June 26, 2000

READING THE BOOK OF LIFE

The Human Genome Abounds in Complex Contradictions

By NATALIE ANGIER

	Related Articles • The Human Genome Project Video • The Composition of Life narrated by Nicholas Wade, science reporter, The New York Times. (Requires Macromedia Flash Plugin) 3D Interactive Images • DNA Replication Process (Requires Hypercosm Player) • The Scale of DNA (Requires Hypercosm Player) Biographies • Francis Collins: Dedicated Researcher, Family Man Heads Public Project • Craig Venter: A Maverick Making Waves Chronology • Timeline: Journey to the Genome Glossary • Genetic Terms Forum • Join a Discussion on DNA Research
	ADD YOUR THOUGHTS
	The Genome Project What are the implications of a decoded human genome? Add your thoughts and see what other readers are saying in Abuzz. Predict the uses humankind will find for this knowledge. Compare this achievement to other milestones in science.

he human genome, the sum of all genetic material encased in nearly every cell of the human body, is very, very long -- at least 3 billion chemical letters long, as many letters as you'd find in 10,000 copies of the Sunday New York Times.

The human genome is pithy. The English alphabet has 26 letters, the Russian 33 letters, and Japanese 1,850 symbols. Yet with just four distinct characters at its disposal, four nucleic acid bases, the human genome has given rise to the creators of every language uttered, every ballad sung, every Pokemon card traded.

The human genome is a pigsty, bulging with non-genes, ex-genes, freeloader genes, viral detritus, pocket lint and chewing gum.

All but a few percent of it appears to be doing nothing at all.

The human genome is a pearl, a model of high performance and reliability. Millions of times a year, egg genome meets sperm genome, and the result is a human baby, its parts all in place, its brain a universe of love and meaning.

In short, the human genome exults in contradictions.

And with their announcement that they have completed a so-called working draft of the entire sequence of the human genome, scientists must traffic in a few contradictions of their own.

They rightly regard the sequencing of the genome as a major scientific landmark.

"This is a milestone in biology unlike any other," said Francis S. Collins, director of the National Human Genome Research Institute.

"We only have to do this once, reading out the sequence of our own instruction book, and here we are on brink of it."

At the same time, scientists know that the great bulk of their work in deciphering that sequence has yet to be done.

"Complexity is the word on everybody's lips these days when they see what the genome really looks like," said David Baltimore, the molecular biologist and Nobel laureate who is president of the California Institute of Technology. "We've got another century of work ahead of us, to figure out how all these things relate to each other." Though scientists underscore the importance of their accomplishment by calling the genome a "portrait of who we are," they quickly append that people are not, and never will be, mere products of their genes.

"One of my concerns is that as we begin to glimpse some of the biological contributions to certain personality traits, in people's minds those contributions will loom larger than they should," said Dr. Collins, "and the notion of genetic determinism will gather further momentum that it doesn't deserve."

Even in the case of a seemingly familial disease like schizophrenia, for example, unknown environmental factors still loom large, which is why if one identical twin comes down with the disorder, the other twin has only a 50 percent chance of suffering the same fate -- despite their being genetic clones of each other.

Researchers want to talk about the many medical miracles that are sure to come from a better knowledge of the human genome.

They don't want to promise any cure or palliative too soon. Yet they feel inspired to let their imaginations go, in loftiness and gravitas, as they fantasize about what the sequence may reveal, and what it may forever conceal.

For some, the emerging details of the genome sequence are most fascinating for what they say about the fraternity between the human species and all other creatures on earth.

"Looking at the genome, and taking it as a kind of image of who we are, places us squarely with the rest of nature," said Jon Seger, an evolutionary biologist and geneticist at the University of Utah in Salt Lake City.

"You can see the same genes in flies, worms, monkeys mice and people. It's evolution laid out for all to see. There's nothing peculiar or distinctive about us."

Except, perhaps, for our species-wide homogeneity.

Some scientists emphasize the genetic fraternity of humanity. We may be genomically similar to mice and monkeys, but it turns out that we are extraordinarily similar to each other: there are far fewer genetic differences, or polymorphisms, among different peoples, and populations of peoples, than are observed in individual members of other species, including our ape relatives.

This discovery, scientists say, has a profound implications for our understanding of the various human "races." Kelly Owens and Mary-Claire King, geneticists at the University of Washington in Seattle, argued last year in the journal Science that whatever genetic differences exist between, say, Africans and Europeans, or Asians and Aborigines, they are likely to be literally skin-deep.

The researchers describe how the recent analysis of the so-called melanocortin-stimulating hormone receptor gene, which is involved in melanin production, indicates that small discrepancies in this receptor gene appear to account for most of the variations observed in human skin and hair color and texture. If true, they write, then variation at a single, tiny genetic locus in charge of "superficial traits" has been "the cause of enormous suffering."

"Of course, prejudice does not require a rational basis, let alone an evolutionary one," they continue.

"But the myth of major genetic differences across 'races' is nonetheless worth dismissing with genetic evidence."

Scientists are also falling over each other for the prize of aptest analogy. What is the genome really? Is it the Book of Life, the Booklet of Life, a blueprint for a human being, an atlas, a master parts list? Martha Stewart's "How to Replicate?"

"There's a metaphor contest going on," said Harold Varmus, the former director of the National Institutes of Health and now president of Memorial Sloan-Kettering Cancer Center in Manhattan. "I've used quite a few of them myself." These days, he says, "I've decided we've got to get away from the idea of this as a blueprint. That doesn't convey what we have.

Because we don't just have the linear sequence, we have the physical parts, too."

In other words, he said, computer databases may hold the sequence information, the lineup of billions of A's, T's, G's and C's.

But the segments of the genome also exist in physical form, in the bellies of bacterial and yeast cells, which can be manipulated.

"The important thing is having pieces of DNA in your hand, and being able to figure out how they work by modifying and mutating them," he said. "That's where the game is now."

Which is why his favorite metaphor is a kid with a clock.

"You can take the clock apart, lay the pieces out in front of you, and then try to understand what makes it tick by putting it back together again," he said. Yet, as any would-be inventor soon discovers, it's easier to deconstruct than reconstruct. And scientists are having a difficult time making sense of even the most basic springs and gears of the genome. They don't yet know how many genes the 3 billion bases hold, for example, with estimates ranging from a low of 25,000 to a high of 150,000.

"The fashionable arguing over gene number," said David Page of the Whitehead Institute in Cambridge, Mass., who is studying the sequences of the human sex chromosomes, "reveals just how difficult it is to deliver anything concrete with the current state of sequence analysis."

Biologists also disagree vehemently with one another on the meaning of the vast stretches of non-gene material in the genome, the estimated 2.5 to 2.8 billion bases that do not appear to take part in the synthesis of proteins, which are the worker bees of the body, the molecules that comprise us and keep us alive.

"More than 95 percent of our DNA is just there, and it's described as not functional," said C. Robert Cloninger, who is studying personality and genomics at Washington University in St. Louis.

"But I don't know of anything in nature that's just laying around and is not functional."

But "functional" from whose perspective? The human body may not recruit the sequences for protein duty, but if the sequences do us no harm, natural selection may not have bothered to get rid of them.

Just as microscopic mites live on our cheek cells and eyelashes, so our genomes may carry a plethora of nucleic squatters.

"We can identify almost 50 percent of the genome as being so-called repetitive elements, or transposable elements, which are like little viruses that have taken advantage of the cell's machinery to replicate themselves," said Phil Green, a genomics researcher at the University of Washington.

"And the real number may be more like 95 percent of the genome, although a lot of these transposable elements are so ancient that they're hard to identify."

In Dr. Green's view, the notion of the human genome as a haven for transposable elements is humbling.

"Not only aren't we the center of the universe," he said, "we're not even the center of our own genome."

As he sees it, the human genome, compared to the genomes of fast-breeding organisms like bacteria, is "distinctly suboptimal. A bacterial genome is densely packed with genes, and there's almost no junk -- bacteria just can't afford the baggage." But because humans live long and reproduce slowly, and historically have existed in small numbers, their genomes have not been under competitive pressure to streamline themselves to Swiss-watch efficiency.

Still another insight into ourselves that emerges from a meditation on our genome is: not only is no man or woman an island, no gene is, either. Genes work in groups, and the performance and specific architecture of each intimately affects the performance of the others.

"It's the law of universal epistasis, which means that nothing is simple, and everything depends on everything else," said Dr. Cloninger. For a number of years, he and his colleagues have been working on genome scans to link personality traits with specific genes and genetic patterns.

The more they look, the more tangled the portrait of ourselves becomes. From the study of twins and similar research, scientists had estimated that, as with schizophrenia, about half of the observed variations in many personality traits was environmental in origin, and half genetic.

But now comprehending the genetic half is complicated by the fact that it's not enough to tally up the impact on a trait of this, that and the other gene, said Dr. Cloninger. "You must consider the complex and nonadditive interactions between the different genes," he said.

For example, he and his colleagues have studied the trait called novelty seeking -- the thirst for new experiences -- and found it to be influenced by three genes: one involved in the brain's use of the neurochemical dopamine, another in the neurochemical serotonin, and a third in catecholamine production, part of the body's fight-or-flight response.

If two siblings share identical forms of all three of these genes, they turn out to correlate in their degree of novelty-seeking behavior by about 40 percent. But if just one of the three genes differs in form between the siblings, the correlation drops, not to 20 or 30 percent, as one might expect, but to 10 percent or less.

The three genes clearly work as a tightly knit team, together with other tightly knit teams that have yet to be discovered.

"We tend to like to think in terms of separate things operating causally in linear sequence," said Dr. Cloninger.

"But that's not an accurate picture of the way biology works."

So maybe another metaphor for the human genome is a human dream: rich with significance, personal yet universal, stuffed with nonsense, all out of order yet infused with its own mad logic.