Sci. Aging Knowl. Environ., 27 August 2003
The Mouse That Roared
Andrzej Bartke began studying reproductive hormones in dwarf mice as a grad student. Thirty years later, his lab serendipitously discovered that the midget mice are long-lived
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/34/nf16 This article comes to you through a collaboration between SAGE KE and Science's career development Web site, Next Wave. The joint venture is supported by the AARP Andrus Foundation. A decade ago, Andrzej Bartke, a Polish-born physiologist at Southern Illinois University (SIU) in Carbondale, was studying reproductive endocrinology in giant mice that had been engineered to overproduce human growth hormone. The brownish-gray rodents quickly grew "big and slick and nice," Bartke says, but he noticed that they started deteriorating early, at 7 months old. They began losing weight, grew sluggish, and developed problems in the spine, and their hair turned gray. Many of them dropped dead early, before age 1. The oversized mice seemed to grow old prematurely.
That observation set Bartke and two postdocs, Holly Brown-Borg and her husband Kurt Borg, wondering: If having too much growth hormone could make an animal age faster, perhaps having no growth hormone would postpone aging. Downstairs, the researchers maintained a colony of mice at the other end of the size spectrum: the Ames dwarf line, which Bartke had been studying since the '60s. The tiny creatures lacked growth hormone and insulin-like growth factor-1 (IGF-1). But no one knew whether they lived especially long. "When this question came up, I said, 'Well, I have no idea,' " recalls Bartke, because the mice were always killed in the lab's endocrinology experiments before reaching old age.
To find out the answer, Brown-Borg set aside a bunch of the miniature rodents and allowed them to live out their natural life spans. Three years later, in 1996, the researchers reported in Nature that Ames dwarf mice, which carry a mutation in a gene called Prop1, live 50% longer than normal mice. The paper was a landmark, demonstrating "that a single gene mutation in the mouse could extend life span," says gerontologist Richard Miller of the University of Michigan Geriatrics Center in Ann Arbor. "It was the first time anyone had ever shown that."
The work eventually put IGF-1 on the map as a potentially important player in mammalian aging, Miller says. Earlier studies had revealed that a mutation in roundworms extended their life span, but skeptics questioned the generalizability of those findings. In 1997, however, researchers showed that the mutation was in an insulin/IGF-1 pathway. Having shown that IGF-1-deficient mice also live longer, Bartke's study suggested not only that these pathways are important in mammals, but that they might have been crucial in controlling life span in a range of creatures evolving over hundreds of millions of years from a common ancestor of worms and mammals, says Miller.
It was an impressive debut for someone who had just stepped into the field of aging. The Nature paper marked a new direction for Bartke, a well-respected classical endocrinologist with 30 years of research successes under his belt. Now based at SIU's medical campus in Springfield, Bartke has written 548 scientific articles and book chapters over the course of his career. His investigations have made him one of the world's leading experts on the physiology of how growth hormone influences aging and longevity, says friend and gerontologist George Roth of the National Institute on Aging in Baltimore, Maryland. Before the 1996 Ames dwarf study, scientists knew that growth hormone and IGF-1 help preserve muscle and bone, and that they stimulate brain cell growth as well. But Bartke's work has shown that the hormone has bad as well as good effects with respect to aging and longevity, says Roth. "He's used all of these [mouse] strains very elegantly to show that growth hormone really is a two-edged sword" (see Bartke Viewpoint).
At 64, Bartke is a soft-spoken man with thinning gray hair who wears a ring made from a trilobite fossil. "He's self-effacing and modest," says Roth, and has the manners and charm of an old-fashioned gentleman: He still kisses a woman's hand in greeting. "He could've been a Polish count in an earlier life." Bartke was born in Krakow, Poland, in 1939, the year Hitler invaded, triggering World War II. Times were hard during the Nazi occupation, but as a boy, Bartke found pleasure in gathering beetles and displaying his collection in a glass case. His father, a banker who had a passion for biology and ecology, encouraged the hobby. Biology completely absorbed Bartke, and by the time he was in grammar school, he loved to walk in the woods and observe animals. To this day, he is an avid outdoorsman; when he isn't going on 4-hour-long weekend hikes with his girlfriend, he's swimming or fishing in lakes close to home.
The Iron Curtain Opens Twice
Bartke's scientific inclinations led him to enroll in 1956 at Krakow's Jagiellonian University--where Nicolaus Copernicus studied--and undertake a 5-year program that gave him the equivalent of a master's degree in zoology. Determined to become a biologist, he thought that English skills would be key to succeeding in that profession, so he began taking English lessons and studying on his own with a dictionary. In 1960, his fourth year at Jagiellonian, opportunity knocked. The Polish Academy of Sciences had an agreement with North Vietnam to collaborate on geophysics studies at a field station in the mountains of the Southeast Asian country. The Polish scientists were looking to send someone to set up monitoring of radioactive contaminants in the upper atmosphere, the legacy of atomic-weapons testing by the Soviet Union, the United States, and other countries in the 1950s. But the academy also wanted to broaden its work at the station to include biological research. So it arranged through contacts at Jagiellonian University to send Bartke, a straight-A student, to help with both projects. Bartke was thrilled: "[It] was like a dream come true. I was 21, had never been anywhere, always lived at home." To get ready for field collection work, he asked several biologists in other departments at Jagiellonian for guidance. "Most of them thought that I was an undergraduate nuisance, so they would give me a liter of formalin and a liter of alcohol and wish me good luck," he says.
For a year, in addition to testing air samples for radioactive isotopes, Bartke collected soil organisms, insects and other invertebrates, and a few snakes and lizards, making do with the little equipment and few supplies that he had. "I didn't have specimen bottles, so I made a deal with the local clinic to save me glass bottles from antibiotics," he says. He made his way home to Poland by freighter, arriving after 40 days at sea with a trove of field specimens. Taxonomists at Jagiellonian described several new species of mites and primitive insects from his collection and even named one--a parasitic mite that lives on the bellies of beetles, he recalls--bartkei in his honor. "I don't know how happy I should be about this decision," he says wryly, "but anyway, it was meant as a thank-you." Despite enjoying the research project, Bartke wasn't interested in taxonomy. "Collecting was fine as a hobby and as a diversion, but I really wanted to do something functional. I was [growing] more and more interested in genetics."
Six months after Bartke's return, the Iron Curtain lifted a second time. The head of the comparative anatomy and embryology department, Zygmunt Grodziski, heard from a Polish colleague who had recently returned from a visiting-scientist stint at the University of Kansas, Lawrence. The American school was eager to host a grad student from Poland, and Grodziski thought of Bartke, apparently impressed by the student's work in Vietnam. Grodziski, an excellent but intimidating and demanding scientist, called Bartke into his office.
"Most people in the department were deadly scared of him," Bartke recalls. "He was never wasting any more time than was required, so when I walked in, he just told me, 'There is an opportunity to go to the United States to do graduate work, get a doctoral degree. Why don't you think about it, talk to your parents, and tell me tomorrow if you're interested.' And I hadn't left the room [yet], and he kind of looked at me over his desk like, 'Why are you still [in my office]?' ... And I said, 'Excuse me, but I don't want to think or talk to my parents. I want to go.' " So Bartke applied to the university; with recommendation letters from Grodziski and others, he got in.
It was a rare stroke of luck. At the time, Poland, a satellite of the Soviet Union, permitted foreign exchanges only for university faculty. "In fact, I had a hell of a time convincing the government to give me a passport and let me go, because they thought it was unusual," he says. Bartke finally won permission to leave, but the haggling delayed him; he didn't arrive in Lawrence until a month after the semester had started. "So in addition to having to adapt to coursework in English--which of course was an uphill battle--I also had to catch up," Bartke says.
Life in Lawrence was nothing like what he had anticipated. From books and movies, he had imagined that all American cities were like New York City. "I sort of expected high-pressure, fast, supermodern, urban," he says. "So when I came to Lawrence and I saw single-family dwellings and big trees and quiet streets with no pedestrians, and everything kind of slow and quiet ... this was just a total shock."
From Pint-Sized Mice, a Prolific Career
Bartke had indicated his interest in genetics on his grad school application, and John Weir, a geneticist in the zoology department, was willing to take him on. Weir helped arrange a scholarship to support Bartke's Ph.D. studies. The financial support came from a National Institutes of Health (NIH) training grant that Weir, who was studying the genetics of sex ratios in mice, had won to fund graduate students--a grant, it turned out, that was intended only for American citizens and permanent residents. "I guess Weir was so excited about his training grant that he forgot to read the instructions," Bartke says. When NIH officials saw from the paperwork that Bartke was a foreigner, they called Weir. Weir explained his mistake and told them it would be terrible to have to send Bartke home. "And they said 'OK'!" Bartke recalls. "So I went to graduate school in Kansas on an NIH fellowship for which I shouldn't have even been considered." He received a stipend of $222.22 per month, which freed him from having to teach to make ends meet. "I could just study, do research. So I was lucky again."
In the Weir lab, Bartke worked with a postdoc named Bob Schaible on experiments comparing two mutant strains of midget mice. One was the Snell dwarf, first identified in 1929, which lacks growth hormone and thyroid-stimulating hormone (TSH). The other strain was the Ames dwarf, a new line that Schaible had discovered in 1961 while he was a grad student in geneticist John Gowen's lab at Iowa State University in Ames. The preliminary research from Iowa suggested that Ames dwarves lack only growth hormone, but Bartke's experiments showed that they are also missing TSH. With guidance from Jerome Yochim, a professor who taught his endocrinology class, Bartke was the first to demonstrate that both the Ames and Snell mice are deficient in a hormone called prolactin as well. Females of both strains are infertile, and Bartke's dissertation research established that the problem arose from the absence of this hormone; treating the animals with prolactin restored their ability to have pups. At Yochim's suggestion, Bartke began using the dwarf mice to investigate prolactin's role in male fertility, an unexplored area. That interest led him away from genetics and into reproductive endocrinology.
A workaholic, Bartke finished his Ph.D. in 2 years and 3 months. To make the most of his 3-year visa, he spent the remaining time at the Institute for Cancer Research in Philadelphia, studying the hormones of a different mouse mutant--the lethal yellow mouse--in the lab of geneticist George Wolff. In fall 1965, Bartke went back to Jagiellonian University to take up an assistant professorship. But he soon found himself unhappy. At the time, he says, scientists in Poland had relatively little equipment or funding. They grappled with an inefficient bureaucracy, and their ability to attend scientific meetings and maintain contact with foreign colleagues was tightly restricted by the government. Bartke's salary was so meager that he spent 3 to 4 hours every day tutoring others in English or doing translations to earn extra money. He itched to return to the United States. "Maybe, like my friends and colleagues often told me, I got simply spoiled in the United States and I wanted it easier," he says. But as a researcher in Poland, he felt that he would be "spinning [my] wheels. I couldn't possibly compete with people who worked in the United States or in comparable circumstances."
In 1967, Wolff helped arrange a postdoctoral fellowship for him at the Worcester Foundation for Experimental Biology, a private research institute in Shrewsbury, Massachusetts. Bartke obtained permission to leave Poland again for the training stint. Because he had dutifully returned home after his previous 3-year visit to the United States, he says, "I guess I had a pretty clean file with [the government] security folks, so they let me go again. This time, they made a mistake, because I went with premeditated intent not to come back. And I did not." After a year and a half in Massachusetts, he applied to the U.S. Immigration and Naturalization Service (INS) for a "green card" conferring permanent resident status, which the agency granted. Bartke was at the time married to an American citizen, and he immediately filed the paperwork to become a naturalized citizen. Bartke was no fan of Communism, but when he wrote to colleagues at Jagiellonian University that he would not be returning, he said he desired to stay in the United States only because of his wife; the INS approved his request several years later in the mid-1970s.
Hooked on Longevity Studies
At the Worcester Foundation, Bartke continued his investigations of prolactin in male reproduction and joined the staff after 2 years. He stayed there for 11 years before moving to the department of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio (UTHSCSA) in 1978. Although UTHSCSA was a hotbed of research on calorie restriction and aging (see "Hungry for Science"), it wasn't until Bartke moved to SIU in 1984 that questions about aging began percolating in his mind. A few years after he arrived in Carbondale to run SIU's physiology department, he began collaborating with Thomas Wagner, a geneticist at Ohio University in Athens who was a pioneer in engineering transgenic animals. Wagner had created giant mice that churned out growth hormone, and he noticed that the females were infertile. An acquaintance at NIH, who also knew Bartke, suggested that the two scientists study the animals' abnormal reproductive endocrinology together.
Other investigators studying mighty mice that overproduce growth hormone had found that the rodents had shorter lives, but most of their research focused on causes of death from disease. Based on his own observations of how the animals seemed to age quickly, Bartke realized that the mice could provide a wonderful means of studying the biological aging process, and in 1990 his lab began investigating the idea. A year later, a colleague at SIU, endocrinologist Richard Falvo, asked Bartke to help organize an international symposium on some area of biology, to be held every other year at the proposed site of a university satellite campus in Bregenz, Austria. Bartke suggested focusing the conference on aging. The First International Symposium on Neurobiology and Neuroendocrinology of Aging was held in 1992, and Bartke's lab presented some of its findings on aging in the giant mice. He began meeting biogerontologists, including Roth, and learning more about the field. His second research career was under way.
Dogged Pursuits of Aging Mice
Throughout his years of studying reproductive endocrinology, Bartke had obtained major grants from NIH. Among other achievements, he found that an excess of prolactin can suppress sexual behavior in males, and he published some of the earliest work showing that testosterone is released into the blood in pulses. But getting funds for biogerontology studies was a different story. In the early '90s, Bartke wrote a grant application proposing to study the giant, growth-hormone-flooded mouse as an example of accelerated aging. "I got some of the most negative critiques I have ever seen," he says. Reviewers said the rodents were probably just sick from an excess of growth hormone. Although he resubmitted the proposal several times, NIH never funded it.
After publishing the Nature paper on the Ames dwarf's increased longevity, Bartke secured a $50,000, 1-year NIH grant to further investigate aging in the mutant mouse. But he was unable to win a more substantial grant afterward. "I again had an uphill battle," he says. Some reviewers questioned whether dwarves survived longer simply because they were eating less and reaping the life-prolonging benefits of calorie restriction. But in a collaboration with Miller, Roth, and other colleagues, Bartke showed in 2001 that cutting the animals' calorie intake gave them an additional increase in life span, results suggesting that the two mechanisms for achieving longevity act through different pathways (see "Dieting Dwarves Live It Up"). Furthermore, Bartke's work got a boost from two other studies: a 2000 paper by scientists at Ohio University documenting extended longevity in another line of midget rodents called Laron mice, which are engineered to lack growth hormone receptors, and a 2001 report by Miller and colleagues showing that Snell dwarves survive 42% longer than normal mice. In 2001, Bartke finally won a 5-year NIH grant to further investigate the effects of calorie restriction on aging in Ames dwarves and Laron mice.
Colleagues admire his persistence. "I give him real credit for sticking with it for years under conditions in which a less dogged scientist might have just given up," says Miller. Bartke has "really paid his dues" in three different phases of his career, says Roth: grappling with the challenges of doing science during the Cold War in Eastern Europe, building his reputation in endocrinology in the United States, and then making his largely unbacked foray into biogerontology. "Bartke really had to do a lot of this stuff on a shoestring," says Roth. "Now he's starting to get support, and he's carved out this really enviable niche with regard to the [aging and] growth hormone business."
Looking back, Bartke says that if he hadn't had "a rather happy history of funding" in reproductive endocrinology, "I don't know if I would've had it in me to reapply and reapply and reapply. But I kept telling myself that the system had been good to me and has supported my research for all these years; I have to trust the system."
Bartke clearly has an abundance of patience, which he also puts to use when pursuing one of his favorite out-of-the-lab activities: fishing. "When he takes a break from research, which is not often, he's outside and he's either fishing or hiking," says Brown-Borg, now at the University of North Dakota School of Medicine & Health Sciences in Grand Forks. Every year in Carbondale, Brown-Borg remembers, the lab would enter SIU's annual fishing tournament. "We fished through the rain, we fished through nasty weather, and cooked [the catch] up at the end of the day. [It] was always a lot of fun, and Andrzej was always very much involved ... and very competitive," she says, laughing. Bartke is known for recounting stories of the bluegill and bass beauties that he's caught. But in the grand old tradition of fishermen--and unlike the dwarf mice that have played such a prominent role in his latest career twist--the fish in his tales get bigger with each telling.
August 27, 2003
Ingfei Chen is a SAGE KE contributing editor based in Santa Cruz, California. Her stories get longer with each telling.
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