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Truants from Medicine

Jonathon with dog MartyWhen Alan R. Shuldiner, MD, first approached the Old Order Amish in Lancaster County, Pa., about taking part in a study to find the genes that cause Type 2 diabetes, he wasn’t certain how receptive they would be to this kind of cutting-edge medical research. Other researchers had studied rare single-gene disorders affecting Amish children, but this was the first time, he says, that anyone had sought to explore a more common complex disease such as diabetes.

“Nobody knew how cooperative the Amish would be for these much larger-scale studies,” recalls Dr. Shuldiner, professor and head of the division of endocrinology, diabetes and nutrition at Maryland, adding that the Amish are ideal for genetic research because they trace their ancestry back 14 generations to a few individuals and share a similar rural lifestyle. “It wasn’t enough to just recruit a couple of families. We needed to recruit hundreds, if not thousands, of Amish.”
With an introduction from famed Johns Hopkins genetics researcher Victor A. McKusick, MD, who had deep ties to the Amish community, Dr. Shuldiner enlisted the help of an Amish woman who had 11 children and more than 70 grandchildren and had been diagnosed with diabetes herself. She introduced him to her children and many of her 13 brothers and sisters, several of whom also had diabetes, and the list of potential recruits grew. Before long, Dr. Shuldiner was driving to Lancaster County nearly every day, leaving Baltimore at 4 a.m. to arrive before dawn to take blood samples from early-rising Amish farmers who were asked not to eat beforehand.

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e went to their homes, performed glucose tolerance tests, drew blood and asked them to fill out questionnaires. It became apparent within a year that the Amish were very receptive to these studies. We saw about 100 people in the first year,” Dr. Shuldiner says. “At that point, I had no research support and was basically working out of the trunk of my car.”

Since that modest beginning in 1993, more than 3,000 members of the Old Order Amish community in Lancaster County have participated in Dr. Shuldiner’s groundbreaking genetics research. The 47-year-old Harvard-educated endocrinologist has received millions of dollars of funding for his studies, including a $10.6 million grant from the National Institutes of Health (NIH) to study risk factors for cardiovascular disease. He has opened a research clinic in Strasburg, Pa., and the small pilot project has spawned at least eight other studies. Dr. Shuldiner and his Maryland colleagues are searching for genes that cause not only diabetes, but also obesity, osteoporosis, hypertension and cardiovascular disease. They are also studying longevity in the Amish, testing people who are age 90 or older and their children.

“One of the qualities that makes Dr. Shuldiner so successful is that he really cares about the people that
he works with,” says Howard B. Dickler, MD, senior associate dean for research and graduate studies at Maryland. “Because of that, the people in the Amish community have a great deal of trust and respect for him, and therefore he has had success in working with them where others may not have. Trust and respect are such important components of their society.”

Nir Barzilai, MD, director of the institute for aging research at the Albert Einstein College of Medicine in New York, who is collaborating with Dr. Shuldiner on longevity studies, agrees. “It’s one thing to be a scientist. It’s hard to go out and form good relationships with a community,” he says.

“He has paved the road for research in the Amish community,” says Naomi Esh, an Amish woman who has worked with Dr. Shuldiner since he opened his clinic in February 1995.

Dr. Shuldiner’s quest to find the cause of diabetes in Amish DNA already has produced significant results. Using highly sophisticated molecular, genetic and statistical analyses, he and his colleagues have identified regions on four chromosomes that likely harbor genes for Type 2 diabetes, and areas on other chromosomes that may affect blood pressure, obesity and eating behavior. They have also made one surprising discovery: The Amish have only half the prevalence of diabetes of the general population, although they have the same level as obesity. The reason? The Amish are very physically active. However, researchers believe their genetic makeup might play a role as well.

A genetically homogenous people, the Old Order Amish of Lancaster County are descendants of a small group of individuals who immigrated to the United States from Europe in the mid-1700s. Many trace their ancestry to a single founder, Christian Fisher, who lived to be 83. They have large families, keep detailed genealogical records and share a common lifestyle. They have no electricity in their homes and travel along the back roads of Lancaster County in horse-drawn buggies. Although they shun most technology, they have shown a remarkable willingness to participate in modern genetic research.

“The Amish really are an altruistic group. Even though they don’t understand all of the things that we are doing, they have faith that in volunteering for these studies they are helping mankind in one way or another. And that’s very important to them,” Dr. Shuldiner says. “One of the important messages of the Bible is that you should help your fellow man. They believe in volunteering for these studies because they are helping out the human condition.”

An Amish liason and research sonographer Patrick Donnelly use ultrasound equipment to check and study a participants brachial arteryThose who participate in the studies receive small monetary incentives, but Dr. Shuldiner doesn’t believe that money is the main reason for their cooperation. “Because the Amish have no health insurance, they benefit greatly from the free testing and medical care,” he says.

“The Amish help us immeasurably with the research, and in every study, we have gone out of our way to provide immediate benefits to our volunteers and the community,” Dr. Shuldiner says. “We make house calls. When we find someone who has diabetes, we try to care for them the best that we can and refer them to local doctors. We give them a blood glucose monitor, and our nurses spend countless hours teaching them about diabetes and diet.”

D. Holmes Morton, MD, a pediatrician and founder of the clinic for special children in Strasburg, Pa., who is renowned for his work with Amish children with rare genetic disorders, says that Dr. Shuldiner is providing much-needed medical care. “He has linked clinical service—management of chronic, complex problems—with basic research, not only providing diagnoses but also getting people into care,” Dr. Morton says.

More than 1,400 people took part in Dr. Shuldiner’s first project, the Amish Family Diabetes Study, focusing on diabetes, obesity and hypertension and produced a number of published results. That study led to the Amish Family Osteoporosis Study, looking at bone density, and later expanded to include coronary artery disease and renamed the Amish Family Calcification Study. More than 1,200 people participated in the study, led by one of Dr. Shuldiner’s colleagues, Braxton Mitchell, PhD, MPH, a professor of medicine and epidemiology and preventive medicine at Maryland. Last year, with a four-year, $10.6 million grant from NIH, Dr. Shuldiner launched his most ambitious project to date—the HAPI (Heredity and Phenotype Intervention) Heart Study, which will evaluate how genes and lifestyle factors influence people’s risk of developing cardiovascular disease. He hopes to enroll 1,000 people within the next year and a half, recruiting individuals who have undergone extensive genetic testing as part of the calcification study. The longevity study, started in 2001, is still recruiting participants, and researchers are also conducting smaller studies of rare genetic disorders such as osteogenesis imperfecta (brittle bone disease).

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rom the outset, the slender, soft-spoken physician has worked hard to earn the trust of the Amish community and has relied heavily on a small group of Amish liaisons. “We don’t go anywhere without an Amish liaison. We don’t start a study until I talk to the liaisons and tell them what we’re planning,” he says. He has also sought to build good relations by sending 3,000 Christmas cards every year to participants and delivering birthday cakes to the homes of the 90-year-olds in the longevity study.

Mrs. Esh, one of the liaisons, says, “He’s more than a scientist in the community, talking about the genes that he has found. He cares. He takes the time to sit down with patients and talk to them about their diabetes.” Another liaison named Barbara adds, “He has such a good name. He’s more than careful. It makes a difference that people know he is not going to use their names all over the place. They still want to keep their privacy.”

Much of the fieldwork revolves around Dr. Shuldiner’s clinic, located on the ground floor of Dr. Morton’s clinic for special children in a spacious, two-story clapboard and stone building constructed by the Amish. The Amish Research Clinic has a comfortable waiting area with a small kitchen, exam rooms equipped with state-of-the-art ultrasound machines and a bone density scanner, as well as a small laboratory to process blood samples.

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n weekdays, the Amish start arriving at 7 a.m., the men in wide-brimmed straw hats and straight leg pants with suspenders, the women in dark-colored dresses with white aprons and caps. They speak Pennsylvania Dutch to one another and the Amish liaisons, but English to the clinic staff. Because the Amish don’t drive, the clinic pays for a car service to pick them up and take them home. Some come for a full day of testing, others for a short follow-up visit.

Dr. Shuldiner meets with clinic office manager Shawn HendricksonTeams of nurses and liaisons visit several Amish homes each day to sign up those who have expressed an interest in the studies. Armed with church directories and the Fisher Family History, they fan out across the county, traveling through small towns with names like New Holland, Leola and Intercourse. Mary Morrissey, RN, one of the nurses, drives an average of 100 miles a day. She is enrolling people in the HAPI Heart Study, which is looking at how participants respond to four interventions—a high-fat meal, a high- and low-salt diet, aspirin and a cold stress stimulus. Using sophisticated computer programs that can take days, if not weeks, to run, researchers will search the entire genome for genes that might explain the differences in people’s cardiovascular responses.

On a recent morning, a farmer named Samuel comes to the clinic for the first of his tests—the cold stress test and the high-fat meal. He lies down on a stretcher while the staff prepares to monitor his blood pressure and measure the diameter of the brachial artery in his arm with ultrasound equipment. “Just think of it as a hot June day,” advises a nurse as Samuel plunges his hand and wrist into a container of icy water for two and a half minutes.

Later, a nurse takes a blood sample before Samuel drinks a whipping cream milkshake flavored with vanilla. For six hours, staff members take blood samples and repeat the ultrasound examination to find out how his brachial artery responds to the high-fat meal. By the end of the day, he also will have had an electrocardiogram, an echocardiogram and several other cardiovascular tests. In the coming weeks, he will take aspirin, eat specially prepared high- and low-salt meals (meat loaf, roast pork and chicken potpie, prepared by Amish cooks) and undergo testing to see how his cardiovascular system responds.

Asked why he decided to take part in the study, Samuel said that he has a few health problems. “Sometimes I feel short of breath,” he says.

Patrick Donnelly, a research sonographer, says that many of the Amish who take part in the studies have family members who died of a heart attack. “All of my grandpa’s brothers died of a heart attack,” Samuel volunteers.

“We’re finding a lot of variation in how different people respond to the tests that we do,” Dr. Shuldiner says. And, genetics is likely to play an important role. Preliminary data indicate that 35 percent of the variation in people’s blood pressure after they eat the high-salt meals is probably related to their genes.

Dr. Shuldiner, who majored in chemistry at Lafayette College and earned his medical degree from Harvard Medical School, first became interested in diabetes research when he was a fellow at NIH from 1986 to 1990. He turned his attention to genetics after joining the Johns Hopkins University School of Medicine in 1991. While he was at Hopkins, he began his work with the Amish and was involved with another research study that produced a major discovery: a mutation of the beta-3-adrenergic-receptor gene linked to the development of obesity and Type 2 diabetes. In 1997, Maryland recruited Dr. Shuldiner as professor and head of the division of diabetes, obesity and nutrition, combined later with the division of endocrinology. He was also named medical director of Maryland’s Joslin Diabetes Center, a position he held until stepping down this year to concentrate on his research.

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ell-known in the research community, Dr. Shuldiner has received financial support from a number of institutions, including the NIH, the American Diabetes Association, the American Heart Association, the Ellison Medical Foundation and pharmaceutical companies. Colleagues describe him as intelligent, highly capable and low-key.

Dr. Barzilai, a fellow researcher from the Albert Einstein College of Medicine, calls him “an outstanding scientist” and a “terrific administrator.” He predicts that Dr. Shuldiner’s work with the Amish will be “a major shortcut in determining which genes are associated with certain diseases. It’s an amazing approach to human genetics and a very cost-effective way to do it. I think he’s going to beat everyone in finding the genetic causes of diseases.”

Research lab technician Maryann Drolet with Dr. Shuldiner in the lab at the Amish Research ClinicDr. Dickler notes that Dr. Shuldiner also has been instrumental in recruiting and training young researchers. “His laboratory is literally a factory, if you will, for the production of young, bright, well-trained physician-scientists,” he says.
Looking to the future, Dr. Shuldiner says that he and his colleagues are targeting regions on chromosomes 1, 14, 15 and 18 for Type 2 diabetes and on chromosome 2 for hypertension. They are particularly interested in a region on chromosome 1, as are seven other groups of researchers studying diabetes in Pima Indians, British Caucasians, Chinese, French Caucasians and other populations.

“So we’ve gone from about 30,000 genes in the genome down to 450 genes on chromosome 1. Now
we have to go from the 450 genes to the one,” Dr. Shuldiner says. “It’s a very collaborative field. We have realized that it’s a huge effort, and none of us have the resources to do it alone.”

He predicts that ultimately, researchers will discover a number of diabetes genes “that interact in complicated ways.” Armed with that knowledge, scientists should be able to design a genetic test to detect diabetes in people long before they would get the disease and to develop more effective medications to prevent or treat it.

Dr. Shuldiner hopes to continue his relationship with the Amish for years to come. His goal is to recruit all 30,000 members of the Amish population in Lancaster County into a longitudinal study, provide all of their routine medical care and follow their progress for the next 50 years. “The Amish offer this very unique opportunity for state-of-the-art genetics that very few other populations offer,” Dr. Shuldiner says.

Officials at Maryland are excited about the prospect. “We are very actively exploring options for the way we can shape this study so that it is financially feasible and yet will still yield the maximum amount of information and the maximum benefit to the Amish themselves,” Dr. Dickler says. “It is very much a project the medical school would like to do.”


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