September 2010

Richard Hanson: A Maestro of Metabolism

 

Artist, educator, biochemist and more...learn about longtime ASBMB member Richard Hanson.

 

Richard HansonCleveland may be a fairly big city, but even amongst its masses, Richard W. Hanson sometimes finds it hard to hide.

“I often joke around that it is impossible to have an affair in this town and keep it a secret,” says Hanson, who, incidentally, has been married happily for nearly 50 years. “Quite often, someone comes up to me and says, ‘Hi, Dr. Hanson, do you remember me? I took your class back in so-and-so year.’”

“In fact, I visited a proctologist recently who turned out to be one of my former students.”

The class in question is an introductory biochemistry course, which Hanson, when he’s not hard at work in the lab elucidating the physiological role and regulation of the metabolic enzyme phosphoenolpyruvate carboxykinase, has taught at Case Western Reserve University School of Medicine in Cleveland for more than 30 years now. Each year, more than 230 students enroll in the biochemistry course, and, each year, almost all of them leave happily— and more knowledgeable about biochemistry than when they started.

To understand the secret behind these positive reviews— Hanson’s classes routinely are the highest rated each year— one needs only to consider one of his favorite authors, William Shakespeare. (Hanson regularly quotes the Bard in his writings, and even has an iPhone app with Shakespeare’s complete works.) For, if “all the world’s a stage,” then that includes university auditoriums.

“He views teaching biochemistry as theater,” says William Merrick, Hanson’s longtime colleague in the biochemistry department. “Once he comes in, the show begins.”

Not only does his teaching style help students understand a complex subject that most fear and only take because the course is a requirement, but it keeps Hanson spirited as well. “My colleagues often ask me if I get tired of teaching the same material over and over again, and I say never, for every class is different, and every year is different; it is always a challenge to have students leave your course feeling that they actually understand biochemistry and to tell you it was their favorite course.”

“In my view, there are two types of teachers, ‘simplifiers’ and ‘complicators,’” he continues. “The latter take a complicated subject and make it more complicated. I am a simplifier, always concerned about the complexities of the biochemistry, and I try to make the subject clear to the students; this approach has worked very well for me over the years.”

He employs a similar style in lab, always looking to simplify matters and be as supportive as possible, and, with those modest guidelines, he has successfully shepherded more than 80 graduate students and postdoctoral fellows onward in their careers. He obviously has had some success in this regard, since his first graduate student, Shirley M. Tilghman, is the current president of Princeton University.

Science-Focus---Hanson
Richard Hanson and colleague Parvin Hakimi, who developed the PEPCK-Cmus mouse strain, stand by one of the treadmills where the “mighty mice” strut their stuff.

And, this has made Hanson one of Case Western Reserve University’s most celebrated educators; he has won numerous awards for his teaching and service, including the Hovorka Prize, one of the university’s highest awards, and was recently appointed a “Distinguished University Professor,” an honor that he shares with only six other current members of the university faculty. And, this month, the university will honor Hanson’s career in the lab and classroom with a special one-day symposium in his name.

However, official honors take a back seat to the personal acknowledgements from former students. “When I began my career in science, I thought that the most important thing that I would do was research, but, as I grow older, I realize that the greatest contribution that anyone can make in our society is to be a positive influence on the lives of those you teach,” he says. The fact that so many people still remember me and my course is touching, because it means that, in some small way, I have made a positive impact on their lives and careers. So, truthfully, some of the best things I hear start with, ‘Do you remember…?’”

A Lifelong Commitment

Part of Hanson’s dedication to teaching comes from remembering his own experiences; he notes he was fortunate to have several valuable mentors during his educational period— which, if you ask him, is still continuing.

It all started at high school in New Jersey in the 1950s, when his biology teacher, Sister Mary Cephus, helped instill a passion about the life sciences into a bright-eyed adolescent boy.

A pivotal moment, though, occurred at the next step in his education. Coming from a modest background, Hanson did not have much money for college, but, he found a great opportunity at Northeastern University in Boston, which offered a cooperative work program; students went to school for half of the year and then worked the other half to pay for it.

Hanson ended up working as a technician in the laboratory of Peter Bernfeld at Tufts University School of Medicine and experienced firsthand the many facets of biochemical research; these included science’s frustrations, but also the joys, such as the publication of his first-ever journal article in 1960, in the Journal of Biological Chemistry.

“That was a proud moment,” recalls Hanson, “because, in what was the golden age of biochemistry, I was a co-author on a paper that was published in the most prestigious biochemistry journal.”

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A Renaissance Man

In addition to his exceptional work in the lab and lecture hall, Hanson also is known for his work as an artist (as illustrated above and on our cover). As typical, Hanson takes a more modest view of his abstract drawings, which developed from his penchant for doodling during meetings and seminars; “I see it as a sickness I have that every once in a while results in something nice to look at,” he says. Hanson, though, is certainly appreciative of art in general, and, over the years has bought many pieces from local Cleveland artists and put them up in the biochemistry building. As Merrick likes to joke, “he’s established a lovely gallery here consisting of all the art his wife wouldn’t let him take home.”

In fact, Hanson became committed to the JBC over the years, a reflection of his loyal nature. He would serve on the journal’s editorial board for 10 years before becoming an associate editor, a post he has held since 1985. A longtime member of the American Society for Biochemistry and Molecular Biology, Hanson also has given exceptional service to the society as a whole, including serving as ASBMB president from 1999 to 2000 (during which time he helped usher in the society’s third journal, Molecular and Cellular Proteomics).

And, whenever his research produces exciting biochemical discoveries, Hanson, who never got caught up in the pressure of trying to continually publish in Science or Nature— he sees them more as magazines that publish what is trendy and exciting at the moment— always immediately thinks about publishing the findings in the JBC.

And, that has led to frequent contributions over the years (more than 90 articles in all, including many reviews), for, while remaining true to the JBC, Hanson also has remained true to his science. Though he’s adapted his studies to make use of new advances, he’s always been a basic biochemist at heart.

“I’ve had a lifelong love affair with metabolism,” he says. “And, even with the ups and downs of the field, I’ve never thought of doing anything else.”

PEP, PEP Hooray

The romance began in 1960. Following his graduation from Northeastern University, Hanson headed to Rhode Island and began graduate school at Brown University, joining Paul F. Fenton’s group in the department of biology. He had met one of Fenton’s recent graduates while working with Bernfeld and had heard positive reviews, so, he decided that studying under Fenton would be a good choice.
 
“I tell my students that life is like walking down a road and reaching a fork,” Hanson says. “You don’t quite know where either path will take you, and it is often very difficult to go back once you choose one of the forks in the road, so each decision is important.”

In Hanson’s case, the seemingly innocuous decision of picking an adviser would lead to a decades-long journey elucidating the details of intermediary metabolism, or, as Hanson likes to describe it, “a series of happy accidents that were superimposed on each other.”

He started this accidental adventure with his graduate project comparing the metabolic differences in two strains of mice that differed in their propensity to develop obesity, a subject that would become one of great interest in the current era of molecular genetics. He then continued studying lipid metabolism as an officer at the Army’s Nutrition Laboratory in Denver. That experience, followed by his subsequent postdoctoral fellowship at the Fels Research Institute at Temple University, beginning in 1965 with renowned biochemist and cancer researcher Sidney Weinhouse, really would launch his career.

Under the tutelage of another supportive mentor, and in a lab full of great colleagues, Hanson first began working on the protein that would become his calling card: phosphoenolpyruvate carboxykinase, better known as “PEPCK.”

The enzyme, which is involved in glucose production, along with the related enzyme pyruvate carboxylase recently had been discovered by Merton F. Utter in the department of biochemistry at Case Western Reserve University School of Medicine— where, in another happy accident, Hanson would end up moving in 1978 to become chairman of the department— and Hanson was examining their role in the initiation of glucose homeostasis in developing rat livers. Along the way, he and colleague John Ballard had, surprisingly, found PEPCK in adipose tissue, which seemed bizarre, as adipocytes do not make glucose.

Soon, together with Gilbert Leveille and their longtime collaborator Lea Reshef, they realized that PEPCK was involved in an abbreviated pathway that converted pyruvate into glycerol-3-phosphate for triglyceride synthesis, which was hence named glyceroneogenesis.

That discovery highlights just one example of the many wonderful collaborations Hanson has had; he likes to note that the numerous excellent scientists he has worked with have given him much more than he has given back. He especially acknowledges Reshef, an Israeli scientist who worked closely with him for more than 30 years, studying the factors that control PEPCK-C gene transcription. “Lea has been a wonderful collaborator; I am not a molecular biologist, so I owe a great deal of my success in studying gene expression to her insights,” he says. “She was full of ideas and always willing to share with me her vision and enthusiasm for studying PEPCK-C.”

Following that 1967 glyceroneogenesis breakthrough, which resulted in a paper in the JBC’s Classics series, Hanson began a fruitful series of studies on the factors that regulate the levels of PEPCK-C in mammalian tissues; he and his colleagues isolated the genes for both the cytosolic (PEPCK-C) and mitochondrial (PEPCK-M) forms of the enzyme and began focusing on the hormonal and dietary factors that affected PEPCK-C gene transcription. He never wavered in his pursuits, even as the prominence of metabolism gave way to the era of molecular biology, though he commented that at times it made funding more difficult to come by.

During the past decade, though, partially spurred by the rise in interest in the causes of obesity and diabetes, metabolism studies have made a very strong comeback. This certainly came as a welcome turn of events to Hanson, at least until he found himself thrust right in the middle of the metabolic resurgence.

PEPCKOf Mighty Mice and Men

Going back to his graduate school days, Hanson had significant experience with animal models as tools to understand metabolic function and, over the years, had developed strains of mice in which PEPCK was either deleted or overexpressed in specific tissues. For example, in 2002, in collaboration with Reshef and her student Yael Olswang, they found that ablating PEPCK-C gene expression specifically in adipose tissue produced lipodystrophy in many affected mice, validating the enzyme’s central role in adipose-tissue glyceroneogenesis.

As a follow-up, in 2007, Hanson, together with his longtime colleague Parvin Hakimi, decided to generate mice in which PEPCK-C was overexpressed in skeletal muscle, another tissue like adipose tissue that has PEPCK-C activity but does not synthesize glucose. “I didn’t know exactly what to expect,” Hanson says, “but I was pretty sure these mice would only have subtle changes in their metabolic profile; boy, was I in for a shock.”

These PEPCK-Cmus mice turned out to have a dramatic phenotype, which included exceptional endurance (they could run on a treadmill 30 times as long as a regular mouse), hyperactivity even at advanced ages and lean, muscular bodies despite eating twice as much as normal. They also displayed incredible longevity, with one female reaching more than 4.5 years of age (typical lab mice live 2–3 years), though Hanson notes they didn’t quite break the record and win the Methuselah Prize for the longest-living mouse (which, for the curious, currently stands at 1819 days).

 


It’s a scientifically fascinating discovery, the mechanistic basis of which his lab currently is trying to unravel, and, not surprisingly, one that produced intense media interest as well, much to Hanson’s chagrin. “It was nonstop action for a while; I think our video of the mice running on the treadmill got more than 300,000 hits in the first few weeks after the study came out, not to mention all of the interview requests I received, even a few from documentary film producers who wanted to include our mouse video in movies about athletic performance and potential sports doping.”

The attention was a bit too much for the modest scientist, a man who says that “he never wants to work at a university where he is the smartest; it’s surely not a good place to work!”

“It was wonderful that our lab and the university received some positive attention, but, at the same time, this kind of sensational news worries me as a scientist, because we still are far away from developing performance-enhancing treatments in humans, and we really do not understand the factors that lead to the phenotype we observe with these mice.”

He often quotes the famous dictum of Euripides that was modified by Sidney Brenner in his review of the book by James D. Watson, “Avoid Boring People,” “Whom the gods would destroy, they first expose to the public press.”

A Promise of a New Day

Considering that Richard Hanson still is going strong with his teaching, research and editorial duties at 75 years of age, one might suspect that he shares some genetic traits with his PEPCK-Cmus mice.

However, Hanson admits things don’t get easier as one gets older and already is preparing for the next fork in the road of life. He’s getting ready to close up his lab and officially will become an emeritus professor in 2014.

However, he plans to continue collaborative research with his friend and close colleague, Satish C. Kalhan at the Cleveland Clinic, on studies of whole-body metabolism in mammals. “I especially am interested in amino-acid metabolism, and working with Satish is a learning experience for me,” he notes. In addition, he will continue to study the PEPCK-Cmus mice, which now are being used, in collaboration with Nathan A. Berger, to better understand the effect of exercise on the development of colon cancer.

And, he definitely will keep on teaching for as long as he is able; “I think Hanson could give up doing research,” Merrick says, “but you would have to drag him kicking and screaming out of that classroom before he’d ever stop.”

The education won’t be confined to the students in his biochemistry class. Given his scientific expertise, he’s going to act as a mentor-of-sorts to other scientists who are interested in the “new metabolism.”

“Following the rise of molecular biology and genomics, a lot of researchers veered toward what they saw as a more exciting area of science,” he explains. “And now, even though we have a revival of interest in metabolism, we have a ‘lost generation’ of scientists who perhaps truly don’t understand many of the fundamentals of metabolism.”

And, although today’s scientists typically are focused on broader scientific queries than just a single enzyme or pathway, Hanson notes that PEPCK makes a fine ambassador to new science.

“Through all of our work, we’ve shown that PEPCK is a great example of a tightly regulated gene with tissue-specific activity, as well as differing developmental expression patterns,” he says. “And, there are still many unanswered questions regarding its function.”

“So, even though it’s been around for a while, like me, I think PEPCK is a very modern and appealing protein.”

 

 

References

• Hanson, R. W. (2009) A Perspective on the Biology of Phosphoenolpyruvate Carboxykinase 55 Years after Its Discovery. J. Biol. Chem. 284, 27021 – 27023.
• Hakimi, P. Yang, J., Casadesus, G., Massillon, D., Tolentino-Silva, F., Nye, C. K., Cabrera, M. E., Hagen, D. R., Utter, C. B., Baghdy, Y., Johnson, D. H., Wilson, D. L., Kirwan, J. P., Kalhan, S. C., and Hanson, R. W. (2007) Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse. J. Biol. Chem. 282, 32844 – 32855.
• Hanson, R. W. (2005) Metabolism in the Era of Molecular Biology. J. Biol. Chem. 280, 1705 – 1715.
• Hod, Y., Yoo-Warren, H., and Hanson, R. W. (1984) The Gene Encoding the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) from the Chicken. J. Biol. Chem. 259, 15609 – 15614.
• Reshef, L., Hanson, R. W., and Ballard, F. J. (1969) Glyceride-Glycerol Synthesis from Pyruvate: Adaptive Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Carboxylase in Adipose Tissue and Liver. J. Biol. Chem. 244, 1994 – 2001.
• Bernfeld, P., Nisselbaum, J. S., Berkeley, B. J., and Hanson, R. W. (1960) The Influence of Chemical and Physicochemical Nature of Macromolecular Polyanions on Their Interaction with Human Serum β-Lipoproteins. J. Biol. Chem. 235, 2852 – 2859.

Nick Zagorski (nzagorski@asbmb.org) is a science writer at ASBMB.


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