Putting human genes on the map Biological cartographers: Imagine mapping a human being's entire genetic makeup, with its 50,000 to 100,000 genes.

THE BALTIMORE SUN

In 1969, the year man first walked the moon, Dr. Victor A. McKusick proposed that scientists map the genes that help make people what they are: blond or brunette, giant or dwarf, daring or reluctant. The proposal must have seemed as realistic as a mission to the sun.

"It took a little nerve," says the Johns Hopkins physician, who admits that nobody had the tools to pull it off.

Then again, nobody envisioned that science would move as fast as it has. Thanks to rapid advances in biology, scientists now regard the complete mapping of the human genome as an inevitability. Researchers engaged in the Human Genome Project, a multinational effort to map the genome by 2005, are ahead of schedule and, they say, under budget.

And what a map it is. The genome is the complete complement of genes -- 50,000 to 100,000 of them -- contained in each cell of the body. The genes are scattered along 23 pairs of chromosomes, coiled strands of DNA that in each cell would measure 6 feet if stretched straight.

Genes churn out proteins that make everything from your hair to your toes. Each cell has the same complement of genes, but only certain ones are "switched on" in a given cell. They are specialists, called into action to do things like making hair curly or straight, toes stubby or long.

"Biologists in the next century will look back on the 20th century as a barbaric time, when scientists attempted to understand life without understanding the basic elements," says Dr. Eric Lander, director of the Center for Human Genome Research at the Whitehead Institute in Cambridge, Mass.

The Human Genome Project has been to the biological sciences what President John F. Kennedy's space program was to rocket travel: an organized effort to reach a remote destination on deadline.

"We could easily have found all the genes but it would have taken a hundred years," Dr. Lander says. "The genome project compressed it to 15 years."

A complete accounting of the human genome would function like the periodic table, the chart found in the back of high school chemistry texts that lists the building blocks of matter. A genome chart would list all the elements of a person's inheritance, not just the genes but their chemical makeup and location on the chromosomes.

The genes have long recipes -- sequences of chemicals that number in the thousands for each of the tens of thousands of genes. Mapping really means deciphering the complete sequences and learning where each sequence falls on the chromosomes.

In December, scientists at the Whitehead Institute announced that they had achieved an intermediate goal: completion of a "physical map" of the genome. Using the latest tools of molecular biology, the Whitehead Institute isolated 15,000 chemical markers -- landmarks, in a sense, that divide the chromosomes into distinct segments. Scientists hoping to locate traits can use the markers to tour the genome quickly, much as readers use chapter headings to find their way through volumes of text.

What's left is the immense task of isolating the genes themselves and figuring out what they do. Already, scientists have mapped about 3,500. A thousand are "disease genes," responsible for 1,200 distinct disorders.

These genes and their locations on the chromosomes are neatly cataloged in "Mendelian Inheritance in Man," Dr. McKusick's encyclopedia of genetic diseases that is in its 11th printing. Its readers can find the genetic basis of a textbook's worth of disorders, such as Huntington's disease, night-blindness and forms of epilepsy, dwarfism and cancer.

L Already, society is benefiting from some of the discoveries.

When scientists found the gene that causes cystic fibrosis, a deadly respiratory disease, one reward was a test that detects the disease in young children and even fetuses. Couples concerned about passing the illness to their offspring can also learn if they are carriers.

Now, carriers can take another step -- costing about $7,000 -- to prevent the birth of an afflicted child. They can conceive by in-vitro fertilization in labs where scientists screen out embryos that carry the genetic flaw in question. Once that is done, only the healthy embryos are implanted.

Scientists also are experimenting with gene therapies, which are attempts to cure diseases by implanting healthy, disease-fighting genes in people who lack them. This is being tried for diseases including cystic fibrosis, kidney cancer, an inherited form of emphysema and a congenital immune deficiency.

Many authorities say it will be many years before researchers safely deliver genes to their targets and in sufficient quantities to do any good. Perhaps the therapies have been oversold, raising unrealistic hopes among the afflicted.

The same knowledge could bring faster rewards in drug development. Rather than supplying new genes, it may be easier to make drugs that supply the same disease-fighting substances that are produced by healthy genes.

Dr. Beryl Rosenstein, a cystic fibrosis specialist at the Johns Hopkins Medical Institutions, says genetic sequencing may also help doctors understand the perplexing variability of the disease. Why, for instance, do some patients have milder symptoms than others? Why does cystic fibrosis afflict the lungs and pancreas in some patients but only the lungs in others? The secrets could be hidden in the sequences -- the subtle differences that occur when the code is jumbled ever so slightly.

Shifting into his Jules Verne mode, Dr. McKusick envisions a day when a newborn baby would get a "genome screen," a full chromosomal accounting that could be encoded on a plastic card. "So whenever you went to the doctor, you'd put your card in a reader and find out what should be looked at," he says.

He and others in the field recognize the potential threats to privacy and the need for safeguards. Insurers could use genetic information to deny coverage or raise people's rates. Employers could demand access, too, hoping to learn something about an applicant's intelligence or behavior.

"Politically, how much information on the genome of a candidate for high office should the public have access to?" Dr. McKusick asks. Should the public know about a candidate's predisposition toward Alzheimer's disease? What about depression? What about cancer?

People eager for immediate payoffs from the map of the human genome are going to be frustrated.

When scientists found the gene for Huntington's disease a decade ago, they produced a useful test. It tells people if they carry a time bomb that probably will cause them to die from nerve degeneration. Such knowledge is terrifying but important to people whose parents had the disease and wonder if they should have children of their own.

Isolating the Huntington's gene, however, has not produced a cure. Nor have discoveries of genes for breast or colon cancer, though they give people strong reasons to be screened earlier and more often than they otherwise would.

So the mapping of the genome may create a paradox.

"It is likely to increase the gap," says Dr. McKusick, "between what we think we know and what we really know."

"You could have mapped the entire United States by waiting until people made their homes in every nook and cranny in the country."

4 Instead, he notes, we sent out Lewis and Clarke.

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