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Photo by Graham P. Perry

After Nearly a Half Century at the National Institutes of Health, William Eaton Continues to Make Biophysical Breakthroughs

By Jon Caroulis

It was the fall of 1967. The war in Vietnam was escalating. The University of Pennsylvania’s medical school dean Samuel Gurin, PhD, had told William Eaton, BA’59, MD’64, PhD’67, that if he did not take an internship that it was unlikely he’d be drafted into the armed forces, and that he could continue a career in basic research after graduation from medical school without interruption.

The dean was wrong.

Eaton received his draft notice, but learned he could fulfill his military obligation by joining the U.S. Public Health Service as a medical officer. He landed a research position at the National Institutes of Health (NIH) in Bethesda, Md. Now approaching the 50th anniversary of his arrival, Eaton is still there as an NIH Distinguished Investigator.

Eaton has enjoyed a prodigious career buffeted by lucky breaks—from landing in his dream job as a basic scientist instead of at the Vietnam warfront, to carrying out research alongside a gaggle of Nobelists thanks to a well-timed airmail letter—and distinguished by important insights on the physical properties of the molecules of life and disease. And at 78, he has no plans of stopping.

“When I left Penn for the NIH—a relatively unknown federal research institution at the time to my fellow chemical physics graduate students—they felt sorry for me since I was not headed for academia,” Eaton recalled. “It did not take long before they started to envy my position as a basic researcher in what I believe is arguably the greatest research institution in the U.S.”

He has served for the past 30 years as chief of the Laboratory of Chemical Physics, the major biophysical science laboratory at NIH, where he has made important discoveries on the molecular basis of sickle cell anemia and the folding of proteins. These research accomplishments have been recognized by his election to the National Academy of Sciences and many prestigious awards, including the Perelman School of Medicine’s Distinguished Graduate Award in 2014. Since 1986, Eaton has been the scientific director of the NIH’s Intramural Aids Targeted Anti-viral program (IATAP), taking time away from his own research to oversee a significant part of NIH’s basic research on the human immunodeficiency virus (HIV) and recruiting scientists to come to the NIH to work on HIV structural biology.

In West Philadelphia, Born and Raised

Eaton grew up not far from the Penn campus within a family of Penn graduates. Family members who are also Penn alumni include his mother—who Eaton said might have been the first woman to earn a graduate degree from Penn in the classics, and whose intellectual inclinations Eaton cited as a major influence—his brother, sister, and a daughter. (His wife, Gertrude, BA’59, MA’62, PhD’72, whom he met as an undergraduate, as well as both of Gertrude’s siblings, also graduated from Penn. So did her parents; her father, Thomas D. McBride, BA’24, JD’27, later an inspiration to Eaton as a man who earned success through hard work, was a legendary trial lawyer, Pennsylvania attorney general and state Supreme Court justice, whose pro bono defense of eight teachers accused of communist activities put a halt to the McCarthy hearings in Philadelphia.)

Eaton’s interest in science did not begin by playing with chemistry sets, but when he was 11 he did conduct a chemistry “experiment.” An adventurous friend whose father owned a pharmacy enlisted Eaton to collaborate on building a bomb from chemicals found in the store. On an empty lot at 44th and Locust Streets, Eaton and his friend packed a Campbell’s soup can with potassium nitrate and sulfur and inserted a fuse to ignite the incendiary. It worked, causing an explosion big enough for the police and fire departments to investigate, but the culprits escaped undetected.

Though Eaton had always wanted to be a doctor and was thrilled to be accepted into medical school at Penn, early in his educational career he decided he might want to pursue research. His interest was sparked by his work as an undergraduate with the research group of famous electrochemist and professor John O’Mara Bockris, PhD, DSc.

“They had no access to computers, and I was recommended by the math department as someone who could perform calculations reliably,” Eaton recalled.

Global Intrigue

After graduating with a degree in chemistry and an interest in using the methods of physics and physical chemistry in research, Eaton was the first recipient of the Willy Brandt exchange fellowship between Penn and the Free University of Berlin, which provided him with an opportunity to study in Germany for a year before beginning medical school—taking a brief, unplanned turn as a Cold War spy along the way. 

In December 1959, a year and a half before construction of the Berlin Wall began, Eaton and two friends crossed over to East Berlin to inquire at the Soviet embassy about getting visas to visit the Soviet Union. He was met there by the embassy’s cultural secretary, whose parting comment after a friendly discussion was, “Mr. Eaton, perhaps we can meet again sometime.” A month later, the cultural secretary telephoned Eaton requesting a book about Abraham Lincoln, and the two arranged a meeting in a West Berlin café. Once Eaton disclosed the contact to a close friend who worked as a Russian language specialist with the U.S. Army, he became wrapped up in covert activities. The U.S. Army Counter Intelligence Corps (CIC) asked him to report as much as he could remember about each of his several subsequent meetings with the cultural secretary who, he was told, was a member of the KGB.

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Eaton lived in a basement apartment at Sophie-Charlotte Strasse 33a, Berlin-Dahlem, during his year as Penn’s first Willy Brandt exchange student. After getting mixed up with anti-Soviet counterintelligence in December 1959, he said, “I spent the last six months in that apartment scared.”

In retrospect, Eaton came to believe that the secretary was testing to see if he was a candidate for defection, while the CIC sought to understand the Soviets’ recruitment tactics. He gave a full accounting of all of his experiences to the FBI, sitting in a car at 37th and Spruce streets, upon his return to Philadelphia. He still hopes to someday see a transcript of that interview, which arrived largely redacted and marked “SECRET” in response to his Freedom of Information Act requests after the Cold War’s end.

(Not to be outdone, the second Willy Brandt exchange fellow who went to Berlin from Penn after Eaton, Marvin W. Makinen BA’61, MD’67, was arrested for spying in the Soviet Union and was imprisoned in Russia for two years.) 

When he started pursuing his medical degree, Eaton received several opportunities to carry out basic research, one of which brought him back to Europe.

Though Eaton stayed at Penn for the summer after his first year to work on muscle biochemistry with Robert E. Davies, PhD, his second summer brought him into contact with a larger group of scientific luminaries overseas, thanks to a terse but career-defining communication. He went to work at the Medical Research Council Laboratory of Molecular Biology in Cambridge, U.K., with Sydney Brenner, MBBCh, DPhil, one of the founders of molecular biology.

“I’d heard Sydney give a lecture [at the Federating meeting] in Atlantic City on the genetic code, which was simply spellbinding,” Eaton recalled in a 2009 profile in Proceedings of the National Academy of Sciences (PNAS). “I wrote a letter asking if I could come to work with him. His response was characteristically Sydney, a thin aerogram that read:

‘Dear Bill, Come if you like. Sydney’”

And so Eaton worked on purifying an enzyme involved in protein biosynthesis for a summer in the company of scientists who had six Nobel prizes among them: Brenner, Fred Sanger (two prizes), John Kendrew, and Francis Crick, in addition to Max Perutz, the head of the Laboratory of Molecular Biology.

“Listening to Sydney and Francis discuss and define the major outstanding problems of modern biology at coffee, lunch and afternoon tea in the canteen was a great experience,” Eaton told PNAS. “That summer convinced me that I wanted to do research full-time as a career.”

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Biophysical Insights into Cell Sickling

Eaton was among the earliest Penn alumni to earn a PhD and an MD from the University. He credits Robin M. Hochstrasser, his PhD thesis supervisor, who also became a close friend, as the most important faculty member at Penn for igniting his initial interest in a science career into much more. “Robin’s brilliance, charisma and encouragement turned that [interest] into a deep and lasting passion for science, which I retain to this day,” he said. 

Working with Hochstrasser, Eaton developed microscope techniques to make optical absorption measurements in polarized light on very small, single crystals of proteins including myoglobin, which carries oxygen in muscles, and hemoglobin, which carries it in blood.

The application of these techniques made it possible for Eaton to use his medical and scientific abilities together to make significant discoveries in sickle cell anemia, which was emerging in the early 1970s as a “hot” area of research in both hematology and biochemistry. A large investment by the NIH and the creation of the Sickle Cell Disease Branch in the National Heart Institute to distribute the funds in grants and contracts to universities partially fueled this surge in interest. 

Sickle cell anemia is a hereditary disease  that results in chronic damage to multiple organs and acute episodes of pain so severe that they are called “sickle cell crises.” In the U.S., it is considered an “orphan disease” because there are only about 100,000 patients, almost all of African descent. However, many millions are afflicted worldwide, primarily in Africa, but also in the Middle East, the Mediterranean, and India. The disease is caused by the formation of fibers when red blood cells unload oxygen in the small vessels of the tissues. The hemoglobin fibers distort and stiffen the cells into a fixed shape resembling a shepherd’s sickle, instead of the round, squishy healthy cells that can squeeze through narrow vessels. The less-flexible sickled cells getting stuck and occluding vessels is the root cause of the disease. 

“I knew of an experiment on the optical properties of single sickled cells in polarized light, which was given the wrong interpretation by a prominent sickle cell researcher at the time,” Eaton said. “This was a subject that I knew well because of my PhD thesis research.”

Shortly thereafter, he learned of work by Perutz and John Finch, PhD, at the Laboratory of Molecular Biology which proposed a structure for the sickle hemoglobin fiber.

With a postdoc, James Hofrichter, PhD, Eaton carried out model-building studies based on their optical experiments on the orientation of the hemoglobin molecule. The pair determined from their model building that the Perutz/Finch structure could not be correct. Eaton wrote a letter to Perutz, pointing out their mistake. In response, Perutz invited Eaton to show why he was wrong in a presentation at the Royal Society of London in January, 1973—the major meeting on hemoglobin of the era—with all travel expenses paid by Perutz. 

“Bill’s lecture on the optical properties of the sickle hemoglobin fiber was brash, ebullient and brilliant,” said H. Franklin Bunn, MD’61, a professor of medicine at Harvard Medical School and recipient of the 2003 Distinguished Graduate Award, who first met Eaton at that Royal Society gathering. “From that day on he has remained in the top echelon of biomedical research.”

John Hopfield, PhD, the Howard A. Prior Professor of Molecular Biology, Emeritus, at Princeton University, also met Eaton during this time. “I still remember his clarity of thought, both in his writings and in his lecture presentations, where he was clear not just about what he knew, but also refreshingly frank about what he did not know,” Hopfield recalled.

His presentation was so well-received at the meeting that it motivated Eaton to devote his career full-time to learning how the sickle cell fibers form, and he went on to do so—with some time instead focused on protein folding—at the NIH. 

Working with Hofrichter and Philip Ross, PhD, Eaton's key discovery was that there is a marked delay period before the appearance of fibers, and that the delay time is enormously sensitive to the sickle hemoglobin concentration. He immediately recognized that these highly unusual kinetics could explain and predict numerous aspects of the disease.

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Years after Eaton (right) completed his studies at Penn, his thesis advisor, chemist Robin Hochstrasser, PhD (left), regularly traveled to attend the Eaton family’s annual Christmas Eve parties. The gentleman at center also travels regularly to visit homes on Christmas Eve.

Factors which decrease the delay time before cells sickle, or that increase the time blood cells spend in transit, make the disease worse because they increase the likelihood that the blood cells sickle while passing through the narrowest vessels, he realized. Conversely, increasing the delay time before sickling or shortening the transit time can benefit patients. This idea suggested that therapies that decrease sickle hemoglobin concentration by a small amount would allow more cells to escape the small vessels before fibers form.

“I was absolutely thrilled when I found that out,” Eaton said. “You don’t get too many chances in science to make a real discovery.” 

 The only drug for treating sickle cell disease that is approved by the Food and Drug Administration, hydroxyurea, works by precisely this mechanism.

Several years later, working with Hofrichter and postdoc Frank Ferrone, PhD, who had then recently completed his PhD with Hopfield and is now a professor of physics at Drexel University, Eaton and colleagues revealed a new kind of mechanism to explain the unusual sickle hemoglobin kinetics. Not only do hemoglobin fibers aggregate into polymers as a first step toward stiffening the cells, but the polymers themselves induce the formation of new polymers on their surfaces.

“It explained how so many polymers could form so rapidly, and was a process that was previously unknown in the realm of biological polymerization,” Ferrone wrote for Scientific American in 2013, remarking on the new adoption of an equivalent mechanism to explain the aggregation kinetics of the peptide that causes Alzheimer's disease.

After learning that there had been little progress in finding additional drugs after the approval of hydroxyurea in 1998, Eaton returned to work on sickle cell anemia about 10 years ago. His current research uses a drug-screening method initially developed by a former postdoctoral fellow, Jeffrey F. Smith, PhD. (Before working with Eaton, Smith received undergraduate degrees in business and chemical engineering, a master’s degree in bioengineering, and an MBA at Penn, and did so in only four years and one summer with an A in every course but one. In order to attract Smith to his lab, Eaton sponsored his graduate studies at the University of Cambridge through an NIH partnership program.)

Hard Problems and Lasting Legacies

“Why don’t you start working on a ‘hard’ problem, like protein folding?” Peter Wolynes, PhD, a renowned scientist and the leading theorist in the protein folding field, asked Eaton in 1991 at a meeting on protein dynamics in Chernogolovka, near Moscow, organized by the Soviet and U.S. academies. That question launched a new chapter in Eaton’s professional life. Though Eaton regards his work on the kinetics of sickle fiber formation to be his most significant achievement, he has received more recognition and awards for his work on protein folding.

Protein folding is a process by which a chain of amino acids assembles from a myriad of random structures into a distinct three-dimensional structure that is necessary for the protein to perform its biological function. Understanding the physics of protein folding is essential for understanding protein misfolding that leads to aggregation, the cause of many diseases, including Alzheimer's disease, type II diabetes and Parkinson's disease.

Eaton used an experiment he learned of from Penn biophysicist Heinrich Roder, PhD, using a laser pulse to initiate the folding of a protein and monitoring the process with a high-precision spectrometer developed in Eaton’s own lab. The experiment allowed Eaton to observe the early events in the folding of the protein cytochrome c, dramatically improving the time resolution of kinetic studies in this field from the millisecond to the nanosecond time scale and launching what has come to be known as the “fast folding field.” 

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Eaton met his wife, Gertrude McBride, at the Fisher Fine Arts building at Penn, then the University Library. Both the Eaton and McBride families contain numerous Penn alumni. (Photo by Graham P. Perry)

More recently, Eaton pioneered the application of fluorescence measurements on single protein molecules to study the fastest events of crossing the energy barrier between folded and unfolded states. Both advances now play a critical role in scientists’ evolving understanding of how proteins fold.

Eaton’s efforts are further having a powerful and lasting impact through his work in building the Laboratory of Chemical Physics and his “good citizen” job as scientific director of the IATAP, funding and recruiting NIH scientists to study the basic science of AIDS. The laboratory is reputed as one of the best groups of biophysical scientists anywhere, according to Eaton, and the AIDS program is now a model for new special granting programs within NIH in areas such as bioterrorism and translational research. 

“Exercising the extraordinary scientific taste that resulted in his own research success, Bill Eaton has built an intramural grant program supporting an outstanding group of scientists who study the structural and cellular biology of HIV/AIDS,” said Michael Gottesman, MD, the scientific director of NIH. “Bill is one of the pillars of a powerful basic science research program at NIH that has helped move basic biomedical research forward.”

In addition to his election to the National Academy of Sciences, Eaton’s many honors include The Max Delbruck Prize in Biological Physics from the American Physical Society; the Founders Award of the Biophysical Society; the Neurath Award of the Protein Society; The John Scott Award of the City of Philadelphia; the Humboldt Research Award for Senior Scientists; the 2015 Penn Chemistry Distinguished Alumni Award; election to the American Academy of Arts and Sciences and to the Accademia Nazionale dei Lincei of Rome; and in 2016, an honorary doctorate from the Free University of Berlin sponsored by its physics department. 

Now that his daughter, Helen Eaton, a Penn graduate (BA’93) and Juilliard-trained violist, is settled in Philadelphia with her family as chief executive officer of the Settlement Music School, Eaton makes frequent visits to Philadelphia and calls himself “a born-again Philadelphian.”

Though he has no interest in retirement, Eaton acknowledges he has slowed down a little and no longer works late into the night—“only” about 60 hours per week.

“There is no reason for me to retire,” he said, “since I have nothing that I would like to do every day more than research.” 

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