Fifty years ago a department of genetics, medical or otherwise, didn't exist at IU. In fact, the field of medical genetics didn't exist anywhere. Hundreds of thousands of lives were devastated each year by genetic diseases such as Huntington, Alzheimer and bipolar diseases, alcoholism and Down Syndrome, most of which were not yet recognized as genetically based. Few remedies or resources were available for patients and their families. And their hardship was made even worse by a general lack of empathy toward conditions which society accepted as being the result of a "weak character."

Today, a different story is unfolding. While cures remain elusive for most genetically based disorders, investigators have begun gene therapy trials to correct disorders such as cystic fibrosis and some cancers. And advances made by geneticists in recent decades have greatly improved the quality of life for patients and families the world over. At IUSM, the faculty of the Department of Medical and Molecular Genetics continue to make major contributions to this fascinating revolution.

The principles of genetics were born from Mendel's experiments with peas about the time of the Civil War, but it wasn't until the turn of this century that these principles were first applied to medical problems by Archibald Garrod. It took another half century before it was proved that the DNA (deoxyribonucleic acid) of chromosomes was the carrier of genetic traits and provided the physical basis for Mendel's genetic principles. The helical structure of DNA, which is essential for both the replication of genes and their mode of action, was elucidated by Watson (a doctoral student at IU during the '40s) and Crick in the '50s.

While the basics of molecular genetics were being assembled, "classical" geneticists at IU such as the late distinguished zoology professors Tracy Sonneborn, PhD, and Hermann Muller, PhD, (a 1946 Nobel laureate) were urging their students to seek broader applications for the basic observations made in their laboratories. One of those students was Catherine Palmer, PhD, ('53) now professor emerita of medical and molecular genetics. She joined IUSM in 1955 as part-time instructor and in 1962 established the cytogenetics laboratory for analysis of human chromosomal disorders.

Soon after, A. Donald Merritt, MD, joined the faculty as professor of medicine. Dr. Merritt started the interdepartmental program in medical genetics at IUSM which, in 1966, evolved into the Department of Medical Genetics (now Medical and Molecular Genetics) under his chairmanship. He not only performed important work on a number of human genetic diseases but managed the country's third medical genetics department with great skill. Among others, Dr. Merritt recruited P. Michael Conneally, MD, already well known as a population geneticist, Joe Christian, MD, PhD, who like Conneally had made the transition from animal to human problems and who would succeed Dr. Merritt as chairman of the department, and D.E. Hodes, MD, PhD, a self-described eclectic with experience in DNA structure and cancer chemotherapy.

Over the next 20 years, this group and their colleagues described some 30 genetic disorders, and three members of the original team - Drs. Christian, Conneally and Hodes - continue to provide leadership for further advances in the department. Among many other achievements, the department had the first DNA bank in the country, and continues not only to bank DNA but also to provide DNA diagnosis for a number of diseases. For one of these - Pelizaeus-Merzbacher disease - IUSM did the first testing and still provides most of the testing for the world. Dr. Hodes and colleagues have localized a number of genes on the x-chromosome (responsible for x-linked ataxia- dementia and diabetes insipidus, and Christian disease). Dr. Conneally was part of the international team that first identified the marker for the Huntington disease (HD) gene in 1983, and the gene itself in 1993, making direct testing for HD possible. Today he heads the National Huntington Disease Research Roster housed at IUSM. Dr. Christian, now associate dean for basic sciences and regional centers, has amassed three decades of studies involving identical and fraternal twins. In particular, his work has revealed the importance of the prenatal environment on human development, especially on the central nervous system.

This work has created core knowledge and opened the way for further research and collaboration. For instance, Dr. Christian's twin studies have led to a collaboration between IUSM and the Indiana Department of Health to provide consultation services to physicians whose patients have been exposed to environmental hazards during pregnancy. On other fronts, his group has collaborated with many other laboratories to examine the role of genes in complex diseases thought to involve numerous genes.

Among their findings has been the recognition that genes play a role in alcoholism, previously thought to be the result of environmental factors and individual choice. An important outcome of this work is the Center for the Study of Alcoholism and Alcohol-Related Diseases, a multidisciplinary research collaboration among researchers in Indiana headed by T.K. Li, MD, associate dean of research at IUSM, and funded by the National Institutes of Health (NIH). Recently renewed NIH funding will continue support of the array of researchers in the center who study genetic, environmental, psychological and social factors involved in alcoholism and related diseases.

Jay Tischfield, PhD, professor of medical and molecular genetics and director of the Molecular Genetics Program oversees repositories designed to store cell and DNA samples from families affected by Alzheimer disease and alcoholism. "To diagnose illnesses such as Alzheimer disease and to someday, hopefully, diagnose alcoholism, we need to study the DNA of the patient's parents, siblings and children," says Dr. Tischfield. "Knowing this, we established centers to store the DNA of families to help us make these diagnoses."

In his own lab, Dr. Tischfield has developed transgenic mouse models to help researchers better understand the origin of human diseases. One such model is for hereditary kidney stone disease and kidney failure caused by an enzyme deficiency - the same enzyme deficiency (which creates the same problems) in some forms of human kidney disease. This work was supported by the National Institute of Diabetes, Digestive, and Kidney Diseases (part of NIH). Another mouse he created allows testing for environmental toxins that could cause delayed onset of genetically based cancers in exposed individuals or their progeny.

Due to initiatives such as these, diagnosis of genetic disorders has made rapid progress. It has become commonplace for physicians and geneticists to use genetic testing to examine a fetus' chromosomes and genes for congenital disorders such as Down syndrome (DS), sickle cell anemia, cystic fibrosis and Tay-Sachs disease. In cytogenetic laboratories at IUSM under the direction of Nyla A. Heerema, PhD, professor of medical and molecular genetics, studies reveal the condition of the chromosomes, enabling detection of abnormalities which could disturb normal function. In the case of Down syndrome (also called trisomy 21) a third chromosome 21 is present or, less frequently, there is a translocation of chromosome 21 (a piece of it attaches to another chromosome). If the cytogenetic studies disclose any of these anomalies, the physician has concrete information he or she can discuss with the parents.

Yet while most physicians now routinely offer a blood test and amniocentesis to detect Down syndrome, not all parents choose to use them. Dave and Chris Ollier are a case in point. The Olliers wanted children very badly. Still childless after seven years and fertility treatments, they gave up their hopes for a family. Soon after, Mrs. Ollier became pregnant with their son Evan, now 18 months old. He was diagnosed with Down syndrome soon after his birth.

"We chose not to do the amniocentesis or the prenatal blood test because we both said that no matter what, we would raise the child. It is not in our beliefs to abort," Mrs. Ollier says. Still, like all parents, the Olliers prayed for a healthy child. When Evan was born, his small ears and features, slanted eyes and a space between the big and second toe raised the suspicion of DS. A neonatologist was called in to confirm the diagnosis and, that night, the Olliers felt shock and disbelief as their pediatrician, Steven Cline (residency '93), told them that Evan almost surely had Down syndrome. (Further tests would reveal that Evan had inherited three chromosome 21s.)

Facing The Complications Of DS

They spent the next seven months guarding his health in preparation for surgery. Following an arduous corrective surgery, Evan went into cardiac arrest. He was successfully resuscitated, >and then, to allow his heart and lungs to rest, he was put on ECMO (extra corporeal membrane oxygenation - an extended use of the heart-lung bypass procedure) for four and a half days.

Now, six months later, Evan is recovering many of the developmental skills he lost during his recuperation. "We've been through the mill," Mrs. Ollier admits. "In fact, we were on so many roller coasters the first year of his life that we are just now really getting to enjoy our son."

Although the Olliers shunned genetic testing on account of their beliefs, they credit their surgeon's skill and advances in medicine with saving Evan's life. "If Dr. Brown (John W. Brown, MD, Harris B. Shumaker Professor of Surgery) had not been there, we would have lost him," Mr. Ollier states. "And 10 years ago they weren't even putting kids with DS on ECMO - but without that we would not have him."

For DS patients, advances in pediatric cardiac surgery and intensive care have grown apace with genetic testing, now making it possible to treat some of the complications of genetic diseases and improve quality of life for many patients. When an infant with a congenital defect is born without prenatal diagnosis, physicians and parents quickly seek options for treatment. In Indiana, they most likely would be referred to David Weaver, MD, professor of molecular and medical genetics and head of the IU Genetics Clinic. Dr. Weaver's ability to provide quality diagnoses and counseling is based on years of research as well as a wealth of new online databases, and the expertise of faculty and staff in both the cytogenetics and the molecular genetics laboratories.

Since 1989, the Molecular Genetics Laboratory, under the direction of Dr. Hodes, has provided diagnoses based on the responses of DNA fragments to probes tagged with radioactive isotopes. Disorders for which a gene has been identified - including Fragile X syndrome (a leading cause of mental retardation), Tay-Sachs disease and cystic fibrosis - can be directly diagnosed with this procedure. "Many questions need to be addressed to determine the medical complications that the baby likely faces, the characteristics of the baby's disorder and the risk of the same or similar problems in subsequent pregnancies," Dr. Weaver says.

For parents like Jeff and Donna Hall, whose daughter Elaina was born with Down syndrome, information about their child's disorder is a double-edged sword. "It still hurts to think about the future and what might happen," Mrs. Hall says, referring to how Elaina will be treated by other children, whether she will ever be able to live independently and, ultimately, who will care for her if her parents are unable to. On the other hand, knowing what to expect lets the Halls do everything they can to help their daughter reach her maximum potential. "Our fears for Elaina aren't any different than they would be with any child," Mr. Hall says. "We want her to be able to achieve as much as she is able to do."

Other Disorders Have Few Treatment Options

The outlook is especially dismal for those affected by early onset HD (a condition identified by Dr. Conneally). HD is an autosomal dominant genetic disorder in which nerve cell clusters in the brain degenerate leading to rapid, jerky involuntary movements and dementia. Patients typically survive 15 to 30 years after the onset of symptoms. Passed on by fathers who themselves suffer from the more common form of HD, early onset HD strikes males and females under age 20. It can be devastating to a family because while a mother is watching her child die, she most likely is watching her husband die from the same disease.

Or consider the dilemma faced by another young couple, "Kristen" and "David." Kristen is six weeks pregnant. Her husband David is at 50 percent risk for HD. Kristen wants to have the fetus tested for the HD mutation to enable her to decide whether to continue her pregnancy. Although she feels strongly that she does not want their child to be at risk for HD, David does not wish to know whether he carries the HD mutation.

This example is one of 29 case studies presented by Kimberly Quaid, PhD, and Gail Vance, MD, in their book "Early Warning: Cases and Ethical Guidance for Presymptomatic Testing in Genetic Disease" to be published in early 1998 by Indiana University Press. Dr. Quaid, clinical associate professor of medical and molecular genetics and of psychiatry at IUSM and head of the School's predictive genetic testing program for HD, and Dr. Vance, assistant director of the IUSM cytogenetics laboratory and director of the Indiana Familial Cancer Program, are nationally known for their work in the ethics of genetic testing. They counsel individuals and families interested in presymptomatic genetic testing as well as those who already know they have a heritable disease. In "Early Warning," Drs. Quaid and Vance bring their experience to bear on the challenges society faces with the rapidly expanding knowledge of human genetics.

For even the most scientifically uninformed, the recent efforts in medical and molecular genetics are hard to miss. In what may prove to be among science's most ambitious undertakings, The Human Genome Project directed by Francis Collins, MD, PhD, director of the National Human Genome Research Institute (part of NIH), aims by the year 2005 to map the entire complement of human genes (some 100,000 in all), to create genetic maps to study how diseases are inherited in families, and to describe the order of the nucleotide bases in DNA. The project also supports efforts that focus on the ethical, legal and social implications (ELSI) of genome research. With their peers the world over, scientists at IUSM will continue to contribute to these fascinating developments.

"We must maintain our present base of good genetic research and expand our bench research in cancer as well as Alzheimer, Huntington and Parkinson diseases," says Merrill Benson, MD, who followed Dr. Christian as chair of the Department of Medical and Molecular Genetics last year. "As a department, our sights are set on expanding our research and treatment of diseases that affect the lives of individuals as they age." The department is currently applying for a grant to establish IUSM as a Center for the Genetics of Aging. This funding would allow IUSM researchers to pursue several projects. One would involve the collection of DNA from WWII-era twins for studies on aging. It also would allow additional research into the aging factors involved in the onset of HD and amyloid diseases, which affect nearly every organ of the body as well as the central nervous system. Much of this work will build on the twin studies done by Dr. Christian and the research of Dr. Benson who identified the genetic error that causes amyloid plaques to form in some Alzheimer disease patients and in patients with amyloid kidney disease. This funding would also allow IUSM to establish a registry for Parkinson disease and to continue its collaborative research to locate the genes that cause it.

"The future physician must be prepared to understand the genetic basis of health and the metabolic processes of aging," Dr. Benson concludes. "We are seeking to answer the questions we know - Is death preprogrammed? How does aging occur? How much is desirable?' - as well as the questions we don't yet know to ask." For the faculty and staff at IUSM, teamwork and collaboration will continue to provide the answers ... and the questions.