Robert Alpern, Diane Jorkasky, Richard Levin and Pfizer CEO Jeffrey Kindler

PET Center opens on Howard Avenue

New tools for diagnosis and treatment are available to clinicians and patients.

Despite recent advances in molecular medicine, physicians are still in the dark about many diseases, gleaning clues to a therapy’s effectiveness only by studying changes in symptoms. Even as doctors seek the best treatment, patients may deteriorate. At Yale’s new Positron Emission Tomography (PET) Center, researchers hope to bring light into this darkness by discovering novel diagnostic tools for otherwise hidden molecular abnormalities and speeding development of new medications.

PET imaging, said George Mills, M.D., director of the Division of Medical Imaging and Radiopharmaceutical Drug Products at the Food and Drug Administration’s Center for Drug Evaluation and Research, is “the essential foundation” of the agency’s efforts to modernize the process of developing new medicines. Mills spoke at the January 18 opening ceremony for the new 22,000-square-foot facility, located at 801 Howard Avenue.

PET is a noninvasive imaging technique that scans for minute amounts of radioactive material—radiotracers—that have been injected into a patient’s body to bind to specific organ sites, providing images of molecular function. Researchers and clinicians use this information to study changes in organ function as a result of disease or in response to treatment. The radiotracer can also label a drug to determine whether and how much of the compound has reached its target. Labeling enables researchers to study the safety and efficacy of different dose levels and identify biological markers of disease that can aid in diagnosis.

“The work we do here will build the knowledge we need to develop diagnostic imaging agents coupled to therapy,” said J. James Frost, M.D., Ph.D., professor of diagnostic radiology and psychiatry, chief of nuclear medicine at Yale-New Haven Hospital and director of the PET Center. Joining Frost as co-directors are lead physicist Richard E. Carson, Ph.D., professor of diagnostic radiology and biomedical engineering; and lead radiochemist Yu-Shin Ding, Ph.D., professor of diagnostic radiology. Completing the senior faculty team is Henry Huang, Ph.D., a radiochemist and associate professor of diagnostic radiology.

The development of the center was made possible, in part, by Pfizer, the pharmaceutical company, which contributed $5 million to establish it and provides $2 million annually to support PET imaging studies of mutual research interest to both parties. Most research at the center will be supported by federal grants. The company has already used the PET facilities to study a small group of patients to determine how much of a new drug for depression would be required to reach its target in the brain, and how much would generate unacceptable side effects, said Diane K. Jorkasky, M.D., Pfizer’s vice president of clinical pharmacology.

Researchers are usually required to give dosages that escalate over several months to large numbers of patients to establish the safest and most effective dose of a drug. “If we are able to avoid the need to do large-scale clinical studies like that, we’ll be saving tons of money and time, and most important, we won’t expose patients needlessly to a drug that may not have any benefit,” said Jorkasky.

Frost said the center will serve as a core facility for the entire School of Medicine. Some biomarkers discovered in the course of research projects with Pfizer or other companies will be available for faculty research projects.

Along with cardiology and oncology, other major areas of focus are Alzheimer’s disease, schizophrenia, depression, obesity, post traumatic stress disorder and other conditions that are difficult to diagnose and treat. Frost hopes that the center’s research will help to identify biomarkers for subtypes of these diseases, which can help determine the best treatment for a given individual. “Ultimately this will benefit our patients,” Frost said. “That’s the key.”

—Marc Wortman

Hands-on science program for local students brings town and gown together

The students who were asked to identify and explain the function of a muscle in the cadaver they’ve been working with in the School of Medicine’s anatomy lab aren’t enrolled at Yale, but they can take advantage of the school’s offerings. They are high school students participating in the Anatomy Teaching Program, one of several ways in which the medical school collaborates with Hill Regional Career High School, a magnet school located just a stone’s throw from campus.

Ten years ago Yale formalized a partnership with Career High that has enabled its students to benefit from the university’s expertise and resources. The magnet school attracts students from New Haven and its surrounding suburbs who are interested in a career in health, business or computer technology. The partnership began informally with the anatomy program in 1993 and has expanded to include a variety of offerings.

Yale students and faculty instruct and mentor Career High students in a number of settings. In the medical careers class, for example, Yale public health students come to Career High to speak about medical career options during the first semester, while the high school students complete an internship at Yale in the second semester. The Department of Epidemiology and Public Health donated a research-quality electron microscope to help Career students understand molecular structures; it also recommended the types of equipment that would be most appropriate for a certified nurse’s aid room set up to look like a clinic. Another learning opportunity is offered to advanced biology students who come to Yale twice a month after school with their teacher, Shirley Neighbors, to work with medical students who help them with course material.

In the anatomy course, which is also taught by Neighbors, two classes meet twice each month in Yale’s anatomy lab, where first- and second-year med students overseen by William B. Stewart, Ph.D., associate professor of surgery and chief of the Section of Anatomy and Experimental Surgery, volunteer as instructors. In small groups, the students explore such topics as cardiovascular health, energy metabolism and infectious diseases. “One of the ideas is that these kids will become community ambassadors for health,” said Stewart. For the students, it’s a rare opportunity to see firsthand the effects of disease. “We actually get to touch the [cadavers] and feel what we’re looking for,” said Career High junior Lorraine Gabriel.

In the SCHOLAR (Science Collaborative for Hands-On Learning and Research) program, a three-week summer residential science program for students entering grades 10 through 12, Career students have a chance to become fully immersed in campus life. They not only study science subjects at the college level and conduct research under the supervision of Yale faculty, but they also get a taste of college life by living in the dorms. The students normally participate in the SCHOLAR program for three years. For Minerva Ruiz, who now works in the Family Support Services section of the Yale Child Study Center, the summer program was an eye-opening experience. Attending classes in which professors treated her as a college student, conducting a study on the ways in which smoking affects the brain and tasting ethnic food at local restaurants helped make her a more open person, she said. “We were able to go off to college and be comfortable with that.”

Like many of her classmates, Ruiz, who graduated from Florida International University and plans on getting a Ph.D. in psychology, takes education seriously. More than 96 percent of Career graduates went to college in 2005 (the college-bound rate for New Haven students in general is 83 percent); for those who participate in the SCHOLAR program, the college attendance rate is 100 percent.

The collaboration between Yale and Career High doesn’t benefit only the high school students, however. As Neighbors watched second-year med student Rebecca Bruccoleri explain how food is converted to energy, she observed, “If they can find time to do this as a med student, you can imagine what kind of doctors they’ll be.”

—Jill Max

Training physicians—new ways of teaching in a changing medical landscape

For the past 32 years, Yale faculty from the Department of Internal Medicine have taught at 10 hospitals throughout Connecticut through the Yale Affiliated Hospitals Program (YAHP). Begun in 1975, YAHP is currently the largest consortium of internal medicine training programs in the United States. Its goal has always been to improve the quality of medical education throughout the state. With 446 full-time faculty among nine residency programs and more than 6,500 attending physicians, the program trains more than 450 residents in internal medicine each year. It also provides opportunities for collaborative clinical and educational research as well as selected subspecialty clerkships at Yale for affiliated medical residents. Each year 100 residents from other hospitals take electives at Yale-New Haven Hospital. Member hospitals include the Hospital of St. Raphael in New Haven, Bridgeport Hospital, Waterbury Hospital, Greenwich Hospital, Norwalk Hospital, Griffin Hospital in Derby, St. Mary’s Hospital in Waterbury, Danbury Hospital and Lawrence & Memorial Hospital in New London.

“This is a very robust relationship,” said Silvio E. Inzucchi, M.D., professor of medicine (endocrinology) and director of the program, speaking at YAHP’s 30th annual symposium in November. “After 30 years, the program is still evolving—it is clearly of mutual importance to both the department and our affiliates.” Asghar Rastegar, M.D., professor of medicine (nephrology) and associate chair for academic affairs, called it a “unique network.” Yale’s collaboration with smaller, community-based hospitals, he said, allows them to attract better faculty as well as trainees to their programs, enhance training of their residents and maintain academic links that serve as a resource. And, noted Peter N. Herbert, M.D. ’67, HS ’69, vice president and chief of staff at Yale-New Haven Hospital, a vigorous educational program strengthens the overall enterprise. “Training programs are critically important to the retention of our faculty,” he said.

But all is not well in the training of new doctors. More than a dozen speakers cited new challenges to medical education, not only in Connecticut but also in other parts of the country. Among those challenges are young doctors’ desires for a less stressful and demanding lifestyle, lack of financial support for education and the shrinking emphasis on the hospital as the primary training setting. As Herbert noted, patient contact typically takes up an hour or two of a resident’s day, while another six to seven hours are spent “doing largely clerical things that, in a practice setting, would be done by someone else.”

Dean Robert J. Alpern, M.D., Ensign Professor of Medicine cited inadequate funding for education as a major problem, observing that tuition covers only half the cost of a medical education. Clinical practice, which has traditionally brought in money to fill that gap, is increasingly under financial pressure itself. “The ability of the clinical practice to subsidize education is going away,” he said. “You can’t run a medical school without a clinical practice, but what is optimal for education is not necessarily optimal for clinical practice.”

Also of concern, said Jack A. Elias, M.D., the Waldemar Von Zedtwitz Professor of Medicine and chair of medicine, is the aging of the physician-scientist population, whose unique perspective bridges the lab and the bedside. Ten years ago, he said, 57 percent of the physician-scientists who received grants from the National Institutes of Health were 45 or older. “We are losing ground in this area at a time when translational research is blossoming.”

Panelists also cited the importance of mentorship for medical students and young doctors. Mary E. Tinetti, M.D., the Gladys Phillips Crofoot Professor of Medicine (geriatrics) and professor of epidemiology and public health, said that in the past students of either gender were linked with experienced older men, because the majority of available mentors were men. Today, however, there are women who can mentor other women and members of minority groups who can guide others from their respective backgrounds—even from afar—because they are “people who share many life experiences.”

Despite their concerns about the future of medical education, speakers also noted cause for optimism in efforts to address the challenges. Elias cited a one-year master’s program in public health at Yale that is geared to practicing physicians. Alpern said that while the financing of medical education is built on a shaky foundation, “each school figures out a way to get around it.” And Rastegar, in an interview after the symposium, said that the education at Yale rests on a core belief shared by faculty.

“Everyone feels that there are significant structural challenges we are facing,” said Rastegar. “A great deal of education depends on an environment that nurtures the trainees. Yale’s power has always been that.”

—John Curtis and John Dillon

Two decades after its founding, immunobiology becomes a department

Ever since Edward Jenner injected a young English boy with cowpox virus in the 1790s to prevent smallpox, scientists have tried to conquer infectious diseases by understanding and strengthening the human body’s immune response. Yet as recently as three decades ago, the most basic principles of modern immunology eluded researchers.

All that would change, however, when the medical school decided to continue the work of the late Richard Gershon, M.D., who had established an immunology group within the pathology department. In 1988, a visionary scientist was recruited to create one of the first free-standing immunobiology sections in the world.

Almost 20 years later, Richard A. Flavell, Ph.D., Sterling Professor of Immunobiology, remains chair, but in January the section became a full-fledged department in the School of Medicine. The group that started out as a handful of scientists has grown to include 13 world-renowned researchers, whose publications appear regularly in top-ranked scientific journals. “We strategized about it and planned very carefully what we wanted to build, and that’s what we built,” said Flavell.

Representative of the group’s far-reaching influence is the discovery of the workings of the innate immune system in the 1990s. While most researchers focused on the adaptive immune system, which creates B and T cells that target specific bacterial or viral invaders, the late Charles A. Janeway Jr., M.D., wondered how these immune responders are able to act so effectively and precisely every time the body is invaded by an infectious microbe. In a scientific tour de force, he and Ruslan M. Medzhitov, Ph.D., professor of immunobiology, showed that components of the innate system known as toll-like receptors provide the adaptive system with the necessary advance intelligence to do its job.

“It was like saying there are only four planets in the solar system and then one day somebody comes along and says no, there are eight,” said David G. Schatz, Ph.D., professor of immunobiology.

Uncovering the role of toll-like receptors in the innate immune system is just one of the advances made by the department. Flavell’s lab has identified molecules that are involved in activating and differentiating T cells and that could have implications for HIV and cancer.

Other areas of research are the similarities between allergens and microbes that jump-start the immune system; how proteins get broken down and then “presented” by antigen-presenting cells that allow T cells to recognize them; proteins that are involved in antibody production; and a protein that allows toll-like receptors to send signals and is involved in every inflammatory process.

The explosive growth of knowledge coming from the department over the last two decades has increased the awareness that the clinical relevance of immunobiology goes far beyond protection against disease. Immune mechanisms may lie at the root of numerous chronic diseases, including cancer, congestive heart failure and Alzheimer’s disease.

—Jill Max

et cetera

New grant for rickets study

Yale University has received a five-year, $5 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to form a Center of Research Translation (CORT), one of four in the country, to provide models of translational research in academic medical centers. The Yale CORT will focus on X-linked hypophosphatemic rickets (XLH), the most common form of inherited rickets in the United States. XLH can lead to deformed bones, fractures and debilitating arthritis.

The Yale Center for XLH, directed by Thomas O. Carpenter, M.D., professor of pediatrics, and co-directed by Karl L. Insogna, M.D., professor of medicine (endocrinology), has as its goals the identification and validation of mediators of skeletal disease in XLH and the development of therapeutics based on this knowledge. The center will support an educational program, a pilot projects program and three scientific studies, as well as a research core.

—J.C.

Four named AAAS fellows

Four Yale faculty members have been elevated to the rank of fellow by the American Association for the Advancement of Science.

Arthur L. Horwich, M.D., professor of genetics and pediatrics, was honored for contributions to the understanding of the role of chaperonins in mediating protein folding.

John R. Carlson, Ph.D., the Eugene Higgins Professor of Molecular, Cellular and Developmental Biology, was cited for contributions to the molecular neurobiology of olfaction.

Oswald J. Schmitz, Ph.D., the Oastler Professor of Population and Community Ecology in the School of Forestry & Environmental Studies, was named a fellow for his contributions to the understanding the emergence and maintenance of ecosystem structure and functioning, and for relating ecosystem patterns to individual behaviors.

Kurt W. Zilm, Ph.D., professor of chemistry and chemical engineering, was named a fellow for his applications of solid-state NMR spectroscopy to molecular structure and reaction mechanism determination.

—J.C.


			Originally published in Yale Medicine, Spring 2007. Copyright © 2007 Yale University School of Medicine. All rights reserved.