Sci. Aging Knowl. Environ., 10 December 2003
Mission (Not) Impossible
Endocrinologist Nir Barzilai, a former chief instructor of medics for the Israeli army, is determined to elucidate the relations among body fat, blood lipids, insulin, and aging
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/2003/49/nf20 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. For the first decade of his professional life, Israeli-born Nir Barzilai toiled to aid people ravaged by war, poverty, and disease. In 1973, at age 18, he began training as a medic in the Israeli Defense Forces (IDF) during the Yom Kippur war with Egypt and Syria; he was promoted to chief instructor of medics 2 years later. In 1979, after Vietnam had invaded Cambodia, sending hordes of refugees fleeing to the Thai border, Barzilai led an Israeli medical team that joined an international emergency relief effort in the area. For 3 months, he and his crew treated tens of thousands of Cambodians for malaria, measles, hookworm infections, and war wounds. Later, while earning a medical degree, he chose to do clinical rotations at hospitals in South Africa, as a statement of support for black people against apartheid.
Barzilai, a short and compact 48-year-old who looks younger than his age despite his close-cropped gray hair, sums up these experiences. "It was all kind of my ideology of helping the world and repairing the world through action as a medic or a physician," he says.
Today, Barzilai's instincts are no less humanitarian, but his objectives and methodologies have changed. Instead of treating refugees or injured combatants, he seeks to defend people against a different kind of enemy--the decrepitude of aging and its attendant diseases. He is an endocrinologist and internist at Albert Einstein College of Medicine in New York City and also directs its Institute for Aging Research. Since immigrating to the United States in 1990, he has taken a lead in parsing the metabolic consequences of aging in rodents and the genetics of longevity in centenarians. The latter work, which pursued the controversial idea that certain genes can extend human life span, culminated last October in a headline-grabbing paper: Barzilai and his colleagues demonstrated that very long-lived Ashkenazi Jews and their children possess a mutation that gives them larger-sized particles of cholesterol--a trait that seems to protect them against cardiovascular disease and contribute to their longevity (see "Greasing Aging's Downward Slide").
Barzilai's focus on the genetics of not just centenarians but also their offspring is one example of the "extremely creative and innovative ideas" that he has brought to the study of aging, says Evan Hadley, associate director of the geriatrics and clinical gerontology program at the National Institute on Aging in Bethesda, Maryland. Researchers have realized that by the time people reach 100, the biological characteristics that allowed them to stay healthy for so long might not be detectable, so it's valuable to study their children as well--seeking protective traits that they might have inherited, says Hadley: "Nir has been one of the people who's developed that concept most fully."
Identifying Barzilai in a crowd is easy: He's the one walking fastest down the corridor in his department or regaling colleagues at conferences with riveting tales from his past. "When I go to meetings with him, I notice that everyone is immediately drawn to him," says Meredith Hawkins, an endocrinologist at Einstein. It also doesn't hurt that Barzilai has a quick and subtle sense of humor. The first time they met, Hawkins recalls, they were headed out to lunch and he asked, "Would you be interested in food from Nauru?" She had just read about Nauru--a South Pacific island whose residents have a high incidence of diabetes, possibly because of a relatively recent shift to a fatty Western diet--so she got the joke. "It set things off on a very sort of jocular but scientific tone."
Barzilai seems to run on a bottomless fuel tank. After a full day's work, he goes jogging or exercises at the gym from 6:30 to 7:30 p.m. while listening to an audiobook. A gourmand who cooks French cuisine, he confesses in a bantering tone, "I love everything about food. I'm really exercising a lot so I can eat." Then he has dinner and spends time with his wife, Laura, a part-time partner in a large New York law firm, and their two school-age children. From 9:00 to midnight, he hunkers down in his home office to read and write papers and grant proposals. (He is also a SAGE KE contributing editor.)
Those who know him well attribute Barzilai's work ethic partly to his upbringing and military training in a small country that has long felt itself to be under siege--a training ground that toughened him for pushing onward when his research proposals have been rejected or seemed too risky to win major funding. "He's very determined, very resilient," says collaborator and friend Luciano Rossetti, who heads the Diabetes Research and Training Center at Einstein. "If he goes down, he's always going to get up and keep fighting for what he wants to achieve. And in science, that's very important."
Growing Up Fast
Barzilai was born in Haifa, Israel, in 1955. His mother, a Holocaust survivor, was a nurse; his father, an internist and endocrinologist, helped build the medical school of the Technion-Israel Institute of Technology and served as its first dean. When he was 9, Barzilai's ambitions extended no farther than the nearest trash dump: He wanted to be a garbage collector. "I thought hanging on the back of a truck and just going around the city all day was worth the smell," he recalls. But a few years later, his father began taking him to Rambam Medical Center, Technion's major teaching hospital, on Saturday mornings to see patients on rounds. One of Barzilai's uncles was a surgeon, and Barzilai, inspired by a growing appreciation for medicine, focused one of his high school science projects on kidney transplants and tissue typing.
Like all Israelis, Barzilai spent 3 years after high school in the IDF, choosing to specialize as a medic because he didn't want to drive tanks or fly attack helicopters. "I wanted to be somebody who helps the victims of war rather than somebody who's making some of the damage," he says. "The army was tough, but it was an unbelievable maturing period of my life." As chief medic in his third year, at age 21, he was in charge of teaching the 50 instructors who trained the IDF's medics and ensuring that new treatment methods trickled down to the battlefront. "I had an office; I had a secretary; I had a car. I did routine visits with helicopters. [In New York today,] I'm doing very well, but I still don't have a full-time secretary, my car, and my helicopter to take me around," he says, chuckling. One of the highlights of his army career was a supporting role in the IDF's legendary rescue of hostages from a passenger jet that had been hijacked by terrorists to Entebbe, Uganda, in 1976. Barzilai headed a team of medics who flew to Uganda, then Kenya, where they waited on standby while army commandos successfully carried out their mission. Although he and his crew didn't see any action, he cherishes the experience as an instance of being part of "something that's a little bit greater than yourself," he says.
A Doctor Without Borders
Returning to civilian life in 1978, Barzilai enrolled in a 7-year medical school program at Technion, but he remained in the IDF reserves and was called for active duty 1 month each year. He had some close calls--such as the time a Special Forces helicopter dropped him off in the middle of a gunfight in Lebanon to treat the wounded leader of a terrorist group. As Barzilai worked on the man--whom the IDF wanted to capture--bullets were whizzing through the air. One of them hit the patient's leg, missing Barzilai by centimeters. After the helicopter returned and picked them up, Barzilai collapsed, succumbing to feelings of fear and anxiety that he had suppressed as he did his job. "All of a sudden I realized how vulnerable, how close to death I was," he says.
In winter of 1979, when Prime Minister Menachem Begin decided to send a medical relief crew to help Cambodian refugees, Barzilai was selected to head the team. It was the middle of the semester, but he informed medical school administrators that he would take his exams when he returned. Later, recounting his days at a refugee camp near the Cambodian-Thai border in the Einstein Quarterly Journal of Biology and Medicine, Barzilai wrote, "The number of dead at the doorstep of the screening ward kept mounting by the minute. However, I think that in all my years I will not save as many lives as I did in one hour in that camp."
In keeping with his desire to help heal the world, in 1981 Barzilai also spent a 2-month clinical rotation in family medicine in Kwazulu-Natal province, South Africa, building a "nutritional village"--a cluster of huts near the local hospital where mothers of malnourished pediatric patients could learn cooking techniques that preserve the nutrients in food. Barzilai's various stints overseas gave him "confidence that you can [make] something out of nothing," he says. But working with the poor and sick, particularly in Cambodia, also taught him about the limitations of humanitarian efforts. Medical teams can save the lives of people in underdeveloped parts of the world, he realized, but the needy will remain miserable in the long run if they remain underprivileged. "The way to save young people is political," he says. "You have to have peace, you have to have a country. You have to have opportunities." Seeking a more enduring way to help people that also fit his talents and training, he turned his energy toward studying the origins of diseases.
Diabetes--in particular, the role of glucose and insulin metabolism in that disorder--grabbed his interest during a research internship in summer 1982 at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. After finishing his M.D. in 1985, he did his residency training in internal medicine at Hadassah Hospital of Hebrew University in Jerusalem, which included a rotation in a geriatrics facility. Aging had always fascinated him, and he grew curious about why 70-year-olds and 30-year-olds differ so much physiologically. "I had this feeling that aging is very much a metabolic state," he says, because some of the complications associated with diabetes, such as nerve degeneration and organ failure, are also seen in old age.
Like all medical residents in Israel, Barzilai was obliged to spend 1 year doing basic science research. A mentor, diabetes specialist Eddy Karnieli of Rambam Medical Center, had introduced him at a conference to diabetes specialist Ralph DeFronzo, then at Yale University in New Haven, Connecticut, and DeFronzo later agreed to take Barzilai into his lab to study how a new diabetes drug, metformin, works. Mastering a new technique called insulin-clamp measurements, Barzilai assessed glucose uptake by the liver and muscles in response to insulin before and after people received the medication. Afterward, he went back to Israel to finish his residency, and in 1989, he married Laura, whom he'd met at Yale. The following year, the newlyweds returned to the United States--where Barzilai became a naturalized citizen--when he landed a 2-year clinical fellowship in endocrinology and metabolism at Weill Medical College of Cornell University in New York City. The young couple planned to live in the States for 2 years before trying Israel for 2 years. But the research opportunities that Barzilai found in the Big Apple would ultimately keep them there.
On top of his clinical duties, Barzilai started ramping up his studies of metabolic aging as a senior fellow with Rossetti, who had just started his lab at Einstein. Conducting insulin-clamp studies, Barzilai found differences between young and old rats in their glucose uptake. In 1994, he was hired onto the faculty as an assistant professor, and 7 years later, in 2001, he spearheaded the creation of Einstein's Institute for Aging Research. An institute "without walls," the gerontology center has three cores to its research agenda: metabolic aging, cognitive aging and dementia, and the genetics of longevity.
Barzilai's research has called attention to the potential roles of fat in contributing to age-associated changes. As the body grows old, its ability to absorb glucose decreases, a condition called insulin resistance that often precedes the onset of diabetes; the greater the degree of insulin resistance, the sooner in life the disease tends to develop. Barzilai's experiments have shown that calorie restriction, which prolongs life span in rodents (see Masoro Review), can blunt an old rat's insulin resistance, so that its glucose metabolism resembles that of a young rat. He thinks that calorie restriction works by preventing the accumulation of fat, a still-controversial idea others had previously dismissed, and that minimizing fat buildup helps keep an animal's glucose metabolism running smoothly. In an elegant surgical experiment, Barzilai and his colleagues demonstrated that removing abdominal fat from middle-aged rats eliminated their insulin resistance and restored their glucose uptake to rates similar to those seen in calorie-restricted rodents (see "All Fat Is Not Created Equal").
Barzilai's research interests expanded to genetics in the mid-'90s after he read a paper by geriatrician Thomas Perls of Boston University School of Medicine (see "Chasing 100") that concluded that siblings of centenarians live longer than members of the average population. Like Perls, Barzilai became convinced that, in the shuffle of the genetic card deck, 100-year-olds must have drawn aces that allow them to survive longer. At the time, most scientists viewed the idea of longevity genes with great skepticism: Several demographers told him it was "the stupidest thing they've ever heard," Barzilai recalls. But starting with small grants from Einstein and the American Federation for Aging Research (AFAR), he scraped together funding to build his study of extremely old Ashkenazi Jews, an ethnic group ideally suited to such scrutiny because of its relatively homogeneous genetic makeup. Later, in 1997 AFAR awarded him a prestigious 3-year, $450,000 Beeson scholarship, a career development award that requires the sponsorship of a mentor--in his case, Rossetti. And today, Barzilai's genetics project includes more than 300 centenarians and their siblings and children, recruited from across the Northeastern United States.
Barzilai is unafraid to take gambles and jump into projects beyond his immediate ken. "He's very versatile in terms of his ability to learn new areas of biology and science ... to move into another area," says endocrinologist Alan Shuldiner of the University of Maryland School of Medicine in Baltimore, who studies the genetics of diabetes and longevity in the Amish and collaborates with Barzilai. "He never trained in genetics in any way, shape, or form," Shuldiner says, but through their collaboration, Barzilai quickly learned and applied the principles of genetic epidemiology to his research.
The "Lone Ranger" in American Science
Reflecting on his journey in gerontology, Barzilai says his military training had a "major impact" on his life as a scientist, by filling him with confidence that no task was impossible. As a child watching old black-and-white westerns on TV, Barzilai grew up picturing the United States as a country of Lone Rangers--strong, independent, risk-taking individuals. But once he got to the United States, he decided that a better metaphor for the role of the individual in American society is the corporate employee. Just like at a large company, people in society can "just hang in there at midlevel [ranks]," playing along as the corporation makes all the decisions, he says. The parallel in the life sciences, he says, is that most investigators are funded by the National Institutes of Health (NIH), which takes a fairly cautious approach to research. Scientists generally can't win government money to support risky research proposals or ideas that they haven't already virtually proven through preliminary work, Barzilai says. Many immigrant scientists from poor or war-torn countries do well in the United States because they tend to be highly creative types who had to do "something extra" just to get here in the first place, he adds. Their advantage, he says, is that they're more likely than American-born scientists to persist and be innovative in finding ways around obstacles. "In my case, Israel has prepared me to a great extent to be a Lone Ranger," he says. As a researcher, "the risks I was taking are larger than what people usually do." And despite his imperfect command of English--which he says makes grant writing the "most anxiety-provoking stage" of his work--he has soldiered on with the perspective that because only one in five grant applications win funding, he will submit proposal after proposal until he gets an approval: "I'm an optimist, and I keep moving on."
Barzilai has found that Lone Rangers can still work within the corporate structure and benefit from its help. After winning starter grants from AFAR as well as the Ellison Medical Foundation (the major sponsor of SAGE KE), Barzilai eventually secured NIH funding. Most immigrants come to the United States because they believe life will be much improved not for them, but for their children, yet he says that he has already reaped rich rewards. "I came here and from the first moment, from my first grant, I was reviewed just like everybody else. And although many people tell me that I don't write the [English] language well," he says with good-humored humility, "or that I have spelling mistakes, still I was judged by my work and not by my immigration status or my accent. I think this is absolutely great in the United States. And I cannot tell you how proud I am to be an American for that."
Passing the Baton
Barzilai says that his top priority these days is mentoring: "I think my real impact from now on will be how many people I've trained and are able to go on and think independently and take [new] directions and just grow up and be the hot stuff." True to his word, Barzilai is raising a crop of young scientists whom he says he'd like to see inherit several of his grants and even join the faculty at Einstein. For instance, he's decided that in 2005, he won't renew one of his major NIH grants, on the metabolism of aging, because he wants one of his postdocs to take it over and run with it.
Hawkins, one beneficiary of Barzilai's mentoring, remembers how he took her "under his wing" when she first arrived at Einstein in 1994 to work as a research fellow in Rossetti's lab. Barzilai, who was then a junior faculty member in the group, offered to put her up at his house for the first few days. He loaned her his car as well as some furniture for a couple of weeks. "He was remarkably hospitable," she says. "Then he proceeded to teach me a lot about the lab"--how to do everything from performing insulin-clamp studies to interpreting results. Hawkins, who eventually became an independent investigator at Einstein, branched into research on aging with his encouragement. This year, she won a Beeson scholarship with Barzilai's sponsorship.
Spreading the word on the importance of research on aging is also important to Barzilai, and on several occasions he has accepted AFAR's invitations to give lectures to its board members and to the community. "We've supported a few thousand grantees in AFAR's lifetime, and Nir is one of the people who really stands out," says AFAR executive director Stephanie Lederman. As a dynamic speaker who's approachable, Barzilai brings the point home convincingly, she says. "Many people are very talented and they certainly are terrific speakers, but he has a way of commanding the audience that very few people have. It's a gift."
Although Barzilai says his best days were when he worked as a medic in a tent, he has happily traded the adrenaline rush of saving lives for the exhilaration of discovery in gerontology. Now, as then, whether he's directing experiments, giving talks, or mentoring others, he thrives on being part of something bigger than himself.
December 10, 2003
Ingfei Chen, a SAGE KE contributing editor in Santa Cruz, California, belongs to the tribe of freelancers, the Lone Rangers of writing.
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