Sci. Aging Knowl. Environ., 3 March 2004
Tying It Together
Rudi Westendorp is one of those rare individuals whose work unites geriatrics, clinical epidemiology, and the biology of aging
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/2004/9/nf23 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. In 1985, Rudi Westendorp was a first-year medical resident in internal medicine in Leiden, the Netherlands. Like the other male residents in his department, he initially went without a tie under his white lab coat, but senior doctors wanted him and the rest of the junior staff to spruce up. He and his peers didn't like the idea of conforming, so they came up with an alternative: They decided that, starting on a particular Monday, the men would wear bow ties and the women, neck scarves.
More than 2 decades later, the bow tie has become Westendorp's hallmark. A slim, graying 44-year-old with a sharp nose, he never goes to his job as head of Leiden University Medical Center's (LUMC's) gerontology and geriatrics section without wearing one. Always neat and tidy in appearance, he is equally meticulous at bringing together diverse areas of knowledge in his work as a geriatrician, clinical epidemiologist, and gerontologist. The bow tie "expresses his love for elegant and creative solutions," says David Vinkers, a physician who is earning a Ph.D. in Westendorp's lab. For instance, in addition to presiding over the long-running Leiden 85-plus study, which tracks cognitive decline and risk factors for heart disease, stroke, and other illnesses in people 85 and older, Westendorp came up with an innovative and inexpensive way to explore the evolutionary tradeoff between longevity and fertility: analyzing old genealogical records of British aristocrats. He's also hunting for a biological explanation for this tradeoff by investigating whether immune defenses might play a role. He is "an unusual character" who's distinctive for "bringing epidemiological thinking and methodology into dialogue with molecular and cell biology" to answer important questions about aging, says gerontologist Thomas Kirkwood of the University of Newcastle in Newcastle-upon-Tyne, U.K.
Westendorp has always enjoyed taking things apart to understand how they work. Born in Huizen, a small village in the middle of the Netherlands, he spent his early teens tinkering with motorcycle and car parts with his brother and a neighbor. Monkeying around in the garage, they jury-rigged a motor and steering handles to a wood frame and careened through the woods in their go-cart. His father, a commercial pilot, bought them fuel when they were short on money. "Everybody had the idea that I would have some kind of career within the technical realm," Westendorp says.
But he surprised the pundits. When he was 16, his older sister almost died from an asthma attack and was hospitalized. He didn't fully understand how dangerous her situation was, but the experience opened his eyes to the ways in which the medical profession can help when people are sick. "I wandered for 1 week in and out of the hospital together with my parents," he recalls. "And then I realized that maybe this is the way to go, to become a doctor." In 1977, he embarked on a 7-year track toward an M.D. at Leiden University. When he graduated in 1984, he decided to specialize in internal medicine and continued at LUMC for 5 years of residency education.
From Bedside to Bench and Back
As a first-year resident, he trained at Bleuland Hospital, a teaching institution affiliated with LUMC. While rotating through the wards, he discovered that he liked working with the elderly the most, because his conversations with them about illness and death were refreshingly candid. "If you are honest, they give you an honest answer back. And they immediately grasp when you're hiding something or when you're not speaking from the heart." In contrast, he found that younger patients--such as middle-aged corporate CEOs with stiff upper lips--were often reluctant to reveal their feelings, such as fear of dying.
Despite his interest in old people, Westendorp also found emergency care appealing, so after completing his residency in 1990, he took a consultant position in the intensive care unit (ICU) at LUMC. At the same time, because research science had caught his fancy in medical school, he began working on a Ph.D. with internist A. Edo Meinders. For his thesis, he studied the hormonal signals that the heart sends to the lungs to regulate the volume of blood in circulation.
By late 1992, Westendorp was feeling burned out, he recalls; between his residency and his job in the ICU, he had been running night and day for almost 8 years. He also recognized that his thesis was only "mediocre": "I realized I didn't know enough to have a brilliant career in clinical science. And that's what I wanted to do." The previous year, he had met Jan Vandenbroucke, a well-respected clinical epidemiologist at LUMC. Trained as an internist, Vandenbroucke had left medical practice to use epidemiology--essentially, the counting of people--to study the risk factors linked to the pathophysiology of disease. Westendorp, who enjoyed observing people rather than cells, was intrigued by his conversations with Vandenbroucke about this approach to medical research. The idea of developing his skills in defining clinical research questions, designing studies to test them, carrying out statistical analyses, and interpreting the data seemed like a good fit. So when Vandenbroucke, who at the time headed the clinical epidemiology department, invited him to learn the ropes, Westendorp said yes. In January 1993, Westendorp walked away from the intense, high-pressure treadmill of the ICU and started "writing, counting, [and] working with data structures" instead. His fellow physicians found the shift baffling. "They said, 'How on earth can you do that, forget about patient care?' " He finished his Ph.D. that March and took an assistant professorship in clinical epidemiology.
Vandenbroucke says that he enjoyed working with Westendorp because they engaged in lively debates about research. "He never believed anything I said," recalls Vandenbroucke. "He's one of those people who will never accept anything in the scientific and medical field on authority. ... That's his greatest characteristic--to always question things, to always argue about things, until he understands them profoundly himself." And then, once he accepts an idea, he will pursue it "relentlessly like a terrier," Westendorp's former mentor adds. Such a direct and argumentative style can rub some people the wrong way or intimidate them, but Westendorp explains that his intent is to stimulate intellectual discourse and sharpen a line of reasoning. Vandenbroucke concurs, saying, "That's his way of thinking through things. And once you appreciate that, it's enormous fun. Because if he has a wrong argument, he'll be the first to concede."
Despite his intense intellectual approach, Westendorp looks after the younger colleagues in his group and gives them full credit for their work, Vandenbroucke adds. Not long ago, a journal rejected one of the group's papers. Westendorp asked Vandenbroucke, who was a co-author, to explain to the journal's editor, a friend of the more senior epidemiologist, why one reviewer's comments were misguided. The paper was not important for either of the two faculty members, but it was crucial for the career of a junior colleague who had contributed to the research. "So he told me, 'Will you do it not for us, but for that young person?' " Vandenbroucke did so, and the journal has agreed to take a second look at a revised version of the paper.
A 38-Year-Old Takes on 85-Year-Olds
In 1997, after several years of training in clinical epidemiology, Westendorp was ready to bring doctoring back into his work. In order to fine-tune clinical research questions or extrapolate findings back to the patient's bedside, he says, "you need to know what's happening in the clinics." At first, his colleagues in medicine were wary about his return. "I left them quite so suddenly and I went away for 3 to 4 years. And they said, 'He's a strange character. What is it that he's interested in? Is it science or is it medicine? And now he wants to come back again.' " Despite those reservations, Westendorp found an opening. Gerontologist Dick Knook, then the head of the geriatrics section at LUMC, was looking to hire someone just like him to do both science and medicine. Many doctors view the specialty of geriatrics as "boring, uninteresting, [and] completely without esteem," Westendorp says. But he saw it as an opportunity, with room to make a contribution.
So in addition to his faculty position in clinical epidemiology, he began working half-time in geriatrics. He took over the division's Leiden 85-plus study, which had been established in 1987 by immunologist Willy Heijmans, who had just retired. Heijmans and his colleagues had collected an enormous amount of information on the blood pressure, cholesterol concentrations, and health histories of 977 elderly volunteers, but much of it hadn't yet been analyzed. Westendorp and Knook also initiated a follow-up study, enrolling a new cohort of 600 elderly volunteers from 1997 to 1999. Under Westendorp's direction, the project began churning out papers as he identified opportunities to explore many questions using the data. The project was, he says, like going into a favorite store with "a lot of money in your pocket" and being able to pick out whatever you desire.
For instance, Westendorp and colleagues published a key study in The Lancet showing that, contrary to the widespread view, high cholesterol concentrations are not a risk factor for heart disease in old age. Taking that observation one step further, the researchers then asked whether cholesterol-lowering statin drugs, which other reports had shown could dramatically reduce the risk of a heart attack in middle-aged people, benefit the very old (see "Greasing Aging's Downward Slide"). The result was a randomized clinical trial, called PROSPER, testing a statin versus a placebo in 5804 elderly patients. The experiment revealed that, for reasons that remain unclear, the cholesterol-reducing treatment protects the heart in old age, although it doesn't guard against strokes or cognitive decline. In total, the Leiden 85-plus survey has published more than 40 articles in the past 7 years. The project "came to full productivity under his guidance," Vandenbroucke says.
Even as he pursued clinical questions, Westendorp wanted to expand his knowledge base, he says. Vandenbroucke had urged him to go abroad for a sabbatical to broaden his scientific horizons. Initially, Westendorp was reluctant to do so; he and his wife, Silvia Zwaaneveldt, a teacher, had two young daughters, and a trip overseas would uproot the family. Knook knew Kirkwood and suggested that Westendorp contact the British gerontologist, then at the University of Manchester, about a visiting fellowship. Reading up on Kirkwood's theories on aging, Westendorp realized what he was lacking: a background in the biology of old age and the evolutionary explanation of why or how that biology might have arisen. He contacted the senior scientist, and they arranged to meet over coffee in the Amsterdam airport when Kirkwood was in the Netherlands for a meeting. At the end of an hour's conversation, Kirkwood invited Westendorp to spend a year in his lab.
The Epidemiologist and the Biologist
The Westendorp family packed up for Manchester in 1998. "I had the most marvelous year of my whole life," Westendorp reminisces. His last exposure to the topic of evolutionary biology had been reading about Darwin in high school. Learning from Kirkwood "electrified me," he says. Westendorp and Kirkwood lived in small neighboring villages in the Pennines, hills to the east of Manchester, and often took the train to the university together. On the ride, they talked shop, with Westendorp sharing his medical observations and Kirkwood explaining his evolutionary hypotheses. "So we actually turned commuting into something that was a really fun scientific discussion," says Kirkwood. "He would come up with great ideas [and] argue his case for them."
Recalling what he learned from those daily conversations, Westendorp says, "Every morning, I was struck, because it was completely new to me." He learned, for instance, that aging is not necessarily inevitable, because evolution does not program it (see "Aging Research Grows Up"). And he listened as Kirkwood explained his "disposable soma" theory of senescence: Keeping the body in good shape requires maintenance and repair, but those investments compete with the demands of growth and reproduction. Our genes settled for a balance that puts a higher priority on reproduction. So from an evolutionary perspective, once a creature has produced children, the body becomes "disposable."
Support for this tradeoff between fertility and life span had come from experiments in which fruit flies that had been selected and bred for longevity produced few offspring early in life. Hearing this, Westendorp immediately wanted to look for evidence of the tradeoff in humans using the power of epidemiology. Not so fast, Kirkwood said, observing that a human study would be undoable because people make conscious decisions about whether or not to have children, and that situation would bias the results. Westendorp recalls mulling it over for a few days before realizing that Kirkwood's argument did not hold water. People make choices about having a family without knowing the age they will survive to or considering that those decisions might influence their life span. So although human decision-making might introduce a degree of bias, it would be a random error and shouldn't skew results one way or the other. Westendorp spent a week hashing out the idea further with Kirkwood, until they were both convinced a human study was feasible. "He's tenacious," says Kirkwood. "If he's working on an idea, he really worries at it until he's got a result to his satisfaction."
The challenge, the two colleagues decided, would be finding the right set of human data to scrutinize. Westendorp had noticed advertisements in newsmagazines for a CD-ROM loaded with the genealogical histories of 33,497 British aristocrats dating back to the year 740. For the sum of about £20, people could buy the disc and search the database to find out if they were related to any blue bloods. "That's what we needed. Because on the CD-ROM ... we had all the names, as well as the records of the age of birth and the age of death, of their progeny." The data set was ideal because it came from a population that was homogeneous in its social and economic circumstances. Their analysis, published in Nature in 1998, found that women who lived beyond 80 years of age had fewer children than did those who died in middle age.
Aging Into Professorhood
Westendorp has continued this line of research since returning to Leiden in 1999, by investigating whether genetic factors that control innate immunity and inflammation could explain the fertility-longevity tradeoff. His work suggests that a feisty immune defense--as measured by the quantities of certain proteins called cytokines--allows survival in the face of infectious diseases; but it might also hamper fertility because a woman's immune system must temper its reaction to a growing fetus in order for a pregnancy to succeed. To further test that idea, Westendorp and his group are now hunting for immunogenetic factors associated with fertility or long life span among several thousand people in Ghana, a country that still tends toward large families while also experiencing the evolutionary pressure applied by prevalent--and deadly--infectious diseases. In some areas of Ghana, up to 40% of newborns die from infectious illnesses.
In 2000, Westendorp was appointed full professor and head of LUMC's gerontology and geriatrics section. His colleagues celebrated by presenting him with an antique wood case containing 15 bow ties, each with a label of purpose. "It looks just like a collection of exotic butterflies," says Ph.D. student Vinkers. There is a bowknot for every occasion that a scientist is likely to encounter, including one for celebrating publications that has the titles of famous journals all over it; a golden one "for golden moments"; a transparent bow tie for "a clear statement of a question"; and one made from a banknote, for "when in financial need."
Like his stylishness in dress, Westendorp's tastes run to the cultured. He enjoys wine tasting (and keeps a private cellar stocked with his favorite ports) and modern dance. Minimalist artwork graces the walls of his office and home, which he has furnished with sleek chairs of steel and leather by famed Bauhaus-era architects Mies van de Rohe and Marcel Breuer. But Westendorp also likes to get down and dirty. He and his wife met through the Boy Scouts during Westendorp's medical school training; he was a group leader, and she worked for the organization as a professional trainer. Before they had children, he and Silvia made two 5-week treks through the Himalayas of Nepal. In the past 4 years, they've begun taking their daughters hiking in the Alps, and last summer, they went backpacking with friends in Lapland, in the far north of Norway. The girls carried their own packs, tents, and food for 5 days. "I tell people about it, and they say, 'Rudi, you are monstrous to do something like that with your children.' "
Given Westendorp's research on evolutionary biology and the fertility-survival tradeoff, parenting takes on a different light. He is obviously fertile, which, according to the theory, is "bad for my longevity," he says, joking. But, seriously speaking, he clarifies that genes control reproductive success and survival, so his life span prognosis is established, regardless of his decisions about having children. Like any parent with rambunctious teenagers, however, Westendorp might still accuse his daughters of taking years off his life once they start dating.
March 3, 2004
Ingfei Chen, a SAGE KE contributing editor in Santa Cruz, California, marvels at how parents survive raising children.
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