A mouse offers a new way to test vaccines

By implanting a human immune system into mice, scientists plan to study vaccines.

The laboratory mouse—resilient, easy to breed and ideally suited to the genetic manipulations that form the basis of much of modern biomedical research—has been invaluable to immunologists such as Richard A. Flavell, Ph.D., chair and Sterling Professor of Immunobiology. But there are limits to the usefulness of this most versatile of research animals in immunology, because the mouse immune system has been tailored over evolutionary time to deal with pathogens different from those that infect humans. To compensate, scientists like Flavell supplement their work in mice with studies of human immune cells in culture, but here, too, there are inherent compromises. The immune system, a multifaceted mechanism distributed throughout the body, is difficult to emulate in a petri dish, and the behavior of cells in culture can be a poor predictor of how a drug will work in the living human body.

Since ethical considerations prohibit testing drugs in humans before they’ve been proven safe and effective, these intrinsic limitations of the tools available to immunologists mean that bringing vaccines and other cures from the laboratory to the clinic often requires a leap across an unavoidable knowledge gap.

“You don’t really want to be studying mouse cells; you want to study human cells, and ultimately you study humans in clinical trials,” said Flavell, who is also a Howard Hughes Medical Institute investigator. “There are enormous difficulties making sure that what you do in clinical trials is safe and isn’t going to adversely affect the patient.”

But a remarkable advance in a Swiss laboratory may provide a long-sought bridge between the bench and the bedside for immunologists. In 2004, Markus G. Manz, M.D., and colleagues at the Institute for Research in Biomedicine created a rudimentary human immune system in mice by injecting human umbilical-cord blood containing stem cells and other progenitor cells into a mutant strain of mice that lack immune systems.

Manz’s paper appeared just as the Grand Challenges in Global Health initiative was accepting final proposals for grants. The initiative, funded by the Bill & Melinda Gates Foundation, the Canadian Institutes of Health Research and the Wellcome Trust, and administered by the Gates Foundation, planned to distribute more than $436 million to support innovative research on diseases that afflict the world’s poorest people. Flavell proposed that his team join forces with Manz and with Tarrytown, N.Y.-based biotech company Regeneron Pharmaceuticals to perfect a mouse model of human immunity for testing vaccines. In late June, Flavell learned that the initiative would award $17 million to the project.

“It’s akin to a ‘Manhattan Project,’ to make this work like a true human immune system, so you could really do experimentation that is predictive of the human response,” Flavell said.

A mouse model of human immunity, for example, would allow scientists to test a vaccine for HIV, which has heretofore been impossible because mice are normally not susceptible to the virus. But Flavell said that the technique will have any number of applications. “This system, once it’s up and running, could be used to study all kinds of things,” he said.

Elizabeth E. Eynon, Ph.D., a research scientist in Flavell’s lab, said that the model could make clinical trials much more efficient. “The FDA will require people to do just as many Phase I and Phase II trials as they do now,” she said, “but the likelihood of failure at those stages would be reduced if we can show safety and efficacy beforehand.”

—Peter Farley

Marna Borgstrom named to lead Yale-New Haven Hospital and Health System

Since she joined Yale-New Haven Hospital (YNHH) as a junior adminstrator in 1979, Marna P. Borgstrom, M.P.H. ’79, has become a vice president, the chief operating officer and, as of October 1, the CEO and president of the hospital and the Yale New Haven Health Systems (YNHHS). She succeeds Joseph A. Zaccagnino, M.P.H. ’70, who retired on September 30 after a 35-year career at the hospital.

During more than a quarter-century at the hospital she has watched it grow into the 944-bed flagship of a health system that stretches along Long Island Sound from Rye, N.Y., to Westerly, R.I. It is the hub of a New Haven health care delivery network that includes a children’s hospital, a psychiatric hospital, two independent ambulatory surgical centers, a large radiology practice and the Shoreline Medical Center in Guilford.

Working with Zaccagnino, Borgstrom oversaw the hospital’s $850 million budget and served as the primary liaison to the School of Medicine. She led the planning and construction of the children’s hospital, and headed up a patient safety program that trained 40 senior managers under General Electric’s process-improvement initiative known as Six Sigma. As the second- in-command at the hospital for more than a decade, Borgstrom helped develop YNHHS, an affiliation of several dozen organizations including YNHH and two other large hospitals, in Bridgeport and Greenwich, that encompasses their networks of physician practices, surgical centers, diagnostic facilities, rehabilitation centers, pharmacies and visiting nurses.

“We want to be the provider of choice—locally, of course, but also regionally and nationally,” she said. The hospital’s regional and national distinction, which Borgstrom intends to build on, reflects joint investments in unique clinical programs with the School of Medicine. She is looking forward to the construction of a $440 million clinical cancer center, currently awaiting approval from New Haven zoning officials, that will provide needed capacity for current and emerging clinical initiatives.

Other recent achievements of YNHHS include the creation of an emergency angioplasty program at Greenwich Hospital in collaboration with YNHH and physicians at the School of Medicine. Previously, emergency patients in Greenwich had to be transported out of town for the procedure. Now they can be treated locally, and elective angioplasty cases and cardiac surgeries will be referred from Greenwich to New Haven.

A revamped liver transplantation program that began operations in July has the potential to draw pediatric patients from the region and beyond, and many joint programs—in epilepsy, endocrine surgery and maternal-fetal medicine, to name several—already bring patients to New Haven from across the country. Borgstrom would like to see the list grow, so that more out-of-state patients come to the city for care.

Her appointment came a little more than a year after the arrival of medical school Dean Robert J. Alpern, M.D., in June 2004. Based on her work with Alpern during his first year here, Borgstrom sees “unprecedented opportunities” ahead for the hospital and medical school. Alpern called Borgstrom “an excellent choice for the job of CEO.”

Borgstrom earned her public health degree in hospital administration at Yale in 1979. She said the program gave her a footing in how to analyze and solve problems at a large health care organization, and also an appreciation for the public health challenges facing health care executives.

—Michael Fitzsousa

Portraits in light—artists blend medical imagery into their work

In the 1990s, when Bettyann H. Kevles, M.A., asked listeners of the National Public Radio program Science Friday to imagine their bodies intertwined with medical technology, she received seven responses, all from artists. All seven had experienced imaging techniques such as X-rays, magnetic resonance imaging, computed tomography (CT) scans and other routine procedures. One described them as “portraits in light.”

A lecturer in Yale’s Program in the History of Medicine and Science, Kevles studies how new technologies become a part of everyday life. But having grown up in a family of painters and having studied painting herself, Kevles has a long-standing interest in art. Over the years, she has built up a library of work by visual artists who explore their medical conditions in their paintings. She explored this theme, in part, in her 1997 book, Naked to the Bone: Medical Imaging in the 20th Century, and in Picturing DNA, written with Marilyn Nissenson and published online in 2000.

At a symposium on brain imaging at the annual meeting of the American Association for the Advancement of Science in Washington in February, Kevles presented the work of visual artists who had used medical imaging to create self-portraits. The survey reached back to the early 20th century and the work of Mexican painter Frida Kahlo, whose spine was severely injured in an accident when she was an 18-year-old student, and whose self-portraits show her body and spine from the inside in a manner reminiscent of X-rays. Many contemporary artists have incorporated more modern techniques. New York artist Laura Ferguson, who suffers from scoliosis, studied anatomy, consulted with orthopaedic surgeons and radiologists and imaged her body with a 3D spiral CT scan, which allowed her to visually manipulate her skeleton to observe it from different angles and in different postures. Her Visible Skeleton Series, a visual autobiography created by blending many layers of colors on paper, was on display at the National Museum of Health and Medicine in Washington this spring.

Since writing her 1997 book, Kevles has continued her study of artists such as Jennifer Hall of Boston, who has temporal lobe epilepsy and used an electroencephalogram to capture her brain waves during a seizure. She then used a computer program to transform the erratic spikes into a three-dimensional image and cast it in silver in the shape of a tiara.

In her more recent work, Kevles has explored the idea that turning medical imaging techniques into tools of self-exploration allows artists to work through their illness so they can get past seeing themselves as victims of it. “Having seen whatever it is—plaques in their brain, or an EEG of a crazy electrical storm—they no longer think of themselves as epileptics, for example. They’re people with particular parts of their bodies that don’t work,” Kevles said. “Many artists feel that their art, in this way, gives them power over their conditions.”

—Alla Katsnelson

Grey named dean of nursing

Margaret Grey, R.N., Dr.P.H., was named dean of the School of Nursing in July. Grey, previously associate dean for scholarly affairs, joined the faculty in 1993. She succeeds Catherine L. Gilliss, D.N.Sc., who served as dean from 1998 until last year. Grey, an internationally known researcher in the natural history of adaptation to chronic illness in childhood, is the author of more than 160 publications.

Yale endowment earns 22 percent, as investment steward earns plaudits

News of outstanding returns on Yale’s endowment came as the university’s chief investment officer was already riding a wave of favorable publicity. David F. Swensen, Ph.D. ’80, had recently published his book Unconventional Success: A Fundamental Approach to Personal Investment (Free Press), and finance journalists were calling him the best money manager in academia. They pointed to Swensen’s track record as manager of Yale’s endowment over the past 20 years, which has seen average returns of 16 percent. For the 2004 fiscal year, the endowment earned returns of 22.3 percent, bringing total assets to $15.6 billion. And under Swensen’s leadership, the Yale endowment routinely outperforms Standard & Poor’s 500. He credits his success to a nontraditional asset allocation with an emphasis on equity investments.

In numerous interviews with the press, however, Swensen cautioned that individual investors are unlikely to reap his returns, even if they read his book. Those who spend a few hours a week on their portfolios simply can’t compete with institutions such as Yale that have a team of full-time professionals actively managing the endowment.

“The outstanding performance by the investments office in the past year has matched a record of achievement over time that has earned David Swensen and his colleagues the highest possible praise and admiration from their peers,” President Richard C. Levin said in a press release. “Yale’s capacity to fulfill its ambitious mission has been greatly enhanced by their superb stewardship of the endowment.”

Because of Swensen’s efforts, the endowment’s share of the university’s operating budget has more than doubled over the past decade. The endowment now contributes almost a third of the university’s revenues—$610 million this fiscal year—the largest single source of support.

—John Curtis

et cetera

Goldman-Rakic fellow named

Susheel Vijayraghavan, a graduate student in neurobiology at the School of Medicine, has been selected as the recipient of the 2005 Patricia S. Goldman-Rakic Fellowship. This fellowship, established by Yale and the pharmaceutical maker Pfizer in 2003, honors the memory of the late Yale professor Patricia Goldman-Rakic, Ph.D., and highlights excellence in neuroscience research at the medical school. According to Lynn Cooley, Ph.D., director of the Combined Program in the Biological and Biomedical Sciences, Vijayraghavan’s selection is a “tribute to Dr. Goldman-Rakic’s distinguished career and to Susheel’s developing career.”

Vijayraghavan studies the effects of dopamine on working memory in primates and was Goldman-Rakic’s final graduate student before her death in 2003. As the fellowship recipient, he will receive tuition, a stipend and health care coverage, as well as additional funds for travel to scientific meetings.

—J.C.

Yale website designers honored

Patrick J. Lynch, M.S., director of the Med-Media Group of Yale’s Information Technology Services, and C. Carl Jaffe, M.D., professor of medicine (cardiology), received the 2005 Pirelli Prize for Multimedia Education and the Top Pirelli Prize for 2005 for the educational website “Introduction to Cardio-thoracic Imaging.” The prizes, which they received in Rome in June, honor technical innovations and contributions to science education through the outstanding communication of science and technology.

The Pirelli S.p.A. Group, one of Europe’s major telecommunications and manufacturing firms, has underwritten the awards since their inception in 1996. The Pirelli jury cited the extraordinary depth and breadth of the cardiothoracic imaging site (http://info. med.yale.edu/intmed/cardio/imaging).

“At no time in history does the intersection of media and science education matter more,” said Jaffe, who retired in July after 35 years on the faculty of the School of Medicine. “Ignorance of or, more importantly, denial of the truths of science obscures recognition of our common humanity.”

—J.C.


			Originally published in Yale Medicine, Autumn 2005. Copyright © 2005 Yale University School of Medicine. All rights reserved.