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Piecing together our future

The new map of the human genome will change our lives forever

Sunday, June 25, 2000

By Byron Spice, Science Editor, Post-Gazette

Reading the book of life
A four part series: How genetics will transform medicine

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.

All 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 expected to announce as early as tomorrow 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.

Reading the
Book of Life

Genetic artist with an edge

Some members of a family susceptible to a treatable blood-iron disorder reject testing

Q & A: The shape of the future

About the authors

Sunday, July 2:
* Will new discoveries create genetic outlaws?
* One woman's life-changing test
* A genetic exam that can bring salvation and doom at the same time.

Sunday, July 9:
* A trip to the doctor in 2010
* Individualizing your drugs
* Pitt's genetic guru.

Sunday, July 16:
* Who owns the keys to life?
* Making the perfect baby
* A theologian's view of genetics.


It's a journey of discovery with special meaning here, because the University of Pittsburgh already 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.

Two-edged sword

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 in medical offices 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 also 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 come 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 also prompt an abortion when tests reveal problems.

Farther 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, Mass. "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.

Profiling our genes

We are already 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 are still not completely understood.

Dr. Francis Collins, the geneticist who heads the National Human Genome Research Institute in Bethesda, Md., and coordinates the international consortium known as the Human Genome Project, says 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 some new drugs or other interventions that will help stave off disease. But at a more basic level, the information may simply provide patients with motivation to follow preventive measures such as exercise, weight control and smoking cessation that are already known, but too often ignored.

"We give a lot of lip service to preventive medicine, but we're not very good at it," 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.

"We know how to prevent colon cancer, but who is motivated to have regular colonoscopies?" he said. "If you knew the one-in-100 who are at risk, perhaps they might be more receptive to having this done."

A mysterious malady

Keith Stewart would have done anything to avoid the trip he made to a Columbus, Ohio, emergency room. A young man with a bright future, he had just taken over his family's used car dealership and was engaged to be married. He was a scuba diver with his own boat, and he considered himself healthy.

"I thought I was invincible," he said.

Yet here he was, a young buck who seldom hit the sack before 1 a.m., doubled up in pain, his chin pulled down tight against his chest. He felt pressure building up inside and pain radiating down his arms and up his neck.

At age 34, Stewart was dying. His heart was failing. His liver was shutting down. His blood sugar was skyrocketing.

Congestive heart failure, his doctors said. Cirrhosis of the liver. Maybe diabetes. These were diagnoses for old men, not for Stewart. But within days the doctors added one more ailment to the list, a genetic disease that made sense of all the others: hemochromatosis.

It's a condition that causes the body to absorb an abnormal amount of iron from food. Iron is an essential nutrient and has long been promoted as an enhancement to health; it is routinely added to cereals, processed foods and multivitamins to reduce the risk of anemia. But excess iron is poisonous, accumulating in tissues and causing heart failure, cirrhosis, arthritis, diabetes, impotence, early menopause, infertility and thyroid disorders.

Like most people, Stewart had never heard of it. But hemochromatosis may be the most common genetic disease in the land. It was killing Stewart and it's probably killing millions of other Americans, too.

Geneticist Collins predicts that hemochromatosis may well prove to be the "poster child" for genetic medicine. Lots of people will soon be learning about hemochromatosis and, as they do, they will be gaining a new appreciation of genetic diseases.

Within a few years, Collins predicts, medical societies will recommend that all adults, particularly those of northern European descent, be screened for hemochromatosis.

The only real debate, Collins maintained, is whether it is more effective to screen for the gene mutations that cause hemochromatosis, or to do blood tests looking for iron overload.

"It's such a compelling case," Collins said. "Lots of people are dying needlessly."

Surprisingly common

Despite Stewart's protests of good health, he had been complaining of fatigue and poor muscle tone for years prior to the April 1999 crisis that sent him to the hospital. Doctors explored blind alleys, checking the function of his pituitary gland and screening him for depression.

Yet they failed to note his perpetual tan. This "bronzing" is a common symptom of hemochromatosis -- so common that the very word hemochromatosis in Greek means "iron-colored skin."

In fairness, generations of doctors have been told that hemochromatosis is exceedingly rare, striking maybe one out of every 500,000 people. But Dr. Geoffrey Block, director of the UPMC Center for Hemochromatosis and Iron Overload Disorders, said it now appears that one out of every eight Americans is a carrier of the disease; that is, they carry one mutated copy of the so-called hemochromatosis gene. As many as one out of every 100 have two copies of the gene mutation, causing them to absorb twice as much iron as normal and putting them at risk of iron overload.

That means the actual risk of hemochromatosis may be 5,000 times higher than doctors were traditionally taught.

In Pittsburgh, incidence may be particularly high, Block said. This has nothing to do with the city's steel-making history, but with its large number of residents of northern European descent. One of the genetic mutations that causes hemochromatosis arose about 40,000 years ago, he explained, when hunter-gatherer societies were giving way to agricultural societies. The mutation made it easier for people to subsist on crops grown in the iron-poor soils of northern Europe.

That doubled absorption rate only worked against Stewart, living in a land of iron-fortified cereals. By the time he landed in the hospital, his iron levels were a hundred times higher than normal.

Without a transplant to replace both his heart and liver, doctors told Stewart, he would die. Yet he was so sick that transplant programs in Columbus and Cleveland refused to list him. He eventually found his way to the University of Pittsburgh, where transplant doctors were willing to make him a transplant candidate.

"I was in and out of the hospital constantly after the diagnosis," Stewart said. In mid-October, he was transferred by ambulance to UPMC Presbyterian. He underwent a procedure to correct heart rhythm disturbances and was released at Thanksgiving to a Penn Hills apartment, where he waited for transplant organs to become available.

He also began getting treatments from Block. Besides reducing iron in the diet, the only treatment for iron overload is to draw blood. Stewart underwent these therapeutic phlebotomies two or three times a week. Normally, about a pint of blood is removed at each session, the same as a normal blood donation, but Block said that is sometimes halved to avoid strain on severely ill patients.

Stewart is back in Columbus now. His iron levels have dropped down to the normal range and, though he is technically still a candidate for a double transplant, his condition has improved so much that his case has become a low priority and he likely won't be offered any organs.

The impact on the Stewart family is still being felt. After Keith got sick, both his mother and father were tested and found to be carriers of the hemochromatosis gene. A younger brother and sister have been tested, revealing the brother is also a carrier. An older sister, however, has refused to be tested.

"I'm not sure why she hasn't been tested," said Stewart, who worries that excess iron might be wreaking the same silent damage on her that he has suffered. "She sees what I'm going through. There should be no excuses."

From gene to disease

If Stewart's sister was looking for an excuse, she might take comfort in the fact that having hemochromatosis -- inheriting a mutated copy of the gene from each of your parents -- isn't the same thing as having iron overload disease.

Even if iron absorption is greater than normal, a person might not suffer iron poisoning. A diet low in iron, regular blood donation and youth are factors that can protect such a person. Conversely, a person with no hemochromatosis genes can still suffer iron overload disease if dietary intake of iron is high.

That is why Eric Juengst, a bioethicist at Case Western Reserve University in Cleveland, likens the predictive value of most genetic tests to a TV weather map -- it gives you a good idea of what might happen, but you aren't shocked if it doesn't turn out quite as expected.

This variability in hemochromatosis symptoms long bedeviled scientists trying to make sense of the disease's inheritance patterns.

When researchers at the University of Utah finally figured out how to tackle the problem, they inadvertently stumbled onto a technique that helped accelerate the hunt for new genes, and planted seeds for what would become the Human Genome Project.

In the late 1970s, no one had yet found the hemochromatosis gene. But a team headed by Mark Skolnick found that they nevertheless could trace the presence of the gene through extended Mormon families in Utah 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 located 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.

Speeding the sequence

About the same time, researchers such as Frederick Sanger, the 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 -- usually referred to in shorthand as A, C, G and T -- 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 -- most of which is thought to consist of "junk" DNA that has no known function -- gained momentum in the mid-1980s. About 2 million base pairs were then 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 -- two strengths of DOE's national laboratories -- could dramatically accelerate DNA sequencing.

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 DOE weapons scientists. But by the end of the decade, the National Institutes of Health and England's Wellcome Trust were on board and 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 has since been expanded to include additional goals, such as building a catalog of racial and ethnic genetic variations, and its pace has been accelerated. Under current budget projections, DOE and the NIH expect to spend $2.8 billion by the time the project ends, said Collins, who succeeded Watson as genome institute director in 1993.

Much of the past decade was spent completing gene maps and developing sequencing technology. The actual sequencing, which began in earnest only last spring, will cost about $250 million, he added.

"I think it's fair to say we're under budget," Collins said.

Bytes of DNA

Inside the Whitehead/MIT genome center, row after row of tiny red, yellow, blue and green squares march up the screen of a computer monitor. This is the raw data being spun out of an adjoining DNA sequencer.

Eric Lander, the center's director, runs his index finger down the first column of colored squares. "That's the sequence -- A, T, T, G, A, C..." Each column represents one of 96 DNA segments being simultaneously read in this one machine and each color represents one of the four bases, A,C, T and G.

This particular sample, he said, could be from an anonymous man from Buffalo, N.Y., one of a host of people who donated DNA to a researcher there. Or it could be bits of the yeast, mouse or bacterial DNA also being sequenced here.

In addition to varying by its creature of origin, the DNA also could be part of a gene, or it could be junk.

"It all looks the same at this stage," Lander said, shrugging as he spoke above the musical din of the sequencers.

The very similarity of human genes is why it doesn't matter much whose genome is sequenced. The final sequence will be based on the DNA of several individuals.

The Whitehead center, the largest of the 16 sequencing centers in the Human Genome Project, occupies a two-story cinderblock building in an industrial area just north of the Massachusetts Institute of Technology campus. Its neighbors are a muffler shop, a taxi dispatch center and a plumbing supply house; a few blocks away, sleek high-rises house such biotech firms as Genzyme and Biogen.

Only about half of the 150 people at work here are involved in physical sequencing, which is highly automated.

In one high-ceilinged room, robotic arms and conveyor belts whirl away as DNA samples are cloned into millions of copies. The DNA clones then are broken into snippets of varying lengths, the strands of DNA are unzipped and fluorescent dyes are attached to the letter at the end of each snippet, a different color for each of the four letters.

In the next large, windowless room, these DNA samples are fed into the sequencers, which arrange the snippets in order of length, from shortest to longest. As the snippets zip by, lasers illuminate the dyes and sensors record the colors.

This color-tagging technique, combined with the speed of powerful computers, can make sense out each DNA segment. It's as if you made thousands of copies of the word "SCIENTIFIC" and broke them into lots of little pieces. If you arranged all the pieces that begin "SCI..." in order of length, you could reconstruct the rest of the word just by reading the last letter in each snippet: xxxE, xxxxN, xxxxxT, xxxxxxI, xxxxxxxF, xxxxxxxxI, xxxxxxxxxC.

By using this matching process, the machines can produce sequences of 500 to 700 letters from each snippet. Ultimately, Whitehead's 123 sequencers can produce 50 million letters of raw data each day.

Each segment is sequenced five times for accuracy's sake. The segments are fed into computers, where these pieces of the puzzle are assembled into longer sequences corresponding to specific areas of the genome map.

At the end of the day, the Whitehead center, along with all of the other Human Genome Project centers, downloads its completed sequences to a publicly accessible Web site, where it is available to anyone.

"We release it, warts and all," Lander said. "I'm proud of that."

That's a not-so-subtle dig at the other major player in genome sequencing, Celera Genomics, a private company in Rockville, Md.

J. Craig Venter, the iconoclastic scientist who heads Celera, announced in April that the company had finished sequencing the genome of a person. As Lander spoke, Celera's bioinformatics specialists were assembling those bits into a completed genome. This week, officials of Celera and the Human Genome Project are expected to announce that they will combine their independent sequencing efforts and jointly publish the results later this year.

Venter, who left the National Institutes of Health in 1992 to form the Institute for Genomic Research, got under the skin of the Human Genome Project leaders two years ago when he announced that Celera would spend hundreds of millions of dollars to sequence the human genome by itself. The company would finish by 2001, four years before the public consortium planned to finish.

"Speed Matters. Discovery Can't Wait," is the motto at Celera. It is a subsidiary of PE Corp., the instrument manufacturer that makes all those $300,000 DNA sequencers used by the genome centers, and was established to accelerate work on the genome. Its sequencing center is the world's largest, boasting 300 robotic sequencers.

The public consortium responded by speeding up its timetable, announcing that a rough draft -- a sequence that's 90 percent complete with 99.9 percent accuracy -- would be completed by this spring. The remaining gaps would be filled in by 2003, two years earlier than the original plan.

The two sides sniped at each other over which sequence would be more accurate, even as they secretly talked about combining their efforts. Those negotiations came to light in March after they apparently collapsed. Last week, however, the New York Times reported that the consortium and Celera had reached agreement on some level of cooperation and would make a joint announcement tomorrow.

The agreement would end what has been perceived as a race between the public and private efforts, though both sides always denied they were in competition.

Eugene Myers, a University of Arizona computer scientist who developed Celera's computer software for assembling the genome, said the company has been concerned about its business plan, not one-upmanship.

"I'm in a hurry because we're a company and we have customers we want to serve," he said. Celera plans to make money by selling information gleaned from analysis of its genomic database. A researcher who has narrowed her search for a gene to a particular region of a chromosome, for instance, might purchase sequence information for that region so she can pinpoint the gene, or find similar genes in other animals that might clarify its function.

Other companies, such as DoubleTwist Inc. in Oakland, Calif., are popping up to provide similar analytical services using the Human Genome Project database.

A humanitarian impulse also underlies the rush to finish the sequencing, said Myers, Celera's vice president for informatics research. "Every year that goes by is a year we're not advancing knowledge and not finding cures for disease," he explained during a scientific meeting at Carnegie Mellon University in May.

But an awful lot of hype surrounds talk of completing the genome sequence, Lander contended. "It's not like the transcontinental railroad, which is useless until the last spike is driven," he said. Most of the sequence already is available on the Internet and is being used every day.

For instance, an endocrinologist on the Whitehead staff recently found a gene that appeared to be linked with diabetes, although he didn't know its full sequence.

The next day, he logged on to the Internet and found that, by chance, both the Whitehead center and a lab in China had sequenced that gene and that a Texas lab had sequenced a similar gene in the mouse.

"By the end of the day, he had found five non-coding regions (areas of the gene not involved in producing protein) that appear to be regulatory regions of the gene," Lander said. Not long ago, it might have required 15 person-years of work to accomplish what he did in a day.

It's the same thing in labs everywhere. In Dr. Michael Gorin's lab at the University of Pittsburgh's Eye and Ear Institute, for instance, computers have sprouted on almost every lab table.

"More and more time is spent searching the genetic databases," said Gorin, interim director of human genetics at Pitt's Graduate School of Public Health. One lab member studying a retinal disease estimates she spends half her time checking the online databases. "It's really changed the way we do research," Gorin said.

In rough draft form, the genome sequence will be punctuated with a number of gaps -- segments that didn't get sequenced, either by chance or because they were impossible to clone. Some sequences will be ambiguous. A second pass through the genome in the next year should close many of the gaps, Lander said, leaving gaps of two to four letters every 50,000 base pairs.

"Finishing the genome is as much an art as a science," said Aravinda Chakravarti, a geneticist at Case Western Reserve University in Cleveland and the architect for the Human Genome Project's accelerated timetable. Assembly line techniques won't work for filling in the last gaps, he explained, and the pace will slow as segments are sequenced using methods that can't be automated.

But these incremental improvements will be important, Collins said.

"From the perspective of the researcher, you can learn a vast amount from what's already there," he noted. "But this is the human book of life. If we're going to be reading it, we better get it right."

Additional information is available at these Web sites:

General information about the Human Genome Project is available through this Department of Energy site:

The Genomic Lexicon provides a glossary of genetic terms:

The National Human Genome Research Institute's home page is

Follow the progress of the Human Genome Project's sequencing effort at

Celera Genomics, a private company performing DNA sequencing, includes genomic news and tutorials on its home page at

Correction/Clarification: An earlier version of this story included one or more photos by Allan Detrich. The photos have been removed. This action is explained in a note from the editor.

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