Taking The Clinic To The Patients Gave Researcher Sense of Purpose

More than five million people visit Lancaster County, Pa., annually. They crowd small towns to catch a glimpse of a Mennonite family on the way to church in a horse-drawn buggy, and they jam country backroads to marvel at an Amish farmer and his mule plowing a field. To many visitors harried by the pace of modern living, the Amish and Mennonites represent a simpler, purer, and more pious way of living. To others, they represent a rich source of scientific data. Each year investigators in medical genetics and other disciplines descend on Lancaster County to inquire about family histories of disease and gather DNA samples from these plain people. A number of factors make the two groups appealing for research in medical genetics. Their religious conservatism and selective use of technology isolate them from the population at large. Extensive genealogical records kept by the Amish and Mennonites make them one of the "best-defined" inbred groups in the United States (J.A. Hostetler, Amish Society, 4th ed., Baltimore, Johns Hopkins University Press, 1993). While many scientists come to the farms of Lancaster County only to soon return to their laboratories, biochemist and pediatrician D. Holmes Morton is one of the few who have come to call Lancaster County home. After receiving an M.D. from Harvard University and serving a fellowship in biochemistry at Children's Hospital of Philadelphia, Morton opened the Clinic for Special Children (CSC) in 1990 in Strasburg, Pa, a small town known more for its operating steam railroad and other tourist attractions than for cutting-edge research and treatment of genetic disorders. Photos: Stephen P. Hoffert RESEARCH EPIPHANY: D. Holmes Morton, at right, says his experience working closely with Amish and Mennonite children with genetic disorders has changed how he views the practice and purpose of research. His clinic, above, stands at the end of a road and next to a field. One of the most common diseases he sees in children at the clinic is maple syrup urine disorder (MSUD), an inherited disorder so named for the characteristic smell it produces in the urine of afflicted patients. The disorder affects the way the body metabolizes the amino acids leucine, isoleucine, and valine. The accumulation of these amino acids in the blood has a toxic effect on the brain, leading to severe mental retardation and eventual death. Among the Mennonites of Lancaster County, about 1 in 400 newborns have the disease. This compares to 1 in 225,000 newborns nationwide. Biochemical research at CSC on inherited disorders afflicting the Amish and Mennonites has had striking success. Morton and his staff at CSC manage 32 children with MSUD. Before opening the clinic, many afflicted children suffered from loss of brain function and faced inevitable death, he says. Now, more than half of his patients who are diagnosed with MSUD as newborns and receive immediate therapy do not require hospitalization and lead healthy lives due to a special diet and close medical monitoring. Others require occasional hospitalization, averaging only four days per year. In contrast, MSUD patients on average required 19 days of hospitalization per year just over a decade ago. Morton's success has captured the attention of peers and the popular press. In 1993, he won the Albert Schweitzer Prize for Humanitarianism. Four years later, he was featured in a Time magazine special edition, Heroes of Medicine, where he won the praises of a former U.S. surgeon general, C. Everett Koop. Although Morton admits that his work with Amish and Mennonite children has had a dramatic effect on their health and well-being, he is much more eager to talk about how the children have profoundly shaped his views on the purpose of research and pursuit of scientific knowledge. Nearly a decade of work in the field has opened his eyes to issues in medical genetics and research that some scientists working at universities and government institutions often do not have to confront head-on. Questions over the use of repositories in genetic research, the availability of cutting-edge screening systems for newborns, and improved collaboration between research disciplines have acquired a sense of urgency here. Most concerning to Morton is the increasing numbers of researchers who descend on Lancaster County to gather DNA samples and other laboratory specimens only to leave and never be heard from again. Morton describes this situation where investigators use the Amish and Mennonites in research without providing health-care services or medical advice to them as "medical tourism." He says increased interest in medical genetics research--in part generated by the Human Genome Project--has contributed to the increasing potential for medical tourism in Lancaster County. Through the use of genetic material in repositories, many studies now occur in laboratories far from Amish and Mennonite settlements. "Investigators searching for genes linked with disease have become the big game hunters in biomedicine," Morton explains. "This kind of research is done primarily at the laboratory bench. This is not necessarily bad, but it minimizes involvement with the research subjects." The current situation contrasts with that of an earlier generation of researchers in medical genetics. In the 1960s, investigators--including Victor A. McKusick, a professor of genetics at Johns Hopkins University who is widely hailed as the father of medical genetics--made crucial inroads for researchers into the Amish and Mennonite communities of Lancaster County. To gain access to the communities, he enlisted the help of John A. Hostetler, professor emeritus of anthropology and sociology at Temple University and author of several definitive ethnographic studies of Anabaptist groups. Through the 1970s and early 1980s, research involving the Amish and Mennonites was centered primarily at Johns Hopkins, according to NIH grants award data. In 1997, seven institutions, some of which are located in regions far from settlements, had received funding for projects studying genetic disorders in the two sects. "All of the gene therapy in the world will make no difference to permanently disabled and dying children." McKusick acknowledges Morton's concerns about medical tourism taking hold in Lancaster County. The potential for exploitation has become greater now that years of study have made scientists almost as common a fixture in the countryside as sightseers, he observes. Researchers in regions less known for their Amish settlements make similar observations. Sharon J. Hewner, an assistant professor of health services administration at D'Youville College in Buffalo, N.Y., says Lancaster County's dense population and close location to some of the nation's major research universities increase the potential for exploitation by scientists. Hewner recently completed a study examining mortality rates among the Amish in upstate New York (S.J. Hewner, Collegium Anthropologicum, 21[1]: 67-82, 1997). Hewner says the settlement's remote location has protected the Amish from hit-and-run researchers. "I have never seen another researcher during the seven years of fieldwork to complete the study in this community and don't expect to see them any time soon," Hewner states. "I don't think intensive medical research is as likely here because these settlers left Pennsylvania and Ohio over 40 years ago in search of a more isolated locale and in hopes of preserving a more conservative way of life. Contact with the outside world has been limited and is closely guarded by leaders in the community." But Janice A. Egeland, director of the Amish Affective Disorders Project (AADP) in Hershey, Pa., and a professor of psychiatry and epidemiology at the University of Miami School of Medicine, says long- distance research has not given rise to medical tourism in regions of Pennsylvania. Egeland's experience as a scientist working with the Amish is perhaps unmatched. As a Ph.D. candidate at Yale University (1960-65), she developed close ties to Old Order communities while working on her two-volume dissertation, Belief and Behavior As Related to Health (Yale University Press, New Haven, Conn., 1965). By 1976, she initiated genetic and epidemiology studies of affective disorders among the Amish. Since then, she has been in continuous contact with them and has opened two medical and research offices in Hershey, Pa. "If there is some kind of 'medical tourism' [taking hold in the region], I don't encounter or know who has fostered it," Egeland says. Increasing use of DNA repositories in research, however, has raised ethical and protocol questions in genetic research involving specific populations. Once DNA specimens are collected for a research project, they can be used in many more studies as the samples are "immortalized" and stored away in university and government repositories. The existence of this resource has made it easier to carry on research in labs far away from Amish settlements. While Morton does not oppose the use of archived specimens and data in research, he is concerned that this situation keeps valuable information out of the hands of patients. "Too often, the results of this kind of research are sequestered by NIH," Morton says. "The attitude is that by making research subjects anonymous donors, we're protecting them from any discrimination or other misuse of data resulting from genetic studies. But from my point of view, the guidelines have been written to protect investigators and minimize the responsibility that they have to help people." OBJECT OF INVESTIGATION: A number of factors, including their close proximity to major universities and research hospitals, have made the Amish and Mennonites of Lancaster County one of the most studied populations in genetics. Egeland, however, says the use of repositories has benefited the Amish, who prefer to minimize contact with the outside world. Cell lines from AADP now in the National Cell Repository of the Coriell Institute for Medical Research in Camden, N.J., were the first such resource to become available to scientists for study on manic-depressive illness. The use of repositories "represents an important protection for the group to have fewer scientists in direct contact," she notes. Current opinion on the creation and management of DNA repositories is divided. A recent NIH-Centers for Disease Control and Prevention workshop recommended that if the type of research proposed by an investigator was agreed on by a DNA donor, then there is no need for further consent for prospective research before the DNA sample is anonymized (E.W. Clayton et al., JAMA - Journal of the American Medical Association, 274:1786-92, 1995). For samples collected in clinical-care settings, the panel recommends that consent be obtained before anonymizing and that issues such as the difficulty of recontacting subjects and the availability of effective medical interventions be considered. Early in the development of medical genetics, researchers in the field combined expertise in both clinical and basic science. But the division of labor in medical genetics research, which has developed with the advancement of the field, has not contributed to medical tourism, according to Michele C. LaBuda, an assistant professor in the division of child and adolescent psychiatry at Johns Hopkins University. Her research interests as a geneticist have focused primarily on genome searches for affective disorder predisposition loci on chromosomes. One of her recent studies included searches of DNA from the Old Order Amish (M.C. LaBuda, American Journal of Human Genetics, 59:1343-62, 1996). "Pioneers in medical genetics [such as] McKusick were medical and scientific renaissance men who worked at the cutting edge as both physicians and researchers," she notes. "Since then, the field has become more and more specialized." LaBuda adds that this hasn't minimized the responsibilities of the basic researcher to research subjects. "Your ability to help patients directly may be limited," she says. "[But] you want to take measures to guard against the exploitation of research subjects and improve the situation of patients." Morton says that some degree of separation between basic research, clinical research, and health care is necessary for advances in understanding inherited disorders. But he fears that gene-based explanations of disease have come to dominate the research scene. "It's easy to find money to search for a gene believed to cause a disease, but it is very difficult to get funding if you want to understand the biochemistry of that same disease," Morton states. "Many scientists assume that molecular genetics will eventually tell us the biochemistry of a disease. However, as a biochemist, I can do something for these children now. But these insights come only from understanding the natural history of the disease. All of the gene therapy in the world will make no difference to permanently disabled and dying children." Some recently funded projects by NIH reflect Morton's concerns for better collaboration and cooperation in fighting disease between fields such as molecular genetics and biochemistry. Maria I. New, a professor in the department of pediatrics at Cornell University Medical College in New York City, has been studying childhood androgen metabolism defects such as apparent mineralocorticoid excess (AME) for 32 years. In her successful 1997 proposal to continue past investigations and look at a mild form of AME discovered in a Mennonite family, she wrote that the strengths of the program include "the harmonious interaction of molecular geneticists, biochemists, . . . and clinicians with great experience in dealing with patients." Morton admits that not every researcher in inherited disorders can be expected to work closely with patients. However, he says that often it is necessary for scientists to remind themselves of the purpose of their work. "I think I've gained a reputation for showing pictures of children at my lectures and talks on the diseases I've studied," Morton relates. "To some people, this is an unusual thing for a biochemist to do. But it is easy to get caught up in science itself and forget that our purpose is to help people and ease their suffering. Not too long ago, I can recall the director of a genetics laboratory at a major university telling me that he no longer needed to see children. He had all of the genetic samples he would ever need for his research. That's why I always show pictures of children." Given his past, you might think D. Holmes Morton, a biochemist and director of the Clinic for Special Children in Strasburg, Pa., was taken out of his element in Lancaster County. Born and raised in West Virginia, Morton joined the Merchant Marines soon after graduating from high school. He worked Great Lakes iron ore and coal barges before serving in the U.S. Navy for six years. It was this sailor's experiences at some of the nation's premier universities and hospitals that eventually led him to open a laboratory and clinic on the edge of a field at the end of a quiet country road. He began to see the need for more field-based research and acute care when he was a fellow in 1988 in metabolic diseases at Children's Hospital of Philadelphia. During that time, an eight-year-old Mennonite girl died with MSUD at a community hospital in Lancaster County. Before her death, she was ill at home with a cold and then admitted to the hospital for pneumonia. Physicians at the hospital consulted with a doctor from the metabolic group in Philadelphia. In three days, her condition rapidly deteriorated and she died from herniation of the brain. "This was an eye-opening experience for me." Morton recalls. "Meetings in the metabolic division tended to lay blame on the Lancaster doctors. We discussed the potential for grant money to study the origin of cerebral edema in patients with MSUD. We also decided that any child with MSUD and a respiratory tract or other such infections should be hospitalized in Philadelphia. Yet, we never talked about the need for studies and chronic care in the field. Despite the clear need to get closer to a large population that needed help, all strategies in research and care we discussed focused on the services based in Philadelphia." Soon after the tragedy, Morton made a discovery at the labs at Children's Hospital that would eventually lead him to lay down permanent roots in Lancaster County. While running diagnostic tests on a urine sample from an Amish child with cerebral palsy, he discovered a case of glutaric aciduria type 1 (GA1), an autosomal recessive disorder caused by an enzyme necessary for the degradation of amino acids. In children with GA1, episodes of biochemical intoxication by the amino acids cause irreversible neurological damage and progressive paralysis. Before Morton's discovery, most researchers believed that cerebral palsy was caused by oxygen deprivation or trauma at or before birth. At the time, GA1 also was thought to be a rare disease. But a trip from Philadelphia to Lancaster County disproved that notion. Going from farm to farm surveying families, Morton discovered that the disease was quite prevalent in the Amish community. After collecting urine samples from the Amish, Morton found that every major family group in the community carried the gene for GA1. A founder effect obviously was at play here. From 0.25 percent to 0.5 percent of all newborns could be expected to have the disorder, making GA1 one of the more common genetic disorders of the Amish community." In the months to come, Morton wrote a grant proposal to acquire funds to study the disorder and open a clinic that was more accessible by horse and buggy. "You can imagine my disappointment when the proposal was ultimately rejected for funding," he recalls. "The review board said the project wasn't fundable because GA1 was limited to a very small portion of the population and would have limited appeal to the research community. This rejection turned out to be a blessing in disguise." Morton turned to the Amish and Mennonite communities for help. Grandparents of children with GA1 donated land where the Clinic for Special Children would eventually be built by more than 60 members of the Amish and Mennonite communities. "NIH's rejection forced us to look for alternative sources for funding," Morton says. "Besides, the grant would have run out in three years. Community support made it apparent that we could achieve a permanent presence in Lancaster County."--SPH

Taking The Clinic To The Patients Gave Researcher Sense of Purpose

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