Michael Brown delivers the graduation address
What does Stanley B. Prusiner, MD 1968, have in common with Michael S. Brown, MD 1966, besides graduating from the Perelman School of Medicine? Both are members of an exclusive and celebrated group -- recipients of the Nobel Prize in Medicine or Physiology. In May, both returned to the Penn campus to attend different events.
Prusiner, who also earned his bachelor’s degree in chemistry from Penn in 1964, has been a professor of neurology and biochemistry at the University of California at San Francisco for many years. It is there that he also completed his clinical training. In addition, Prusiner is director of the UCSF Institute for Neurodegenerative Diseases. Brown works at the University of Texas Southwestern, where he is a Regental Professor, the Paul J. Thomas Professor of Molecular Genetics, and director of the Jonsson Center for Molecular Genetics. He, too, was a chemistry major as a Penn undergraduate -- when, that is, he wasn’t creating some controversy as an editor of The Daily Pennsylvanian.
Prusiner was awarded the Nobel Prize in 1997 for his discovery of “prions,” a new biological principle of infection. Appearing as the first guest speaker at the Department of Medicine’s “Celebration of Research,” Prusiner described prions as alternatively folded proteins that undergo self-propagation. “We thought of proteins as static -- but they change.” After presenting his research, he had to withstand years of skepticism and even scorn in the scientific community. Now, however, prions are widely accepted as a new class of pathogen implicated in diseases marked by slow onset and progressive deterioration of the brain and the nervous system. One of the most common forms is mad cow disease, aka bovine spongiform encephalopathy. In sheep with scrapie, it manifests as abnormalities of gait, severe itching of the skin, and invariably death. In humans, prions cause Creutzfeldt-Jakob disease (resulting in progressive dementia) and kuru (characterized by tremors, lack of coordination, and death). According to the Nobel Committee’s release, “Stanley Prusiner’s discovery provides important insights that may furnish the basis to understand the biological mechanisms underlying other types of dementia-related diseases, for example Alzheimer’s disease, and establishes a foundation for drug development and new types of medical treatment strategies.”
In his recent remarks at Penn, Prusiner pushed further. There was “mounting evidence,” he said, that prions also cause most, if not all, neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. As some comments on Alzforum a couple of years ago suggest, however, he will probably have to produce more evidence to convince some of his scientific colleagues on that score as well. But Prusiner has demonstrated determination and persistence throughout his career. At the Celebration of Research, he began by stating how delighted he was to be back on campus: “I come back whenever I can. My time at Penn changed my life.” As he went on to explain, he would marvel at all the Penn professors doing research, and he discovered his calling in science. One of the scientists he worked with as a medical student was the late Britton Chance, PhD, the celebrated professor of biochemistry and biophysics. When Prusiner won the Nobel Prize, Chance called him “one of the most meritorious of winners, because he had to work against so much doubt and adversity.”
This Year's Graduation Speaker
For Michael Brown, the return to Penn this May came about because of an anniversary he could not ignore -- it would be 50 years since his medical class graduated. Even more, he was selected as the medical school’s graduation speaker. But before the graduation exercises, Brown sat down for a Medical Alumni Weekend Q. and A. with J. Larry Jameson, MD, PhD, dean of the Perelman School. The chat was wide-ranging, informative, and often humorous.
“What is in the water at Cheltenham High School?” asked the dean, suggesting that many of the school’s alumni, like Brown, have gone on to make their marks in the world. Brown, parrying, replied, “the most famous graduate of Cheltenham High School is Reggie Jackson,” the baseball Hall of Famer. “I hate to admit this,” Brown said. “I wanted to go to Princeton.” He was admitted there but not offered a scholarship. So he came to Penn, which did offer him one.
Talking about his time spent at The Daily Pennsylvanian, Brown noted that the period from 1958 to 1962 was the beginning of a social, economic, and scientific transition. The staffers of the D.P., he said, “were pretty brutal in our criticisms of Penn traditions” -- among them, the student government and . . . cheerleaders. Back then, there was a separate College for Women, and The Daily Pennsylvanian put out a parody issue of that school’s paper. It was no surprise that the University administration closed the D.P. down. Not to be outdone, the student reporters got in touch with other newspapers and even local TV stations, complaining that Penn “was against freedom of speech.” Brown said that he almost lost his scholarship. But, as Dean Jameson pointed out, “you still got into med school.”
Meeting a Scientific Collaborator
It was as an intern in internal medicine at Massachusetts General that Brown met the person who was to be his scientific collaborator, Joseph L. Goldstein, MD. Then both of them were accepted into the exclusive fellowship programs at the National Institutes of Health. During that time, they saw two very sick children as patients. The girls had very elevated cholesterol, about 10 times normal. Brown recalled that they had angina and couldn’t run across the room without chest pain. There was, he and Goldstein decided, very little they could do for the girls. Putting them on a zero-cholesterol diet was not successful. “The cholesterol,” Brown said, “didn’t go down one iota.” The physicians eventually realized it was a genetic issue. “We decided to work together to solve the problem.” At the end of their time at the NIH, Goldstein was heading back to Southwestern Medical School in Dallas, where he had been promised a faculty position if he returned to establish a division of medical genetics. As Brown explained, he and his wife, Alice, who grew up in New York, were reluctant to join Goldstein in Dallas, especially when Brown had an option to go to San Francisco. But he chose to continue the work together with Goldstein.
As Jameson interjected, “It’s such a powerful stimulus” to try to solve unsolved problems.
What Brown and Goldstein went on to discover was the low-density lipoprotein (LDL) receptor, which controls cholesterol in blood and in cells. In people who have complete or partial lack of functional LDL receptors, the level of cholesterol in the blood increases; it may accumulate in the wall of arteries, causing atherosclerosis and eventually a heart attack or a stroke. Their work laid the groundwork for drugs called statins that block cholesterol synthesis, increase LDL receptors, lower blood cholesterol, and prevent heart attacks.
Reaching such insights, Brown emphasized, takes time and hard work and, indeed, luck. It also requires proving or disproving your hypotheses: “The ones you learn the most from are the ones that fail.”
In addition to the Nobel Committee, both Prusiner and Brown have been honored by many other scientific and professional organizations. Each has also received the highest honor the Perelman School of Medicine bestows on its alumni – the Distinguished Graduate Award. Brown received his in 1985, Prusiner in 1991.