Angier, Natalie. "A Pearl and a Hodgepodge: Human DNA," New York Times, 26 June 2000, p.


Angier, Natalie. "A Pearl and a Hodgepodge: Human DNA," New York Times, 26 June 2000, p.
1, A21.

The human genome, the sum of all genetic material encased in nearly every cell of the human
body, is very, very long - at least three billion chemical letters long, as many letters as you would
find in a thousand copies of an entire Sunday issue of The New York Times. The human genome
is pithy. The English alphabet has 26 letters; the Russian, 33 letters; and the Japanese, 1,850
symbols. Yet, with just four distinct characters at its disposal, four nucleic acids, 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 nongenes, 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 scientists, with their announcement that they have completed a so-called working draft of
the entire sequence of the human genome, 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 6enome 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 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," Dr. Collins said, "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 being
genetic clones.

Researchers want to talk about the medical miracles they expect 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 the species-wide homogeneity of humans.

Some scientists emphasize the genetic fraternity of humanity. Humans may be genomically
similar to mice and monkeys, but it turns out that people 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 ape

This discovery, scientists say, has profound implications for understanding the various human

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 existed between, say,
Africans and Europeans, or Asians and aborigines, they were likely to be literally skin-deep.

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

"Of course, prejudice does not require a rational basis, let alone an evolutionary one," they said
in the article. "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 for the most apt 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 said, "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 Edison 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 three billion chemical letters 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 on the meaning of the vast stretches of non-gene material in
the genome, the estimated 2.5 billion to 2.8 billion chemical letters that do not appear to take part
in the synthesis of proteins, which are the body's worker bees, the molecules that comprise the
body and keep it alive.

"More than 95 percent of our DNA is just there, and it's described as not functional," said C.
Robert Cloninger, who 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

"Not only aren't we the center of the universe," he said, "we're not even the center of our own
genome. We only have a small part of our own genome that's really us."

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.

"Even the genes that are there may be suboptimal," he said. "Many genes may have picked up
mutations that cause their protein products to work not quite as well as they could, but there
hasn't been selective pressure to weed out all mutations."

Another insight that emerges from a meditation on the human genome: 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.

"Nothing is simple, and everything depends on everything else," said Dr. Cloninger. 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 human portrait becomes. From studies
of twins and similar research, scientists had estimated that, as with schizophrenia, about half of
the observed variations in many personality traits were environmental in origin, and half were

But comprehending the genetic half is now complicated by the fact that it is 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 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 percent or 30 percent, as one might expect,
but to 10 percent or less. The three genes 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.