BY JOAN COCHRAN

t the age of 19, Michael was six feet tall but still in diapers. Unable to speak and with no measurable IQ, the young Baltimore man had been born in the early 1950s with phenylketonuria (PKU), a genetically-determined enzyme deficiency that can lead to profound mental retardation. His physician, a young Johns Hopkins University faculty member named R. Rodney Howell, had little to offer the youth or his parents in the way of hope for Michael's future.

Today, newborns are routinely screened for this disease, and a diet free of the amino acid, phenylalanine, is prescribed for affected infants. Most children go on to live normal lives. And, 30 years after treating Michael, Howell, now chairman of the Department of Pediatrics at the School of Medicine, and his fellow geneticists can proudly speak of patients such as Joshua, a gifted high school student who was born with PKU but treated early.

When Howell and University geneticists Karl H. Muench and Herbert A. Lubs started their careers three to four decades ago, there were only about 1,000 recognized genetic disorders. Now nearly 10,000 such disorders have been identified, and an international project is underway to unlock the secrets of the human genome, which is the blueprint for every trait, disease, perhaps even behavior of the human being.

"The Human Genome Project is a worldwide effort to develop a map of all the genes that make up the 46 chromosomes in each of our cells," explains Howell, who is now president of the American College of Medical Genetics. "So if your patient has a problem that might be influenced by a gene on chromosome 3, you'll know what a normal chromosome 3 looks like and see where your patient's genetic information differs."

At the University of Miami, genetic research is having a dramatic effect on medical practice. Genetic testing is being used to clarify diagnoses and direct patients toward appropriate treatments, help parents avoid having children with devastating conditions, and identify people at high risk of diseases that may be preventable.

The University's medical campus, particularly the pediatrics department's Division of Genetics, represents the largest concentration of physician and Ph.D.-level geneticists in the region. As such, these professionals see a greater number and wider variety of genetic diseases than would be possible in a non-academic environment. They also are seeking the genetic basis and gene therapies for many disorders.

In the Department of Pediatrics-affiliated Mailman Center for Child Development, at clinics throughout the medical campus, and at 11 locations from Fort Pierce to Marathon in the Florida Keys, thousands of sick children and would-be parents come for genetic testing.

Many couples consult University genetic counselors to determine if they are carriers for Tay-Sachs disease, sickle cell anemia, and other conditions that occur with greater frequency in specific ethnic groups. Others want to establish paternity, seek counseling about marriage between first cousins, or find out if multiple miscarriages signal chromosomal problems in the parents' or fetus' DNA.

Muench, the chief of the Division of Genetic Medicine in the Department of Medicine whose one-hour genetics lecture to University medical students 34 years ago is now a 35-hour course, fondly recalls many of the patients with whom he has shared good news about parenthood. His lectures are punctuated by stories and slides showing the children born to these families.

One such slide shows a young couple proudly snuggling their healthy newborn as Muench looks on. At first glance, it's the routine delivery room photo taken by every parent.

The difference here is what you can't see: the eight years of grieving over their first child's death-thought to be due to a rare genetic disorder. The hours spent by Muench researching the disorder and tracking down the infant's autopsy reports. The look of joy in the young couple's eyes when they realize that, yes, they can be parents. And the relief they all felt when the baby emerged into the world with a healthy little wail.

or each patient, whether it be an adult seeking prenatal counseling or a teen with vague symptoms that other physicians cannot diagnose, the University's geneticists spend hours hoping to find good news, or at least a diagnosis. With the vast amount of information available, the only way to research possible diseases and locate a lab that performs the genetic test they need is to spend hours on the Internet.

Before and after testing, geneticists meet with the family to take a genetic history, known as a pedigree, to discuss parents' options should the fetus have a disorder, and to review the prognosis for healthy children and the likelihood that other family members are at risk.

Not every story has a happy ending, and delivering bad news demands compassion.

"You have to be objective and straight-forward," says Virginia Carver (M.P.H. '89), an adjunct professor of pediatrics and clinical geneticist. "It has to be the parents' decision (of what to do about a fetus with a disorder), not yours."

Besides prenatal counseling, the University's Division of Genetics is the primary resource in the region for infants diagnosed with PKU, hypothyroidism, galactosemia, and maple syrup urine disease, all of which are routinely screened for at birth. These physicians also are a valuable community resource, handling most of the patients with rare and difficult-to-diagnose hereditary conditions.

Lubs, director of the Division of Genetics and Metabolic Disease in the Department of Pediatrics, for example, is internationally recognized for discovering the Fragile X syndrome, a genetic condition responsible for one-third of all mental retardation linked to the X chromosome. He continues to see patients with X-linked diseases and spends much of his time on a multicenter National Institutes of Health study aimed at finding and cloning the other genes on the X chromosome. In the past two years, he has identified more than half of the 33 new genes leading to mental retardation found on the X chromosome by research worldwide.

In seeking the genetic basis of various diseases, Lubs explains, he and his colleagues at the medical campus are working the other side of the coin of the Human Genome Project.

"That project is designed to crack the code, to give the DNA sequence for human beings from beginning to end. But it doesn't say what the genes are doing," he says. "Work such as this is critical because once you locate a gene responsible for an inherited problem you can hook it up to the entire project. It helps provide information as to what the genes are, what functions they serve, as they are found."

oward this end, faculty members often focus both their research and clinical practice in specific areas. In addition to his work on X-linked mental retardation, Lubs is involved in patient care and research on genetically-related dyslexia. Carver runs the division's Florida Teratogen Information Service, one of three in the state that provides information to physicians about agents that cause birth defects. She is collaborating on a study of the effects asthma medication has on pregnancy. Paul Benke, a pediatric geneticist, is doing research on such genetic diseases as systemic lupus erythematosus, the CHARGE syndrome, which causes developmental delay, and a type of cerebellar ataxia, a movement disorder, which runs in families in the Cayman Islands.

Lisa Baumbach, a molecular geneticist involved in testing for both clinical and research projects, is collaborating with scientists around the world in her search for a gene that leads to a form of spinal muscular atrophy, a neuromuscular disease that can be fatal in male babies. Having identified numerous families with similar patterns for this disease and studied their genetic profiles, the associate professor of pediatrics and neurology has narrowed her search to a particular site on the X chromosome. Her research in this area has been funded by the Muscular Dystrophy Association. Finding the exact location of this gene, she says, will help scientists understand how the disease occurs in all children with SMA. It may lead to better treatment as well.

"Once we know the different changes in the gene, we can develop a DNA test we can apply to all kids with hypotonia (decreased muscle tone)," she says. "We'll also be able to test fetuses prenatally and women to see if they're carriers."

Baumbach, whose adult and pediatric patients have disorders such as amytrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), muscular dystrophy, and myotonic dystrophy, says that collaboration with physicians has been a major factor in the success of her research. For example, many of the families she's enrolled in her search for a genetic basis for ALS were identified by University neurologists treating family members.

ther investigations of genetic disease and therapy are underway school-wide. Giovanni Piedimonte, associate professor of pediatrics and director of the Division of Pediatric Pulmonology, runs the Cystic Fibrosis Center and does laboratory research on an as-yet-experimental gene therapy for this disease.

Scientists at the Diabetes Research Institute are attempting to use genetic engineering techniques to protect insulin-producing islet cells from assault by the immune system and to alter muscle, pancreatic, and skin cells to produce insulin. Researchers affiliated with the UM/Sylvester Comprehensive Cancer Center are awaiting U.S. Food and Drug Administration approval to begin clinical studies using gene therapy to boost the immune systems of individuals with lung cancer and melanoma.

In their experimental cardiology laboratory, Keith Webster and Nanette Bishopric, both associate professors of pharmacology, are working on novel techniques for delivering genes that promote the supply of blood and antioxidants to heart muscle. And, in the Department of Neurology, associate professor Richard Bartlett is trying to counter the genetic defect responsible for Duchenne muscular dystrophy, a disease that causes progressive muscle breakdown and death by age 20.

n recent years, breast cancer has become one of the most exciting areas of both research and clinical practice. About two years ago, scientists identified mutations on two genes, BRCA1 and BRCA2, that point to greater susceptibility to the familial, early onset form of breast cancer. Women with mutations on these genes are also at greater risk for ovarian cancer and a second "primary" breast cancer, while men may be more susceptible to cancers of the prostate, colon, and pancreas.

Baumbach is working with Fernando Arena, an adjunct associate professor of pediatrics, to identify the genetic basis for the earlier onset and more aggressive form of breast cancer found among some African-Americans. So far, Baumbach and Arena have identified three mutations in one of the breast cancer-associated genes that may account for this more virulent disease.

The availability of a DNA-based test for breast cancer also means Muench can provide more accurate counseling to women at high risk for this disease. But it isn't simply a matter of collecting blood and sending it out. Test results are complex and require special genetic training for interpretation. The results can be devastating, and some women may choose to first undergo psychological counseling to decide whether to take the test. Then, if a woman has the mutations, her choices can be overwhelming. Should she have a double mastectomy, increase the frequency of mammograms and manual exams, or begin taking tamoxifen or raloxafene, estrogen-like substances that protect against breast cancer? Should she remove her ovaries to eliminate that cancer risk?

To complicate matters, while genetic tests can tell if you have a certain gene mutation, being predisposed doesn't mean you'll get the disease. And lacking the mutation is no guarantee you won't develop breast or another cancer, especially if you have a family history. Thousands of genetic mutations have yet to be identified.

One of the first diseases for which gene testing is becoming widely available, breast cancer illustrates the broad spectra of ethical, legal, and social issues that confront the medical genetics community. At both the medical and Coral Gables campuses, University faculty members are exploring such issues as the privacy and confidentiality of personal genetic information, the cost-effectiveness of genetic testing, and job and insurance discrimination against people or ethnic groups susceptible to genetic disorders.

or Kenneth Goodman (Ph.D. '91), director of the University's Forum for Bioethics and Philosophy, a chief interest is health informatics, or what he describes as the "intersection of ethics, medicine, and computing." Among his concerns are whether genetic information stored on computers is anonymous, who should have access to it, and how to prevent this information from getting in the hands of, for example, organizations that might use it to deny life or health insurance on the basis of a "pre-existing genetic susceptibility" or otherwise discriminate against people.

Goodman, who holds academic appointments in philosophy, medicine, nursing, and epidemiology and public health, teaches ethics to a broad range of students. The questions he asks are perplexing: "What's the limit of appropriate genetic intervention? Eliminating Alzheimer's disease and cancer? How about short stature or male pattern baldness? What if we discover a 'violent behavior gene' or find we can use genetic engineering to promote a trait such as musical or athletic ability? Would it be appropriate to use genetic interventions to alter those traits?"

Goodman's concerns are very real to members of the University's genetics community. Muench's files, for example, cannot be released without written notification from the patient. Even so, many patients are hesitant to be tested for fear the results may slip through to their insurance companies or employers. Sharlene Weiss, director of the Courtelis Center at the UM/Sylvester Comprehensive Cancer Center, where much of the genetic testing is done, says many women use false names or assign numbers, rather than names, to their test results. When these results are sent to a patient's physician, that doctor is asked to keep genetic information out of the patient's chart to prevent its being viewed during routine hospital, health maintenance organization, and insurance company patient record reviews.

But medical centers and physicians' offices can do only so much to ensure confidentiality. "It's extremely important that laws be in place so people will feel free to have important genetic tests done and not be at risk of having that information used in an adverse way," Howell says. He has been involved in reviewing Florida's legislation and in national efforts to increase physician awareness of medical and ethical issues.

At this point, federal law regarding the confidentiality of genetic and other medical information is still being made. Anita Cava, associate professor of business law at the School of Business Administration, lectures widely on legal and ethical aspects of health care. She notes that several bills dealing with the privacy of medical information and discrimination based on genetics never made it out of committee during the 1998 legislative session.

Whatever happens on the legislative front, medical practice will be radically altered over the next decades as powerful new technologies emerge for diagnosing and treating genetic disorders. Many experts predict a significant shift from disease treatment to prevention as it becomes possible to determine susceptibility to a greater number of disorders, replace defective DNA through gene therapy, and find out how environmental agents trigger genetic disease.

"By the time they finish mapping the human genome, we'll find that we all have a predisposition to some genetic illness," says Weiss. "This is important to everyone because none of us have perfect genes."

Joan Cochran is a frequent contributor to Miami magazine. Photography by Donna Victor (Dr. Meunch),
Tipp Howell/FPG (Introduction), and John Zillioux (Drs. Baumbach and Goodman).

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