Contents:
Surgery
Organ transplantation surely represents a great triumph of modern medicine. Or is it really a near triumph? Nicholas Tilney, the Francis D. Moore professor of surgery at Brigham and Women's Hospital, points out that a persistent, if often overlooked, shortcoming prevents organ transplantation from being the resounding success it should be.
Fully half of all transplants fail within eight years, and that rate has not improved since the mid-1960s, when the practice began. "The long-term results of organ transplantation are really unsatisfactory. This is a huge and expensive problem," says Tilney.
| Nicholas Tilney and his collaborators are trying to understand why half of all transplanted kidneys fail after eight years. |
With his colleagues in the Quad-based Surgical Research Lab, Tilney is trying to focus the interest of his peers on the problem of chronic rejection. "We were so happy to get patients through the first year with an increasingly excellent survival rate that we paid scarce attention to what happened thereafter," he says.
Damaged Goods
In a recent string of papers, his group has begun to change the understanding of what causes grafts to fail over time. Their research suggests that early injury to the transplant organ, occurring before it ever meets its host, or within hours of surgery, may be crucial to how well the organ holds up over time. This injury occurs in two major ways: either by interrupted blood flow--called ischemia/reperfusion--or as a consequence of brain death.
Textbooks generally attribute transplant failure to the host's tendency to direct an immune attack on the graft as a foreign object, dispatching T cells to destroy the graft despite immunosuppression. Yet Tilney claims that there is much more to late organ rejection than the host's battle with non-self antigens. Indeed, the matching of host and donor tissue--and the industry that has sprung up around it--may make but a minor contribution to the graft's prospects, he says.
Tilney notes that in 1995, other scientists reported in the New England Journal of Medicine their surprising analysis of more than 50,000 kidney transplants, proving that kidneys from living, unrelated donors--whose tissue type did not match that of the donor--were functioning better than kidneys from cadavers. That raised the question, says Tilney, of whether circumstances related to cadaver organs and their transplantation led to their damage.
Last June, Tilney and his collaborators reported in the Journal of Clinical Investigation a study of ischemia/reperfusion injury as it occurs in transplantation. When cadaver organs are removed, stored or shipped on ice, and newly suffused with the host's blood, the organ's vasculature and surrounding tissue are somehow injured. In ischemic kidneys of rats, the researchers found soaring expression of cytokines that inflame the organ. Within hours of reperfusion, they detected a threefold increase of E-selectin, an adhesion molecule that coats the inside of blood vessels and invites leukocytes to leave the blood stream and enter the kidney. There, the leukocytes trigger lymphocyte- and macrophage-associated inflammation, evident in the expression of several interleukins and tumor necrosis factor alpha after three days. These rats rejected their transplants within a year, whereas rats receiving kidneys free of ischemia and the subsequent changes did not.
Early Injury--Late Rejection? Only hours after removal of a transplant kidney, the adhesion molecule E-selectin is expressed on the inner surface of the kidney's blood vessels (left). E-selectin causes leukocytes to infiltrate the tissue, where they set off an inflammatory cascade. Within days, macrophage- and lymphocyte- associated cytokines appear (right), inflaming the organ even before it is implanted into the host.
The second major clue to early injury of transplant organs may lie in the state of brain death, says Tilney. Brain dead people are the most common source for transplant organs. But researchers' knowledge of the physiology of brain death is largely limited to the phenomenon of "autonomic storm," in which the sympathetic nervous system causes blood pressure to fluctuate wildly and arteries to become temporarily constricted.
Tilney's team developed a rat model for brain death, asking how that vegetative state affects peripheral organs. In a short paper published last October in Surgical Forum, the researchers describe the sudden expression in peripheral organs of inflammatory mediators. A complete report of this study has been submitted for publication.
Tilney suggests that brain death acts on peripheral organs through as yet unidentified factors in the circulation, turning these organs into "cytokine bombs" that ultimately doom the transplant. He still needs to sort out, however, which of the molecular changes in these organs are due specifically to brain death, and which ones result from ischemia brought on by the autonomic storm. "Brain death and ischemia are very intermingled, and together can probably explain the difference between the cadaver donors and living donors," he says.
Different Donors
Understanding exactly what happens during brain death is important, says Tilney, because the donor population is changing. About 30,000 people in this country are waiting for a kidney at any given time, according to the United Network of Organ Sharing. The usual donor population of young, healthy accident victims is shrinking thanks to seat belts, airbags, and helmets, forcing transplant surgeons to use more kidneys from people 60 and older, who have had strokes and often have underlying sclerotic diseases.
The study of the molecular underpinning of early graft injury may open up new treatment strategies. Tilney's group collaborated with researchers at the Cambridge biotechnology company Genetics Institute. They provided a soluble ligand to bind the selectin molecules that appear so rapidly after ischemia, preventing passing leukocytes from recognizing the selectin. The treated rat kidneys developed neither the early inflammatory changes nor the late rejection observed in the other rats.
And in the December 1997 Kidney International, Tilney and his collaborators report that blocking T cell activation with an antibody has similar effects: the expression of inflammatory cytokines as well as chronic graft rejection were significantly reduced, suggesting that both T cell activation and selectin upregulation are early triggers to the molecular cascade leading to kidney failure. "You block the trigger, and the gun does not go off," says Tilney.
To understand chronic rejection, researchers will have to take a broader view and study where inflammation stops and immunology starts. Organ rejection is still a T cell- and antibody-mediated process, says Tilney. In both studies, his group also noted the upregulation of MHC class 2 molecules in the rats' kidneys, suggesting that cadaver organs might present antigens to the host's immune system more readily than organs from living donors.
But that explanation tells only half the story. In early injury, inflammatory processes and immune processes work hand in hand. "We transplantation biologists have been remiss, I think, in not investigating non-specific inflammation," says Tilney. "This is a hole in our thinking. The inflammatory people have their meetings, we have ours, and the twain just do not mix."
--Gabrielle Strobel
Nature has evolved a variety of mechanisms for regulating the activity of proteins inside the cell but none more elegant than the process known as phosphorylation. Worker enzymes, called kinases, attach bulky phosphate molecules to proteins, usually at one of three amino acids--serine, tyrosine, or threonine. For decades, scientists have tried to understand what effect this simple addition has. They observed phosphorylation occurring in many processes--from cell division to cell death--but did not uncover what change it causes in the protein.
| Lewis Cantley, Michael Yaffe, and Kun Ping Lu (clockwise from above) have made a series of discoveries that take some of the hocus pocus out of phosphorylation. One of their recent studies identified the amino acid sequence that is responsible for the binding of a well-known protein to phosphorylated serines. |
"When I was in medical school, they would say, "This is the protein and it gets phosphorylated on serine or tyrosine, and then something magic happens--somehow it's more or less active," says Michael Yaffe, Howard Hughes research fellow in surgery at BID.
Working with colleagues Lewis Cantley and Kun Ping Lu, Yaffe has recently made a series of discoveries that are helping to take the hocus pocus out of phosphorylation. The findings build on discoveries made several years ago by Cantley, an HMS professor of cell biology, and others. They found that attaching phosphates to tyrosines could cause proteins to create binding sites for partner proteins having special amino acid sequences, or motifs, that enable the two to pair up. Recently, a well-known protein, called 14-3-3, was shown to recognize proteins with phosphorylated serines. But it was not clear how this partnering occurred or if other proteins could accomplish it.
Yaffe and Cantley identified the structural basis--the amino acid motif--that is responsible for the binding of 14-3-3 to phosphorylated serines. With Lu, an assistant professor of medicine at BID, they showed that the protein Pin1 also binds phosphorylated serines. In addition, their investigations suggest that once bound, these proteins may act upon their serine-phosphorylated partners in a wide variety of ways--to sequester them, pair them up with other phosphorylated proteins, or change their shape so they may be acted upon by other proteins.
Protein Pals
The researchers, for example, identified the 3-D structure of 14-3-3 as it bound a phosphoserine peptide and discovered it bound two peptides--showing that 14-3-3 has two binding pockets. They speculate that 14-3-3 uses these two pockets to grab phosphorylated serines on the same protein, perhaps to prevent it from binding with another protein--or to bring together two phosphorylated proteins. "Proteins might say, 'I'll meet you over at the 14-3-3 for a drink and let's exchange some information. But you can't get in unless you have a phosphate,'" says Cantley. The study appears in the December 26 Cell.
Cell death and cell division are two processes regulated
by
phosphorylation. Normally,
cell death occurs when the protein
Bad
binds BCL-X (see left inset). Putting a phosphate on Bad's
serine enables 14-3-3 to bind and keeps Bad
from binding BCL-X.
Similarly,
the binding of Pin1 to serine-phosphorylated mitotic
proteins slows down cell division.
In addition, the scientists found that both 14-3-3 and Pin1 bind phosphorylated serines in a curious way. They attach to phosphoserines located near the amino acid proline and, in binding, pin down the proline bond in a particular orientation. This pinning of the proline bond may change the shape of the phosphorylated protein, which could ready the protein for the next step in a signaling cascade. The findings on Pin1 were published in the December 12 Science.
"I think these discoveries broaden how people are now going to think about phosphorylation," says Cantley.
They also shed light on two hot proteins--one old and one new. The protein 14-3-3 was first identified in the 1960s, but it was not clear what it did, and so it was forgotten. "People got interested again in the '90s because the protein began showing up associated with a whole variety of signaling proteins," says Cantley. In 1995, Tom Roberts, professor of pathology at DFCI, showed that it associated with a viral protein, called polyoma middle T. Other labs discovered it bound a protein called Raf, but only when Raf was serine-phosphorylated.
Intrigued by the parallels to the phosphotyrosine-binding proteins, Cantley and Yaffe investigated the 14-3-3 binding motifs of a whole variety of binding proteins. They sent their best motif--which came from the polyoma middle T protein--to a crystallography lab in London. But when the British crystallographers, joined by Yaffe, tried to see how the polyoma middle T peptide and the 14-3-3 protein interacted, they ran into a stumbling block: they expected the peptide to fit into 14-3-3 in a stretched out structure, but it did not.
An Answer Takes Shape
"We're sitting there staring at the console. A colleague came in, took one look, and said, 'I wonder what the proline looks like in a cis [or bent] structure,'" says Yaffe. It is unusual to find amino acids in such a structure, but Lu and his colleagues had just discovered that Pin1--which Lu identified in 1996--had the habit of pinning proline into a position midway between its stretched and bent structures. "Because my mind was primed from Pin1, I thought, 'Yes, that's it--that'll work,'" Yaffe says. They changed the orientation of the proline to the bent structure and everything fit.
Understanding the structure of 14-3-3 and Pin1 could have a clinical payoff. Both play critical roles in important signaling pathways (see illustration p. 5), which may be defective in certain diseases such as cancer. Targeting 14-3-3 and Pin1 with drugs that look like serine-phosphorylated proteins could prevent them from participating in important signaling cascades, which might cause unwanted cells, such as tumor cells, to self-destruct.
The combination of motif identification and crystallography that led to the discovery of 14-3-3's structure could make this fantasy-scenario a reality. "I think the approach is going to open up big doors for the design of new drugs and other types of therapeutic agents," says Yaffe.
--Misia Landau
The Association of American Medical Colleges, along with its member schools and teaching hospitals, has begun a major national communications campaign to improve the understanding and support of academic medicine's teaching and research missions among the general public, and ultimately, within the halls of Congress.
The campaign, launched in October, follows more than a year of extensive survey research among "opinion leaders" within the general public and among staff members on Capitol Hill. Both groups gave much more credit for medical breakthroughs to industry in general and drug companies in particular than to medical schools or teaching hospitals. Even more troubling, while the respondents generally supported the well-trained physicians and innovations that come from academic medicine, there was a near complete disconnect between support for the outcome and support for the process: they did not tend to back the educational mission.
The two surveys and a dozen focus groups also documented that despite widespread awareness of changes in the health care system, none of the groups perceived much, if any, threat to the innovation and clinician pool supplied by academic medicine. The Hill survey had a clear conclusion: until the staff there and their constituents understand what medical schools and teaching hospitals do and appreciate that their missions are in jeopardy, academic medicine's attempts to create more secure funding for teaching and research are likely to fail.
The task is large, considering the survey data. When asked, "What would you say is the most responsible for gains in medical innovation?" just 18 percent of the public and 11 percent of Hill staff credited medical schools. Even fewer of the public--12 percent--and a few more staffers--15 percent--credited teaching hospitals. Among Hill staff on key health care committees the numbers were even bleaker, with schools getting just 4 percent of the credit. Corporate research and drugs developed by the pharmaceutical industry got the majority of the credit from each group, with the two categories tallying 22 and 16 percent from the public and 24 and 21 percent from the Hill staff.
The national communications plan has several components, including media outreach, editorial board meetings with newspapers in the top 10 markets, a speakers bureau, coalitions with patient support groups and business groups, and an advertising campaign. The campaign's initial ad series ran weekly in October and November in the Washington Post and several "inside-the-beltway" publications read by policymakers, including The National Journal, The Congressional Quarterly, Roll Call, and The Hill. The three separate ads addressed the missions of research, education, and innovative clinical care.
"Strong, vocal and broad-based public support is essential to convince lawmakers that America's medical schools and teaching hospitals merit financial support," wrote the AAMC. "Essential to generating this support is increased public awareness of the important discoveries and innovations brought about by medical schools and teaching hospitals .... The public must understand that unless America makes a renewed commitment to support its medical schools and teaching hospitals, pressures to cut health care costs will slow life-saving medical research and compromise the quality of their care in the future."
The Harvard medical community is actively involved in the communications plan through the public affairs offices at HMS and many of the affiliated institutions, and through the backing of Dean Joseph B. Martin.
--Don Gibbons
Chronic inflammation is the root problem in a host of diseases, from atherosclerosis to rheumatoid arthritis. Macrophages--phagocytic white blood cells--initiate and maintain these inflammatory processes by producing chemical distress signals known as cytokines. In the January 1 Nature, a team of HMS researchers identify a receptor that appears to suppress the production of these inflammatory signals.
The receptor, called peroxisome proliferator-activated receptor-* (PPAR-*), participates in glucose regulation and fat cell development, but its role in inflammation was unknown. To explore this, the researchers, led by Brian Seed, professor of genetics at Massachusetts General Hospital, exposed monocytes (immature macrophages) to a new class of drugs. The drugs, called thiazolidinediones, acted through PPAR-* to block cytokine production. The study suggests that thiazolidinediones, which have been used to treat diabetes, may be useful in the treatment of rheumatoid arthritis and other inflammatory diseases.
Eating one meal of fish as part of a weekly diet may cut in half a man's risk of sudden cardiac death (death within one hour of the onset of symptoms), according to a new study by HMS researchers. They studied 20,551 male physicians and found that those who ate fish at least once a week had a 52 percent lower risk of sudden death compared with men who ate fish less than once a month. Weekly fish consumption did not relate to risk of heart attack, death from coronary heart disease, or nonsudden cardiac death. The findings are published in the January 7 Journal of the American Medical Association.
Approximately 250,000 sudden cardiac deaths occur in the United States every year. Of these cases, 55 percent have no previous history of heart disease and most patients die prior to reaching the hospital.
"Part of the association between fish consumption and lower risk of sudden death may be explained by the fact that fish consumption was a marker for a healthier lifestyle--fish consumers were more likely to exercise regularly and to take antioxidant vitamin supplements," says Christine Albert, instructor in medicine at Brigham and Women's Hospital and lead author of the study. "On the other hand, fish consumers were more likely to have high cholesterol or hypertension and a family history of coronary heart disease."
Albert and her colleagues examined questionnaire data over an 11-year period from male physicians, aged 40 to 84, participating in the Physicians Health Study at Brigham and Women's. Respondents were asked to indicate how often on average they consumed four types of fish or shellfish: canned tuna; dark meat fish (e.g., mackerel, salmon, sardines, bluefish, or swordfish); shrimp, lobster, or scallops; and other fish.
All levels of fish consumption were associated with a decreased risk of sudden death but the size of the reduction did not appear to differ substantially at levels of consumption greater than one fish serving per week. The authors say this small portion of fish may provide an essential amount of long-chain n-3 polyunsaturated fatty acid or some unidentified nutrient.
The researchers also tested red meat, chicken, vegetables, fruits, dairy and fried foods, but found no association between these foods and sudden cardiac death.
"Our findings support the belief that fish consumption is an important component of a heart-healthy diet," Albert says. "However, further large-scale randomized trials clearly need to be done to reconfirm our findings regarding fish consumption and sudden cardiac death."
Physical and sexual abuse in early childhood leads to sleep disruption that may continue through adulthood, according to a study by McLean Hospital researchers. The team, which also included a Boston College researcher, found that abused children were twice as active at night as normal and depressed children.
Abused children in the study also took three times longer to fall asleep, awoke more frequently during the night, and slept for shorter periods. All abused children exhibited these sleep problems, but physically abused children tended to have more impaired sleep than sexually abused children.
"This was one of the first studies to measure sleep and nighttime activity in abused children," says Carol Glod, lecturer on psychiatry and lead author of the study, which appears in the September Journal of the American Academy of Child and Adolescent Psychiatry. She and her colleagues compared three groups of prepubertal children: 19 with documented abuse, 15 nonabused children, and 10 suffering from depression. The children wore ambulatory activity monitors--which record all bodily movements--for three consecutive nights.
"Contrary to popular belief, by separating out depression, we found that it is the abuse that causes sleep problems. Just as important, even when the abuse goes away, the sleep problems can still exist and often become chronic or intractable," says Glod. These sleep problems can, in turn, impair the children's functioning during the day.
"This may explain behavior problems abused children often exhibit, as well as learning difficulties," says Glod. "However, this is not to say that all children who exhibit sleep disturbances, behavior problems, or have learning difficulties are in abusive situations."
Lissencephaly--or "smooth brain"--is one of the most severe malformations of the human cerebral cortex, resulting in the arrest of virtually all migrating cortical neurons before they reach their normal destination and producing mental retardation and seizures. One gene that causes lissencephaly is located on chromosome 17. A team of HMS researchers has recently identified a second gene--this one located on the X chromosome--called doublecortin, which may be responsible for some forms of lissencephaly. Their report appears in the January 9 Cell.
The researchers found that the doublecortin gene encodes a protein that contains several sites for phosphorylation by kinase proteins, suggesting tyrosine kinase signal transduction pathways may control neuronal migration. The research team includes lead author Joseph Gleeson, clinical fellow in neurology at Children's Hospital, Christopher A. Walsh, associate professor of neurology at Beth Israel Deaconess, and their colleagues.
To strengthen the research environment at Brigham and Women's Hospital, the institution has formed the BWH Research Council, whose objectives are to enhance collaborations, support new research programs, and develop strategic plans for future research.
Leading the effort were Victor Dzau, (left) BWH chairman of medicine
and the Hersey professor of theory and practice of physic, who was named
the BWH director of research, along with the associate directors of research,
Dennis Kasper, executive dean for academic programs and the William Ellery
Channing professor of medicine and professor of microbiology and molecular
genetics, and Michael Gimbrone, the Elsie T. Friedman professor of pathology.
The hospital seeks to maintain its position among those at the forefront of medical research in a time of great change in the way research grants are awarded. Through the council and its working committees, more than 70 faculty members are participating in the task of developing a research organization for the hospital's 400 faculty scientists.
Historically, BWH has supported research indirectly, contributing prized building space, but not specific project costs. Now, however, the hospital has committed to a direct annual investment in the research organization as well as direct support of department programs. The council, in turn, has already allocated $1.9 million to new programs. Among this year's initiatives are four two-year fellowship grants of $30,000 per year each and four two-year interdisciplinary seed grants of $50,000 per year each. A series of "Grantsmanship" seminars to teach young physician-scientists how to write better grants and a seminar on corporate joint ventures are also among the initiatives.
Five committees will administer the programs: Research Infrastructure, Career Counseling/ Career Development, Interdisciplinary Research, Clinical Research, and Translational Research. These committees took shape in January 1997, following a retreat at which researchers considered recommendations from the chiefs of service and other physicians across BWH.
Dzau says the creation of the council reaffirms the hospital's mission to bring medicine into the next millennium: "Our researchers are dedicated to finding cures and benefiting patient care, and the institution is committed to supporting them in this effort."
The council has approved support for core facilities of a clinical trials unit, biostatistics program, DNA sequencer, and confocal microscopy facility. Dzau says the council will create "bench to bedside" translational centers and increase the availability of transgenic mouse strains. The hospital also has committed six new jobs as part of an increased research information system support team.
--Matt Villano
On December 18, the Cabot Primary Care Series presented "Doctor as Writer: Medicine and the Literary Life" by Elissa Ely, HMS '88, a psychiatrist at Tewksbury State Hospital and clinical instructor in psychiatry at Cambridge Hospital. Ely, who is a commentator on NPR's All Things Considered and writes regularly for the op-ed section of The Boston Globe, read nine excerpts to the Vanderbilt Hall common room crowd.
"There are two responses to the kind of writing I do that give me pause for thought," Ely began. "Responses that come not only from other people but from myself. The first is that by writing about patients in the way that I do, I have violated their confidentiality. The second is that by writing about myself in the way that I sometimes do, I have violated my own confidentiality. And so with those responses in mind, I have decided that tonight, I am only going to read pieces that may have violated someone's confidentiality."
Opening Up
With that, Ely acknowledged a dilemma that all writers and thoughtful clinicians face, some with less humor, regarding how much of themselves and others to reveal. Ely explained that under the tutelage of a mentor at Cambridge Hospital, she learned that it was acceptable to reveal private thoughts to a patient. If you are going to miss a patient when therapy is over, tell him; if you love a patient, tell her, he had said. This counters the standard psychiatric creed of preventing personal issues from invading the therapeutic alliance.
Perhaps this philosophy encouraged a natural tendency in Ely (she started writing at age six after the death of her father) to do what all good writers do to their subjects: examine them. Ely began writing for the Globe in 1985, when she had the "luxury of being a medical student." Then she had more time to consider and write than she has now as a practicing psychiatrist, inundated with paperwork, patients, procedures, and psychotropic drugs.
She wrote of things such as love, teeth, refugees, and death. She shared stories about her grandfather and his journey from Ely's childhood to the hospital bed where he died. She read several pieces about patients, and how seemingly minor occurrences in their daily lives were imbued with great meaning, if only by giving them a voice.
Finding an Audience
After the readings, when asked how her colleagues have responded to her writings, Ely quietly acknowledged that "the most positive comments don't come from colleagues." She may have explained herself best in "Love Letters," when she said that "under the best of circumstances and with the greatest of efforts, few of us really speak the same language, but that's no reason not to write."
Thomas Inui, chair of ambulatory care and prevention at HMS, closed the evening by putting Ely's writings into context. In terms of primary care, he said, a goal for physicians is to "appreciate the attributes of the people we serve. We hope to build narratives that include us, but are about the patients." Ely not only builds narratives as a doctor, but goes one step further as an author: she writes them down.
--Tiffany Doyle
Joslin Diabetes Center and CareGroup--the parent company of Beth Israel Deaconess, Mt. Auburn, and other health care providers--have agreed to a joint venture making Joslin the leader in diabetes treatment and education in the CareGroup system. The details of the agreement will be worked out over the next three months.
This much is known: Joslin and CareGroup will remain separate entities. The venture will be governed by a board having an equal number of regular members from Joslin and CareGroup, with the Joslin president, Kenneth E. Quickel Jr., as an additional member and board chair.
Joslin will provide ambulatory specialty diabetes services at its own facility and other sites in the CareGroup network. The center will also provide services through the inpatient diabetes programs of CareGroup hospitals. The agreement does not prevent Joslin from continuing its collaborations with other providers such as Lahey Hitchcock, Children's Hospital, and Brigham and Women's Hospital.
Appointments to Full and Named Professorships
The following faculty members were appointed to a full or named professorship in December.
James Herndon
Partners Professor of Orthopedic
Surgery
Brigham and Women's Hospital
Herndon, chair of the Department of Orthopedic Surgery of Partners HealthCare System, trained in orthopedic surgery, specifically hand and upper extremity surgery. One of his key research interests has been fat embolism syndrome, a form of adult respiratory insufficiency following musculoskeletal trauma, nerve regeneration and repair, and arthritis of the upper extremity. His current interests include the development of finger joint prostheses, the structure and function of the interosseous ligament of the forearm, and gene therapy in rheumatoid arthritis.
Steven E. Seltzer
Professor of Radiology
Brigham and Women's Hospital
Seltzer, acting head of the Department of Radiology at BWH, focuses on improving the radiologist's ability to detect and diagnose abnormalities in diagnostic imaging studies. He has developed and tested novel contrast media for MRI and CT, display methods for viewing cross-sectional imaging studies, and computer-aided diagnostic systems that improve image-based differential diagnosis.
Editor's Note: In the last issue, we inadvertently listed the wrong Dr. Rosenthal as being promoted to professor of radiology. Following is the correct appointment, which was made in November.
Daniel I. Rosenthal
Professor of Radiology
Massachusetts General Hospital
Rosenthal is interested in diseases of the musculoskeletal system. His research focuses on quantitative analysis of imaging data for evaluation of bone and bone marrow in various metabolic conditions. He also studies interstitial application of radiofrequency energy for treatment of neoplasms, work that has resulted in a novel treatment for certain small bone tumors.
Thomas A. Horrocks (left), who was director of
historical programs and services at the College of Physicians of Philadelphia
from 1992 to 1997, has been appointed curator of the Rare Books and Special
Collections Department of Countway Library of Medicine. He has directed
collections totaling more than 300,000 volumes, one million manuscripts,
and 20,000 prints and photographs. He received his MS in library science
from Drexel University and is currently a doctoral candidate in American
History at the University of Pennsylvania. He succeeds Richard J. Wolfe,
who was with Countway Library for more than 30 years.
Dominick P. DePaola has been named president and CEO of Forsyth Dental Center. He will assume responsibilities in January 1998 from Donald I. Hay, the interim president. Under DePaola's leadership, Baylor College of Dentistry successfully merged with the Texas A&M University system. Of his agenda for FDC, DePaola said, "The oral health research agenda for the next century must be linked with systematic health and well-being and must include the breadth of basic, behavioral, clinical, and translational research. The opportunity to lead the planning for an integrated research focus of Forsyth is exciting and should result in the establishment of strategic alliances and partnerships between Forsyth and selected centers of excellence."
* Preventing coronary heart disease--the leading cause of death in the industrialized world--will be the focus of a Harvard-wide, five-year, $6.4 million investigation into the use of gene transfer technology based at Brigham and Women's Hospital. Led by Victor Dzau, the Hersey professor of theory and practice of physic and head of the Department of Medicine at BWH, and Richard Mulligan, the Mallinckrodt professor of genetics and professor of pediatrics at Children's Hospital, the Gene Transfer Program for Heart, Lung, and Blood seeks to identify ways to target defective cells and modify them to inhibit blood clotting and to induce normal blood vessel functioning.
* The Harvard Center for Children's Health, Children's Hospital, and the City of Boston will present the 1997 Harvard Award for Excellence in Children's Health to Crittenton Hastings House on January 21. The $10,000 award aims to recognize, promote, and strengthen community programs that improve the health of Boston's children. Crittenton was chosen for its "Services to Teen Parents and Their Children" program. The ceremony will be hosted by James Ware, acting dean of the Harvard School of Public Health, Mayor Thomas Menino, and David Weiner, president and CEO of Children's Hospital.
* Gabriel Corfas, assistant professor of neurology at Children's Hospital, has received a 1997 EJLB Foundation Scholar Research Programme award for his project, "Molecular Basis of Neuronal Migration." Corfas will receive $300,000 (Canadian) over three years. EJLB grants go to young scientists pursuing independent research careers.
* Carl Salzman, professor of psychiatry and director of education and psychopharmacology at MMHC, has received the Heinz E. Lehmann Research Award from the New York State Office of Mental Health, for his research accomplishments in clinical psychopharmacology.
* Sue Levkoff, associate professor of social medicine at HMS, was honored by Central Boston Elder Services, Inc. (CBES) for her research on caregiving to dementia-impaired elders in ethnic minority families from the Boston area. CBES, a private, nonprofit corporation committed to neighborhood-based long-term care to help elders remain self-sufficient, recognized the importance of this research in helping elders remain as independent as possible.
* Alfred Goldberg, professor of cell biology at HMS, delivered the 1997 Francis L. McNaughton Lecture at Montreal Neurological Institute-McGill University on November 28. Goldberg was selected for this honor due to his distinguished contributions to the understanding of neuromuscular disease.
* Peter Libby, professor of medicine at Brigham and Women's Hospital, was named chief of the Division of Cardiovascular Medicine at BWH on December 8. He had served as director of the Vascular Medicine and Atherosclerosis Unit since 1990. He succeeds Thomas Smith, who died in March after serving as the division's chief for 23 years. Libby's research, which centers on the pathogenesis and treatment of acute coronary syndromes--specifically, unstable angina pectoris and acute myocardial infarction--has helped to improve survival and quality of life for heart transplant recipients.
* Blair Marshall, former fellow in the Children's Hospital Surgical Research laboratory, received the 1997 Young Investigator Award at the World Congress of Pediatric Cardiology and Cardiac Surgery, for research she did at Children's between 1995 and 1997. Marshall worked with Richard Jonas, the William E. Ladd professor of child surgery at CH and cardiovascular surgeon in chief, and Brian Duncan, former assistant in cardiovascular surgery.
Roy Orval Greep (left), professor emeritus of anatomy, died December
5 at the age of 92.
Born in 1905 in Kansas, Greep earned his masters and doctorate in zoology from the University of Wisconsin. There, he became a research assistant in endocrinology in the laboratory of Frederick Hisaw. Greep's work in the field led to his interest in dental research. While studying rats, he began to investigate problems related to tooth development and decay. He joined the Harvard School of Dental Medicine in 1944 when the School was recruiting general scientists. He went on to teach anatomy at Harvard before becoming a professor of dental science at HSDM in 1949, then dean of the School in 1952. In 1967, he was named the John Rock professor of population studies and director of the laboratory of human reproduction and reproductive biology at HMS. He retired in 1974.
Over the course of his career, Greep edited medical textbooks on endocrinology and histology and was editor in chief of the journal Endocrinology. He served as president of the Endocrine Society and the International Society of Endocrinology. He was also a trustee of the Worcester Foundation for Experimental Biology and adviser to the Ford Foundation and the World Health Organization. His research with Gregory Pincus contributed to the development of the birth control pill.
Greep is survived by three daughters, Ann Louise Hogan of Shelburne, Vt., Marjorie Franko of Concord, Mass., and Nancy Greep of Long Beach, Calif.; three sisters, Luella Mauch of Clay Center, Kan., Gladys Romberger of Longford, Kan., and Norma McHugh of Grosse Pointe, Mich.; and seven grandchildren and five great grandchildren. He was predeceased by his eldest sister, Alta Greep.
Galileo was not impressed.
Eager to dazzle my visitor with the latest advances in neuroscience, I had tried to bring him up to speed in the field, reviewing centuries of discoveries. I stammered a little bit about Franz Joseph Gall and phrenology, Cajal and the neuron doctrine, the contributions of Sherrington to neurophysiology, and the concept of Hebbian plasticity.
Galileo had been on his way to meet with Einstein somewhere in the 1940s, but had overshot his destination by about 50 years.
"Ahh, these projections can be so imprecise," he complained. "The agency has misrouted me once again. Well then, you will have to suffice." That sure made me feel good.
I gave him a tour of the lab, but the only thing that caught his attention were our pipetters. He became obsessed with ejecting pipetter tips into the trash. Click-click.
"So, what have you written?" he asked.
When I explained that I was 75th author on my first paper, his reply was swift and devastating: "Is that all? At your age?" Click-click.
"Well, you know, it's not like in the old days," I retorted. "Training takes a lot longer today. There's so much more to learn, thanks to the discoveries of people like you. And I'm training to be a physician, too. I'm just getting started."
Galileo stared at me impassively. Click-click. "I must go."
"Besides, you guys were lucky! You got to solve all the easy problems ...." A bright flash interrupted my tirade. Galileo had been spirited away, and a tall, wispy woman had replaced him.
A Little Perspective
Great, I thought, I'm losing it. "Let me guess. You're looking for Galileo. ... No? Then you must be the ghost of publications-yet-to-come, sent to warn me that I will die destitute and unpublished if I don't get cracking, right?"
"No, Alex. But you got the future part right. I'm a neuroscientist, too, but I'm really just a student. Even though I'm much older than you, I still have many years of study ahead of me." She went on to explain that she was doing a little research on the history of neuroscience, to complement her BAs in history and biology, her PhDs in neuroscience and philosophy, and her law degree. She'd figured she should visit the 1990s, it being the "decade of the brain," and would I mind showing her around the lab?
She walked around looking at all the equipment with the eye of an antique collector. I told her about the Galileo fiasco.
"Wow!" she exclaimed. "I didn't get listed as an author on a paper until I was quite a bit older than you."
"But maybe he's right," I moaned. "I mean, look at Galileo. He was only 19 when he discovered that the period of a pendulum's oscillation is independent of its amplitude. And it's not just the prodigies like Newton and Einstein. History is full of examples of scientists making their mark while they're young. De Broglie was in his mid-30s when he showed that particles could exhibit wavelike properties. Heisenberg won a Nobel at age 31. The first ophthalmoscope, Geiger counter, and cyclotron were all devised by minds 31 and under." I was getting depressed. "It's not enough to just go around reading other people's work. I don't know. Maybe the longer you wait to prove that you've got the right stuff, the less likely you are to have it at all."
There's Hope Yet
"Don't be so hard on yourself. You're just getting started. Besides, Galileo is a physicist. Not all branches of science emphasize the intellectual contortions and single-minded focus most easily performed in youth. Some require a wisdom only time can bring. Especially the more interdisciplinary fields."
"Like neuroscience?" I suggested, warmed by the realization that opportunities to make contributions to my field would not just dry up when I turned 35.
"And others," she replied. She indicated that her time was almost up.
"Before you go, do you think you might help me out?" I asked. "Can you give me a little hint about the next big advances in neurobiology? It would really help me get going with my PhD thesis, you know, jump-start my career. How about something catchy like the neuroscience equivalent of E=MC2?
"Sorry, Alex. It's against the rules. But it'll turn out OK. Trust me," she said and was gone.
"Well, the future of neuroscience may be secure," I thought, "but as far as my thesis is concerned, looks like I'm on my own."
--Alex Carter
Alex Carter, a fourth-year MD-PhD student in the neuroscience program, acknowledges that this column was inspired by Dance for Two, a book by Alan Lightman.
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