Human genome draft sequence offers clues to health

Drugs that are genetically tailored to patients' needs are on the horizon.

By Susan J. Landers, amednews staff. March 5, 2001.

Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

Washington -- Scientists can now read the "book of life" and its genetic instructions for making a human being. And the implications for medicine are huge.

The book is actually in three volumes, noted Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute. It's a history book, a shop manual and a textbook of medicine.

Numbers that shape our world -- or at least our bodies
Links

The textbook will provide physicians "immense new powers to treat, prevent and cure disease," Dr. Collins told scientists and reporters packed into a hotel ballroom on Feb. 12. He predicted -- but asked that he not be held to a certainty -- that by 2010, many primary care providers will begin to practice genetic medicine.

Dr. Collins, who leads a consortium of scientists at 20 institutions worldwide, and J. Craig Venter, PhD, CEO of the private U.S. firm Celera Genomics, were unveiling the draft sequence and initial analysis of the human genome.

These two rival initiatives, one public, one private, and each working independently, arrived at surprisingly similar conclusions about the number of genes -- many fewer than originally thought -- and a gene's ability to do double and triple duty in each cell.

Armed with a genetic map that is more than 95% complete, the search for applications will now be where the action is. The quantities of new research material that accompany the findings are expected to rapidly generate, for instance, more information on individuals' genetic predisposition to increased numbers of diseases.

Physicians also point to the likelihood that new prescription drugs will be developed that tailor treatment to a patient's genetic profile. The information may also help predict which patients are likely to have adverse reactions to certain medications.

Wylie Burke, MD, PhD, professor and chair of the Dept. of Medical History and Ethics at the University of Washington, Seattle, has the perfect use for such applications. Some children with acute leukemia lack sufficient levels of an enzyme that enables them to effectively break down a chemotherapy agent so it is not toxic to bone marrow, she explained. The ability to determine which children lack the enzyme before beginning a chemotherapy regimen could help avoid that adverse consequence.

The latest announcement marks the end of the first stage of the project, which reached a milestone in June 2000 when researchers had collected 90% of the DNA letters representing chemicals that control the body's manufacture of proteins.

"It is just a beginning," said Henri Begleiter, MD, a psychiatry professor at the College of Medicine at the State University of New York in Brooklyn. "But what a wonderful, wonderful beginning. I can hardly think of a more fascinating advance that will have as much benefit as this will to the human condition."

Dr. Begleiter is the lead researcher for the Collaborative Study on the Genetics of Alcoholism. He has already used project findings in conducting his own research.

The pace of discovery is expected to get even faster because the research findings are continually posted on publicly available databases. The project began posting its data five years ago because "delaying the release of either unfinished or finished genomic DNA sequence data serves no scientific or societal purpose," according to project materials.

"We've seen the project evolve from something that seemed 'pie-in-the-sky' to something that we have in our hands," said Michael A. Williams, MD, chair of the AMA's Council on Scientific Affairs and an assistant professor of neurology and neurosurgery at Johns Hopkins University in Baltimore.

Research has already led to identification of at least 30 disease genes, including those indicating susceptibility to forms of breast cancer, epilepsy, muscular dystrophy and deafness.

Next up could be predictive genetic tests for cancer, heart disease and diabetes, suggested Dr. Collins. And how these technologies can be used will create additional clinical challenges.

Like many others, Dr. Burke already uses genetic tests in her work counseling women who have strong family histories of breast and ovarian cancer. She welcomes the new genetic findings but cautioned that additional research on treatment options is badly needed. Although screenings at an earlier age are recommended for women at increased risk for breast and ovarian cancer, the effectiveness of mammography for women in their 30s has not been studied, she noted.

Meanwhile, others are looking optimistically toward specific areas of progress. David Flockhart, MD, PhD, director of the Pharmacogenetics Core Laboratory at Georgetown University Medical Center, Washington, D.C., is convinced that the first treatment advance to result from the project will be "genetically defined precision prescriptions."

The development of the new drugs will change medicine profoundly, if incrementally, said Dr. Flockhart.

Meanwhile, one of the most surprising project findings is that there are only about 30,000 to 35,000 genes in the human genome rather that the 100,000 to 120,000 many had predicted. The finding that humans have only about twice as many genes as the worm or fly "instills a sense of humility," said the CSA's Dr. Williams.

But it also reduces the size of the challenge at hand. "Now we only have to do one-third as much work to really understand the human genome and to use that knowledge to the benefit of patients," he added.

However, additional, unknown puzzles remain. "And we're going to spend the next 100 years, at least, figuring that out," said Dr. Flockhart.

Congress may need some of that time to develop policies that afford protection from genetic discrimination. Sen. Tom Daschle (D, S.D.) and Rep. Louise Slaughter (D, N.Y.) have reintroduced a bill they authored two years ago. "Scientists have made dramatic progress in deciphering the genetic code," Daschle said, "but Congress has done nothing to make sure this new knowledge will be used to help people, not hurt them."

ADDITIONAL INFORMATION:

Numbers that shape our world -- or at least our bodies

Among the recent findings of the Human Genome Project:

The total number of human genes is somewhere between 26,383 and 39,114 -- many fewer than the 100,000 or so originally thought to exist and only twice as many as a fly or a worm.
On average, each human gene probably makes three proteins, more than worms and flies do.
Only a tiny fraction of the human genome, about 1.5%, is made up of protein-coding regions. The vast majority consists of repetitive sequences -- "junk DNA" -- that have been hopping around the genome for 3 billion years.
A 0.1% difference, or one in every 1,000 letters, between human beings contributes to our individuality and can explain the genetic basis of disease.
Scientists have catalogued 1.4 million single-letter differences, or single nucleotide polymorphisms, and their exact locations on the human genome. This map promises to revolutionize the mapping of disease.