Scientists Unlock Start Of Genome Sequence

By Byron Spick

Block News Alliance

PITTSBURGH - The sound is the first thing you notice. A pure, even tone, too high-pitched to be a hum, too sweet to be a squeal, fills a two-story-high room the size of a small gymnasium.

The source of this ethereal note proves disappointingly humdrum: 123 beige boxes, each the size of a chest-high refrigerator, aligned in rows and separated by computer monitors. But within these dull-as-dishwashers exteriors, the inner workings of human life are giving up their secrets.

This is the sound of revelation.

Cloned bits of DNA donated by an anonymous man from Buffalo are being pumped through the boxes' tubular innards, where lasers read the order in which chemical letters are arranged along the DNA fibers. This assembly line of discovery is running full blast at the Whitehead Institute/MIT Center for Genome Research in Cambridge, Mass.

This information is being used to compile a complete sequence of the human genome, a submicroscopic text with 3 billion letters. Officials of an international consortium and a private U.S. firm are scheduled to announce today that they have completed the first drafts of that sequence.

The human genome includes all the genes and other genetic information contained in human cells, and sequencing it is a monumental feat that's been compared to the U.S. moon shot or even the Manhattan Project, minus the fireworks.

It is a text 3.5 billion years in the making, and the fact that it is written in a language we don't fully understand doesn't diminish the excitement. It might take a century to completely decipher the genome, but year by year, that quest will provide fresh insights into what sets humans apart from other animals.

It's a journey of discovery with special meaning here, because the University of Pittsburgh receives the fifth-largest amount of annual funding - $11 million - from the National Institutes of Health for genetics research.

If we ever become adept at tweaking the spelling of the genetic text, it could provide a means of altering the course of the human race.

Even in the near term, the sequencing of the genome could have dramatic effects, particularly in medicine.

One of the first notions that is likely to disintegrate is that genetic diseases are rare.

We all carry at least a handful of harmful genetic defects in our chromosomes. Almost every disease may be caused or influenced by our genetic makeup.

Swabbing the inner cheek to remove cells for genetic analysis may become almost as common as blood pressure and temperature checks. Doctors will use this information to identify disease-causing microbes and to match medications to the patients best able to benefit from them. The tests will let doctors prescribe diet, lifestyle, and drug interventions to prevent or delay diseases that a person is genetically prone to develop.

Yet with this flood of potentially beneficial information comes risks.

Some of the information could be used against people. Some employers may want to rid themselves of disease-prone workers. Some health insurers may not want to extend coverage to them.

Prenatal testing can reassure couples who are carriers of genetic diseases that a fetus is free of the disease, encouraging them to go ahead with the birth, but it may prompt an abortion when tests reveal problems.

Further into the future, the ability of some people to enhance the genetic makeup of their offspring could lead to a world inhabited by genetic haves and have-nots.

"This is a revolution unlike anything you've seen in your lifetime," said Richard Young, a molecular geneticist at the Whitehead Institute for Biomedical Research in Cambridge. "For someone who's spent his career studying the expression of one gene at a time, seeing the entire genome is absolutely shocking."

That's because the genome is more than the sum of its parts. Though it's been called the Book of Life, or a set of blueprints for life, it is not a simple set of instructions. A more apt analogy might be that the genome is a computer software program.

Just as computer novices find that an errant click of the mouse can activate unknown features of their computers or cause the machine to crash, scientists are learning that no gene or other piece of the genome can be viewed in isolation. All the pieces interact, and most seem to have multiple duties. Small perturbations in one part of the genome - the equivalent of a mouse click - can cause ripple effects elsewhere.

We are acquainted with some of these. Change a few critical letters in a boy's genetic code and he will be crippled by muscular dystrophy or be overwhelmed by the thick mucus of cystic fibrosis. A woman with a certain gene mutation faces a high risk of breast or ovarian cancer, while another with a different mutation can succumb to an agonizing death from brain-destroying Huntington's disease.

But even in the dawn of the Genomic Age, it is clear that these devastating diseases caused by a single error are the exception, not the rule.

Most ailments - including major killers such as heart disease, cancer, stroke, diabetes, and Alzheimer's disease - are caused or influenced by how dozens of our genes interact with each other, in ways that still are not completely understood.

Dr. Francis Collins, a geneticist who heads the National Human Genome Research Institute in Bethesda, Md., and coordinates the international consortium known as the Human Genome Project, said doctors will be using genetic profiles to predict a person's risk for diseases such as stroke, heart disease, and cancer within 10 years.

That, in turn, will give people an opportunity to act to prevent or delay the onset of those diseases. Insights gleaned from genetic studies may lead to new drugs or other interventions that will help stave off disease. At a more basic level, the information simply may provide patients with motivation to follow preventive measures such as exercise, weight control, and smoking cessation that are known but too often ignored.

"We give a lot of lip service to preventive medicine, but we're not very good at it," Dr. Collins said. "And one of the reasons we're not very good at it is we tell everybody to do the same thing. And the same thing doesn't work for everybody."

Genetic profiling, however, may make it possible to individualize medicine - to recommend a no-salt diet to individuals whose blood pressure is most sensitive to it, but to let others shake away; or to prescribe cholesterol-lowering drugs to people whose cholesterol levels have more to do with genes than with high-fat diets.

In the late 1970s, a team searching for the hemochromatosis gene found that they could trace the presence of the gene by looking for something called HLA proteins. These are found on the surface of cells and vary among individuals; transplant surgeons use HLA typing to perform tissue matching between organ donors and recipients.

The genes for HLA happen to be near the hemochromatosis gene on Chromosome 6, so when people inherit the gene for the disorder, they usually inherit the same HLA genes.

Daniel Botstein, a yeast geneticist at the Massachusetts Institute of Technology, realized this technique could be expanded to hunt for other genetic abnormalities throughout all 23 pairs of chromosomes by finding markers that were spread throughout the genome and thus could be used to study a wide variety of inheritance patterns.

Until the marker technique came along, gene hunters first had to find proteins involved in a disease process, analyze them and then try to find genes that manufactured the proteins, by working backward from the chemical makeup of the proteins.

With the new technique, the pace of gene discovery began to accelerate and researchers started to assemble genetic maps, identifying the location of the new genes on individual chromosomes.

About the same time, researchers such as Frederick Sanger, a Nobel Prize-winning English chemist, were developing ways to rapidly sequence DNA, the famous molecule in the shape of a double helix that comprises chromosomes.

The long, twisting strands of the double helix are connected by pairs of chemical bases - adenine, cytosine, guanine, and thymine - that are analogous to rungs on a ladder. These bases serve as the alphabet of the genetic code. The order in which these bases are repeated is the sequence. Several thousand of these base pairs might encode a typical gene.

The idea of sequencing the entire genome gained momentum in the mid-1980s. About 2 million base pairs then were being sequenced each year, a pace that would have required more than a millennium to complete the genome.

But Charles DeLisi, head of environmental and health research at the Department of Energy, became convinced that automation and high-performance computing could accelerate dramatically DNA sequencing.

Mr. DeLisi proposed a Genome Initiative that would be on a scale unprecedented in biological science. Many biologists feared such a project would siphon funding from other programs, and some dismissed it as an employment program for energy department weapon scientists. But by the end of the decade, Congress had approved funding.

The Human Genome Project officially began in the fall of 1990 under the direction of James Watson, the co-discoverer of DNA's helical structure, with plans to complete the mapping and sequencing of the human genome by 2005, at a cost of $3 billion.

The project since has been expanded to include additional goals, such as building a catalog of racial and ethnic genetic variations, and its pace has been accelerated.

The private effort is by Celera Genomics of Rockville, Md., which said it will announce "the first assembly of the human genome."

Celera started its project later, but is using a faster method powered by the world's largest private assemblage of supercomputers. The firm announced earlier this year that it had sequenced all of the genes from one human being, an unidentified male, and that it expected in June to have those genes reassembled into the correct order and location on the 23 pairs of human chromosomes.

For months, the parallel public and private efforts were seen as competing and contentious, with bitter criticism and harsh words exchanged in public. But leaders of the two groups publicly shook hands and exchanged compliments last month. Later, sources said, they agreed to the joint announcement.

The public gene sequencing program is a joint effort of the Human Genome Research Institute at the National Institutes of Health; the Department of Energy; the Wellcome Trust in Britain; the Whitehead Institute in Cambridge, Mass.; the Washington University School of Medicine in St. Louis; and Baylor College of Medicine in Houston, along with contributions from researchers in Germany and Japan.

The Associated Press contributed to this report.

Copyright © 1999, 2000 The Blade.

This article posted July 5, 2000.