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When President Richard C. Levin outlined his vision for the University’s future—“Preparing for Yale’s Fourth Century”—in these pages in December 1996, many on the campus wondered what exactly he meant by the piece’s main theme, the pursuit of “selective excellence.” While many sympathized in principle with the President’s wish to “take advantage of the substantial interconnectedness among our schools, departments, and programs,” and agreed that Yale may not be able to be all things to all people, they wondered aloud what it was going to be and to whom.
A telling answer to that question has now emerged in the form of a recently inaugurated undergraduate program. Drawing on expertise in medicine, high technology, and the basic biological and physical sciences, the emerging area of study is generally known as biomedical engineering. And according to D. Allan Bromley, the Sterling Professor of the Sciences and dean of Yale’s once-embattled engineering department, the new major is a perfect expression of the President’s goals. “ We already had world-class expertise in such areas as microelectronics, combustion research, separation science, and catalysis,” says Bromley, “but we were also looking for new and emerging areas to focus on—areas that would tie together loosely connected activities and achieve synergies with other schools and departments at Yale.”
The result is that in various parts of the Yale campus, some biotechnologists are creating genetically engineered organisms, while others are figuring out how to separate the molecular wheat from the chaff to produce useful bioengineered end products. In related efforts, researchers are developing information systems that can keep physicians up-to-date on the latest medical news, and communications systems that enable surgeons to operate by remote control on patients thousands of miles away. There are scientists studying artificial vision, and at least one team of investigators is trying to cure bad backs.
Although the new program embraces several formerly discrete disciplines, it traces its origins to the study of medicine. But in 1996, with a three-year, $750,000 Special Opportunity Award from the Whitaker Foundation, the concept began to grow. While not yet represented by a department of their own, biomedical engineers are now engaged in activities as diverse as uncovering new ways to provide images of the body at work and developing artificial organs and biomaterials. According to John Gore, professor of diagnostic radiology and interim chair of the program, the rapid development of this relatively new subdiscipline makes perfect sense in the era of molecular biology. The division of engineering along mechanical and chemical lines, he says, “reflected the major technologies of the Victorian era.” The more recent addition of electrical engineering to the mix dovetails with the digital age. The evolution of biomedical engineering is simply the logical next step.
Gore, a physicist who directs Yale’s Center for Nuclear Magnetic Resonance Imaging Research, explains that while it’s “difficult to draw precise perimeters” around biomedical engineering, the discipline as it will be practiced at Yale offers students a choice among three tracks: medical imaging, biomechanics, and biotechnology. Imaging, particularly the technique that relies on what is known as magnetic resonance (MR), has long been employed by physicians. In recent years, says Gore, it has also become a “ powerful tool for understanding structure and function.” MR images of the brain, for example, are being used by Patricia Goldman-Rakic, professor of neuroscience, to investigate schizophrenia (Yale Alumni Magazine, Dec. 1996). Bradley Peterson, the Elizabeth Meers and House Jameson Assistant Professor in Child Psychiatry, works with the technique to understand how the brain loses the ability to control impulsive behavior, a hallmark of Tourette syndrome. MR also figures heavily in research into topics as diverse as the biology of thought and emotion, and techniques are now being developed to provide physicians such as Dennis Spencer, the Harvey and Kate Cushing Professor of Neurosurgery, with highly detailed anatomical maps that will help surgeons perform delicate operations on the brain with minimal damage.
“MR is a valuable navigation tool,” says James Duncan, professor of diagnostic radiology who holds a joint appointment in electrical engineering. “In one kind of operation, parts of the brain are cut out to attempt to stop epileptic seizures, and the surgeons have to be very precise,” says Duncan. But even the most accurate pre-surgery map currently available is, at best, an approximation because “ during an operation, the brain swells,” he continues. The expansion—on the order of five to seven millimeters (between two- and three-tenths of an inch)—is large enough to place scalpels in dangerous territory if a surgeon doesn’t adjust for the deformation. “ One goal of our research in biomedical engineering is to develop imaging techniques that will help us understand and estimate how the brain’s shape changes,” says Duncan.
Another goal is to bring together a variety of imaging methods that will make it possible to diagnose ailments such as heart disease without surgery, and to determine how well various treatments work. Duncan and his long-time collaborator, cardiologist Albert Sinusas, an associate professor of internal medicine, recently received a $1.2-million grant from the National Institutes of Health to develop techniques that can produce maps of the heart’s left ventricle, the main pumping chamber. “This is the spot that gets especially hard hit during many heart attacks,” says Duncan. “When the blood supply is cut off, the heart muscle dies and its mechanical properties change. It’s no longer an efficient pump.”
The researchers are using a combination of MR, X-ray, and ultrasound imaging methods to determine precisely how the left ventricle is altered both before and after the attack. Every sixteenth of a second, a computer compiles data on the stresses and strains inherent in a heart beat, and then quickly converts the measurements into a picture of the ventricle that rhythmically opens and closes on the computer screen. Damage is clearly visible as both a change in the thickness of the muscle and an alteration in the pumping pattern. This ability to watch the heart in action—without actually opening up the chest, or, as is common practice now, inserting a dye-injecting catheter—may, says Duncan, enable doctors to track how well drugs or surgery have worked to heal heart disease.
On a related front, Sinusas is currently working with the U.S. Surgical Corporation of Norwalk, Connecticut, to determine the usefulness of laser revascularization, an experimental technique in which a laser is used to “drill” holes in muscle damaged during an attack. In response, the muscle gets a new life. “ There is some evidence that this method seems to work,” says Duncan. “The ability to provide images of the ventricle as it pumps should help us determine the usefulness of this strategy.”
This combination of basic science and practical application is typical of biomedical engineering, says Pengcheng Shi, a postdoctoral fellow in diagnostic radiology who works with Duncan and Sinusas to develop the heart-imaging techniques. “ In this field we often try to accomplish two goals at once,” says Shi. “No one really knows how the heart moves, so we’re trying to find out. At the same time, we’re attempting to develop strategies that can help the heart move right.”
Or cure a bad back. During a person’s lifetime, “lower back pain is a problem experienced by 60 to 80 percent of the population, and it causes $50 to $100 billion in lost productivity each year,” says Jacek Cholewicki, assistant professor of orthopedics and rehabilitation. Cholewicki teaches the biomedical engineering program’s core course in biomechanics, a subject that employs engineering, electrical, and mechanical principles to understand the fundamentals of biology. Working with Manohar M. Panjabi, professor of orthopedics and rehabilitation, the researcher has used those principles to help figure out the answer to a puzzling and eminently practical problem: why headrests in automobiles don’t necessarily prevent whiplash. At present, Cholewicki and post-doctoral research associate Andrea Radebold are also attempting to determine how the complex arrangement of vertebrae, ligaments, disks, and muscles in the lower back work—and, too often, don’t.
“There are many reasons for back pain, such as inflammation, disk problems, and nerve impingement,” says Radebold, a physician from Germany, “but in the majority of cases, everything looks normal.” To understand the modus operandi of healthy backs, the two researchers place subjects—some of whom have never experienced problems and others who have had bad backs but are currently fine—in a device Cholewicki built that has at least some resemblance to a medieval torture chamber. With the 12 major muscle groups wired with electrodes, the subject, who stands upright, has to carry increasing amounts of weight.
Cholewicki knows a thing or two about this activity. “ I got into biomechanics hoping to find a better technique for powerlifting,” he says. The sport’s heavyweight champions (Cholewicki, though still powerful, does not include himself among them) can lift 600 to 800 pounds, an activity that puts a compressive force of some 4,000 pounds on the disks of the spine. But in clinical tests, the disks have popped when exposed to compressive forces of 1,000 pounds or less. So, he wondered, how did the system work? Cholewicki quickly discovered a partial answer. “Much of the testing was conducted on cadaver spines removed from bedridden 80-year-olds, and these were obviously a lot weaker than the spines of 24-year-old power lifters in their prime.”
Another critical difference lay in the musculature developed through training. “The spine is inherently unstable, and the muscles act like guy wires to stabilize it,” says Cholewicki. To prevent injury, people (and powerlifters) often use belts as a kind of brace, but in recent studies, the researchers have found that the “ effectiveness of belts is questionable,” says Radebold. “They might be useful in the beginning phase of rehabilitation, but over the long term, they may allow the muscles to get lazier.” So far, the researchers have not come up with a way to avoid bad backs, but exercise will undoubtedly figure prominently in any reengineering strategy.
Exercise is also important in the work of Steven S. Segal, an associate fellow at the John B. Pierce Laboratory, a Yale-affiliated research center that specializes in studying the interaction between human health and the environment. Segal, who is also an associate professor of cellular and molecular physiology at the Medical School, teaches “Physiological Systems,” one of the biomedical engineering program’s core courses.
“The beauty of physiology is the dynamic interaction between systems, all of which have to work together,” Segal says. For this kind of cooperation to occur, the various systems of the body need to be able to talk to each other, and nowhere is this more true than during exercise. “When you go from rest to peak aerobic performance, there can be a 25-fold increase in the amount of oxygen consumed by the muscles,” Segal explains.
The matching of oxygen delivery to demand occurs primarily in the microcirculatory system, the network of tiny blood vessels ranging in size from the diameter of a human hair to those one-tenth this width. Blood flow control, says Segal, is “where the action is.”
Over the past century, engineers have devoted considerable study to the problem of “fluid dynamics”—understanding what happens when a liquid flows through a pipe. Every time you turn on a water faucet, you make practical use of some exceedingly complicated theories. “ The cardiovascular system is the living epitome of fluid dynamics,” Segal notes. But unlike the relatively straightforward, if mathematically formidable, models engineers and physicists have worked out to depict the movement of liquid, blood flow can’t be envisioned as “just a bunch of fluid going down a straight, rigid tube.”
Blood vessels branch extensively and follow winding courses. The vessel walls are flexible, and plaque buildup, the hallmark of atherosclerosis, can change, or even stop, established flow patterns. And in the microcirculatory system, the blood cells can be wider than the vessels through which they must pass.
To determine how the body might deliver the goods necessary to fuel the high energy demands of exercise, Segal first had to “ figure out a way to look inside the box."To do so, he uses a new imaging method called “ intravital video microscopy,” and when he and his colleagues focused attention on the tiny arteries that feed muscles, he saw blood vessels increase their diameters almost instantaneously.
Segal was interested in the control mechanism and made a surprising discovery: The rapid dilation wasn’t just under the control of the nerves. Rather, the muscle cells and those making up the blood vessels were also talking directly to each other using electrical and chemical signals.
Understanding this cell-to-cell communication is of more than just academic interest. “ Every tissue in the body depends on blood flow,” says Segal, adding that research into the fundamental nature of the microcirculatory system may lead to better treatments for heart and vascular disease, as well as to the development of artificial organs and the restoration of the function of paralyzed muscles.
In The Fantastic Voyage, a group of adventurers and physicians and their submarine were miniaturized for a journey through the body’s veins and arteries. “That movie remains science fiction,” says Mark Reed, professor of electrical engineering, “ but we’re in the process of developing what we call microelectronic diagnostic systems, micromachines that can be put inside the body to measure tiny things like molecules, even electrons, within living cells. Biomedical engineering is bringing technology to the cellular level.” Adds Allan Bromley: “ We have the pieces to create an enormously exciting field. Now we are putting them together.”
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