Decoding the Human Body

The Secrets Of Life: It Is The Most Expensive, Most Ambitious Biology Mission Ever. The Human Genome Project, At $250 Million And Counting, Is Biology's Moon Shot. In The Eyes Of Boosters, It Promises To Provide No Less Than The Operating Instructions For A Human Body, And Will Revolutionize The Detection, Prevention And Treatment Of Conditions From Cancer To Depression To Old Age Itself. In The Eyes Of Critics, It Threatens To Undermine Privacy And Bring On "Genetic Discrimination" In Insurance And Employment. Near The Finish Line, One Effect Is Indisputable: The Genome Has Reignited The Biotech Industry. Explaining The Genome - And What It Means For You.

Every Friday morning at 11, the directors of the five labs leading the race to decipher the human genome confer by phone to assess their progress. In mid-March, it was clear they were closing in on the next big milestone: reading the 2 billionth chemical "letter" in human DNA. But since some of those letters were redundant, a count of 2 billion would not really tell how close they were to the finish line of 3.2 billion.

Greg Schuler, a molecular biologist turned computer jock at the National Institutes of Health, had just spent the weekend, sitting on the sofa with his laptop in front of his fireplace at home, writing a 674-line program to reanalyze the overlaps. When he sicced it on the redundant sequences, the answer popped out: the Human Genome Project had already passed the 2 billion mark, on March 9. It had taken four years to determine the first billion letters in the human genome, but only four months for what Schuler calls "that next odometer moment." The actual chemical letter was--drumroll, please--T.

All right, so it didn't really matter which of the four letters making up DNA claimed position number 2,000,000,000 in the largest, most expensive, most ambitious biology project ever undertaken. But after 13 years and $250 million, through the work of some 1,100 biologists, computer scientists and technicians at 16 (mostly university) labs in 6 countries, the announcement meant that the Human Genome Project was two thirds of the way toward its goal of determining the exact chemical sequence that constitutes the DNA in every cell of every human body. With competitors in the private sector goading them on, scientists in the public project have tripled their pace, sequencing 12,000 letters every minute of every day, 24/7. By last weekend the project, financed by the U.S. government and Britain's Wellcome Trust, had sequenced 2,104,257,000 chemical letters. At this rate, it will complete its "working draft"--90 percent of the genome, with an accuracy of 99.9 percent--in June. And science will know the blueprint of human life, the code of codes, the holy grail, the source code of Homo sapiens. It will know, Harvard University biologist Walter Gilbert says, "what it is to be human."

That knowledge promises to revolutionize medicine and vault the biotech industry into the Wall Street stratosphere. But just as no one foresaw eBay or Amazon when Apple unveiled the first home computer in 1977, so there is no crystal ball clear enough to reveal how knowing the entire human genome will change the way we live and even the way we think about who we are. It is a pretty good bet, though, that doctors will drip droplets of our genes onto a biochip to figure out if we have the kind of prostate cancer that will kill or not, or to figure out if ours is the kind of leukemia that responds to this drug rather than that one. They will analyze our children's genes to rank their chances of succumbing to heart disease or Alzheimer's. Scientists will learn which genes turn on when a wound heals, when a baby's fingers grow, when a scalp becomes bald or a brow wrinkled, when a song is learned or a memory formed, when hormones surge or stress overwhelms us--and they will learn how to manipulate those genes. Babies will be designed before conception. Employers will take your genetic profile before they offer you a job, or withdraw an offer if they don't like the cut of your DNA. The human genome sequence "will be the foundation of biology for decades, centuries or millennia to come," says John Sulston, director of the Sanger Centre, the genome lab near Cambridge, England, where a spiral staircase in the lobby twists upward like the double helix itself.

And all of it will emerge from something like this: ATGCCGCGGCTCCTCC... on and on, for about 3.2 billion such letters. Each letter represents a molecule--adenine, cytosine, guanine, thymine. Every cell of every human body, from skin to muscle to liver and everything in between (except red blood cells), contains a copy of the same DNA. The totality of DNA present in the cells of a species is its genome. Although the genetic age has brought incessant reports about genes "for" homosexuality, risk-taking, shyness, anxiety, cancer, Alzheimer's and more, the only thing a gene is actually "for" is a protein. The A's, T's, C's and G's constitute a code. Each triplet of letters instructs special machinery inside a cell to grab onto a particular amino acid. TGG, for instance, snatches the amino acid tryptophan. If you string together enough amino acids, you have a protein--a stomach enzyme that digests food, insulin that metabolizes carbohydrates, a brain chemical that causes depression, a sex hormone that triggers puberty. A gene, then, is an instruction, like the directions in a bead-making kit but written in mole-cule-ese. Humans have perhaps 80,000 genes, and we are 99.9 percent identical. That is, at only one in 1,000 chemical letters does the genome of, say, Woody Allen differ from that of Stone Cold Steve Austin.

Even at its inception, the creators of the Human Genome Project suspected that it would transform biology, vaulting it past physics as the hot science. But at the moment of its creation, the project was an unwanted child. Charles DeLisi, newly arrived at the Department of Energy, was in charge of research into the biological effects of radiation. In October 1985, he was reading a government report on technologies for detecting heritable mutations, such as those in the survivors of Hiroshima. It hit him: given the slow pace at which biologists were deciphering genes, which you need to do in order to assess mutations, they would finish... oh, about when humans had evolved into a new species. "We just weren't going to get there," says DeLisi. So he dashed off memos, ordered up reports, begged scientists to serve on planning committees--and got responses like "I don't want to spin my wheels" on a project that had little chance of happening.

For biologists and the genome, it was far from love at first sight. Critics pointed out that some 97 percent of the human genome--3.1 billion of the 3.2 billion A's, T's, C's and G's--does not spell out a gene. Why bother sequencing this "junk" DNA, whose presence no one can explain, especially when there was no known way to tell what was junk and what was a gene? But when a panel of leading scientists, including skeptics, unanimously endorsed the project in 1988, and it wrested funding from Congress, the Human Genome Project was out of the gate, headed toward a completion date of 2005 at a nice, sedate pace. It didn't last. In May 1998, gene-hunter extraordinaire J. Craig Venter and his newly formed Celera Genomics vowed to trounce the public project by finishing the human genome sequence in just three years. That made Francis Collins, director of the National Human Genome Research Institute, scramble. His labs had sequenced less than 3 percent of the genome at the original halfway point, so he ordered everyone to forget about the double-checking and the exploring of cool scientific puzzles and just churn out the *#@*ing A's, T's, C's and G's. It worked. In October 1998 Collins announced that his team would have a rough draft in 2001; in March 1999 he pushed it to this spring.

What will it mean to know the complete human genome? Eric Lander of MIT's Whitehead Institute compares it to the discovery of the periodic table of the elements in the late 1800s. "Genomics is now providing biology's periodic table," says Lander. "Scientists will know that every phenomenon must be explainable in terms of this measly list"--which will fit on a single CD-ROM. Already researchers are extracting DNA from patients, attaching fluorescent molecules and sprinkling the sample on a glass chip whose surface is speckled with 10,000 known genes. A laser reads the fluorescence, which indicates which of the known genes on the chip are in the mystery sample from the patient. In only the last few months such "gene-expression monitoring" has diagnosed a muscle tumor in a boy thought to have leukemia, and distinguished between two kinds of cancer that require very different chemotherapy. Soon, predicts Patrick Brown of Stanford University, expression analysis will distinguish prostate cancers that kill from prostate cancers that don't, neurons in a depressed brain from neurons in a normal brain--all on the basis of which genes are active.

Humankind's history is also written in its DNA. "Rare spelling differences in DNA can be used to trace human migrations," says Lander. "Scientists can recognize the descendants of chromosomes that ancient Phoenician traders left behind when they visited Italian seaports." Genetic data support the oral tradition that the Bantu-speaking Lemba of southern Africa are descendants of Jews who migrated from the Middle East 2,700 years ago. And they suggest that 98 percent of the Irish men of Connaught are descended from a single band of hunter-gatherers who reached the Emerald Isle more than 4,000 years ago.

But decoding the book of life poses daunting moral dilemmas. With knowledge of our genetic code will come the power to re-engineer the human species. Biologists will be able to use the genome as a parts list--much as customers scour a list of china to replace broken plates--and may well let prospective parents choose their unborn child's traits. Scientists have solid leads on genes for different temperaments, body builds, statures and cognitive abilities. And if anyone still believes that parents will recoil at playing God, and leave their baby's fate in the hands of nature, recall that couples have already created a frenzied market in eggs from Ivy League women.

Beyond the profound ethical issues are practical concerns. The easier it is to change ourselves and our children, the less society may tolerate those who do not, warns Lori Andrews of Kent College of Law. If genetic tests in utero predict mental dullness, obesity, short stature--or other undesirable traits of the moment--will society disparage children whose parents let them be born with those traits? Already, Andrews finds, some nurses and doctors blame parents for bringing into the world a child whose birth defect was diagnosable before delivery; how long will it be before the same condemnation applies to cosmetic imperfections? An even greater concern is that well-intentioned choices by millions of individual parents-to-be could add up to unforeseen consequences for all of humankind. It just so happens that some disease genes also confer resistance to disease: carrying a gene for sickle cell anemia, for instance, brings resistance to malaria. Are we smart enough, and wise enough, to know how knocking out "bad" genes will affect our evolution as a species?

From the inception of the genome project, ethicists warned that genetic knowledge would be used against people in insurance and employment. Sorting out whether this is happening is like judging whether HMOs provide quality care. Systematic surveys turn up few problems, but horror stories abound. One man underwent a genetic test and learned that he carried a marker for the blood disorder hemochromatosis. Although he was being success- fully treated, his insurer dropped him on the ground that he might stop treatment and develop the disease. Another had a job offer withdrawn for "lying" during a pre-employment physical. He was healthy, but carried a gene for kidney disease. And last December Terri Seargent, 43, was fired from her job as an office manager after she tested positive for the genetic disease that killed her brother. She began receiving preventive treatments. When her self-insured employer got the first bill, she was fired.

So far 39 states prohibit, at least in part, discrimination in health insurance based on genetic tests; 15 have some ban on discrimination in employment. But many of the laws have loopholes. (One of the 15 is North Carolina, where Seargent lives.) Employers still, apparently, want genetic information about their workers. A 1999 survey by the American Management Association found that 30 percent of large and midsize firms obtain such information on employees. Seven percent use it in hiring and promotions. "It is still possible to have information about your genome used to take away your health insurance or your job," says Collins. "As yet, we have not seen effective federal legislation [to prevent this]. With genes getting discovered right and left, the opportunities for mischief are on an exponential curve."

Perhaps the greatest unknown is how the completion of the Human Genome Project--not just getting C's, G's, T's and A's, but learning the function of every gene--will shape our views of what we are. There is a great risk of succumbing to a naive biological determinism, ascribing to our genes such qualities as personality, intelligence, even faith. Studies of twins have already claimed (to great criticism, but claimed nonetheless) that genes even shape whether an individual will favor or oppose capital punishment. "We do ascribe some sort of quasi-religious significance to our DNA," says Collins. "We have a tendency to be more deterministic than we should." For now, the power, and the limits, of the genome can only be guessed at. The stage is set. The players are ready. After millions of dollars and millions of hours, the curtain is rising on what our children will surely, looking back in awe, see as the dawn of the century of the genome.

Comments