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June 27, 2000
READING THE BOOK OF LIFE
Now, the Hard Part: Putting the Genome to Work
By NICHOLAS WADE
he human genome is in hand. The set of instructions embodied in the ancient chemical deoxyribonucleic acid, at least 3.5 billion years in the making, has been made fully visible for the first time.
The manual with the specifications for the human species comes in 24 tapes of DNA, one for every chromosome, each carrying one long, punctuation-free sentence in evolution's four-letter programming code. On first inspection, these ancient texts are as incomprehensible as a message from another planet.
And the genome, as any message from another world, will surely change this one when its full meaning is understood.
Although exploration of the genome has already begun, it will be decades before every detail is thoroughly known.
The first practical impacts will be in health. The genome is widely expected to revolutionize the practice of medicine. Its sequence is already being mined for the levers of the body's own communications system, including the signals that direct cells to repair damaged tissue and fight off invaders. The use of these signals as drugs may develop into a new mode of therapy, one that Dr. William Haseltine, president of Human Genome Sciences, has termed "regenerative medicine."
Another predicted advance, though not so immediate, is that of personalized medicine -- treatment and preventive programs that are tailored to the individual based on a genomic analysis.
But the genome's writ reaches beyond medicine and will in time redefine knowledge of ourselves, our history, our innate capacities and our relationship to the rest of creation.
The conditions of human existence, the reach of human abilities, the purpose of life -- at least in a biological sense -- have boundaries that are engraved in the genome's gnomic text.
In defining the human species, the genome assumes distinctive flourishes in the major ethnic groups that developed as humans spread throughout the world, and specifies the genetic endowment of individuals. All individuals, save identical twins, are unique because their genomes are one of a kind. These underlying differences, for good and for ill, can now be spelled out for the first time. In making the announcement yesterday at the White House, President Clinton emphasized the similarities, rather than the differences, inherent in the results.
"In genetic terms all human beings, regardless of race, are more than 99.9 percent the same," Mr. Clinton said. "Modern science has confirmed what we first learned from ancient faiths. The most important fact of life on this earth is our common humanity."
For the many who are fascinated by their origins and family history, the human genome will provide answers. Already a company that is called Oxford Ancestors (www.oxfordancestors.com) offers to tell people which of 30 founding human lineages they belong to, based on their DNA.
Less beneficial may be the power of genetic differences, even entirely inconsequential ones, to divide or be cited as the justification for division and discord. "Most geneticists wax euphoric that so many of our genes are in common, that the genome map will show us to be a happy band of brothers and sisters," says Dr. Arthur L. Caplan, an ethicist at the University of Pennsylvania. "I doubt it."
Dr. Caplan fears people "will use this information to bolster racial and ethnic prejudices and other exclusivity groupings they believe in."
The genome, once interpreted, is knowledge that will provide the means to change the human genetic inheritance, usurping control of human biological destiny from the blind forces of natural selection and random change that have shaped it up till now.
In principle, it may be possible to correct disease-causing genes, even design a genome optimized for health and longevity. Whether to try to improve the human genetic allotment, at the risk of changing human nature as well, will not be a straightforward choice.
"There is no doubt that knowledge about different alleles will create the temptation to optimize one's offspring in terms of their genetic endowment," said Dr. Robert Weinberg of the Whitehead Institute in Cambridge, Mass., referring to the different forms one gene may take in different people.
Discovery of the genes that may underlie intelligence, for example, would open "a whole Pandora's box of possibilities, where someone like myself is no more qualified than someone with a minimal understanding of genetics to make ethical and moral choices," Dr. Weinberg said.
"This has to be a societywide debate," he said, "not one involving just geneticists or bioethicists."
Prime Minister Tony Blair of Britain, who shared the announcement with Mr. Clinton, agreed. "We, all of us, share a duty to ensure that the common property of the human genome is used freely for the common good," he said. "To ensure that the powerful information now at our disposal is used to transform medicine, not abused, to make man his own creator or invade individual privacy."
Annotating the Genome
Biologists face years of preparatory work in understanding the various levels of the genome's operation.
Possession of the genome will transform biology from a cottage industry, where one gene and protein were studied at a time, to a far different scale of operation in which all of a cell's genes, or all its proteins, are examined in parallel.
To generate and analyze the genomic information, a slew of new disciplines is emerging.
There is bioinformatics, or computational genomics, the art of writing computer programs to "annotate" the genome, which includes finding and analyzing all its genes. There is proteomics, a set of methods for examining all of a cell's many different proteins en masse, instead of one by one. There is pharmacogenomics, the matching of drugs to individuals on the basis of genetics.
With the human genome sequence now in hand, the first task is annotation, a word borrowed from computer programmers' practice of writing explanations alongside the major routines in a piece of software. The genome is biological programming, but evolution has neglected to provide even the punctuation to show where genes stop and start, let alone any helpful notes as to what each gene is meant to do.
The lack of punctuation makes the genes very hard to identify. Each gene is broken into several separate parts, known as exons, and the exons are strung out along the ribbon of DNA so sparsely that they account for only 3 percent of the genome's three billion letters.
Human cells have no trouble spotting the genes and regularly make copies of active genes. Biologists have learned how to capture these copies and analyze fragments of them.
By comparing the sequence of DNA letters in each part of the genome with a library of these fragments, annotators can pick out many of the exons.
Once a gene has been identified, annotators can often guess what it does by comparing its sequence of DNA letters with that of genes whose function is already known. The genomes of many bacteria and two animals (the roundworm and the fruit fly) have already been sequenced and annotated, and the roles of many of their genes have been identified.
Because of the unity of evolution, the sequence of every human gene is recognizably similar to the equivalent gene in other organisms.
Even more useful for interpreting the human genome will be that of the mouse, whose genome is now being deciphered by a public consortium of academic centers and the Celera Genomics Group of Rockville, Md., the two groups that have been working to decode the human genome.
Indeed the best way of finding the human genes may be simply to lay the human and mouse genomes side by side and look for places where the sequence of DNA letters is similar.
Biologists expect that the DNA sequence in the genes will have stayed much the same in the 100 million years since the two species shared a common ancestor but that the rest of the DNA will be different.
In the organisms whose genomes have been decoded so far, about a third of the genes are novel, with no matches in the databases. The mouse will help assign roles to novel human genes too because its counterpart genes can be deleted to create strains of "knock-out" mice.
Knock-out mice often reveal by their defects the natural functions of the gene they lack.
Proteins and Cells
The role of most genes is to make specific proteins, which are the working parts of human cells. Depending on the nature of its string of subunits, which are specified by its gene, a protein can serve a structural purpose, like a collagen fiber, or catalyze some chemical reaction important to the cell's metabolism.
Although many proteins of interest have been studied in great detail, the annotated genome will provide for the first time a comprehensive parts list of all the proteins the body makes.
Defects in these working proteins, caused by mutations in their parent genes, are responsible for much of the burden of human disease.
Understanding the role of every human protein -- proteomics -- will be one of the goals of the post-genome era.
The sequence of a protein, meaning the composition of its subunits, can be predicted from the sequence of DNA letters in its parent gene, but many proteins are further processed by the cell in ways that cannot yet be predicted.
Another initiative made possible by the genome is the complete understanding of the human cell. Thousands of genes may be active in a cell at any time, and the cast of players changes when the cell performs different roles, like responding to a hormone or slipping into cancerous activity.
Until recently it has been out of the question to study so many genes simultaneously. But new instruments known as gene expression chips allow researchers to track which of a cell's genes are active.
Gene expression chips are made in different ways but all require prior knowledge of the genes' DNA sequence, now available from the genome.
The chips may also help elucidate the differences between the 220 known cell types of the human body.
Although every cell possesses its own full copy of the genome, each type is thought to use only its own special subset of the genes, the rest being permanently switched off.
The body is a kind of repressive socialist state where every cell is equal but each must respond precisely to collective authority or receive orders to self-destruct. The genome is the authority's archive, containing the plans for each type of cell, the master program for generating a 10-trillion-celled organism from a single egg, and the life cycle instructions that guide it from birth to adolescence and maturity.
Tracking Human Variations
In parallel with finding all the genes in the genome, biologists will also try to track the major variants in DNA sequence found in the human population. Any two individuals differ on average in one nucleotide, or DNA unit, in every thousand.
These one-unit changes are known as single nucleotide polymorphisms, or SNP's, and are a principal source of human genetic variation.
Analysis of SNP's, or "snips," should help track down the variant genes that contribute to disease.
Many common diseases, like diabetes and heart disease, are thought to be caused by several variant genes acting together. Because each variant makes only a small contribution to the disease, these genes have hitherto been particularly hard to identify.
"I truly feel this is going to revolutionize medicine because we are going to understand not only what causes disease but what prevents disease," said Dr. Stephen T. Warren, a medical geneticist at Emory University in Atlanta and editor of The American Journal of Human Genetics.
"We will understand the mechanism of disease sufficiently to do rational therapy. We will be able to predict who is at higher risk for particular disease and provide advice to individuals as to how best to maintain their health."
Ethical Implications
The ability to diagnose vulnerability to disease on a genomewide basis will multiply the quandaries already raised by the present level of genetic testing. Probably almost everyone possesses many gene variants associated with adverse health effects.
This information could be used to the individual's detriment, if not kept confidential, and could be psychologically devastating if diagnosis runs ahead of treatment and the physician has no therapy to offer.
Dr. Eric S. Lander of the Whitehead Institute has contemplated a "snip chip" that would diagnose all the major SNP's, or gene variants, found in the population.
Such information would hold considerable potential for forecasting an individual's medical fate.
These SNP chips are unlikely to be developed soon and their predictive powers should not be feared, said Dr. James Watson, president of the Cold Spring Harbor Laboratory on Long Island.
"I think young people are the ones who are afraid to see the future," Dr. Watson said. "Old people see the future and would like to reverse it."
Single nucleotide polymorphisms and other genetic elements are useful in a quite different dimension, that of tracking the movements of the earliest human populations within Africa and as they spread throughout the rest of the world. By selecting SNP's that arose in the course of this expansion, population geneticists can track genetic differences that are specific to particular continents and major ethnic groups.
Most of these SNP's lie in regions of the genome that do not code for genes and have no effect on the body.
Population geneticists know that all people are extremely similar to one another in genetic terms and believe that the similarities overwhelm the very minor differences that they are studying.
But others fear the differences may not be used so benignly.
Dr. Caplan, the University of Pennsylvania ethicist, believes geneticists underestimate both the appetite for this genetic information and its potential for misuse.
"People don't realize how important that drive is to understand ourselves," he said. "In most parts of the world we define ourselves by blood and kin, and those are just surrogates for genes."
But once the genetic kits have been developed to determine who is of American Indian ancestry, say, "It would not surprise me to see eligibility for casino gambling profits requiring a genetic test," Dr. Caplan said. "We could find people asking who is the 'real' Jew or black person or Serbian."
He also foresees SNP's being used in conjunction with brain scans to uncover genetic markers for personality traits like antisocial behavior.
"One of the big surprises for the man in the street will be how much of our behavior is hard-wired," Dr. Caplan said. "And the people involved in the mapping are medical people who don't spend much time thinking about the historical and social implications. So there will be lots of bombshells, some of them sadly revisiting some of the bigotry that has cycled around genetics for many years." The New Temptation
Like all powerful knowledge, the genome can be put to good and bad ends depending on how carefully the knowledge is used. The more harmful genetic variants are discovered, the more compelling the logic may seem of fixing the bugs in the genomic programming directly instead of treating the symptoms in each generation, a procedure called germ-line gene therapy.
The danger is hardly pressing: gene therapy applied to treat ordinary body cells has so far been a failure.
But in time the technique will doubtless work, and the knowledge may be developed to reprogram the human genome, perhaps to strip it of many known disease-causing and life-shortening SNP's.
Control of the genome would then fall to some extent under human direction, bringing benefits for health and longevity, but raising a risk of changing human nature in unintended and unwarranted ways.
The genome, the long-sought manual of evolution's biological programming, comes with no warning labels as to careful reading and cautious use.
Maybe neither is necessary.
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