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
We 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
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.”
Those 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).
From 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.
On 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.
Teams 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
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.
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.”
Dr. 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
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
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.”