[Paleopsych] NYT Mag: The Genome in Black and White (and Gray)

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The Genome in Black and White (and Gray)
New York Times Magazine, 4.10.10
By ROBIN MARANTZ HENIG

Imagine that you have heart failure. What can medicine do
for you? It depends: are you white or black? If you're
white, your doctor may prescribe one of the drugs that seem
to ease the symptoms, maybe a beta-blocker or an ACE
inhibitor. And if you're black, your doctor may still
prescribe those drugs, but they might not really help.

That's about to change. In the not-too-distant future, if
you're black and have heart failure, drug-company
researchers predict you'll be able to go to the doctor and
walk out with a prescription tailor-made for you. Well, not
tailor-made, exactly, but something that seems to work in
people a lot like you. Well, not a lot like you, exactly,
except that they're black, too. In this not-too-distant
future, if you're black, your doctor will be able to
prescribe BiDil, the first drug in America that's being
niche-marketed to people of a particular race -- our first
ethnic medicine.

BiDil, expected to be approved early next year by the Food
and Drug Administration, is on the leading edge of the
emerging field of race-based pharmacogenomics. It signals a
shift in perception, a new approach to medicine that has at
its core an idea at once familiar and incendiary: the
assumption that there are biological differences among the
races.

BiDil is also a feat of creative repackaging. Five years
ago, the F.D.A. rejected it for use in the general
population because it was found to be ineffective in the
treatment of heart failure, a common complication of
cardiovascular disease that affects some five million
Americans and leads to 300,000 deaths a year. But in 2001,
the manufacturer, NitroMed, asked permission to test BiDil
exclusively in blacks, whose heart failure tends to be more
severe and harder to treat. The company reasoned that the
drug's effect on nitric-oxide deficiency, more common in
black heart-failure patients than in nonblacks, might make
it especially suited to them. With the collaboration of the
Association of Black Cardiologists, NitroMed embarked on a
large clinical trial involving more than 400 black women
and 600 black men, all of whom had heart failure.

Last summer, investigators called an early end to the study
because they thought BiDil was so effective that it would
be unethical to continue to deny it to people in the
control group. Thus, a drug that had been deemed
ineffective in the population at large seemed to work so
well in one racial subgroup that the scientists thought
everyone in that subgroup should get it.

Pharmacogenomics has for years been touted as the ultimate
benefit of the genomics revolution. But to many, this
revolution has a troubling side. For race-based niche
marketing to work, drug developers first will have to
explore the ways that blacks, whites, Asians and Native
Americans are biologically different. And the more they
explore and describe such differences, critics say, the
more they play into the hands of racists. Even the
broad-minded might inadvertently use such information to
stigmatize, isolate or categorize the races. Could it be
that this terrain is too dangerous to let anyone, no matter
how well meaning, try to navigate it?


In two weeks, a major scientific journal, Nature Genetics,
will publish a special issue on the genetics of race. This
comes on the heels of several conferences on the subject,
most recently one held last Monday by Johns Hopkins
University, as well as editorials in the science press,
including one in the Journal of the American Medical
Association just last week. All of these forums pose some
thorny questions: Can genes tell us anything meaningful
about race, beyond the obvious connection to things like
skin color? Do the races differ biologically in terms of
drug response or disease susceptibility? Can genes say
anything about how ''race'' -- which is itself all but
impossible to define -- is related to complex traits like
behavior and intelligence?

Looking for biological determinants of race is nothing new.
It has a potent history, with poisonous associations dating
back to the early days of eugenics. But contemporary
science has given these efforts a new respectability. In
the wake of the completion of the Human Genome Project,
geneticists are trying to arrange pieces of the genome like
a Rubik's Cube, searching for patterns of variation that
align into some useful matrix. Their goal is to generate
information that will help prevent and treat common
diseases. But in the process, they're generating
information that might also lead to declarations about the
biological meaning of race.

The new interest in racial genetics comes at a time when
the softer sciences, like anthropology and sociology, have
declared that race is a cultural construct, without any
biological significance. The social designations go back at
least to the 19th century, when humans were generally
divided into five races that were loosely tied to skin
color; this has lingered as the basic grammar of race even
into the 21st century. But in a 1998 position paper, the
American Anthropological Association called race a social
invention, with a variety of pernicious consequences
ranging from day-to-day bigotry to the Holocaust. Racial
beliefs are myths, the anthropologists wrote, and the myths
fuse ''behavior and physical features together in the
public mind, impeding our comprehension of both biological
variations and cultural behavior, implying that both are
genetically determined.''

Geneticists, too, have gone on record as saying that race
has no biological significance. ''The concept of race has
no genetic or scientific basis,'' said J. Craig Venter in
June 2000, standing beside President Bill Clinton to
announce the completion of the first draft of the human
genome sequence. Venter was at the time the president of
Celera, the private company that competed with the National
Human Genome Research Institute, a publicly financed
international team, to sequence the genome. (It was
declared a tie.)

Venter's scientific rival, Francis S. Collins, the head of
the genome institute, stood at the podium that day on
Clinton's other side -- two male, middle-aged white
scientists saying we're all brothers and sisters under the
skin. Collins made much of the fact that humans share 99.9
percent of their genome with one another -- and that the
remaining 0.1 percent probably codes for variations, like
skin color, that are for the most part biologically
insignificant. In fact, there is more variation within
races than between them. A few months later he made the
point more informally, playing his electric guitar and
regaling his co-workers with a musical ditty he had written
to the tune of Woody Guthrie's ''This Land Is Your Land'':


''We only do this once, it's our inheritance,
Joined by
this common thread -- black, yellow, white or red,
It is our family bond, and now its day has dawned.
This
draft was made for you and me.''

Today, the two men have parted company on this narrow strip
of common ground. Venter says he still believes the genome
is colorblind. ''I don't see that there's any fundamental
need to classify people by race,'' he says. ''What's the
goal of that, other than discrimination?''

But Collins sees the matter differently now. Maybe in that
0.1 percent of the genome there are some variations with
relevance to medicine, he says. And maybe identifying them
could help reduce health disparities among the races. He is
using his bully pulpit at the genome institute to urge
scientists to study whether these variations can, or
should, be categorized according to racial groupings.

''It's always better to face up to a controversial
scientific issue, to tackle the issue head on and not run
away from it,'' Collins says. ''And if we don't do it,
someone else will -- and probably not as well.''

One reason to focus on the genetics of race is to try to
make a dent in health disparities: the frustrating gap in
the health status of different racial groups that
stubbornly refuses to close or even to be adequately
explained. In terms of national measures of physical
well-being -- life expectancy, infant mortality, some
chronic diseases -- blacks tend to do worse than whites.
Many factors account for this health gap, including the
fact that minorities suffer disproportionately the effects
of low income, lack of health insurance, poor diet,
exposure to environmental toxins, discrimination and
stress. But some geneticists think that at least some part
of health disparities can be explained by genes. Social
scientists think genetic explanations might obscure the
all-too-real social and economic causes.

Take hypertension, which affects black Americans at a
higher rate than white Americans. Geneticists try to
explain this difference in terms of genes: genes for salt
retention, genes for low levels of renin in the kidneys.
But a classic study found that one thing that correlated
most strongly with level of blood pressure was,
surprisingly, skin color. Among black subjects of low
socioeconomic status, the darker the skin, the higher the
blood pressure. Social scientists' explanation is that
people with darker skin are subject to greater
discrimination, and therefore to greater stress.

''If you follow me around Nordstrom's, and put me in jail
at nine times the rate of whites, and refuse to give me a
bank loan, I might get hypertensive,'' says Troy Duster, a
professor of sociology at New York University and at the
University of California at Berkeley. ''What's generating
my increased blood pressure are the social forces at play,
not my DNA.''

But pharmacogenomics researchers presume that health
disparities can be addressed, at least in part, by
exploiting tiny group differences in DNA. If the BiDil
experience pans out, other companies are likely to try
their own versions of race-based drug development. Some
candidates already exist. People known as slow acetylators,
for instance, take a longer time than fast acetylators to
clear certain drugs from the liver. This means they're more
likely to build up toxic levels of some common drugs. The
proportion of slow acetylators in different racial groups
ranges from a low of 14 percent among East Asians to a high
of 54 percent among whites. Some whites, therefore, might
benefit from a different version of medications that are
cleared through the liver.

The ultimate goal of pharmacogenomics would be for
everyone's genome to be analyzed individually, so that
doctors could gauge how much of a medication, and which
type, is most likely to work for a specific patient. Even
the BiDil investigators are moving in that direction.
Michael D. Loberg, the president of NitroMed, says that the
company asked each participant in the BiDil trial for
permission to take a DNA sample and that he hopes to get a
total of at least 400 such samples. These will be
sequenced, he says, ''to see if there's some genetic marker
that predicts which of the trial patients responded to
BiDil favorably and which didn't.''

But at this point, geneticists cannot sequence individual
genomes in a cost-effective way. Until they can, they may
view race as a handy shortcut, a way to make some useful
generalizations about how an individual patient will fare
with a particular drug. But while using race this way might
increase the odds of finding the right medication, it is an
imprecise method, a kind of roulette in which the physician
is making educated guesses based on probabilities.

The temptation of race-based medication is clear: it's
convenient for the investigator, and it suits the way drug
companies' products are sold. ''The mantra of
pharmacogenomics is that drugs will be fine-tuned for the
individual,'' Duster says. ''But individuals are not a
market. Groups are a market.'' And one typical way to
identify markets, in a country where skin color seems to
count for so much, is race.


In terms of our genes, we humans are all the same -- except
for the ways in which we're different. The human genome
comprises 3 billion nucleotides, strung together in a
specific order along the chromosomes. About 99.9 percent
are identical from one person to another, no matter what
that person's race, ethnicity, continent of origin or bank
account.

Among our 3 billion nucleotides, an estimated 10 million
are locations of common variations. Where most people will
have a nucleotide represented by the letter A, for
instance, a big group of people might have a T instead.
Elucidating where those spots are, and whether replacing a
T with an A has any clinical significance, are what
occupies today's geneticists.

The most common type of variants are called single
nucleotide polymorphisms, or SNP's (pronounced ''snips'').
Usually they occur in regions where the nucleotides seem to
be doing nothing. This means the SNP's don't have any
function, either, or at least none that has been discovered
yet; they're just there.

Still, SNP's tend to occur in different patterns in
different populations. Say there's a SNP on Chromosome 12
in which a person might have either an A or a T. At this
hypothetical SNP, 20 percent of Africans might have an A,
and 80 percent a T. At the same spot, the frequency might
be flipped in Europeans: 80 percent might have an A, while
only 20 percent have a T.

So while SNP patterns don't reveal anything about the
function of the genes, they can say something about an
individual's continent of ancestry -- and, by extension,
something about migration pathways through human history.
SNP's tend to be inherited in clusters, called haplotype
blocks. Like SNP's, varieties of haplotype blocks occur at
different frequencies in different regions of the world --
and that's how population geneticists have managed to
reconstruct the story of human migration.

The biggest variety of haplotype blocks occurs in Africa,
because modern humans arose there more than 150,000 years
ago, and variations have had the longest chance to accrue
simply because of random mutations. About 55,000 years ago,
a small group of modern humans, who carried in their
genomes a subset of the original haplotype varieties,
traveled to Australia; later, in sequence and timing that
are still a source of controversy among
paleoanthropologists, other small groups migrated to parts
of Europe, Asia and the Middle East.

As time went on, there were some evolutionary changes in
response to the new environments. In Northern Europe, for
instance, people carrying mutations for lighter skin color
thrived, probably because the scarcity of sunlight made
dark-skinned people especially susceptible to Vitamin D
deficiency and rickets. But most of the variations occurred
in the nonfunctional regions of the genome, with no effect
on an individual's appearance or health. All that the
variations did was allow geneticists, some 2,000
generations later, to assign a continent of origin to the
descendents of these original travelers based on the
descendants' DNA.

To the dismay of Troy Duster, several private companies are
now taking these findings about SNP's to a new level:
scanning the genome for variations that can say something
about an individual's race. Last year, a company called
DNAPrint Genomics made headlines by telling law-enforcement
officials in Louisiana that they'd been looking for a
serial killer of the wrong race. Eyewitnesses had offered
different accounts of the race of the suspect -- some
thought he was black, others white -- and authorities had
focused their search on white males between the ages of 25
and 35 based in part on an F.B.I. psychological profile.
But based on crime-scene specimens, DNAPrint said the
murderer was probably black -- in fact, the company said it
could detect 85 percent sub-Saharan African ancestry and 15
percent Native American -- and even gave an assessment of
his skin tone. When a black male was apprehended, his DNA
was found to match that at one of the crime scenes. He was
convicted of second-degree murder in August.

For some, this would be a story of science advancing police
work. But for people like Duster, the forensic use of
genetic markers raises troubling questions. Can a DNA
screen of a person's blood or hair really tell you anything
more than where his ancestors probably came from? Would it
lead to witch hunts based on some uncertain appraisal of
skin color? Would it be used, wrongly, to give a patina of
scientific authority to group prejudices?

Worried, Duster approached his friend and colleague,
Francis Collins, to suggest that Collins might want to use
his position at the genome institute to mount an
investigation into the genetics of race -- before the drug
manufacturers and genomics companies set the tone for the
public debate.

Collins says he was already thinking the same thing. The
two men approach the venture from different perspectives,
less because Collins is white and Duster is black than
because one is a geneticist and the other a sociologist. As
Duster sees it, race is a relationship, largely dependent
on social context. Take a Tutsi and a Hutu and set them
down in Los Angeles, he says, and they're both the same
race, both black. But put them back in Rwanda, and they're
two different races, different enough to slaughter each
other.

There may be biological dimensions to race, Duster says,
but that doesn't take away from his belief that race should
be understood as a social construction. ''The myth is that
somehow the biology is real and the social forces are
unreal,'' he says. ''In fact, the social forces can feed
the biological forces.''

Collins, for his part, recognizes that social forces
explain many of the observed differences among the races --
but says he thinks something else might be involved as
well. ''We need to try to understand what there is about
genetic variation that is associated with disease risk,''
he says, ''and how that correlates, in some very imperfect
way, with self-identified race, and how we can use that
correlation to reduce the risk of people getting sick.''

Taking up Duster's challenge, Collins knew, meant walking
into a quagmire. A decade earlier, another top government
scientist lost his job by discussing the genetics of urban
violence (though his case was egregious: he compared young
black men with male monkeys). But Collins said he believed
the idea, risky as it was, was worth pursuing because it
offered the best chance of converting new genomic
information into something of medical significance.

The genome institute, part of the National Institutes of
Health in Bethesda, Md., currently spends some $31 million
for studies into human genetic variation. The institute is
also a major contributor to the Hap Map project, a
$110million international collaboration that by late 2005
will have put together a coherent almanac of human
variation using haplotype blocks. The Hap Map is meant to
help scientists in their search for common disease-causing
genes, but in the process it will also generate new
information about the specific ways in which populations
from the places being studied -- China, Japan, Nigeria and,
in the United States, Utah -- differ from one another
genetically.

Collins is clean-cut and homespun, emphatically tall, with
a fringe of sandy hair that makes him look younger than his
54 years. He exudes an aw-shucks earnestness when he talks
about his favorite topics, which include his rebirth as a
Christian during his medical training. Each time he makes a
scientific discovery, he says, he gets a glimmer of insight
into the workings of the mind of God.

But for all his personal sincerity, Collins is finding that
some of his allies are wary of this newest undertaking.
They know that even a man with the best intentions can muck
it up when it comes to race.

While writing this article, I took a trip to the Holocaust
Memorial Museum in Washington. I wanted to see the museum's
current exhibit about eugenics, the scientific movement of
the early 20th century that looked for evidence of
biological racial differences to promote creation of a
''fitter'' species. In a very short time, eugenic ideas
were subverted to support Nazi policies of ethnic cleansing
and racial extermination. Since last spring, when Collins
called to suggest that I might be interested in his
institute's plan to investigate the genetics of race, I had
talked to more than two dozen scientists about the issue.
Uncomfortable questions about where such inquiries could
lead underscored a number of those conversations -- the
sort of questions that, as a white person in America today,
I don't usually have to confront. I went to the Holocaust
museum looking for resonances.

How disturbing it was to see that the activities of the
early eugenicists resembled, from a certain perspective,
the activities of specimen collectors of the early days of
zoology -- as well as those of genomics researchers today,
going around collecting specimens of human variation. The
eugenicists engaged in some straightforward scientific
studies that can seem almost harmless, even ordinary. And
that's what makes it so troubling to look back.

With rulers, calipers, charts of eye shapes and elaborate
reconstructions of family trees, eugenicists of the 1920's
and 30's took great care to describe physical
characteristics of different racial groups. They
photographed subjects, measured their noses and mouths,
made plaster casts of their faces and documented variations
in facial features and head proportions. Is it possible
that the difference between then and now is that the tools
have changed -- that instead of using calipers and scales,
scientists now use DNA-sequencing machines?

Connecting contemporary genomic studies to the Holocaust is
too glib, of course, and it obscures one crucial point:
that the anthropometrics of the early eugenics movement
turned ugly once fanatics perverted the information. But
the exhibit is a sobering reminder of how easy it would be
to travel down that path. ''I think our best protection
against that -- because this work is going to be done by
somebody -- is to have it done by the best and brightest
and hopefully most well attuned to the risk of abuse,''
Collins says. ''That's why I think this has to be a
mainstream activity of genomics, and not something we avoid
and then watch burst out somewhere from some sort of goofy
fringe.''

Collins doesn't quote the Bible often -- he tends to
neither hide nor flaunt his religious faith -- but he
quotes it now. He chooses a line

from the New Testament's Book of John, in which Jesus says
to his disciples, ''And you shall know the truth, and the
truth shall set you free.''


Reducing health disparities and catching criminals are
serious reasons for pursuing the genetics of race, but
there's also a small but growing trend toward something its
practitioners call ''recreational genomics.'' To satisfy
curiosity about their heritage, more and more people are
experiencing race-based genomics as a mail-in test, for
which they pay up to $400, that will tell them how much of
their genome is black, white, American Indian or Asian.
These companies go beyond old-fashioned genealogical
services, the kind that involve scouring archives and
huddling over microfiche machines, and trace genetic
linkages back many generations to a particular geographic
location. Critics say that what these companies are doing
sanctifies the genetic distinctions among racial groups, as
if the question of whether race has a biological basis has
been settled.

The services, with names like GeoGene, AncestryByDNA and
Roots for Real, begin by asking clients to mail in a cheek
swab to get some stray skin cells from which DNA can be
extracted. Though the process may feel like a parlor game,
the results can be deeply affecting. One of those who
traced his genetic lineage through a company called African
Ancestry is Andrew Young, former United States ambassador
to the United Nations and now chairman of an organization
called Good Works International.

Young was looking for information about his maternal
lineage only; he assumed, he told me, that his paternal
lineage would be ''contaminated'' with white DNA, a bitter
memento of slave rape that he didn't feel ready to
confront. (According to Rick Kittles, a cofounder of
African Ancestry and a geneticist at Ohio State University,
about one-third of blacks who do a paternal lineage
analysis, himself included, find that there is European DNA
somewhere in their past.)

When a black client discovers that there's white in his
genome, the results can be shattering. Last year, the ABC
News program ''Nightline'' profiled a 50-year-old
California man who had assumed his whole life that he was
black. But a recreational genomics analysis by DNAPrint
Genomics indicated that his genome was 57 percent of what
the company called Indo-European, 39 percent Native
American, 4 percent East Asian -- and zero percent African.
So what is this man: the race he has always thought himself
to be, or the race his genome says he is?

Young's reaction to his African Ancestry report is an
indication of how much weight we ascribe to genes, how much
we believe our DNA reflects not only our racial identity
but our individual identity, too. When Young heard that the
company had traced his DNA back to what is now Sierra
Leone, he was disappointed because he considered Sierra
Leone to have a ''snobbish'' middle class. But the report
got much more specific: the people whose SNP pattern most
resembled Young's, it said, were from the Mende tribe.
Whether a few SNP matches can allow such precision is a
matter of debate, but it fit happily into Young's
self-image. Young, who got his start in the civil rights
movement, was raised on tales about the Amistad slave-ship
rebellion of 1839, for which the Mende were responsible.
''I always had a spiritual connection to these stories,''
he says. ''Now I have a genetic connection.''


So is there such a thing as race? It depends on whether
you're defining it in terms of culture or biology.
Culturally, there is no denying it. In the United States,
with its race-stained legacy dating back to slavery, the
government has tried for centuries to define a person's
race. The Census Bureau has been asking about race on its
forms since 1790, most recently giving individuals the
opportunity to check off more than one race if they so
desire.

But the more vexing question is whether there's such a
thing as race in terms of biology. Genetic variations do
seem to cluster differently for people with different
continents of origin, but is this race? And what does it
mean if it is -- or if it isn't? Do we need to agree on
whether race is a biological entity, since we can so
readily agree that it's a social one?

''Race is a reality in this country, no matter what the
genome tells us,'' says Vanessa Northington Gamble,
director of the National Center for Bioethics in Research
and Health Care at Tuskegee University. ''If I can't get a
cab in New York, it's because my skin is black. And I can't
hold up my DNA and say: 'Wait a minute! I'm just the same
as you!' ''

Some critics worry that the more we find out about genetic
differences among people of different racial groups, the
more such information will be misinterpreted or abused.
Already there are fears that the biological measures of
racial differences might lead to pronouncements about
inherent differences in such complex traits as
intelligence, athletic ability, aggressiveness or
susceptibility to addiction. Once such measures are given
the imprimatur of science, especially genomic science,
loathsome racist stereotypes can take on the sheen of
received wisdom.

Looking for racial genetic markers does indeed risk
creating categories that can get us in trouble. It bears
remembering, however, that the ''slippery slope'' argument
is itself a danger. Rather than abort a whole field of
research because it might bolster cranks and demagogues,
maybe one solution to our national angst over race is to
let scientists hunt down the facts -- facts that will no
doubt affirm, one way or another, that the human genome is
indeed our common thread.

Robin Marantz Henig is the author, most recently, of
''Pandora's Baby: How the First Test Tube Babies Sparked
the Reproductive Revolution.''

http://www.nytimes.com/2004/10/10/magazine/10GENETIC.html