The day begins early for MDA grantee Margaret (Peggy) Pericak-Vance, a medical geneticist and genetic epidemiologist at Duke University in Durham, N.C. She usually gets up between 3:30 and 4 a.m. to give herself some quiet time for thinking, reading and writing before the rest of the family stirs.

That would be fellow researcher and MDA grantee Jeffery Vance, a neurologist and medical geneticist; Jeffery Joseph (JJ) Vance, 13; and Danica Davies Vance, 10.

By about 6:30, the rest of the household is up, and Margaret or Jeffery (they take turns) is either off to the gym for a workout, or on duty to get the children off to school.

Today is Margaret's turn at the gym. She finishes at about 8:30, drives to a nearby shop for a cup of coffee to go, calls her secretary on the car phone to reserve space for a lunch meeting, and pulls into the underground garage at the Bryan Research Building on the Duke campus.

As she swings down from her van, balancing coffee and briefcase, she notes a bulging canvas carry-all behind the seat. "Oh, those are my receipts from London last month," she says, referring to a scientific conference. "I have to turn those in." Well, maybe not today. it's on to her second-floor office. Colleague Marcy Speer (an MDA grantee studying limb-girdle muscular dystrophy) has been in an accident, she's told, and will be late for a morning meeting. Speer is all right, and her two daughters had already been left at their day-care center, but the car is damaged.

Pericak-Vance sighs and proceeds to the relative quiet of her office, where books, papers and sticky notes surround her computer. "Let's see if there are any crises," she says, checking her E-mail. There aren't, for the moment.

At 45, Pericak-Vance has so many titles even her staff gets confused. She's an associate medical research professor of genetics, a research professor in medicine, an assistant research professor of ophthalmology (because of her work in the genetics of eye diseases), and, most recently, became chief of Duke's newly created Section of Medical Genetics. "The new office is going to be bigger," she says, sweeping away some papers, along with drawings and cassette tapes left by daughter Danica.

Duke was going to name the new section Molecular Epidemiology, she explains, but they thought that might be confusing. It might, but it's a good description of Pericak-Vance's work -- gene hunting.

Her gene team is similar to an earlier breed of epidemiologists, the microbe hunters of the early 20th century. When these researchers traced the causes of killer diseases like cholera, typhus and diphtheria to microorganisms, their work must have seemed as obscure as today's findings that diseases like muscular dystrophy and Alzheimer's can be traced to abnormalities in DNA.

EXCITED BY DATA

"I like looking at data," Pericak-Vance says. "A lod [logarithm of differences] score that's high -- I get excited," she says, referring to the chances that a string of DNA is actually linked to a disease.

Her interest in genetics stems from a chance occurrence in her junior year at Wells College in East Aurora, N.Y., not far from her hometown of Buffalo.

"They had a four-one-four plan," she recalls. "You could take a special course in January, for a month." Pericak-Vance -- then Margaret Pericak -- chose to go to the Medical Center in Brooklyn, N.Y., to study medical genetics in January 1972.

"It was the infancy of genetics," she says. "Pre-banding." (Bands on chromosomes were among the first tools used to identify abnormal DNA.)

But it was enough to interest her in the field. After graduating from Wells in 1973 with a degree in biology, she entered a doctoral program in medical genetics at Indiana University, studying under P. Michael Conneally. (Conneally chairs MDA's Task Force on Genetics and has worked on limb-girdle muscular dystrophy with MDA funding.)

Also studying medical genetics at Indiana was another young researcher, Jeffery Vance, whom Pericak married in 1977.

At Indiana, Pericak-Vance worked on the genetics of Huntington's disease, a fatal neurodegenerative disorder that profoundly affects mental and physical functioning.

There wasn't much known about DNA in those days, she says. On a 1976 exam, Pericak saw the term "recombinant DNA" in only one question. Recombinant DNA results from cutting and splicing genetic material, a technique that would, by the 1980s, revolutionize the world's understanding of how genes function. The 1976 question merely asked the student to define the new term.

Data analysis was equally primitive. For the most part, researchers entered data by hand into notebooks, doing the best they could to analyze it from there. Some brave souls made use of computer punch cards, but there was no software to handle the information, and progress was agonizingly slow. (The Huntington's gene was eventually isolated in 1993.)

Already, Pericak-Vance perceived that there was a need to organize the vast amount of genetic data researchers were collecting, or it would be impossible to use.

In 1978, after finishing her doctoral program in genetics, she moved to the University of North Carolina at Chapel Hill to study statistical genetics under Dr. Robert Elston.

Jeffery Vance came to Duke University in nearby Durham to work under neurologist Allen Roses. He would later go to medical school and do a residency in neurology at Duke. (Roses, a long-time MDA grantee, is chief of neurology at Duke, where he also co-directs the MDA clinic.)

In 1981, Pericak-Vance also joined Roses' division at Duke, bringing with her an unusual expertise in both genetics and statistical methods. "Allen hired me because he thought it sounded good to have a geneticist," she says. It would prove a smart decision.

THE MYOTONIC BUS

"I always liked human genetics," Pericak-Vance says. She says the human, as well as the genetics, part interests her. "I like working with patients and figuring out how to apply things so we can bring results back to the patients."

Once at Duke, Pericak-Vance started attending MDA clinic and doing genetic counseling. Her first grant came in 1981, when MDA funded her to study Duchenne muscular dystrophy genetics.

Roses was researching myotonic muscular dystrophy (MMD) with MDA funding, and Pericak-Vance and Jeffery Vance became part of this study.

Pericak-Vance liberated herself from the laboratory. "The happiest day of my life was when they told me I could do genetics but didn't have to go into the lab."

Early on, the work was divided by special interest. Roses provided the clinical expertise as a neurologist; Vance did the laboratory analyses; and Pericak-Vance did the genetic analyses and the systems to manage the data.

Everyone collected data. The three spent weekends traveling around North Carolina to get blood samples and clinical information from people with myotonic dystrophy. They drove a beaten up station wagon that once had to be pulled out of a ditch by a patient's family. Another patient was disappointed with the vehicle. "I thought you'd at least have a bus," he said. Pericak-Vance recalls, "After that, we called that car the 'myotonic bus.'"

PEDIGENE

To make use of the data they were collecting, Pericak-Vance, along with Roses and computer programmer Carol Haynes, began developing the computerized data management tool that would later become PEDIGENE.

Throughout the 1980s, Pericak-Vance and colleagues, particularly Jonathan Haines at Massachusetts General Hospital, continued to develop and refine the tool.

In the 1990s, Pericak-Vance and Haines used PEDIGENE to combine patient and laboratory data from MDA researchers Robert Brown of Boston's Massachusetts General Hospital and Teepu Siddique of Chicago's North-western Memorial Hospital to look for a gene that might cause the deadly neurodegenerative disease ALS -- amyotrophic lateral sclerosis, or Lou Gehrig's disease.

In 1993, the gene, which is for the protein superoxide dismutase 1, was found. When the gene for SOD1 is abnormal, the SOD1 protein is abnormal. It seems to take on a toxic form that kills nerve cells, probably through interfering with the way they normally clean up cellular chemicals called free radicals.

The SOD1 finding opened up a major new avenue of investigation in ALS that may apply to more than just this one genetic form of the disease.

"People said it was impossible, until we got the gene," Pericak-Vance says. She recalls one long night in the early '80s when she and Haines sat up in his Boston living room and figured out how to combine lod scores for the two patient groups. "We knew chromosome 21 was the place to go after that," she says -- although it would be almost a decade before the gene was finally isolated.

FAMILY STUDIES

By mid-morning, it's time for the department to meet on some of the family studies. Pericak-Vance has MDA funding to look for genes involved in families with ALS, Charcot-Marie-Tooth disease, congenital myasthenia, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, Bethlem myopathy (a form of distal muscular dystrophy) and familial spastic paraplegia (a neurologic disorder). Her non-MDA work includes gene hunting in Alzheimer's disease, multiple sclerosis, autism, Parkinson's disease and several eye diseases.

In some of these conditions, there are genetic abnormalities that directly result in disease. (This is the case in Duchenne dystrophy, for example, where a genetic abnormality in the gene for the dystrophin protein keeps the protein from being made. Without dystrophin, muscle cells degenerate.)

But in other conditions, Pericak-Vance explains, there may only be genes that increase the risk of developing the disease; they don't actually cause it -- not without some sort of "second hit," such as a virus or other environmental factor, or a second genetic abnormality. Pericak-Vance's group, working with Roses, has found this kind of "susceptibility" gene in Alzheimer's disease. When the gene for apolipoprotein E (ApoE) shows up in a certain form -- one of three forms found in humans -- the chance of developing Alzheimer's disease is increased. Pericak-Vance suspects there are similar genes that may increase the chances of developing ALS, multiple sclerosis and other conditions.

The teams have expanded far beyond the three researchers who drove the myotonic bus years ago. They're now composed of genetic counselors, physician assistants and researchers, who travel by plane as well as by car.

In this morning's meeting, Pericak-Vance hears members of the familial spastic paraplegia team report on a recent trip to Boston to see a family with this disease. A physician assistant tells Pericak-Vance that someone with FSP in his family has written from Germany. "I'll e-mail him," she says.

The teams request supplies -- a papoose board for restraining children while their blood is being drawn, and hot and cold packs for the patients. These will be requisitioned. "Can you take that board on the plane?" Pericak-Vance asks. The consensus is that you can. A technician is asked to follow up on missing blood samples.

Pericak-Vance tells the department that a nephrologist has asked them to take on a new project, finding genes for the kidney disease focal segmental glomer-ulosclerosis. Another group wants to find genes involved in osteoarthritis. These projects will be taken under consideration.

None of this work would be possible without PEDIGENE. In its present form, Duke's PEDIGENE Genetic Information Management system is among the most sophisticated data management programs in existence. It can handle family information, including history and diagnoses; DNA test results, including graphic images of the actual DNA sequences; and clinical information, including X-ray and photographic images and audio and video recordings.

"You can pull out information by any criterion," Pericak-Vance explains. "Let's say you want to look at all patients with nerve conduction velocities under 50," she says. PEDIGENE can instantly pull out those patients and then match that factor with any other factor, such as a particular DNA sequence.

Later, Pericak-Vance holds a meeting with the data analyst on the ALS study of susceptibility genes. It involves the same three centers - Duke, Massachusetts General Hospital and Northwestern - - that worked on the original SOD1 gene isolation. The study, which has a large MDA grant, is a difficult one because when a gene doesn't directly cause a disease, finding it is an enormous challenge.

Pericak-Vance and the data analyst discuss how all three centers must report data in the same way, so that it can all be entered correctly into PEDIGENE.

Do any of the scores look interesting? Some look promising, the analyst says, but it's too soon to say.

SOCCER AND LASAGNA

By 4 p.m., Pericak-Vance is thinking about JJ's 5 p.m. soccer game and a dinner she and Jeffery are giving that night for some of the department staff. Marcy Speer, recovered from her early morning car accident, offers to go to the Vances' house and put the lasagna Pericak-Vance made the previous night into the oven.

By 5, they've convened at the soccer field -- Margaret and Jeffery Vance, children JJ and Danica, and Marcy Speer and her two small daughters, Kira and Casey. Unfortunately, no one can locate the referee. After half an hour of small talk with other parents and some encouraging words for the children, the would-be spectators head for home.

Jeffery will soon be off to Tunisia to a limb-girdle conference, and Marcy Speer has another conference to attend. Pericak-Vance has volunteered to take all the children this weekend. "We'll have fun," she says to Speer's baby, pulling a toy from a nearby drawer.

The dinner table talk is of the basketball rivalry between Duke and the University of North Carolina, the public schools in Chapel Hill and Durham, and JJ and Danica's recent course in baby-sitting.

Late in the evening, the guests depart and Pericak-Vance clears up dishes and gathers children. 3:30 a.m. doesn't seem a long way off, but she doesn't appear concerned.

The day will probably end for Pericak-Vance much as it began -- in her cozy downstairs study. The house will soon be equipped with fiberoptic lines, Jeff explains, easing access to the Internet and the university.

"I hope we haven't tired you out," Margaret says.

Editor's Note: As this article was going to press, we received news of two more advances by the Duke team, including finding a small genetic region on chromosome 14 that contains the gene for oculopharyngeal muscular dystrophy, and pinpointing another genetic region that contains a gene for a very late-onset form of Alzheimer's disease. While emphasizing that the Alzheimer's work was funded by the National Institutes of Health, Dr. Allen Roses said, "We wouldn't have been in genetics research in this way if it hadn't been for the original MDA Piton Foundation grants for myotonic research. "I'm forever indebted to MDA for helping us."