Contents:
Nephrology
Behind the kidney's plain, bean-shaped facade lies a world of Byzantine complexity. Hundreds of thousands of "nephrons"--tiny networks of tubules and blood vessels--radiate from the kidney's core. Each nephron is dedicated to carrying out the organ's vital tasks: filtering impurities from the blood and maintaining the proper concentration of water, acids and bases.
In people suffering from a common inherited kidney disorder, called autosomal dominant polycystic kidney disease (ADPKD), this intricate arrangement goes awry. Nephrons fall apart and are replaced by fluid-filled cysts, causing the normally fist-size kidneys to balloon into organs as large as boxing gloves.
Not all nephrons in ADPKD patients follow this destructive course--only 1 to 8 percent give way to cysts. Yet the genetic mutation responsible for ADPKD is present in every cell. Some researchers have suspected that just as cancer cells often require two or more mutations to develop into tumors, tubule cells carrying the inherited ADPKD mutation must endure a second mutational "hit" during the lifetime of the individual in order to develop into cysts.
Two Hits Make an Out
This "two-hit" hypothesis is gaining ground as a result of a new study by Jing Zhou, assistant professor of medicine at Brigham and Women's Hospital, Weining Lu, research fellow in medicine, and their colleagues. The researchers created a breed of mice carrying a homologue of the mutant human ADPKD gene. Mice carrying only one copy of the defective gene appeared completely normal and were able to mate. However, mice carrying two copies of the defective gene suffered massive renal defects and died before or very soon after birth, suggesting that the second mutation is critical for disease. The findings are reported in the October issue of Nature Genetics.
Jing Zhou (left) and Weining Lu have found evidence
that autosomal
dominant polycystic
kidney disease requires two mutations--one inherited
and one experienced during the lifetime of an individual--to
manifest
in disease.
Half a million Americans currently suffer from ADPKD, making it not only the most common kidney disease but also the most common cystic disease--indeed, more common than cystic fibrosis. In addition to suffering great pain, ADPKD patients must undergo dialysis or kidney transplantation to stay alive.
Zhou was drawn to research on renal disease while working in a hospital in her Chinese hometown. "When I was a doctor, I was a bit frustrated at not being able to help patients very much," she says. To get a better understanding of the molecular mechanisms of kidney disease, she went first to Finland, where she earned a PhD, and then to the U.S., where she became a postdoc in the lab of Stephen Reeders, associate clinical professor of medicine.
Reeders had identified the gene responsible for ADPKD in 1985. It would be nearly ten years before he and Zhou, working with colleagues around the world, could glimpse its entire sequence. Even then, it was not clear how the gene, called PKD1, and its protein, polycystin, worked.
While exploring this question, Zhou observed that even though polycystin was present in very high levels in most ADPKD cysts, it was present in very low levels in a small proportion--about 10 percent. The finding suggested that there may be at least two ways to form cysts--by underexpressing or overexpressing polycystin. If so, two mutations could be involved in the formation of ADPKD cysts, the second mutation determining whether polycystin is up- or downregulated. Indeed, Reeders had earlier proposed that two mutations may be involved in ADPKD.
To further investigate the two-hit hypothesis, Zhou and her colleagues took a mouse homologue of the PKD1 gene and mutated it in a way similar to that found in the PKD1 genes of ADPKD patients. They introduced the mutant gene into a lineage of mice, ultimately producing a litter of perfectly normal heterozygotes. However, when they bred these mice, they found that all of their homozygote offspring died before or very soon after birth.
Timing Is Everything
While it is not clear how the mutant genes cause disease, the study hints at an answer. Homozygote embryos were dissected and appeared normal until fetal day 15, which is when normal mice start producing high levels of polycystin. As it turns out, kidney tubules begin a critical stage in their formation around fetal day 15. Zhou believes that mice who carry the double mutants probably lack fully functional polycystin and consequently cannot undergo this stage in tubule formation. Heterozygotes, who carry one normal gene, have enough polycystin to see them past this critical milestone.
Tubules that form normally in the kidneys of heterozygote
mice (left) were replaced by
cysts in mice carrying two copies
of
the mutant PKD1 gene (right).
Unlike mice, most humans do not develop kidney disease until they are adults. If the two-hit hypothesis is right, says Zhou, younger people may not have had the time to acquire--through exposure to environmental mutagens--a second mutation in their tubule cells. (Similarly, heterozygote mice may never develop cysts because they simply do not live long enough to accumulate these second mutations.) Obviously, PKD1 mutations have not affected fetal tubule formation in these adult patients. However, polycystin may help maintain tubules in adulthood, says Zhou. If so, the complete lack of fully functional polycystin, brought about by a second PKD1 mutation, could cause tubules to fall apart and be replaced by cysts. And though the second mutations may be different--one resulting in upregulation and the other in downregulation of the protein--the effect would be the same: the production of nonfunctional polycystin.
Zhou and her colleagues are currently exploring how the lack of fully functional polycystin might help bring about disease. One possibility is that the absence could be causing tubules to fall apart by triggering, directly or indirectly, cell death, or apoptosis. "In the mice, we found that before birth--when the disease is already developing but not yet that severe--there is massive apoptosis," Zhou says. "If apoptosis contributes to ADPKD, then it may be possible to reverse the course of disease by administering apoptosis inhibitors."
Of course, the lack of polycystin could be linked to apoptosis through a long chain of intermediate proteins. "We need to identify which proteins are interacting with polycystin--then perhaps we can target those proteins for therapeutic intervention," says Zhou. "Certainly it's still a long road. We won't arrive there in the near future."
--Misia Landau
One of the biggest turning points in a medical student's career occurs at the end of the second year, with the move from the classroom to the clinic. As the newly appointed master of Castle Society, Orah Platt hopes to help students navigate this critical change.
"I'm interested in the interface between the first two years of basic work and the clinical work. I want to make that a smooth transition, to make sure we're really meeting the needs of our students and what's being demanded of them," says Platt, professor of pediatrics at Children's Hospital. She succeeds Marian Neutra, who last year decided to step down after five years as the society master.
Orah Platt was surprised by her invitation to be the new master of the Castle Society."It was a great honor, but it did come as a bolt from the blue.
Over the past "12 years, Platt has taught in both the academic and clinical programs of HMS, where she has earned a reputation as an innovative educator. Between 1985 and 1992, she directed the core clinical pediatric clerkship at Children's, where she helped implement tutorial-based learning.
For the past three years she has led the basic science course on hematology that medical students take in their second year. The course combines a variety of approaches--lecture, minicase studies, and tutorials--and also uses Web-based learning tools.
What Works?
Platt is currently trying to assess the effectiveness of these various approaches. "We're interested in seeing what the outcomes of student performance are, depending on how the learning took place; what's most effective for certain types of material and certain students; and which methods have the best outcomes. That really hasn't been studied carefully," she says.
One of her goals as master is to extend this self-evaluative approach to other areas of the HMS curriculum, both academic and clinical. "I'm a pediatrician, so one of my goals is to really evaluate the different pediatric teaching programs in the school and to integrate them better into the larger fabric," says Platt.
She also hopes to engage Castle Society students in her research on the molecular basis of sickle cell disease. "This is research that is in large part inspired by Dr. Castle himself. He was a teacher of mine and a great hematologist and innovator in this field," says Platt, who graduated from HMS in 1973.
"Ultimately, I'd just like to concentrate on the students and on doing what I can to be sure their experience is as happy and satisfying as the one that I had when I was in medical school," Platt says. "It was a pure joy to be a student, and I'm really devoted to being sure that spirit continues."
--Misia Landau
Research into Replacing Brain Circuits Holds Faraway Promise for Treatment of Alzheimer's
The notion that some old people become like babies again may take on a new--and decidedly positive--spin if Jeffrey Macklis can realize his goals over the next decade or two.
What if the old, rather than reverting to the neediness of small children as their cognitive faculties succumb to neurodegenerative disease, could somehow reawaken the awesome powers of growth and development that mark the infant brain? Though he uses more modest language, Macklis, HMS associate professor of neurology at Children's Hospital, has for the past seven years worked toward just that goal. "What we would really like to do is to rebuild brain circuits in the adult human," says Macklis.
Cell Transplantation, The Next Generation: While clinical trials are attempting to treat Parkinson's disease by injecting fetal cells into the brains of patients, Jeffrey Macklis is working toward an even more ambitious goal. He hopes eventually to rebuild entire brain circuits by restoring degenerated neurons in their full complexity, with all their connections to distant brain areas. The above image identifies an embryonic neuron transplanted into the cortex of an adult mouse. The image to the right suggests that the transplant has developed into a mature neuron (thick arrow) virtually identical in shape and orientation to its endogenous neighbor (arrowhead).
That reality is still far away. Just this week, however, Macklis and others report they have made a significant step, in mice, toward replenishing some of the brain's dying neurons with immature cells. In the October 14 Proceedings of the National Academy of Sciences, Macklis and BBS graduate student Cliff Yoon describe experiments in which they first killed a selected group of neurons in the cortex of adult mice, the brain region that corresponds to the areas of reasoning and associative functions in humans. Working in collaboration with Evan Snyder, assistant professor of neurology, also at Children's, the researchers then transplanted into the cortex of these mice multipotent lab-grown precursor cells and found that they replaced the dying cells, developing into elaborate neurons indistinguishable from healthy, normal neighbors.
"We think this is the first time that precursor cells have successfully repopulated degenerated neurons in an adult mammalian nervous system," says Macklis. The study chips away further at the dogma, already shaky, that nerve damage cannot be restored in the adult mammalian brain.
Though the current work focuses on the brain's cortex, the general approach should be applicable to other areas of the central nervous system, as well, says Macklis, suggesting that an approach like his might first be tried to repair spinal cord injuries.
Technique Injects Precision into Brain Cell Transplantation:
The
complexity of nerve connections
remains a vexing obstacle to
performing
truly precise experiments in the brain. Faced with a
jumble of glial cells enveloping different types
of neurons that
reach into faraway
areas of the brain, scientists are hard pressed
to document accurately what becomes of transplanted cells. By
comparison, Jeffrey Macklis's approach to remove
and then replace
selected neurons
(see main story) strikes one as downright surgical--
except it isn't. It uses a biophysical trick to extract
powerful
information from the
brain's highest region.
First researchers inject tiny spheres containing a light-sensitive
dye (red dots) into the neocortex
of mice, where it gets swallowed
by
nerve endings and transported back to the cell bodies of neurons
residing on the other side of the brain. Then
they shine near-infrared
light
into the top layers of the cortex, causing the dye to drive the
affected neurons into committing suicide. While
these--but not
other--neurons
die by apoptosis, the researchers inject labeled immature
cells (small triangles). Then to see if the
stand-ins have extended axons
where
they should, the researchers inject into the original neurons
fluorescent particles (black dots) that also
travel back to the cell body.
Then
they scrutinize the area of the cell transplant for adult neurons
harboring both labels to find cells that have
specifically restored
the original
circuit.
This technology models aspects of neurodegenerative
disease in which
certain classes
of neurons die by apoptosis while neighboring cells
remain intact. By contrast, the necrosis occurring
at the center of a
stroke kills
all cells nearby, creating an environment ripe with
inflammatory substances that is less conducive to
nerve regeneration.
What about current trials, at McLean Hospital and elsewhere, using fetal pig brain cells to treat Parkinson's disease? That promising work is different, says Macklis. The patients have cells injected into the target areas of the dopamine-releasing neurons that die in this disease. There, they largely act as live drug delivery vehicles that supply the needed transmitter. The therapy does not attempt to redraw the original circuit and restore the neuron with all its connections. These trials represent the clinical stage of an approach that originated around 1980, says Macklis, whereas his work represents the preclinical stage of an idea conceived around 1988 that aims at an even loftier goal.
Tall Order
Reinstalling entire brain circuits, such as the ones extinguished by Alzheimer's and other types of dementing diseases, requires that the substitute cells perform a series of separate tasks. To be able to function like their predecessors, they need to move to the proper location, differentiate into the right type of neuron, make connections with particular neighbors, send out projections to distant areas, and hook up with the right target cell.
Five years ago, prevailing thought held that transplanted neurons could never blend into the meshwork of an estimated trillion neurons that make up the adult human brain. If that alone were not daunting enough, inhibitory proteins in the white matter of the adult brain were found to stymie attempts at nerve regeneration. Luckily, even though Macklis's goal "was considered crazy, people were willing to fund it anyway," he says.
Since then, research by several laboratories has weakened the dogma. Last year, Macklis and then-postdoc Cynthia Hernit-Grant reported that embryonic neurons, when transplanted into the cortex of adult mice, were able to replace dying neurons that in humans are involved in high-level associative functions (see image). Not only that, but the stand-in neurons extended "cables" through the corpus callosum to the other brain hemisphere, just like their predecessors had done. In effect, the researchers showed that the transplanted cells performed all the required tasks except one. The study could not show whether the new neurons actually function--that is the next big question.
You Can Become Anything You Want...
Obliging Cells Heed Diverse Commands
Besides moving toward the goal of replacing brain circuits (see main story), the study in the October 14 PNAS also addresses an ongoing debate about what determines the fate of undecided precursor cells: intrinsic or environmental cues. Stem cell biologist Evan Snyder has already found that the cells used in this study can turn into both neurons and glial support cells. The cells' apparently seamless integration into the adult cortex means that they were able to listen to the molecular signals in a part of the brain in which neurons were dying.
The repertory of these multipotent cells seems to be quite broad, says Snyder. Apparently they can respond to different types of developmental cues present in a given region at a given time. Indeed, the same precursor cells can also repopulate a lobe of the cerebellum that is underdeveloped in mice carrying a certain mutation, Snyder and his coworkers will report in the November 1 Development.
This week's report, written with Snyder and postdoc Jonathan Flax, explores whether developmentally younger cells, which have not yet decided what kind of cell to become, can replace the dying neurons. Cells of the type used--multipotent precursors that have been processed to multiply indefinitely in the laboratory--would provide a more ready source of transplant material than fetal brain cells.
Several findings suggest that this transplantation approach holds promise, says Macklis. Other studies trying to coax adult axons to extend new projections across the site of injury, for example in the spinal cord of rats, have shown some success, but typically only get 1 or 2 percent of neurons to regenerate. By contrast, this study found 15 percent of the transplanted cells turned into neurons. Moreover, immature cells may be especially well suited to tread amid adult brain tissue, because they do not yet express the receptors for the inhibitory proteins found in white matter.
Macklis's work is based on the rationale that during some types of neurodegeneration, molecular signals briefly reappear that normally guide the formation of the embryonic brain but fall silent after the organ is wired up. The Macklis lab is working to identify these signals to satisfy their curiosity about exactly which factors are necessary for the original wiring of a given circuit. The researchers hope eventually to equip transplanted cells with these molecules to boost the cells' chances of reestablishing specific circuits silenced by disease.
Though too much basic research still needs to be done to even consider human trials, Macklis believes his lab has come a long way. Members of granting boards no longer ask whether it is ridiculous to try to make cortical neurons connect to one another. Instead they wonder how complex it will be to make that process efficient. "That is pretty exciting," says Macklis. "It means our goal is no longer just a pipe dream."
--Gabrielle Strobel
A Culprit Caught in Common Form of Diabetes
In the October 9 Nature, Gökhan Hotamisligil, assistant professor of nutrition at the Harvard Public School of Health, and his collaborators confirm previous suspicions that the hormone called tumor necrosis factor alpha (TNF-*) may hold the key to a molecular explanation of why most obese people eventually become insulin resistant, predisposing them to non-insulin-dependent diabetes (NIDDM).
The researchers created two types of TNF-* knockout mice. First, mice lacking the gene for this hormone were fed a high-calorie diet in a model of dietary obesity. These mice did not develop insulin resistance, unlike the obese control mice that had TNF-*.
Second, the researchers asked which role TNF-* might play in severe, genetic forms of obesity, which always lead to NIDDM. To that end, they crossed mice unable to make the protein leptin with mice lacking the receptors for TNF-*, generating a "double knockout" strain of mice that grow grotesquely obese yet lack TNF-* function. The researchers found that the genetically obese mice without TNF-* receptors developed milder insulin resistance than those with intact receptors. This suggests that in severe cases of obesity, TNF-* is one of several factors that lead to NIDDM, the authors write.
In the same study, the researchers also addressed the mechanism by which TNF-* may cause insulin resistance. For that, they studied the model of milder, dietary obesity, which more closely resembles most human obesity. Their findings support prior indications that TNF-* promotes insulin resistance in three ways. Most important, it thwarts a particular step in the signal transduction cascade triggered when insulin binds its receptor, thus blocking the biological action of insulin. It also somehow increases the levels of free fatty acids in the blood. Finally, TNF-* may weaken the ability of muscle tissue to remove glucose from the blood in response to insulin.
New Risk Factors Found for Gestational Diabetes
A pregnant woman may be at greater risk of developing gestational diabetes mellitus (GDM) if she has been overweight or has smoked cigarettes in the past, according to a new study by HMS researchers. While previous studies had linked GDM to excessive weight, the new report, in the October 1 Journal of the American Medical Association, concludes that even modest increases in weight during early adulthood--approximately 11 to 22 pounds from age 18 to the age at entry into the study--may increase a woman's risk of developing GDM.
This is of particular concern "because weight gain is so prevalent in this country," says Caren G. Solomon, instructor in medicine at Channing Laboratory and lead author of the paper. "Our research indicates that women and their doctors should be aware of the impact of weight gain on gestational diabetes even before pregnancy."
In the new study, Solomon and her colleagues analyzed data from 14,613 women aged 25 to 42 participating in the Nurses Health Study II. All had delivered a baby between 1990 and 1994 and had no prior GDM or other known diabetes. The researchers found that in addition to weight gain, smoking five or more cigarettes a day was a risk factor for GDM. Their study also confirmed previous findings that older maternal age, nonwhite ethnicity, and a family history of diabetes increase GDM risk.
The disorder affects 3 to 5 percent of all pregnancies.
Gene Mutation Linked to Rare Form of Diabetes
Researchers at Massachusetts General Hospital report in the October Nature Genetics that mutations in a gene that plays a critical role in insulin secretion are associated with a rare, inherited form of diabetes. "Learning more about this gene may lead us to greater insights into common forms of diabetes that are associated with a variety of genetic and environmental factors," says Joel Habener, professor of medicine and Howard Hughes Investigator at the MGH Laboratory of Molecular Endocrinology.
The paper describes a new form of maturity-onset diabetes of the young (MODY), a class of diabetic conditions that follow a particular inheritance pattern. The gene in question is insulin-promoting factor-1 (ipf-1). Swedish researchers found that mice lacking this gene do not develop a pancreas. That phenomenon had never been reported in humans until a member of the MGH team heard about a baby born without a pancreas to a family with a strong history of diabetes. The child--who is receiving successful insulin therapy--turned out to have identical mutations in both copies of ipf-1.
For the current study, the researchers tested members of the child's extended family and correlated that information with the appearance of diabetes over six generations. Most of those with diabetes had the same mutation seen in the child in one copy of their genes, as did both the child's parents.
For years, the burden of presenting foreign invaders--or antigens--to T cells was believed to fall exclusively on a collection of cell-surface molecules known as the major histocompatibility complex (MHC). But several years ago, in a series of paradigm-shifting discoveries, HMS researchers Michael Brenner and Steven Porcelli showed that another class of cell-surface molecules--called CD1 molecules--also presents antigens to T cells. What was surprising is that the antigen components presented by CD1 molecules to T cells were lipids. This finding contradicted a long-standing belief that T cells only recognize protein antigens.
Now Porcelli, who is an assistant professor of medicine at Brigham and Women's Hospital, and his colleagues report in the October 10 Science that they have identified a new lipid antigen recognized by one of the CD1 molecules, CD1b.
The findings shed light on the molecular mechanism by which T cells recognize lipid antigens. In particular, they support the view that the recently demonstrated hydrophobic CD1 groove binds the acyl chains of lipid antigens in a fairly nonspecific way, positioning the hydrophilic components for specific interactions with T cell antigen receptors.
Specifically, presentation of the new glycolipid, mycobacterial glucose monomycolate (GMM), to CD1b-restricted T cells was not affected by substantial variations in its lipid tails but was highly sensitive to chemical alterations in its carbohydrate or other polar substituents.
D. Branch Moody, clinical fellow in medicine, was lead author of the study.
This year, to celebrate National Primary Care Day, HMS students planned not one but two weeks of events. They included seminars on primary care and family medicine; primary care in gay, lesbian, and bisexual communities; domestic violence and primary care; community outreach opportunities, such as the Urban Health Project and the Family Van; a program on medical Spanish; and a workshop on suturing and casting. Capping this menu of activities was an address by Dean Joseph B. Martin, which also inaugurated the year's Cabot Primary Care Series. About 350 students, faculty, and staff members came to hear Martin talk about science and the art of communication in medicine.
Inaugurating this year's Cabot Primary Care Series, Dean Joseph B. Martin reminded faculty and students that it is just as important to communicate uncertainty to patients as it is information. Afterward, Thomas Inui (bottom left), director of the Division of Primary Care, gave the dean top marks as a communicator.
Noting that almost three quarters of the first-year class has signed up for the HMS Division of Primary Care's Primary Care/Family Medicine Mentorship Program, Martin said, "The tool of communication is absolutely vital to all physicians, but to those interested in primary care, it had better be the most well crafted tool in their kit." He cited a handful of recent examples to illustrate the challenges physicians face in communicating effectively with their patients.
Martin stressed that the art of communication encompasses not only knowing how to communicate information to patients but also knowing when to communicate uncertainty, especially in the face of new and sometimes contradictory scientific findings. Good communication also means knowing when to be tactful and not lecture patients on scientific findings that fly in the face of their experience, such as a study that failed to demonstrate any association between symptoms of arthritis and changes in the weather.
In other cases, physicians need to determine how best to communicate with patients who are familiar with some but not all aspects of a controversial scientific finding--such as continuing reports that environmental contaminants similar to estrogen could be harming people's health, despite the original research being withdrawn because the results could not be replicated.
Freeing Information
In the past, Martin reminded his audience, physicians have not always been effective in communicating what they know. In his own field of neurology, this includes the well-established connection between dementia and Alzheimer's disease, which was first described in 1907, and the fact that mental disorders are diseases caused by imbalances in brain chemistry; they are not signs of character weakness. Both are cases in which the public has only recently caught up with long-held medical principles.
Martin also noted that patients will have access to more information in the coming years, including printouts from disease-specific Web sites, and physicians may need to spend even more time discussing uncertainties. On the other hand, many patients will not have access to the Web, and this economics-based information gap may often be a racial one. "It is your responsibility to do everything you can to increase communication to all your patients, thereby minimizing the information gap those barriers can cause," he said.
Sometimes the gap will be even wider. When treating patients who come from different cultural backgrounds, physicians must realize that some will not even share the most basic belief that Western medicine, more often than not, works. "Treating your patients means treating your patients' fears and doubts, no matter how ill-founded or strange you think they are, as well as their medical condition," he said.
He closed by outlining five points that the "compleat" physician should keep in mind: acknowledging that patients know science will probably never provide a full understanding of human emotions, such as happiness and hopelessness; that many patients will seek alternative therapies in addition to the conventional; that healing is a complex process, assisted by a physician's scientific knowledge, but also propelled by less well understood factors, such as the patient's will to live and fortitude against all odds; that spirituality, in one form or another, is present in the majority of people; and that a substantial proportion of patients are medically sophisticated and will often come in with questions that surprise the physician.
--Peta Gillyatt
The Freeman Foundation East and Southeast Asian Fellowship Program in the Department of Social Medicine has begun its second year under the direction of Arthur Kleinman, the Maude and Lillian Presley professor of medical anthropology and chairman of social medicine. Anne Becker, assistant professor of medical anthropology, is the academic director. The aim of the program is to improve ties between Asia and the U.S. through the exchange of research scholars between Harvard and China, Taiwan, Thailand, and Indonesia.
The 199798 fellows are:
Xu Yifeng, Shanghai Medical University, lecturer and attending psychiatrist, Department of Psychiatry, who is looking at the effect of sociocultural factors on the course of schizophrenia in modern China;
Yan Fei, Shanghai Medical University, associate professor, Department of Health Statistics and Community Medicine, who is studying the quality of life and health care among the elderly;
Subandi, Gadjah Mada University, clinical psychologist, who researches psychotherapy practice in Javanese Islamic culture;
Tana Milchaikovit, Mahidol University, assistant professor of psychiatry, who deals with patients' life experiences and ways they cope with breast cancer in Thailand.
* The Countway Library has completed its prerenovation projects in preparation for the renovation tentatively scheduled to begin this winter. Involved in the effort were Phyllis Askey, librarian for collection management special projects, Marian Burke, assistant director for resource management, and 20 staff members and consultants who processed and moved 32,485 linear feet (more than 6 miles) of materials out of the library.
* Children's Hospital has received a grant of $1 million dollars from the Modell Foundation. The award will expand research on primary immune deficiency, which affects more than 500,000 children in the U.S. alone. Raif Geha, the Prince Turkibin Abdul Aziz Al-Saud professor of pediatrics at Harvard Medical School, says that "the Modell family gift will ensure the continuation of our work to identify the immune factors missing in immune deficient children, the genes responsible for over 70 forms of the disorder, and, hopefully, lead to gene replacement therapies."
* The Harvard School of Dental Medicine has received an NRSA Institutional Training Grant in biomaterials. The program joins HSDM and MIT in a common effort to educate highly qualified oral health researchers who will develop and apply new biomaterials and techniques to address existing needs in craniofacial, oral, and dental disorders. Students will be admitted through a joint committee of faculty members from both institutions for a PhD in Material Sciences and Engineering with special emphasis on biomaterials, biomimetics, and tissue engineering.
* The Moseley Traveling Fellowship is offering funds to HMS graduates for postdoctoral research in Europe in the basic or clinical sciences. The awards are for no less than one year, and will be determined by the specific need of the individual. Individuals who have already attained faculty rank at Harvard or elsewhere will not be considered. In addition, the Warren-Whitman-Richardson Fellowship is offering funds for research to MD scientists who require further training. This award is not restricted to HMS alumni and does not require overseas travel. For applications and materials, please contact Cheryl Magoveny in Sponsored Programs at 432-2661 or cmagoven@warren. med.harvard.edu.
Honors and Advances
* Matthew Van Vranken, chief operating officer and executive vice president at Brigham and Women's Hospital, has been named one of thirteen health care leaders for the next century by Modern Healthcare magazine in its September 15 issue. He served as executive vice president and CEO at the Hospital of Saint Raphael in New Haven, Connecticut, before joining BWH earlier this year.
* The National Space Biomedical Research Institute has awarded a total of $1,734,400 for the first year to 11 Harvard Medical School faculty members for research projects related to the effects of space flight on the human body. The investigators are Fred Goldberg, HMS; Emery Brown, MGH; Nadia Rosenthal, MGH; David Krebe, MGH; Edward Brown, BWH; Charles Czeisler, BWH; Gordon Williams, BWH; Derk-Jan Dijk, BWH; L. J. Suva, BID; B. H. Lorrell, BID; and Conrad Wahl, MEEI. NSBRI was recently established through a competitive award from NASA to a consortium of educational organizations that includes Harvard and is led by Baylor College of Medicine.
* Timothy A. Springer, the Latham Family professor of pathology at Harvard Medical School, has been ranked number 12 in a list of "Authors of High-Impact Papers in Biomedicine, 1990-96" by Science Watch. His paper "Adhesion Receptors of the Immune System" alone has received more than 3,400 citations. He is also the highest-ranked author in immunology research, according to Science Watch.
* This month, the American College of Surgeons will dedicate the 1997 volume of the Surgical Forum to William Silen, dean for faculty development and diversity, HMS, and surgeon-in-chief emeritus, BID. This honor recognizes Silen's outstanding accomplishments in research and commitment to principles for which the Surgical Forum is widely known.
* McLean Hospital has been awarded a four-year, $2.7 million grant from the National Institute on Drug Abuse to study two classes of new anticocaine medications. Investigators in McLean's Alcohol and Drug Abuse Research Center will identify the safest and most effective medication for cocaine abuse treatment and explore the basic mechanisms of its anticocaine actions.
Harvard is one of six institutions in a consortium that will participate in the U.S.-Europe Medical Educational Exchange Project, beginning in September 1998. Also included is Ludwig Maximilians University, an affiliate of Harvard Medical International. Two to three students per year will be paired with a student at a host institution for a one-month clinical training rotation. They will compare health care delivery systems in Europe and the U.S., following a patient through the health system of the host country to analyze its response to the patient's needs. The students will then write a case study based on the patient's experience. The schools in the consortium plan to publish these studies and use them in their clinical curriculum.
Donald N. Medearis Jr., the Charles Wilder distinguished professor
of Pediatrics at Harvard Medical School and chief of pediatrics at Massachusetts
General Hospital, died of heart failure on September 29 at the age of 70.
In addition to being an expert on virology and the transmission of infections from mothers to newborns, Medearis was an advocate for specialized emergency room services for children. He explained that often emergency rooms and ambulances are not equipped with instruments and medicine appropriate for treating children, who require smaller cervical collars for neck injuries, for instance. He was instrumental in establishing an integrated medicine/pediatrics residency training program at MGH and Brigham and Women's Hospital. He was also appointed by President Jimmy Carter to serve on the President's Commission for the Study of Ethical Problems in Medicine and Behavioral Research from 1979 to 1982.
Medearis continued to be active in teaching pediatric residents and fellows at MGH after stepping down as chief in 1995, working on behalf of "Nobody's Children," a program that brings seriously ill Bosnian children to Boston hospitals for medical care.
Born in Kansas City, he graduated from the University of Kansas and Harvard Medical School and served in the Naval Reserve. He went on to become dean of the University of Pittsburgh School of Medicine, chief of pediatrics at Cleveland Metropolitan General Hospital, and chairman of pediatrics at Case Western Reserve University before joining MGH in 1977.
He is survived by his wife, Mary Ellen Marble; two daughters, Ellen and Jennifer; two sons, Donald and John; two brothers, Kenneth and Robert; and two grandchildren.
Learning from the Beginning About End-of-Life Care
The syllabus is passed out, the introduction is given. Now the group is silent. Thirty students and a handful of faculty members face one man, who sits alone in a chair facing them. He talks about his sickness, about what it's like to know he will die, about God and the afterlife, about the sadness the ordeal has brought his family. He talks about his doctors, about how callously they told him he had one month to live.
The lesson has begun.
From the first day of their Living with Life-Threatening Illness class, HMS students are face to face with the realities of palliative care. After listening to a patient describe his situation, students discuss how the story made them feel and how they, as physicians, might have handled the situation differently. The course is Harvard's first attempt to focus on palliative care as a separate kind of treatment--one that combines clinical medicine with psychiatry, ethics, humanities, spirituality, and religion.
Now in its fourth year, this elective course is the brainchild of J. Andrew Billings, assistant clinical professor of medicine at Massachusetts General Hospital and director of the nine-month-old MGH Palliative Care Service (PCS), and Susan D. Block, assistant professor of psychiatry at Brigham and Women's Hospital. Also involved were two former Harvard medical students, Anne Hallward and Josh Hauser. Though the class is taken primarily by first- and second-year students, third- and fourth-year students can gain similar experience by spending time on the PCS during clinical rotations.
Filling a Generation Gap
"Is there a rotation in which people don't die?" Billings asks rhetorically. "If people are there, especially as the population of elderly in this country increases, there will inevitably be end-of-life issues to address."
Billings and Block started the class to fill what they saw as a need for adequate education in the country's undergraduate medical curriculum to address those issues. Only 11 percent of undergraduate medical programs offer some formal teaching about death and dying, according to an article the two published in the September 3 Journal of the American Medical Association. The same article states that on the graduate level, only 26 percent of residency programs offer classes on end-of-life care.
"Palliative care has, for years, been a subject that many physicians don't like to talk about. It's been an area of grief and sadness--an area that since it almost always ends in death, has long been associated with medical failure," Billings says. "Teaching about palliative care is usually folded into scattered courses in other areas."
Not anymore. During the class, each student is assigned to a terminal patient. Students follow their patients through the course of illness, meeting with them at home, during office visits to the doctor, and when they are hospitalized. Students also spend time with the patients' families and learn what it is like for those relatives to endure the treatment of their loved one. When a patient dies--and last year, one-third of the students' patients did--students are encouraged to attend the funeral and wake to better understand the bereavement process. This practical learning is supplemented by weekly seminars, reading assignments, and small group discussions, when students get together in groups of six and exchange stories from the previous week. In these sessions, students work on interviewing skills, discuss personal reactions to patients, and learn approaches to palliative care.
"Death is always something different for different people in different cultures," Billings says. "Improving communication skills is an essential part of enhancing palliative care education."
Currently, the class offers each group of six students three physician mentors, doctors who can focus on positive aspects of their own palliative care experiences. Block and Billings anticipate receiving funding from the National Cancer Institute to train and support more faculty members as role models. More mentors means more scheduling flexibility, and in the future, Billings says, more classes dealing with end-of-life care.
--Matt Villano
Focus
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