Sci. Aging Knowl. Environ., 28 May 2003
Florian Muller was 12 when he first imagined that genetic engineering might someday extend life span. A dozen years later, he's still pursuing that vision: As a first-year grad student, he is investigating whether interventions that reduce oxidative damage could stretch longevity or ameliorate age-related diseases
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/21/nf11 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. Five years ago, evolutionary biologist Steve Austad offered a graduate seminar entitled "Ecological Genetics of Aging" at the University of Idaho in Moscow. At the start of the semester, a young man from a neighboring university came to his office seeking permission to enroll in the class. As the two chatted, Austad quickly discovered that the boyish-looking visitor had an "exceptional grasp" of the research literature on aging. "It wasn't just that he could cite the papers, but he could synthesize things--he could take six papers and put them all together to make sense out of them, which is [a skill] that takes a long time to develop," Austad says.
Impressed--but also mystified--Austad found himself wondering whether his guest was a grad student or a postdoc. Neither, it turned out. "He was a sophomore--in college," Austad recalls with a touch of disbelief.
The precocious undergrad was Florian Muller, then 19 years old and attending Washington State University (WSU) in Pullman, 13 kilometers from Moscow. Austad welcomed him into the seminar, which entailed reading and discussing scientific papers on major topics in biogerontology, such as calorie restriction and diseases that mimic aging, and Muller became the class star. He contributed intelligently to the group's conversations, and when it was his turn to direct the discussion on a particular paper, he did so with an easy confidence. He was equipped with "a better background in the aging literature than any of the graduate students in the course," Austad says. "It was obviously something that he had been interested in for a long time."
Austad's hunch was correct. Muller, a native of Munich who grew up in Germany and France, had his curiosity captured by the biology of aging when he was 12. Now 24, he is a first-year graduate student in the department of cellular and structural biology at the University of Texas Health Science Center in San Antonio (UTHSCSA), where he is studying the role of oxidative damage--the wear and tear inflicted upon the cell by toxic molecules called free radicals--in the aging process. UTHSCSA physiologist Arlan Richardson describes Muller as a "born-again" biogerontologist who believes that science can unravel the mysteries of old age.
Muller, who wears his brown hair long, in a shaggy page-boy style, and bears some resemblance to a young Jeff Bridges, was not always a model of outstanding achievement. Growing up in an upper-middle-class community in Munich, he was, he says, a "very, very, very bad kid." He and his twin brother, Andreas, hung out with a crowd of boys who vandalized property. "My mother and my father were worried we would turn into delinquents." Once, when Muller was 9 years old, he, Andreas, and a friend broke into an unoccupied house--someone's summer home--and trashed the furniture and walls with a sledgehammer they found inside. "It was completely senseless," Muller says. Another time, the twins ignited a wheat field. "We wanted to see how quickly it would catch fire, and we figured we would put it out very quickly. Well, the wind was blowing, and before we knew it, the whole field was on fire." Evading capture, the brothers and their friends escaped punishment for their misdeeds.
Muller mellowed out after the family moved to St. Martin, a small town in southern France, where his father, who had taught high school French literature and history in Germany, enjoyed retirement and his mother co-owned and ran a small private camp site.
Muller's scientific leanings grew out of his studies of the humanities; like his father, he loved history, particularly Roman history, a passion he maintains today. By the time he was 12, he was reading philosophy in school and debating the existentialist views of French author Jean-Paul Sartre with friends. It struck Muller that many philosophical questions about the meaning of human existence are based on the fundamental assumption that life is finite. But, he wondered, what if it weren't?'' That train of thought stirred Muller's first interest in aging and longevity. Around the same time, he was learning about DNA and genetic engineering in his biology class. With the na�ve optimism of youth, he put the two topics together, concluding that molecular genetics would provide both the techniques to understand why the body grows old and the mechanisms through which to extend life span. "I had looked at different species of animals--some species live very short, some species live very long," he says. "I figured it must be due to DNA, and so if nature can do it, we can do it too."
But Muller's curiosity took a turn toward chemistry and the environment. In the early 1990s, on the television news, he heard environmentalists' dire warnings about the destruction of the Amazon rainforest. "I was worried that because we were cutting down all the trees, someday there wouldn't be enough oxygen left to breathe," he recalls. Although he was only 14 years old, he decided that he could save the world by developing a method for synthesizing oxygen from carbon dioxide and light. Experimenting with a home chemistry kit, he ran electricity through an aqueous solution to generate oxygen and hydrogen. He kept up that work until one of his uncles, Stephan Kemmethmuller, who worked for the pharmaceutical giant CIBA-Geigy (now Novartis) in Basel, Switzerland, informed him that the world would not run out of oxygen. Nevertheless, Kemmethmuller, a pharmacist, encouraged Muller's interest in science, giving him a physical chemistry textbook. Muller also started making shopping trips to buy science books when he returned to visit relatives in Munich.
Roaming Toward Free Radicals
In 1995, when he was 16 and inspired by wanderlust, Muller signed up with a foreign-exchange program to finish high school in the small town of Haines, Alaska. His English skills were poor, but he learned the language in school and from MTV. One of his science classes, which discussed DNA, revived Muller's earlier interests in genetic engineering and longevity, and he began studying those subjects on his own. The local library had an Internet connection, and he started surfing the Web to learn more about the biology of aging.
After receiving his high school diploma in 1996, Muller enrolled at WSU, majoring in biochemistry and biophysics. In his first semester, he signed up for graduate courses in molecular biology and genetics. In his second semester, he started doing research in three different labs, including that of Carolyn Decker, a molecular biologist who was investigating how the cell controls gene expression through the destruction of messenger RNA. During his fourth year at WSU, he joined the lab of biophysicist David Kramer, who taught a graduate biochemistry class that Muller had taken and who was studying bioenergetics, particularly photosynthesis.
By then, Muller's readings of the research literature had turned him on to the widely held theory that free radicals drive the process of aging (see "The Two Faces of Oxygen"). Most scientists were focusing their efforts on disarming the toxic molecules--particularly a bad actor called superoxide--by boosting the production of antioxidant enzymes such as copper, zinc superoxide dismutase (Cu,Zn-SOD) and manganese superoxide dismutase (Mn SOD). But Muller conjectured that another approach to the free radical hypothesis would be to find ways of reducing free radical generation. With Kramer's guidance, he began investigating the mechanisms of superoxide production within mitochondria, the energy generators of the cell, in baker's yeast.
Despite spending much of his time at the bench, Muller graduated from college in 2001 with an overall grade point average of 3.85. Because his wife, Lisa Teodecki, was still working on her neuroscience Ph.D. at WSU, he worked as a research technician in Kramer's lab for another year while considering his options for graduate studies. Richardson, another proponent of the free radical theory of aging who Muller had heard speak at a Gordon Research Conference in March 2001, seemed like a good prospective mentor. In his talk, Richardson presented evidence from his lab that seemed to contradict the hypothesis (see "Is Less Enough?"): Life span was normal, not shortened, in mice that were lacking one of the two genes that normally encode Mn SOD.
Other scientists faced with data contrary to their pet theory might have swept them under the carpet, Muller says, adding "Dr. Richardson has incredible integrity as a scientist. He was willing to draw conclusions that were not necessarily popular." Muller still adheres to the free radical theory; he speculates that the focus on SOD enzymes is painting an incomplete, and therefore misleading, picture. But after considering offers from the California Institute of Technology in Pasadena and the University of Illinois at Urbana-Champaign, he decided that he wanted to train with Richardson at UTHSCSA.
Energy to Burn
Soon after arriving there last fall, Muller started working in Richardson's group while doing rotations in other labs. "He has a tremendous amount of energy," says Richardson, noting that the grad student has already accumulated enough data to write a small paper. Not only does Muller seem to have a remarkable memory, says Richardson, "but he's got a goddamn good retrieval system too. It's kind of like he's sitting there, and all of a sudden he puts it all together." Says Austad, "He's able to think very creatively about published material. ... I think that he's going to be a major contributor in the future." Austad recalls one conversation in which Muller made an insightful connection about telomeres, the DNA-and-protein caps at the ends of chromosomes that shorten with every cell division, eventually pushing cells into a nondividing state called senescence. Muller voiced his view that oxidative damage might cause telomere shortening, Austad says. Not long afterward, biogerontologist Thomas von Zglinicki and his colleagues at Humboldt University in Berlin published a paper suggesting that telomere shortening could be hastened by oxidative damage.
Muller is full of surprises, according to Austad, who remembers receiving a package in 2000 from the then undergrad. "He sent me a reprint in the mail--he had published some of his ideas on oxidative stress!" Austad says, laughing. Muller had written a 25-page review about superoxide production and aging for the Journal of the American Aging Association (JAAA) in which he laid out his ideas about reducing free radical production to increase longevity. He says he was inspired by the example of a colleague, computer scientist-turned-theoretical biologist Aubrey de Grey (see "Wake-Up Call"), who published his first gerontology paper on mitochondrial DNA mutations despite a lack of experimental experience in that area. Muller says he figured, "If he could do it, why not me?" so he wrote up his article and asked de Grey for feedback. As it happened, de Grey was serving as a guest editor for an issue of JAAA.
The same boldness sets Muller apart at scientific conferences: He has no difficulty piping up to ask questions or make comments. "If he's sitting in a room of professors, he'll speak up without any shyness whatsoever," says Austad. "It doesn't matter if they're all leaders in the field; he thinks that his ideas and contributions are just as important as anybody else's. And I like that a lot."
"Florian is no shrinking violet," agrees Richardson, who remembers the first time Muller, then a college sophomore, introduced himself during a conference and started talking shop like a postdoc. Muller speaks emphatically and with confidence--and yes, he can come off as cocky. But, Richardson says, "you kind of think, 'Well, this guy is going to maybe be a little bit overbearing.' But I've not found that at all." What's more, Richardson adds, "when he's wrong--and it's not often--he picks up on it right away."
Muller's admirers have high expectations for him in the coming years. So, for that matter, does Muller. Ask him what he plans to do for his thesis research, and he reels off half a dozen ideas, his words tumbling over each other. One of the experiments that he is willing to divulge--which he calls a "bread and butter" project--involves a mutant mouse strain that develops a disease similar to human amyotrophic lateral sclerosis, or Lou Gehrig's disease. These rodents carry a flawed Cu,Zn-SOD gene whose product not only loses the ability to defuse superoxide but also seems to kill neurons, perhaps by generating more free radicals (see "A Game of Cellular Clue"). Muller intends to investigate whether a lack of other antioxidant enzymes in these mice will worsen their disease symptoms.
Farther down the road, Muller pictures himself setting up an integrative lab, somewhere in the United States, that studies aging in fruit flies, roundworms, and other model organisms. But until then, he has a message for researchers in the field of biogerontology, which he delivers with a slight smirk: "Watch out for me in 10 years."
May 28, 2003
Ingfei Chen, a contributing editor of SAGE KE in Santa Cruz, California, is fond of violets, shrinking or not.
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