The Nobelists Return to Campus

By John Shea

Determination, long hours, patience, insights: it’s no sur­prise that these would be essential for making scientific dis­coveries. What may be less expected in this rigorous realm is another element – luck. But Penn’s two living recipients of the Nobel Prize in Physiology or Medicine, Michael S. Brown, M.D. ’66, and Stanley B. Prusiner, M.D. ’68, both acknowledge that luck does play a role.

In a question and answer session with J. Larry Jameson, M.D., Ph.D., dean of the Perelman School of Medicine during May’s Medical Alumni Weekend, Brown talked about the work that went into the prize-winning research he and his long-time colleague, Joseph L. Goldstein, M.D., performed.  In announcing that they had won the 1985 Nobel Prize, the press release from the Nobel Assembly at the Karolinska In­stitute stated: “Studies on patients with familial hypercholes­terolemia (FH) by Michael S. Brown and Joseph L. Goldstein constitute founding stones for our present knowledge con­cerning the cholesterol metabolism.” 

Reaching such insights, Brown emphasized, takes time and hard work. It also requires proving or disproving your hy­potheses: “The problem is that 99% of your hypotheses turn out to be wrong,” he told the audience. “The ones you learn the most from are the ones that fail.” He also cited what he called “the scientist’s foxtrot” – one step forward, one step back. Then, more surprisingly: “Luck has to play a role.”

Prusiner, who returned to campus in May as the first speaker at the Department of Medicine’s “Celebration of Re­search,” also acknowledged the amount of work involved in making discoveries. Prusiner was awarded the Nobel Prize in 1997 for his discovery of “prions,” a new biological principle of infection. When he began his studies of scrapie in sheep, it was, he said, “a heroic task” – it took one full year to assay a single sample. Advances in technology certainly made part of the research easier. In his book Madness and Memory: The Discovery of Prions (2104), Prusiner also addressed the topic of luck: “Any commentary on scientific discoveries must in­clude a discussion of luck. Extremely intelligent men and women can toil for years in the vineyards of science and never be fortunate enough to make a great discovery. And then there are a few people (I include myself) who are the recipi­ents of a mammoth dose of good luck.”

What separates Brown and Prusiner from the rest of us, however, is what the discoverers can actually do with what luck may have provided. They have the ability to realize its potential. 

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. At the University of Texas Southwestern, Brown 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 (Class of 1962) – when, that is, he wasn’t creating some controversy as an editor of The Daily Pennsylvanian.

A New View of Proteins

Appearing at the “Celebration of Research,” Prusiner de­scribed prions as alternatively folded proteins that undergo self-propagation. “We thought of proteins as static – but they change.” When he began to share his research, however, 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 in 1997, “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. 

Learning at Penn – and at the NIH

At the Celebration of Research, Prusiner 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 soon discovered his calling. One of the scientists he worked with as a medical student was the late Britton Chance, Ph.D. ’40, 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.” In Madness and Memory, Prusiner recalls the stimulating classes at Penn and what he calls “the excitement of intellectual inquiry.” 

One of his early mentors was Sidney Wolfson, G.M. ’59: “Beginning in the summer before my senior year at Penn, I studied brain swelling in rats with Sidney Wolfson, and the experience persuaded me to stay on at Penn and enter the medical school there. Wolfson showed me how to read scientific papers and analyze data. He taught me statistics and how to formulate a scientific problem. He spent an im­mense amount of time helping me delve into the fascinating world of scientific research.”

After earning his M.D. degree from Penn and taking a med­ical internship at UCSF, Prusiner joined the National Institutes of Health as a research associate and lieutenant commander in the U.S. Public Health Service. He spent the next three years in the laboratory of Earl Stadtman, a biochemist who special­ized in enzymes.

Another scientist Prusiner admired at the NIH was the late Louis Sokoloff, M.D. ’46, G.M.E. ’50, a pio­neer in brain-scanning. As Prusiner puts it in his book, “Lou’s enthusiasm for neurochemistry was infectious, and I soon be­came a great admirer.” As it turned out, in Stadtman’s lab, Prusiner also worked for a time with a certain Michael Brown, who had been two years ahead of him at Penn.

The Water at Cheltenham? 

For 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, M.D., Ph.D., 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. He named two other Penn Med faculty members from the school: Lee Fleisher, M.D., chair of the Department of Anes­thesiology and Critical Care, and L. Scott Levin, M.D., chair of the Department of Orthopaedic Surgery. Among those in the school’s official Hall of Fame are Michael and Randy Brecker, who both won Grammy Awards for jazz; Richard Levinson and William Link, Emmy Award-winning TV writ­ers and producers; Mary Ellen Mark, described by The New York Times as “one of the premier documentary photogra­phers of her generation”; and Benjamin Netanyahu, prime minister of Israel. 

But Brown, parrying, replied, “the most famous graduate of Cheltenham High School is Reggie Jackson,” the baseball Hall of Famer. When Brown won the Nobel Prize in 1985, the cur­rent principal of the high school asked his permission to mount a plaque at its baseball field, with the legend “This is where Michael Brown, Nobel Laureate, played baseball.” Brown replied: “On one condition, that there be a similar plaque in the chemistry lab, noting that this is where Reggie Jackson took chemistry.” Neither plaque was placed. “I hate to admit this,” Brown continued, entering dangerous waters, “I wanted to go to Princeton.” He was accepted there but not offered a scholarship. So he came to Penn, which did offer him one.

During his chat with Dean Jameson, Brown recalled the in­fluence of Samuel Gurin, Ph.D., a rarity among Penn Med deans because he did not have a medical degree. Brown also cited Albert I. Winegrad, M.D., a specialist in diabetes. “There were some very, very good people at Penn,” Brown said, “some really inspirational people.”

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, as a result, 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.” In the tumult, Brown said, he almost lost his scholarship. But, as Dean Jameson pointed out, “you still got into med school.”

Finding a Collaborator

It was as an intern in internal medicine at Massachusetts General Hospital that Brown met the person who was to be his scientific collaborator, Joseph L. Goldstein, M.D. Goldstein had come from Southwest Medical School in Dallas. Brown, who had not ventured south at that time, said, “I thought it was a bible school!” But they became friends. Then both of them were accepted into the exclusive fellowship programs at the National Institutes of Health. During that time, Brown said, they saw two very sick children as patients. They 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 children. 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 fellowships 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 ultimately he chose to continue his work with Goldstein.

As Jameson interjected, “It’s such a powerful stimulus” to try to solve unsolved problems.

The Road to Statins

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. 

As the 1985 press release from the Nobel Assembly at the Karolinska Institute stated: “Studies on patients with familial hypercholesterolemia (FH) by Michael S. Brown and Joseph L. Goldstein constitute founding stones for our present knowledge concerning the cholesterol metabolism.” Their work laid the groundwork for the drugs called statins, that block cholesterol synthesis, increase LDL receptors, lower blood cholesterol, and prevent heart attacks. “Everyone in this room understands the importance of statins,” Jameson said.

There were some aspects to winning the Nobel Prize that didn’t appeal to Brown. For example, when he and Goldstein won the honor, they were invited to appear on Today and The Tonight Show. They turned down the opportunity for additional publicity – for themselves, but also, it seemed, for their Dallas base. According to Brown, they were rewarded with a headline in one of the Dallas newspapers, signaling its annoyance, along the lines of “Nobel Prize Winners Retire to Their Cells.”

What he is most proud of, Brown said, are his two partner­ships: with his wife Alice and his colleague Goldstein. “Having a scientific partner is a great thing, he continued. It is a great feeling “being able to share the thrill of discovery.” At present, with students and postdocs doing the experiments, Brown and Goldstein still run their laboratory. “We never had the prize as our goal,” Brown said. “There are still lots of unsolved problems.”

“We’ve Got to Do More”

During Prusiner’s visit in May, he took a few moments to praise the research of Virginia Lee, Ph.D., and John Q. Tro­janowski, M.D., Ph.D., who head Penn’s Center for Neurode­generative Disease Research, and noted “a lot of work by many, many people” that has advanced the field. He also pointed out how newer technology has affected that study. When he began his studies of scrapie, it was “a heroic task” – it took one full year to assay a single sample. He also alluded to some of the recent tragedies involving neurodegenerative diseases: the suicide of Junior Seau, the National Football League star, and even the suicide of a Penn football player in 2010, whose family donated his brain for research. In both cases, there was evidence of chronic traumatic encephalopa­thy. Addressing the younger people in the auditorium, he said, “We’ve got to do more.”

But the talk was not all solemn. Referring to his white hair, Prusiner exclaimed: “I’m not an albino – when I was a college student and a medical student, I had brown hair!” And while still a medical student and considering a future as a cardiolo­gist, he went to see an open-heart operation. To his dismay, as he put it, “A lot of surgery was involved!”

Prusiner also pointed out that there is still resistance to pri­ons – to the name (which he coined) and to what it describes as well. Some researchers, he continued, choose to use differ­ent names for them: proteopathic seeds, transmissible protein, and self-propagating strains, to name a few. “This disingenuous behavior obscures progress in a field that is screaming for effective therapeutics.”

Where Will the Evidence Lead?

As noted, during his visit to Penn, Prusiner argued that there was increasing evidence that prions also cause most, if not all, neurodegenerative diseases – and he includes Alzhei­mer’s disease and frontotemporal dementia. In his book, he wrote that, after years of research, “we are now at the point where the burden of proof is beginning to shift from those who claim prions cause such common illnesses as Alzheimer’s and Parkinson’s to those who deny this etiology.” As com­ments on Alzforum a couple of years ago suggest, however, some scientists maintain the burden of proof remains on him, and he will probably have to produce more evidence to con­vince some of his scientific colleagues on that score as well. But observers have certainly learned that Prusiner is a fighter who has faced, as he put it in his book, “a legion of naysayers” and stayed the course.

A passage in Madness and Memory that shows Prusiner’s grasp of the status of scientific research appears in the Ac­knowledgments section. In addition to thanking many indi­viduals and agencies, he wrote: “I am very appreciative of the opportunities given to me by the American people, who through their generosity, wisdom, and taxes have supported our scientific investigations for more than three decades.”

The Need for More Research 

In Prusiner’s epilogue, titled “The Quest for Therapeutics,” he reported that one of his friends admonished him for not offering a more optimistic outlook on the quest to cure Alz­heimer’s. In response, Prusiner said that he “believed biomed­ical science would eventually come up with effective medica­tions but that it is misleading to tell people that modifying their diet, doing crossword puzzles, or learning a foreign lan­guage would protect them from Alzheimer’s when there was no meaningful evidence to support such an assertion.” He also stated his unfavorable opinion about the drug Aricept, as he did during his Penn visit. Although Aricept and its copies “generate revenues of about $3 billion annually, these drugs do not retard the relentless progression of Alzheimer’s disease.”

But there is at least one topic on which all researchers who study neurodegenerative diseases can agree: the need for con­tinued research – and for expanded support. Using a dramatic but effective metaphor, Prusiner wrote in his epilogue: “Imag­ine a foreign country assaulting our nation and killing 500,000 Americans. We would commit hundreds of billions of dollars to vanquish the enemy. Yet 500,000 Americans die of Alzhei­mer’s annually, and we continue to allocate only 1.5 percent of the budget of the National Institutes of Health to Alzheimer’s research. In contrast, cancer research consumes more than 22 percent of that budget.” As he put it, more accurate reporting would place Alzheimer’s among the top three killer diseases in America, and yet drug discovery for degenerative brain dis­eases lags far behind. A change is long overdue.