore how the brain sees, learns,
and remembers.
One problem that plagues users of fMRI is its slowness. Most researchers have not been able to distinguish fMRI signals less than about 16 to 30 seconds apart, yet many experiments require eliciting responses from subjects every couple of seconds. Dale and Buckner have recently discovered that they can pull apart individual responses that are as close as 2 seconds (see figure).
Buckner has recently used the new technique to conduct experiments on memory. "Our goal is to start to build up a picture of how in everyday life we recollect things and how those functions break down in the disease state," he says.
--Misia Landau
HMS researchers are already using fMRI to see how normal circuits break down in psychiatric disease. Scott Rauch, Hans Breiter, and their colleagues have been using fMRI to study the brains of people suffering from obsessive compulsive disorder (OCD). Affecting between 1 and 3 percent of Americans, OCD typically appears at 10 to 15 years of age and is marked by the intrusion of unwarranted thoughts or obsessions. To rid themselves of obsessions, people perform repetitive acts like ritual hand washing.
Researchers suspected that people suffering from OCD have a defect in a brain circuit running from the orbitofrontal and anterior cingulate cortex in the front of the brain, to the caudate nucleus and thalamus, and back again. This circuit is believed to process emotionally tinged thoughts, outside of consciousness.
"The theory is that if you have problems with circuits that process emotionally tinged thoughts, then you're no longer able to fully process those kinds of things outside of consciousness--so they intrude as obsessions," says Rauch, who is assistant professor of psychiatry. He and Breiter, instructor in psychiatry, and their colleagues did a variety of PET studies to test this hypothesis, including a symptom provocation study. They then elicited a modest obsession in OCD patients and monitored brain activity using fMRI. Both the PET and fMRI studies revealed excessive activation of just those areas predicted by the hypothesis.
"I think the excitement with neuroimaging is that now we're able--in living, breathing human beings--to noninvasively actually go in and look at those systems at work. In the same way that it's tremendously exciting for people who want to study the visual system or learning and memory, it's a way to study psychiatric and neurological disease," Rauch says.
The nation's crime rates may be dropping but violence remains one of America's most debilitating problems. One of the most intractable aspects of violence has been figuring out why crime rates are higher in some neighborhoods than others. Researchers have tried to link high crime to greater levels of poverty and residential instability in neighborhoods. Yet their efforts to show an actual relationship have not panned out.
"Most people's efforts to demonstrate this relationship haven't worked out very well for one pressing reason--variation within neighborhoods was sufficiently great that efforts to detect specific differences were minimized," says Tony Earls, professor of human behavior and human development at HSPH and of child psychiatry at HMS. "So there was a methodological and statistical barrier of some kind that we hadn't been able to overcome."
Hearts Binding Hands
"If there's trust operating
here, how does it come
about, what maintains it?"
--Tony Earls
Earls and his colleagues have recently overcome these barriers. Drawing upon a survey of 8,872 residents in 343 Chicago neighborhoods--poor, middle class, and wealthy--they have traced low neighborhood crime rates to a critical and surprising variable. As they report in the August 15 issue of Science, "collective efficacy," defined as mutual trust and a willingness to intervene for the common good, is the critical feature distinguishing low-crime neighborhoods from their crime-plagued counterparts.
The finding is unexpected because many researchers did not believe that a social factor such as collective efficacy would play such a critical role in reducing neighborhood violence. "They thought our effort to detect this quality would not hold up to careful scientific scrutiny," Earls says.
First Fruit
The finding is the first substantive result to come out of the Chicago Neighborhoods Project. The project, which was begun by Earls in 1991, brings together researchers from such diverse fields as psychology, sociology, and law to identify what contributions neighborhoods make to the development of children and, specifically, how the social setting fosters violence. Whereas most previous attempts to look at crime have been based on census data, Earls and his colleagues conducted systematic face-to-face interviews with the 8,872 residents.
The researchers drew on these interviews to assess levels of neighborhood violence. "In addition to police records of actual homicides, we asked participants about personal victimization. Were they personal victims of violence and, if so, where did it occur?" Earls says. He adds that much neighborhood violence is perpetrated in homes and schools and may go unrecorded. Participants were asked a battery of questions to assess levels of informal social control.
Among other questions, residents were asked about the likelihood that neighbors could be counted on to intervene in various ways (for example, if local children were skipping school, hanging out on a street corner, or spray-painting graffiti on a building). They also were asked how strongly they agreed with such statements as "People around here are willing to help their neighbors" and "This is a close-knit neighborhood, and people in this neighborhood can be trusted." Positive responses were strongly correlated with low neighborhood violence rates. In fact, violence was much more strongly correlated to these two variables than to levels of poverty or residential instability.
Ultimately, neighbors' willingness to intervene depends on levels of mutual trust, says Earls. He plans to address the question of what builds trust in communities. "The next real challenge is to understand what this means from the more personal side of what people do and experience," he says. "If there's trust operating here, how does it come about, what maintains it?"
--Misia Landau
Forty years ago scientists began to suspect that the amino acid homocysteine was somehow related to heart disease. People afflicted with the rare condition--homocysteinuria--abnormally high levels of homocysteine in the urine--had early, severe vascular disease and died in childhood or adolescence. Kilmer McCully, a pathology instructor at MGH in the mid-60s, was one of the first champions of the homocysteine theory. But due to a loss of NIH funding, he was unable to continue his research. Denied Harvard tenure, he eventually left MGH.
More incriminating evidence implicating homocysteine emerged when Australian researchers discovered that many heart attack patients had high homocysteine levels. But that did not convince a lot of scientists. They thought that the heart damage itself or the heart attack treatment was responsible for the elevation--or that it was possibly an unrelated side effect.
"Neuronal injury and smooth muscle cell damage
by homocysteine may both be linked to the
NMDA receptor."
--Stuart Lipton
In the early 1990s, however, Harvard researchers published a report on the Physicians' Health Study in the Journal of the American Medical Association, showing that high plasma homocysteine levels were an effective indicator of future heart disease. Since then, homocysteine has been linked to risk of heart attacks, stroke, and peripheral vascular disease. It seems to be independent of other risk factors such as smoking, hypertension, and cholesterol.
After years of being sidelined by cholesterol theorists, McCully and other proponents of the homocysteine theory are receiving serious attention.
Agents Against
Controlling blood homocysteine levels is actually quite easy. Homocysteine is a multi-use amino acid that is involved in the metabolism of folic acid, a vitamin essential to DNA synthesis and repair. It also is the precursor to the amino acid methionine, which serves as a donor of methyl groups for DNA methylation.
Scientists discovered in the '80s that increasing intake of folic acid or B vitamins lowers homocysteine levels. Since folic acid is found in vegetables and fruit, and B vitamins are found in many animal products, diet can be an effective way to control homocysteine.
Meir Stampfer, HSPH professor of epidemiology and nutrition and Channing Laboratory investigator, notes, however, that most of the population is not getting adequate levels of folic acid. The recommended daily allowance for the vitamin is currently 200 micrograms, lowered several years ago from 400 micrograms when no ill effects had yet been discovered from low-intake diets. Stampfer takes exception to the current standard, saying that "people need to be at 400 micrograms or higher" to keep homocysteine levels down.
Genetics also can play a role in the ups and downs of homocysteine. Jing Ma, an instructor in medicine and Stampfer's colleague, has studied a genetic mutation affecting an enzyme linked to homocysteine levels. The enzyme, methylenetetrahydrofolate reductase, or MTHFR, is involved in folic acid metabolism. A subtle mutation--which affects about 15 percent of the population--results in a slow-down of MTHFR's activity. As a consequence, plasma concentration of the folate product, 5-methylTHF, drops and plasma homocysteine levels rise.
Given the previous link between high homocysteine and heart disease,
the scientists expected that the mutation would increase the risk of heart
attack. To their surprise, Ma, Stampfer, and other Harvard researchers found
there was no significant increase in risk. Their paper, published in the
November 15, 1996, issue of Circulation, showed that in members of
the Physicians' Health Study, the mutation did increase plasma homocysteine,
but not the risk of heart attack. Ma and Stampfer suspect that the relatively
good diet of physicians allows them to get enough dietary folic acid to
compensate for the mutation's effects--a conclusion that underlines the
importance of getting enough dietary folate.
Jing
Ma (left) and Meir Stampfer are studying how
homocysteine, certain vitamins, and genetics
contribute to heart disease and colon cancer.
More Mischief
In addition to being a risk factor for heart disease, homocysteine also may damage the brain. A strong correlation exists between high homocysteine levels and risk of stroke. Recently, Harvard researchers have found that homocysteine seems to kill brain cells through overstimulation. Stuart Lipton, associate professor of neuroscience at Brigham and Women's, showed earlier this year that homocysteine, in combination with glycine, overstimulates a glutamate receptor in neurons, leading to cell death. They found that lethal concentrations are easily achieved during strokes. These findings (published in the May 27, 1997, Proceedings of the National Academy of Sciences) may help to explain some of the consequences of stroke. Jonathan Stamler, a cardiologist who recently left the Brigham for Duke University, collaborated on the study.
Arthur Lee, an associate professor of medicine at HSPH, has studied homocysteine's effects on blood vessels, and has found that it stimulates the growth of vascular smooth muscle cells, which can cause blockage of blood vessels. A recent study by Nebraska researchers suggests that stimulation of NMDA receptors causes this growth.
Taken together, the data suggest that because of folic acid's action on homocysteine and other effects (see sidebar), the vitamin is important in preventing a variety of diseases. Stampfer says that now is the time for a prospective, randomized study that will assess whether folic acid can prevent heart disease by lowering homocysteine levels. A trial of this type is currently under way at Harvard.
Lipton notes, "Folic acid is preventive in lowering homocysteine, but doesn't protect against homocysteine's actions." He suggests that an NMDA antagonist--some are in clinical trials now--will be a useful adjunct for blocking neuronal cell death and the proliferation of vascular smooth muscle cells.
--Philip Downey
The benefits of folic acid have become apparent beyond the vitamin's homocysteine connection. Low levels of folic acid, for example, have been associated with an increased risk of colon cancer. Jing Ma and Meir Stampfer, both of Channing Laboratory, studied data from the Physicians' Health Study to assess how levels of folic acid and a genetic mutation that slows its metabolism are linked to the incidence of the cancer. They found that physicians with adequate folic acid who have the mutation had the lowest incidence of colon cancer. Physicians with a folate deficiency had an increased risk of colon cancer, regardless of their genetic status. Their results were surprising, because the mutation decreases plasma levels of folic acid, which was thought to increase the risk of the cancer. The researchers now suspect that the slower action of the mutated form of the enzyme increases the amount of folate inside the cell. This gives the cell a large supply of folate, which is essential for maintaining the integrity of DNA and protecting against colon cancer. Their results were published in the March 15, 1997, issue of Cancer Research. (Jia Chen, a member of the Channing Laboratory group led by assistant professor of medicine David Hunter, has found similar results.)
The first protein responsible for transporting iron out of the gut has been identified by two independent Harvard groups. The discovery may lead to ways of treating many different iron-related diseases.
The two groups used different methods and species to find the protein. Researchers from the lab of Nancy C. Andrews, assistant professor of pediatrics at Children's Hospital and a Howard Hughes investigator, analyzed an inbred strain of mice with a type of anemia. The second group, from the lab of Matthias A. Hediger, associate professor of medicine at Brigham and Women's, analyzed RNA from rats fed a low-iron diet. The teams published their results in the August issue of Nature Genetics and the July 31 issue of Nature, respectively.
The Andrews study--whose first author is Mark Fleming, clinical fellow in pathology at BWH--looked at mk/mk mice, which have microcytic, hypochromic anemia due to defective iron absorption in the intestine. The team used a technique called positional cloning to identify the suspect gene, called Nramp2, located on chromosome 15. Their study suggests that Nramp2 is probably a key to normal iron transport, and Nramp2 may be the actual iron transporter responsible for intestinal iron absorption.
The Hediger investigation--whose lead author is Hiromi Gunshin, research fellow in medicine at BWH--used expression cloning to study and characterize a metal-ion transporter, DCT1. The team isolated the DCT1 complementary DNA from a library prepared using messenger RNA taken from rats fed a low-iron diet. DCT1 is upregulated when dietary iron becomes deficient.
DCT1 is a member of the Nramp family. Though found primarily in the duodenum, the molecule can be found in smaller amounts in all body tissues. The researchers showed that DCT1 can transport iron and many other metal ions, including zinc, copper, lead, and nickel.
Iron deficiency is a worldwide problem. It is currently estimated that more than a billion people do not get enough dietary iron. In the U.S., approximately 1 in 10 women are chronically anemic. Researchers have traditionally thought that iron levels were related to diet, but these studies show that genetics may play a role.
The Tat protein, made by HIV, activates quiescent T cells, increasing the number of T cells available for HIV infection, according to researchers at the Dana-Farber Cancer Institute and HMS Department of Biological Chemistry and Molecular Pharmacology. The paper's first author is Chiang J. Li, a research associate at DFCI, and the group was led by Arthur B. Pardee, professor of biological chemistry and molecular pharmacology at DFCI. The results were published in the July 1997 issue of the Proceedings of the National Academy of Sciences.
The study demonstrates how HIV continuously replenishes the supply of T cells available for infection. Using Tat to activate cells makes them easier for HIV to infect, and also makes the cell more susceptible to death through apoptosis, or programmed cell death. This self-perpetuating mechanism suggests an answer to a longstanding puzzle in AIDS pathogenesis. Researchers can now look for ways of controlling HIV by blocking Tat's actions with drugs or a vaccine.
The Tat protein activates quiescent T cells by stimulating receptors on the surface and inside the T cell. These receptors appear to be integrins, which are involved in adhesion, not antigen recognition. This stimulation causes the cell to produce receptors involved in programmed cell death. Inside the cell, Tat activates the proteins JNK kinase and MAP kinase, which regulate cell division and contribute to programmed cell death.
Other Harvard authors of the paper are Yutaka Ueda, Bin Shi, Laura Borodyansky, Lili Huang, and You-Zhi Li.
Two genetic mutations involved with early-onset Alzheimer's have been shown to be involved in apoptosis, or programmed cell death. This is the first direct connection between Alzheimer's and apoptosis. The research was led by Rudolph E. Tanzi, associate professor of neurology at Massachusetts General Hospital, and was published in the July 18 issue of Science.
When mutated, the genes presenilin 1 (PS1) and presenilin 2 (PS2) can cause early-onset Alzheimer's. The form of the disease affects people under the age of 65.
The researchers saw that during normal cellular processing, the presenilin proteins are clipped at certain locations. But during apoptosis, the proteins are clipped in different locations by enzymes called caspases. The clipped presenilin fragments that are formed during apoptosis contribute to the cell death process.
If a cell has a mutation in the PS2 gene, the researchers found that PS2 is three times more likely to be clipped into the fragments that contribute to apoptosis.
Researchers must now determine the contribution of these fragments to Alzheimer's. They suggest that the fragments could first cause apoptosis and increase the amount of amyloid-beta42 (a key feature of Alzheimer's), or they could stimulate the production of amyloid, which would trigger cell death.
Tae-Wan Kim, Warren H. Pettingell, and Dora M. Kovacs were other MGH authors of the paper.
McLean Hospital researchers have identified clinical predictors of poor outcomes for schizophrenia patients. The results of the study were presented by Bruce M. Cohen, president of McLean, at the recent American Psychiatric Association Annual Meeting in San Diego. With these new findings, clinicians will be able to better understand and treat patients undergoing a first episode of schizophrenia.
Researchers studied patients with first episodes of psychosis, or other nonaffective psychoses including schizophrenia and delusional disorder. They found that patients with the following characteristics predicted a poor treatment outcome: diagnosis of nonaffective psychosis, insidious onset of the illness, presence of other psychiatric diagnoses, being male, being a minority, and not taking medication.
Erratum
In the June 20 research brief "Leptin Found to Suppress Insulin Secretion," the lines of mice used were not developed by the researchers but were ob/ob mice obtained from Jackson Laboratories.
Dennis Kasper, the William Ellery Channing professor of medicine, has been appointed executive dean for academic affairs at Harvard Medical School, succeeding S. James Adelstein, who is stepping down but continuing at HMS as the first Daniel C. Tosteson University Professor. Kasper will begin his new position on September 15.
"In the past 10 years that I have known him, Dr. Kasper has proven to be an outstanding clinician, scientist, and educator," said Dean Joseph B. Martin, who announced the appointment on July 23. "He has the ability to foster relationships between individuals and among departments and institutions, as well as the familiarity with the Harvard medical community essential to this position."
Dennis Kasper has become
the executive
dean for academic
affairs, succeeding
S. James
Adelstein.
Kasper, who is director of Brigham and Women's Channing Laboratory and executive vice chair of the Department of Medicine at Brigham and Women's, has been a member of the HMS community since 1972. Over the past 25 years, he has made major contributions to understanding the causes, prevention, and treatment of infection by a variety of bacteria, most notably the group B streptococci (GBS) and Bacteroides fragilis. GBS are the major infectious cause of illness and death in newborns and B. fragilis is a common cause of sepsis and abscess in trauma victims and surgery patients.
While his investigations of the molecular composition of GBS and B. fragilis have shed light on bacterial structure in general, they have been directed at the specific molecular elements of these bacteria that cause disease and provoke an immune response. He and his colleagues have been using this knowledge to develop vaccines against several strains of GBS, which cause meningitis in thousands of newborns every year. Recently, they found a way to enhance the effectiveness of such vaccines by coupling individual surface-coat elements (polysaccharides) to carrier proteins. These vaccines are currently undergoing clinical trials.
Kasper and his colleagues also have been exploring how the capsular polysaccharide complex found on the surface of B. fragilis protects against the formation of abdominal abscesses. These explorations could lead to the development of vaccines to protect and treat those at high risk for infection by B. fragilis, such as patients with trauma to the abdomen.
"In my opinion there's a tremendous need for leadership on the academic side of medicine as well as the clinical side, and [the post] happens to fit with my overall interests, which fall on the academic side," says Kasper. "One of the [other] exciting things for me is working with Joe Martin. So there's a great personal satisfaction."
Hidde Ploegh's arrival at the Quadrangle this September means different things to different people. For about a dozen HMS researchers, Ploegh's decision to leave MIT to become HMS Mallinckrodt Professor of Immunopathology brings home a researcher they know well from previous or current collaborations. For immunology students, it holds out promise that their graduate program will be broadened. But his move is also going to put disease-causing viruses in Dutch with their human hosts.
Ploegh (pronounced Plookh) is a basic researcher who has done extensive
work in the area where molecular immunology overlaps cell biology and biochemistry.
He is interested in how cells use their major histocompatibility complex
(MHC) proteins to present snippets of both human and foreign proteins to
patrolling immune cells. His studies have helped unravel the intracellular
routes along which cells ferry MHC proteins as well as protein antigens
to ensure that the MHC proteins can load the right types of antigen for
display at the cell's surface. In the past three years, this work has led
Ploegh and his coworkers at MIT to discover mechanisms by which crafty viruses
sabotage these cellular logistics in their effort to elude immune detection.
At HMS, Hidde Ploegh will head the PhD
Program in Immunology and study how
viruses elude immune detection.
For example, last December Ploegh and HMS researcher Tom Rapoport described in the journal Nature how human cytomegalovirus, once it has entered a cell, prevents this cell from alerting T lymphocytes to the invader's presence. Building on earlier work in Ploegh's lab, the researchers found that the virus dispatches a protein to push newly synthesized MHC molecules out of the endoplasmic reticulum and into the cytosol, where they will be promptly destroyed.
Looking Low
At Harvard, Ploegh will join Peter Howley, head of the Department of Pathology, David Knipe, professor of microbiology and molecular genetics, and Michael Carroll, associate professor of pathology, in an interdepartmental collaboration to uncover other cloaking strategies employed by herpes and papilloma viruses. "Our enthusiasm for this effort stems from the fact that while each of us has different areas of expertise, we will be working in close proximity toward achieving synergy on an important topic where our interests converge," says Ploegh.
This research may open new strategies for developing therapies against opportunistic viruses that can cause severe disease in people with weakened immune systems, including transplant patients or HIV-infected people. Moreover, it may advance efforts at understanding how HIV eludes the immune system. Such basic research is needed in the face of emerging evidence implicating infectious agents in seemingly unrelated human diseases, such as a recent report showing the herpes virus that contributes to Kaposi's sarcoma is also linked to the common blood cancer multiple myeloma.
Making teaching his second focus at Harvard, Ploegh will head the PhD Program in Immunology, one of the five graduate programs within the HMS Division of Medical Sciences. Begun in 1974, the program is ready for reforms reflecting the tremendous expansion of immunology over the past decade that was fueled by contributions from biochemistry, cell biology, and molecular biology, says Ploegh.
Looking High
Most important, he plans to involve more people in the program, especially new faculty and scientists at MGH, the Dana-Farber Cancer Institute, and other affiliated institutions. "We need to assess what the wider Harvard community offers and make sure we are using these resources to maximum benefit in the training of future immunologists," says Ploegh. Working with the Committee on Immunology at Harvard, he will streamline the curriculum and try to improve communication between immunologists and researchers in related disciplines. Ploegh has already met with the first- and second-year students currently enrolled. "I think we need to implement some of what the students want specifically for their interest, as well as bring the immunology program more in line with what has worked well for the BBS program," he adds.
--Gabrielle Strobel
Two Harvard affiliates ranked in the top 16 among U.S. hospitals in the annual U.S. News and World Report Best Hospitals survey, reported July 28. Massachusetts General Hospital was listed third and Brigham and Women's ninth, indicating they ranked high in at least six of 17 specialties.
Children's Hospital came in first among pediatric hospitals--the eighth year that it has topped the list. Massachusetts Eye and Ear Infirmary was number one for otolaryngology and fourth for ophthalmology.
Beth Israel Hospital (which now, along with New England Deaconess Hospital, forms Beth Israel Deaconess Medical Center) ranked seventh in geriatrics and among the top 20 in AIDS, cardiology, gastroenterology, and orthopedics. New England Deaconess Hospital ranked ninth in endocrinology and 14th in AIDS. The Dana-Farber Cancer Institute was fourth for cancer, and McLean Hospital was third in psychiatry. Spaulding Rehabilitation Hospital was 13th for rehabilitation.
Under an agreement announced on August 4, Partners HealthCare System and CareGroup will team up with the Cambridge Public Health Commission (CPHC) to create the Institute for Community Health. This new entity will initiate and test community health programs in Cambridge and Somerville.
In two related but separate agreements, the health care systems affiliated with CPHC, the parent of Cambridge and Somerville Hospitals. As a result, physicians at the two hospitals will choose to participate in one system or the other, but the hospitals can have physicians from both systems on staff. The twin deals mark the first time any hospital has formed an agreement with both Partners and CareGroup.
The systems and CPHC have committed a total of $1 million a year toward the Institute for Community Health, which CPHC will manage. The new institute will work with local residents and health professionals to identify priority health concerns, develop and implement strategies to address them, and evaluate the effectiveness of the approaches.
Both Samuel Thier, president and CEO of Partners, and Mitchell Rabkin, CEO of CareGroup, characterized the move as a significant benefit for the Cambridge-Somerville community.
Worried that hospital-based medical education was preparing future doctors for a world that no longer exists, the Pew Charitable Trusts came to HMS professor of medicine Gordon Moore and other physicians around the country to talk about an idea. The idea was to set up teaching and research partnerships between managed care organizations (MCOs) and academic health centers (AHCs), essentially creating "teaching HMOs," which would train medical students for the world of managed care and investigate ways to improve health care delivery in the cost-managed setting.
Building on those discussions, the Pew Charitable Trusts awarded an $8 million grant to Harvard Pilgrim Health Care (HPHC) to oversee a three-year program to establish eight partnerships between MCOs and AHCs. The foundation asked Moore, who is director of teaching programs in the Department of Ambulatory Care and Prevention, to oversee the program. The grant was awarded in July 1996, and recently, on June 25, representatives of the partnerships met in Seattle to discuss the progress they have made over the past year.
"The truth is managed care and academic medicine not only need one another but have a lot to learn from each other," says Moore.
HPHC and HMS were a natural choice for one of the partnership grants because of their history of collaboration: In 1992, the two cofounded the HMS Department of Ambulatory Care and Prevention at HPHC under the chairmanship of professor Thomas Inui. He and Moore are directors of the HPHC-HMS partnership for the Pew initiative, which received $1.29 million for three years. The seven other partnerships were awarded grants from $150,000 to $400,000 for each of three years.
First Armenise Foundation Symposium: The first annual symposium of the Giovanni Armenise-Harvard Foundation was held on June 18 to 20 in Erba, Italy, and was attended by 100 basic biomedical scientists from Armenise-Harvard centers in Italy and at HMS. The symposium was the occasion for awarding the first Collaborative Agricultural Basic Science Research Grant to Giulia De Lorenzo of the Dipartimento Di Biologia Vegetale of the University of Rome. De Lorenzo is pictured above (at right) with Frederick Ausubel, professor of genetics at Massachusetts General Hospital.
The Murray Professorship: More than 100 people attended
the ceremony in June celebrating the establishment of the Joseph E. Murray
Professorship in Plastic and Reconstructive Surgery. Elof Eriksson (at right),
chief of Plastic Surgery at Brigham and Women's Hospital and Children's
Hospital, is the first incumbent. Murray, professor of surgery emeritus
and winner of the 1990 Nobel Prize in Medicine for his work in transplantation
surgery, is recognized internationally for his contributions to the fields
of plastic and reconstructive surgery and transplantation surgery.
Summer School for Teachers: For some Harvard Medical School professors, teaching is not limited to Harvard students. Every summer, a group of HMS faculty members explains the latest research in neuroscience to Boston and Cambridge high school and middle school science teachers and helps them adopt HMS's problem-based learning in their own classrooms.
In July, 12 teachers attended the week-long program at HMS, where they obtained hands-on laboratory experience, learned how to develop cases, and visited local hospitals for demonstrations of diagnostic tests.
Pictured from left to right, Karen Spaulding, Nelson
Aweh,
Grace Diggs, Charles Hill,
Russell Cook, and Daniel Harrington
look on as Joel Elmquist, assistant professor of neurology at
Beth Israel Deaconess, explains the functions
of various
structures of the
brain.
* The National Institute on Aging awarded a five-year program project grant to Brigham and Women's Hospital. The funds will support an effort to develop and apply new biophysical methods to the problem of Alzheimer's amyloid formation. The total five-year funding exceeds $4.8 million.
* Bruce Spiegelman, professor of cell biology at the Dana-Farber Cancer Institute, was awarded the Heinrich Wieland Prize, which supports research in chemistry, biochemistry, and the physiology of fats and lipids and in other subjects of nutritional, physiological, and clinical importance. Spiegelman will receive the prize in October at the Chemische Institute, Universität München.
* The Media Center at Judge Baker Children's Center has received two New England Emmy Awards for the TV pilot Willoughby's Wonders. Clinical professor of psychiatry Alvin Poussaint received an Outstanding Children's Special award as coexecutive producer along with coexecutive producer and creator Susan Linn (instructor in psychiatry), coproducer Kelly Goode, and coproducer Susan Cohen. Director Consuelo Gonzalez received an award in the category Outstanding Individual Achievement Director--Taped.
* Four residents in the Harvard Longwood Psychiatry Residency Training Program were recently awarded fellowships: John Lloyd, American Psychiatric Association/Glaxo Wellcome Fellowship; Pamela Wine, American Psychoanalytic Fellowship; Mark Alexakos, Group for the Advancement of Psychiatry/Ginzberg Fellowship; and Albert Hyman, American Psychiatric Association/Mead-Johnson Fellowship.
* Andrew Luster, assistant professor of medicine at Massachusetts General Hospital, has been named a recipient of the Charles E. Culpeper Foundation Scholarships in Medical Science for 1997. He will receive $100,000 a year for three years to support his research. The award was presented on June 25 in Washington, D.C.
* Anthony P. Monaco, the Peter Medawar professor of transplantation surgery, has been elected to Honorary Fellowship in The Royal College of Surgeons of England. The induction ceremony took place on July 9 in London.
* Britain W. Nicholson has been named senior vice president and chief medical officer of Massachusetts General Hospital, succeeding Peter Slavin, who was named president of Barnes-Jewish-Christian Hospital in St. Louis. Nicholson has been a member of MGH since 1982. He has served in many positions, including director of Primary Care Development.
* Peter Howley, the George Fabyan professor of comparative pathology and head of the Department of Pathology, has been elected president of the American Society of Virology. He will serve in this position from 1998 to 1999. The society promotes the exchange of information and stimulates discussion and collaboration among scientists active in all aspects of virology.
Check one: Accept/Reject/ Modify/Convert to Note."
My pen hovered indecisively above the options on the confidential assessment form. I had spent the past several days poring over a paper that my adviser had asked me to help her review. Soon I would discuss my comments with her, and together we would submit our recommendations to the editors. Was the manuscript acceptable in its present form? If not, would it require only modest revision, or should it be scrapped altogether?
Peer review is meant to control the quality of articles published
in journals and prevent the spread of misinformation. Reviewers evaluate
the relevance of the work and the adequacy of the data supporting the authors'
conclusions. They send their reports to the journal editors, who determine
if the article will be published in its original form, revised, or rejected
based on the combined recommendations of the reviewers.
During my three years of graduate school, I have read hundreds of papers in various courses designed to encourage critical thinking. Usually these articles have been published years prior to my analysis of them, which gives me the benefit of hindsight. When my adviser requested my help in evaluating a recently submitted manuscript, I found the task much more challenging.
As I worked my way through the study results, one figure's legend caught my eye. Examining it more closely, I was horrified to discover a fundamental flaw in the experimental design, causing me to suspect that the authors' results did not support the main conclusions of the paper. In fact, their evidence suggested that the exact opposite of their conclusions might be true. My adviser and I discussed the manuscript and together decided to recommend that the editors reject it.
Weeks later, I was shocked when I read that the editors had chosen to accept the article. Bewildered, I read the other reviewer's comments. There was no mention of the inappropriate methods, nor any suggestion that there was an alternative explanation for the results. One small yet essential detail buried in the legend of a figure had eluded the other reviewer, leading to the recommendation that the manuscript be accepted with modifications.
"It's completely subjective," my adviser explained, referring to the editors' decision to favor the other reviewer's recommendations. It occurred to me that the same could be said of nearly all aspects of science. Researchers choose what to study, what experiments they will do, what those experiments may mean, and how they will package the data to persuade other scientists to accept their versions of reality. Reviewers decide whether manuscripts measure up to their own subjective standards, and editors determine which opinions they consider to be valid. These decisions are made by human beings with all their biases and natural limitations, so that many of the discoveries reported in journals are fragments of truth, colored by assumptions and inferences. To maintain objectivity, scientists must continually question every assertion, including their own, to separate opinion from fact.
While I am disappointed that the editors did not heed my and my adviser's advice to reject what I believe to be a flawed paper, I find it reassuring that I was able to identify a mistake and reinterpret the results for myself. At one time, I would have accepted the conclusions of a scientific paper without question. Today my blind faith has been supplanted by healthy skepticism, allowing me to formulate my own explanations of data and to challenge those of others.
The paper that I rejected has not yet been published, and I find myself wondering how it will appear in its final form. Will the authors redo the questionable experiments and draw appropriate conclusions? If not, will other scientists discover the error in the fine print and understand the significance of it?
How often do such important details slide by editors and reviewers to adorn the pages of even the most respected journals? Perhaps every scientific article should come with a warning label: "Beware! The claims made by the authors of this paper are not necessarily the only conclusions that can be drawn from the data. Believe at your own risk!"
--Robin Lucas
Robin Lucas is an HMS graduate student in the BBS genetics program.
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