|(from left) Bargmann, who followed Kenyon to MIT and then UC-San Francisco, is making inroads into how the human brain functions and malfunctions. Kenyon is seeking ways to reverse the aging process.|
Through high-level research on the lowly nematode worm, newly elected National Academy of Science members Cori Bargmann (BS 81) and Cynthia Kenyon (BS 76) are changing the way we think about thinking . . . and how long we have to think about it
BY ALEX CREVAR (AB ’93)
PHOTOS BY CARLY CALHOUN (AB ‘02, ABJ ‘02)
rom one of the grassy knobs known as the Twin Peaks, which look down 1,000 feet onto the Bay Area, Cynthia Kenyon and Cori Bargmann have taken time out from their hectic schedules to participate in a photo session. Neither of the two UC-San Francisco professors is a stranger to the media; in the world of molecular genetics, the players dont get much bigger than Kenyon and Bargmann. What is exceptional about this photo shoot is that the two colleagues arent posing behind microscopes. Though its nearly impossible to separate them from their scientific innovations, Kenyon and Bargmann are sitting cross-legged in the grassfor a moment, at least, these two native Athenians are just being buddies from the old neighborhood.
Kenyon (BS 76), the subject of a recent feature story in Smithsonian, has brought the study of aging back from the dead with research that first appeared a decade ago when her lab showed that through the manipulation of certain genes the life span of the tiny nematode worm could be increased six times. Using the same species, Caenorhabditis elegans (C. elegans), Bargmann (BS 81) has made tremendous inroads into how the human brain functionsconsidered by many to be the crown jewel of scientific research. For their respective contributions, both were elected last spring to the prestigious National Academy of Sciences, not just as lifetime achievement award winners but in recognition of the vital research they are conducting right now, in the prime of their careers.
Growing up in the 1960s and 70s on streets that meet behind the Beechwood shopping center, both Kenyon and Bargmann were children of UGA professors. Separated by five years, both attended Alps Elementary and what is now known as Clarke Central High School.
The similarities dont stop there.
Whats really neat, says Kenyon, is that we had the same piano teacher, the same horse riding instructor, we both attended Georgia and were valedictorians, we both went to MIT, and now were at UCSF studying the same worms.
We are also in the same book club, says Bargmann. But back in Georgia we werent around each other. Five years is an eternity in little-kid time . . . she was my sisters age. All the similarities were coincidences until I was applying for graduate school. I knew Cynthia was at MIT and it was then that I really started to be influenced by her because I always admired her so much.
And now theyre both NAS members.
Its a vote of confidence from your community, the ones you respect . . . exhilarating, says Bargmann.
Its the biggest honor an American can have short of the Nobel Prize, says Kenyon.
Okay, can yall stand up for one last shot? asks the photographer, sensing both the waning light and the shortage of time she has with the scientists, whose schedules are consistently pulled to their limits.
Ah, says Bargmann, we like hearing the word yall.
If this trek to the top of one of Americas greatest cities, famed for its music and cable cars, were simply to document a couple of top-notch scientists it would be hard to begrudge any publication. Certainly Smithsonian, the San Francisco Chronicle, Discover, and USA Today had it right when they did feature stories on these two researchers from UCSFamong the worlds top research institutions. For one doesnt have to climb too far on a limb to say that these scientists findings would have given cause for even Ponce de Leon, Sigmund Freud, and Franz Joseph Gall to stand and applaud while simultaneously scratching their heads.
Nowhere is Kenyons research held in higher esteem than at the National Institute on Aging, where the mission is to study ways to promote healthy aging and to reduce the loss of function and increasing disability associated with advancing age in the American population.
To that end, Huber Warner, the head of NIAs Biology of Aging Program needs little motivation to praise the UCSF scientist who was selected in 2000 to give the Institutes annual Florence Mahoney Memorial Lecture, in honor of one of the earliest supporters and influences on aging research.
Dr. Kenyon is an excellent scientist, says Warner. The work of Dr. Kenyon, in addition to research in other areas of aging, suggests that [NIAs mission] may, in fact, be a possibility.
n the December 1993 issue of Nature, Kenyon, a professor of biochemistry and biophysics, reported findings that move science to an arena where once only liniment peddlers and folklorists dared tread. The research was simply titled, A C. elegans mutant that lives twice as long as wild type. The thought that a creature could be scientifically coaxed into a doubled life span was met with immediate applause.
People have always thought that, like a car, our body parts eventually wear out. But we found that over time [when a nematode gene is manipulated] . . . age-related diseases were also postponed.
|By manipulating genes that help C. elegans withstand stress, Kenyon has extended the worms life span up to six times. Similar results have been achieved with fruit flies and mice.Kenyon has founded a pharmaceutical company with the hope that an anti-aging tablet can be marketedperhaps in this decade.|
By manipulating two genetic pathways that allow the worm to withstand environmental stress, Kenyon subsequently found that she could extend C. elegans existence up to six times, keeping it young and active much longer than normal. How does it work? Kenyon discovered that two genesthe daf-2 and daf-16were actually directing an entire team of genes, all of which contribute to the organisms longevity.
The daf-2 gene acts as an orchestra conductor, says Kenyon, who plays the French horn, the guitar, and the massive alpine horn. Its a very powerful regulator that brings together all the instruments in the orchestra. The cellos, for instance, are the antioxidants genes, the piccolos prevent infection, and the French horns are involved in things like fat transport. When we change the way one gene responds to a hormone, we know that about 100 genes turn up or downor on or offfor a large cumulative effect.
If the result of all this were only to extend the life of a worm from 20 to 120 days, the discussion might end right there. But what has garnered Kenyon so much notoriety is the researchs implication for humans. Kenyons findings have been translated to fruit flies and even mice with similar results as those found with C. elegans. Because humans share 50 percent of the nematodes genes and because the daf-2 gene is similar to three human receptorsfor insulin, for a hormone called insulin-like growth factor, and for a third with an unknown functionthe obvious question is, can aging also be manipulated in people?
Seeking real-world applications for her research, Kenyon founded Elixir Pharmaceuticals with the hope that one day a tablet might be createdwhich the press has already dubbed the Fountain of Youth pill.
Such a tablet, says Kenyon, is at best five years away.
For Kenyon and her colleagues at Elixir, excitement isnt only about age extension but in the possibilities such research bestows on age-related diseases.
Without question, Cynthia is a pioneer in the aging field, says Pete DiStefano, Elixirs vice president of research and development and its chief scientific officer. And we believe the fundamental mechanisms of aging will give us a better handle on how to approach age-related diseases.
Above Kenyons desk at the Larry L. Hillblom Center for the Biology of Aging, which she directs, is a statue of Jaroujin, the god of longevity. Below the desk is a dog pad and water bowl for her German Shepherd Nicky.
The cool thing is that we found that the aging process is plastic, says Kenyon. People have always thought that, like a car, our body parts eventually wear out. But we found that over time, when one gene was manipulated, the worm actually remained youthfulin all waysso that age-related diseases were also postponed.
When asked a series of questions that are continually brought up by critics of her research, Kenyon doesnt flinch.
On whether extending humans life span might exacerbate an already tenuous overpopulation problem:
The biggest issue with curtailing the population is to bring down the birth rate. The good news is that if there is a benefit for humans, it will be a gradual one. At first, you might add a couple of years of good healthso there will be plenty of time for society to adjust.
As to whether there is such a thing as a free lunch in nature:
People think that if you extend life span there has to be a trade-off, but how could that be true? Think about it, evolution started with this little primitive animal that is one of your ancestors and that gave rise to C. elegans and then to some animal that gave rise to you. If every time you changed the genes there was a trade-off, we would never be so much superior. We are amazing. If every time there was some downside, we would not live 1,000 times longer than the nematode worm . . . and we are not 1,000 times worse off.
On whether shed like to live to be 200:
If I were healthy and young . . . of course. If I were sitting in this chair, would I want to die just because I was 100? No thank you.
Brenda Starr-like cartoon hangs in Cori Bargmanns office. A woman is lying on a bed with a tear in the corner of her eye and a thought bubble above her that reads, If he only knew about the awesome power of genetics. An opera buff with a cat named Figaro, Bargmann is dedicated to communicating the nature and importance of her work to non-scientists. The public funds research, she says, and deserves to know.
We havent made that link yet [between brain pathways in animals and autism in humans]. Its like youre always looking for your keys under lampposts. I am in the business of turning on lampposts.
C. elegans is so tinyabout the size of a comma on this pagethat it has to be studied and manipulated under a microscope.
|By investigating brain pathways in worms or fish, Bargmann hopes to learn what causes autism in humans. Bargmann will leave her research position at UC-San Francisco this fall to take a similar position at New Yorks Rockefeller University, which has a history of producing Nobel Prize winners.|
In 1991, when her lab began publishing research about the neural biology of olfactory (smell) behaviors in C. elegans, Bargmann, who is vice chair of anatomy at UCSF, began to establish herself as a preeminent locksmith in the pursuit of how brain circuitry is organized and how those connections influence behavior. The idea is actually Cartesian: the mind doesnt perceive the world but merely translates information supplied by the senses. Still, in the 350 years that separate Descartes and Bargmann, only scattered pieces of the process between the senses and the mind have been located.
But as is the case with Kenyons research, the translucent nematodewith only 302 neurons in its nervous system, as compared to billions in humanshas helped provide a macro key to locate the tiny micro keys that show how genes shape the nervous system so specific behaviors can occur. Bargmanns major findings in the last eight years include identifying olfactory receptor genes that enable the worm to recognize many different odors, which in turn generate responses to the environment at large. In 1998, she cataloged the gene that influences social versus solitary feeding behaviors in C. elegans. In 2003, Bargmann pinned down the molecule that directs connections between the intricate synapses necessary for animal behavioral patterns.
I study the brain of a worm instead of a human for the same reason that you would want to first study the 1964 Volkswagen Beetle to gain an understanding of how an engine works before you investigate a Boeing 777, says Bargmann, who will leave UCSF for a position at Rockefeller University in New York City this fall. The approach we have in my lab is that many of the same genes build the brain in all animals. Humans have 10 billion neurons and 10 trillion connections and the worm has 30,000 genes. Which would you chose?
Some people get a lot of motivation from following something all the way through . . . I enjoy setting up the links, says Bargmann, who is also an investigator with the Howard Hughes Medical Institute. The HHMI has agreements with institutions all over the country to facilitate science through an endowment in excess of $10 billion. We know, for instance, that there are profound human disorders in social interaction, like autism, that are devastating to families. But we dont know how autism arises or what pathways are disrupted. To me a good question is, If we learn something about pathways in worms or fish or any social animal, can we figure out if it has something to do with human autistic pathways? We havent made that link yet because its so hard to do experiments. Its like youre always looking for your keys under lampposts. I am in the business of turning on lampposts.
To nearly all who come into professional contact with Bargmann, there is no bulb brighter.
Cori is easily one of the smartest, most interesting, and accomplished people Ive known, says Marc Tessier-Lavigne, whose lab was next to Bargmanns at UCSF for 10 years. In that time, the two scientists collaborated several times. Tessier-Lavigne is now Genentechs senior vice president of research drug discovery. She has both a breadth and depth of knowledge. I can never remember surprising her with anything. I talked to her every day and always came away learning something.
Amongst Bargmanns admirers, appropriately, is Paul Nurse, president of Rockefeller University, who anxiously awaits her arrival on campus this fall.
Cori Bargmann typifies the Rockefeller scientistshe is bold and highly original in her thinking and in her approach to studying the brain and other components of the nervous system, says Nurse, who shared the 2001 Nobel Prize in Medicine for research on how body cells divide and replicate themselves. Nurse is one of 23 scientists associated with Rockefeller University who has been recognized with the Nobel Prize. Considering Rockefeller University scientists remarkable track record of winning Nobel Prizes, I would not be surprised if I awakened one day to hear the news that Cori was being honored.
uring the height of the Civil War in 1863, Abraham Lincoln signed the charter establishing the National Academy of Sciences. Todays NAS enlisteesour nations top scientistsare among the brightest problem solvers in the world. Kenyon and Bargmann are no ex-ceptions. But before they became National Academy members, they were girls growing up behind the Beechwood movie theater on Colonial and Riverhill drives in Athens.
Cynthia would keep a praying mantis on a leash and feed it from a toothpick dipped in honey, recalls her mother, Jane Jarvis Jackson Kenyon, who was the office manager in UGAs physics department for 30 years. She liked to be outside and would go down to the river and just read all day long. She was incredibly inquisitive, and since she came from a family of teachers we never asked any of our children [Kenyon is the oldest of three] a question that ended in a yes or no answer.
The idea was that the kids learned everywhere we went, says Kenyons father, James, a UGA professor emeritus in the geography department, where he specialized in urban geography and transportation. The thing about Cynthia is that shes just plain S. M. A. R. T. As a kid, shed get into poetry and get things published or shed play an instrument and excel. There was never any reason to put any pressure on her to do well. Now she gets so much publicity that we cant keep up.
Likewise, there was never any need to put pressure on Bargmann. In the living room of the house she grew up in, there are posters for German festivals (both of her parents emigrated from Germany in 1955), Beethoven and Schubert album collections, and pictures of the familys four daughters, of which Bargmann is number three.
She had a real ability to twist me around her little finger . . . a real charmer, says Rolf Bargmann, a professor emeritus in the statistics department, where he taught computer science. At about the age of 16, she was a scientist. After eleventh grade she went to the University [as did all the Bargmann girls].
At Georgia, both Kenyon and Bargmann were honor students who were already making waves and coming into contact with current and future NAS members.
Cynthia Kenyon was a really first-rate student, says Norman Giles, an NAS member and the Callaway Professor of Genetics (emeritus), who came to UGA from Yale to start UGAs genetics department. She was in my Introduction to Genetics class. It wasnt hard, of course, to encourage her to go to graduate school and she has since been a real credit to the University of Georgia. Its really remarkable to see them both elected to the National Academyviewed as the top recognition a scientist can achieve during the yearand to see how theyve had such parallel careers.
Both Bargmann and Kenyon went to MIT for their doctorates. And though Bargmann stayed at MIT for her post-doctoral work and Kenyon went to Cambridge University in England, the two were advised by Robert Horvitz and Sydney Brenner, respectively. Interestingly enough, Horvitz and Brenner were two-thirds of the team that won the 2002 Nobel Prize for Medicine, using the nematode worm in their discoveries concerning the genetic regulation of organ development and programmed cell death.
In the 1960s, says Bargmann, Sydney Brenner systematically searched for an organism that could be used for developmental and neuroscience research, auditioning lots of small insects and worms. He decided on C. elegans. Almost everyone who works in the field can trace themselves back to Sydneys lab. There are probably a couple thousand people now who work on this worm.
Wyatt Anderson, dean of UGAs Franklin College of Arts and Sciences and an NAS member, received his Ph.D. from Rockefeller and followed Norman Giles to Georgia from Yale. It was Anderson who gave Bargmann her first lab jobmixing fly food from corn meal and molasses.
It is, indeed, a happy event that two young women from UGA have been elected to the NAS, says Anderson. Maybe the best way I can explain is to quote one of my younger colleagues, who tells me that the NAS is too male, too frail, and too pale. According to The Scientist, NAS membership is still under 10 percent women. Thus, having two young women helps to balance out our membership. It is a matter of pride that our biological sciences has produced two undergraduate majors who were elected to NAS membership in their forties. As best I know, they are the second and third UGA graduates to be elected to the NAS.
But for two highly driven students who went to school when streaking was the rage (Kenyon) or when a burgeoning music scene and a championship football team stole the headlines (Bargmann), college life wasnt just about science.
I loved UGA because there was always something to do, says Kenyon. I rode horses and lived in Five Points in a nine-bedroom house with my boyfriend. We had chickens. The neighbors would come to my house and tell me how much they loved hearing the rooster crow in the morning . . . but the landlord didnt like it.
I remember seeing R.E.M. play behind Legion pool, says Bargmann. UGA was great because there were so many different kinds of people and so many influences. I still have friends from that time period . . . it was really great. Now that Ive been a scientist for more than 20 years, it feels like I only know scientists.
|I loved UGA because there was always something to do. Cynthia Kenyon
I remember seeing R.E.M. play behind Legion Pool. Cori Bargmann
Bargmann and Kenyon grew up in Athens as daughters of UGA professors. In graduate school, they were advised by a pair of future Nobel Prize winners. Theyre even in the same book club.
ucille Ball once said, If you want something done, ask a busy person to do it. The more things you do, the more you can do. Under constant pressure to run world-class labs and manage staffs of 40 people between them, Kenyon and Bargmann schedule their work days down to the minute while remaining quietly focused.
[Bargmann] has a clear vision of the big picture and an incredibly sharp eye as to which are the right questions to ask, says Massimo Hilliard, a Bargmann post-doc from Naples, Italy. She is one of the brightest scientists Ive met. As a person, she is brilliant, kind, thoughtful, and very intense.
Sentiments are similar in the Kenyon camp.
She is, most of all, an unparalleled inspiration to everybodys projects in the lab, says Marlene Hansen, a Kenyon post-doc. She has the most incredibly original ideas, always able to make multiple connections to other data, and she is very enthusiastic. Thats the greatest thing about her.
As the camera shutter clicks for the last time on Twin Peaks with the city of San Francisco fading into its characteristic evening fog, both women shift back into scientist mode. Kenyon walks to her silver Acura and Bargmann to her little black Miata. But before leavingBargmann catching a red-eye flight to a family reunion in Virginia and Kenyon home to feed Nickya question arises as to what messages the two UGA grads delivered in their respective valedictorian speeches.
I didnt give one, says Bargmann.
I talked about how the arts and sciences have much in common, says Kenyon, who draws attention to her UGA diploma with a star on her CV (only six of 35 items, including her NAS membership, receive stars). And how science has a lot of creativity.