CODE WARRIOR

THE BALTIMORE SUN

Now that rival teams of scientists have created first drafts of the human genetic text, they are about to take the next step toward creating tomorrow's wonder drugs. It's called annotation, and it consists of poring through the volumes of DNA to find all the genes and figure out what they do.

No one, perhaps, is more eager to start than Dr. Victor A. McKusick of Johns Hopkins University, 78, one of the founders of modern medical genetics. And few, perhaps, are better poised to influence what path the effort takes.

When President Clinton and British Prime Minister Tony Blair jointly announced the milestone Monday morning , McKusick was there in the East Room of the White House, sitting behind James Watson, co-discoverer of the structure of DNA.

To McKusick, who has spent more than three decades compiling one of the world's most comprehensive public catalogues of genes, it was a "spectacular" moment, the dawn of a new era. "It was of the same momentous nature as the moon landing in 1969," he says.

But, McKusick says, the real age of exploration is just beginning.

Recording the first human genetic text, the genome, is a little like discovering a copy of life's encyclopedia. "But there is no index, no table of contents, no headings, no nothing," says Dr. David Valle, one of McKusick's colleagues at Hopkins. In short, there is no efficient way to extract the ocean of information the genome contains. "Until it's annotated, it doesn't come close to providing the value that is there."

Annotation should pave the way for the discoveries that the genome promises - pinpoint diagnoses of illness; drugs that zero in on their metabolic targets like smart bombs; the identification of the families of genes that predispose people to common disorders such as cancer, Alzheimer's, major mental illness, allergies, asthma. "Almost any disease you can think of has at least some genetic predisposition involved," McKusick says.

Many of the genome's early explorers will likely be guided by McKusick's "Mendelian Inheritance in Man," a compendium of 2,281 genes that, when flawed, have been linked to at least one specific disorder. (Potentially, the malfunction of any of the genome's estimated 50,000 genes could cause disease.) The 34-year-old encyclopedia is now published online by the National Center for Biotechnology Information, and is read by thousands of researchers worldwide each day (www.ncbi.nlm.nih.gov/omim).

McKusick and his colleagues hope the venerable publication will serve as a model for the annotated genome - perhaps even evolve into it.

Both the non-profit Human Genome Project - an international consortium of academic labs led by the National Institutes of Health and Britain's Wellcome Trust - and their rivals, Celera Genomics of Rockville, have already begun annotating their separate genomes.

For now, each is working independently. But McKusick hopes to bring the former antagonists together in the effort, urging the two sides to stage a joint annotation conference. He has influence in both camps. He is close friends with Dr. Francis Collins, chief of the consortium's U.S. labs. And McKusick holds a seat on the scientific advisory board of Celera -- a post that pays him about $10,000 a year, plus stock options.

Celera, though, has so far resisted the idea, saying it will offer its indexed, footnoted genome only to paid subscribers. "Celera can and does have the resources to do a very formidable job of annotation," says Dr. Sam Broder, one of the leaders of Celera's annotation effort.

Still, McKusick is gently urging the company to reconsider. "How Celera can engage in separate annotation isn't very clear to me," he says

A patient peacemaker

If anyone can nudge the two sides together, it is McKusick. He has a reputation for patience and civility in a field filled with rogue egos and brusque personalities. "By nature, I can usually steer clear of making enemies," he says cheerfully.

Tall, erect, with white hair, white coat and a grandfatherly manner, McKusick seems to have stepped out of a Norman Rockwell painting of a country doctor. And the image is partly apt.

Born on a dairy farm in rural Maine, McKusick is 20 minutes younger than his identical twin, Vincent. They were the youngest of five children - and, as with many twins, so close they shared a secret language. The first time the pair spent much time apart was when Victor, 15, developed streptococcus infections in his left armpit and right elbow.

After 10 weeks in Harvard's Massachusetts General Hospital, he was cured by a medical innovation - antibiotics. He knew he wanted to be a doctor and dropped out of Tufts college when the war made it possible for him to enroll early at Johns Hopkins in 1943. He's been there ever since. (Victor's brother, Vincent, went on to become chief justice of Maine's Supreme Judicial Court before his retirement.)

McKusick established one of the first divisions of medical genetics in the country at Hopkins just a few years after Watson and Crick unraveled DNA's structure. He conducted pioneering studies of Marfan Syndrome - a genetic disorder of connective tissue that makes those suffering from the disorder tall, lanky and prone to heart disease. (President Lincoln may have suffered from it.)

Working in the Pennsylvania countryside, McKusick conducted groundbreaking research on Amish families, uncovering 10 new inherited disorders. He studied the genetics of dwarfism - work that earned the 6-foot-2 scientist honorary membership in Little People of America, a support group for dwarfs and midgets.

And in 1966 McKusick launched his magnum opus, "Mendelian Inheritance in Man." The title refers to the laws of inheritance discovered by Gregor Mendel, a 19th-century monk, who conducted breeding experiments on pea plants. Mendel traced mutations in single genes through the generations: the genes that caused smooth or wrinkled peas, for instance.

But many common human illnesses - such as heart disease and high blood pressure - depend on the interaction of several genes. One result of having the human genome in hand is that scientists can now begin to hunt for the genetic roots of illnesses that do not follow Mendel's simple rules.

Straight to the top

Though technically retired, McKusick still spends most days in his book-lined, vault-like office on the 10th floor in the East Baltimore medical complex. Even when he's not at the office, he's working, taking his computer, fax machine and stacks of journals on vacation to his farm in Nova Scotia. On a recent trip to Sardinia, he checked in daily on the "Mendelian Inheritance" Web site to make sure material had been posted.

Reading is his passion. Mostly, it's scientific journals. But he is also an avid student of Hopkins history. And several times a year he conducts what has become a rite of passage for generations of Hopkins interns: He leads them on tours of the old administration building, finishing at the top of its soaring dome.

On Tuesday after the genome announcement, McKusick arrived in front of the statue of Christ under the dome, where he greeted about 40 incoming interns. After a brief lecture on the sculpture and other artwork, he led the group up the building's grand staircase to a closet containing a set of steps. He wound up into the attic, climbed a short metal ladder and then wound up a set of twisting, rickety wooden steps.

At the top, McKusick opened a trap door and stepped into a small cupola sitting atop the dome. (Because McKusick injured his hip in a fall last year, school administrators had a chief resident follow the scientist during Tuesday's climb.)

"The tour is legendary," said Dr. Rebecca J. Hill, one of the interns, as she stood looking out over East Baltimore. McKusick hasn't just read extensively about the institution, she said, "He's witnessed so much of the history of Hopkins."

As McKusick gripped the rail, the wind brushed his hair and tugged at his long white coat. After he pointed out Federal Hill and Fort McHenry, the physician recalled how he gave the same tour to Stephen King, the best-selling author of Gothic horror tales and a fellow Maine native.

"Are you afraid of heights?" McKusick asked the writer, as they began their climb.

"I'm afraid of everything," King replied.

King gave McKusick one of his books, but the scientist says he never finished reading it. He's too busy, he says, compiling his own.

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