DNA analysis /DNA as Destiny

DNA is the book of life. It’s also the book of death. In the future we’ll all be read cover to
cover. Here’s what it’s like to take the world’s first top-to-bottom gene scan.
By David Ewing Duncan
I FEEL NAKED. EXPOSED. As if my skin, bone, muscle tissue, cells have all been peeled back,
down to a tidy swirl of DNA. It’s the basic stuff of life, the billions of nucleotides that keep me
breathing, walking, craving, and just being. Eight hours ago, I gave a few cells, swabbed from
inside my cheek, to a team of geneticists. They’ve spent the day extracting DNA and checking it
for dozens of hidden diseases. Eventually, I will be tested for hundreds more. They include, as I
will discover, a nucleic time bomb ticking inside my chromosomes that might one day kill me.
For now I remain blissfully ignorant, awaiting the results in an office at Sequenom, one of scores
of biotech startups incubating in the canyons north of San Diego. I’m waiting to find out if I have
a genetic proclivity for cancer, cardiac disease, deafness, Alzheimer’s, or schizophrenia.
This, I’m told, is the first time a healthy human has ever been screened for the full gamut of
genetic-disease markers. Everyone has errors in his or her DNA, glitches that may trigger a heart
spasm or cause a brain tumor. I’m here to learn mine.
Waiting, I wonder if I carry some sort of Pandora gene, a hereditary predisposition to peek into
places I shouldn’t. Morbid curiosity is an occupational hazard for a writer, I suppose, but I’ve
never been bothered by it before. Yet now I find myself growing nervous and slightly flushed. I
can feel my pulse rising, a cardiovascular response that I will soon discover has, for me, dire
implications.
In the coming days, I’ll seek a second opinion, of sorts. Curious about where my genes come from,
I’ll travel to Oxford and visit an “ancestral geneticist” who has agreed to examine my DNA for links
back to progenitors whose mutations have been passed on to me. He will reveal the seeds of my
individuality and the roots of the diseases that may kill me — and my children.
For now, I wait in an office at Sequenom, a sneak preview of a trip to the DNA doctor, circa 2008.
The personalized medicine being pioneered here and elsewhere prefigures a day when everyone’s
genome will be deposited on a chip or stored on a gene card tucked into a wallet. Physicians will
forecast illnesses and prescribe preventive drugs custom-fitted to a patient’s DNA, rather than
the one-size-fits-all pharmaceuticals that people take today. Gene cards might also be used to
find that best-suited career, or a DNA-compatible mate, or, more darkly, to deny someone jobs,
dates, and meds because their nucleotides don’t measure up.
It’s a scenario Andrew Niccol imagined in his 1997 film, Gattaca, where embryos in a not-toodistant
future are bioengineered for perfection, and where genism — discrimination based on one’s
DNA — condemns the lesser-gened to scrubbing toilets.
The Gattaca-like engineering of defect-free embryos is at least 20 or 30 years away, but
Sequenom and others plan to take DNA testing to the masses in just a year or two. The prize: a
projected $5 billion market for personalized medicine by 2006, and billions, possibly hundreds of
billions, more for those companies that can translate the errors in my genome and yours into
custom pharmaceuticals.
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Sitting across from me is the man responsible for my gene scan: Andi Braun, chief medical officer
at Sequenom. Tall and sinewy, with a long neck, glasses, and short gray hair, Braun, 46, is both
jovial and German. Genetic tests are already publicly available for Huntington’s disease and cystic
fibrosis, but Braun points out that these illnesses are relatively rare. “We are targeting diseases
that impact millions,” he says in a deep Bavarian accent, envisioning a day when genetic kits that
can assay the whole range of human misery will be available at Wal-Mart, as easy to use as a
home pregnancy test.
But a kit won’t tell me if I’ll definitely get a disease, just if I have a bum gene. What Sequenom
and others are working toward is pinning down the probability that, for example, a colon cancer
gene will actually trigger a tumor. To know this, Braun must analyze the DNA of thousands of
people and tally how many have the colon cancer gene, how many actually get the disease, and
how many don’t. Once this data is gathered and crunched, Braun will be able to tell you, for
instance, that if you have the defective DNA, you have a 40 percent chance, or maybe a 75
percent chance, by age 50, or 90. Environmental factors such as eating right — or wrong — and
smoking also weigh in. “It’s a little like predicting the weather,” says Charles Cantor, the
company’s cofounder and chief scientific officer.
Braun tells me that, for now, his tests offer only a rough sketch of my genetic future. “We can’t
yet test for everything, and some of the information is only partially understood,” he says. It’s
more of a peek through a rudimentary eyeglass than a Hubble Space Telescope. Yet I will be able
to glimpse some of the internal programming bequeathed to me by evolution, and that I, in turn,
have bequeathed to my children — Sander, Danielle, and Alex, ages 15, 13, and 7. They are a
part of this story, too. Here’s where I squirm, because as a father I pass on not only the
ingredients of life to my children but the secret codes of their demise — just as I have passed on
my blue eyes and a flip in my left brow that my grandmother called “a little lick from God.” DNA is
not only the book of life, it is also the book of death, says Braun: “We’re all going to die, ja?”
Strictly speaking, Braun is not looking for entire genes, the long strings of nucleotides that
instruct the body to grow a tooth or create white blood cells to attack an incoming virus. He’s
after single nucleotide polymorphisms, or SNPs (pronounced “snips”), the tiny genetic variations
that account for nearly all differences in humans.
Imagine DNA as a ladder made of rungs — 3 billion in all — spiraling upward in a double helix. Each
step is a base pair, designated by two letters from the nucleotide alphabet of G, T, A, and C.
More than 99 percent of these base pairs are identical in all humans, with only about one in a
thousand SNPs diverging to make us distinct. For instance, you might have a CG that makes you
susceptible to diabetes, and I might have a CC, which makes it far less likely I will get this
disease.
This is all fairly well-known: Genetics 101. What’s new is how startups like Sequenom have
industrialized the SNP identification process. Andi Braun and Charles Cantor are finding thousands
of new SNPs a day, at a cost of about a penny each.
Braun tells me that there are possibly a million SNPs in each person, though only a small fraction
are tightly linked with common ailments. These disease-causing SNPs are fueling a biotech
bonanza; the hope is that after finding them, the discoverers can design wonder drugs. In the
crowded SNP field, Sequenom vies with Iceland-based deCode Genetics, American companies such
as Millennium Pharmaceuticals, Orchid BioSciences, and Celera Genomics, as well as multinationals
like Eli Lilly and Roche Diagnostics. “It’s the Oklahoma Land Grab right now,” says Toni Schuh,
Sequenom’s CEO.
The sun sets outside Braun’s office as my results arrive, splayed across his computer screen like
tarot cards. I’m trying to maintain a steely, reportorial facade, but my heart continues to race.
Names of SNPs pop up on the screen: connexin 26, implicated in hearing loss; factor V leiden,
which causes blood clots; and alpha-1 antitrypsin deficiency, linked to lung and liver disease.
Beside each SNP are codes that mean nothing to me: 13q11-q12, 1q23, 14q32.1. Braun explains
that these are addresses on the human genome, the PO box numbers of life. For instance, 1q23 is
the address for a mutant gene that causes vessels to shrink and impede the flow of blood — it’s
on chromosome 1. Thankfully, my result is negative. “So, David, you will not get the varicose
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veins. That’s good, ja?” says Braun. One gene down, dozens to go.
On the horizon: multi-disease genekits, available at Wal-Mart, as easy to use as home
pregnancy tests.
Next up is the hemochromatosis gene. This causes one’s blood to retain too much iron, which can
damage the liver. As Braun explains it, somewhere in the past, an isolated human community lived
in an area where the food was poor in iron. Those who developed a mutation that stores high
levels of iron survived, and those who didn’t became anemic and died, failing to reproduce.
However, in these iron-rich times, hemochromatosis is a liability. Today’s treatment? Regular
bleeding. “You tested negative for this mutation,” says Braun. “You do not have to be bled.”
I’m also clean for cystic fibrosis and for a SNP connected to lung cancer.
Then comes the bad news. A line of results on Braun’s monitor shows up red and is marked “MT,”
for mutant type. My body’s programming code is faulty. There’s a glitch in my system. Named ACE
(for angiotensin-I converting enzyme), this SNP means my body makes an enzyme that keeps my
blood pressure spiked. In plain English, I’m a heart attack risk.
My face drains of color as the news sinks in. I’m not only defective, but down the road, every
time I get anxious about my condition, I’ll know that I have a much higher chance of dropping
dead. I shouldn’t be surprised, since I’m told everyone has some sort of disease-causing mutation.
Yet I realize that my decision to take a comprehensive DNA test has been based on the rather
ridiculous assumption that I would come out of this with a clean genetic bill of health. I almost
never get sick, and, at age 44, I seldom think about my physical limitations, or death. This
attitude is buttressed by a family largely untouched by disease. The women routinely thrive into
their late eighties and nineties. One great-aunt lived to age 101; she used to bake me cupcakes
in her retirement home when I was a boy. And some of the Duncan menfolk are pushing 90-plus.
My parents, now entering their seventies, are healthy. In a flash of red MTs, I’m glimpsing my own
future; my own mortality. I’m slated to keel over, both hands clutching at my heart.
“Do you have any history in your family of high blood pressure or heart disease?” asks Matthew
McGinniss, a Sequenom geneticist standing at Braun’s side.
One gene seems to shield smokers from lung cancer. “That’s my favorite,” says the
doctor, a smoker. “I wonder what Philip Morris would pay for that.”
“No,” I answer, trying to will the color back into my face. Then a second MT pops up on the
screen — another high blood pressure mutation. My other cardiac indicators are OK, which is
relatively good news, though I’m hardly listening now. I’m already planning a full-scale assault to
learn everything I can about fighting heart disease — until McGinniss delivers an unexpected
pronouncement. “These mutations are probably irrelevant,” he says. Braun agrees: “It’s likely that
you carry a gene that keeps these faulty ones from causing you trouble — DNA that we have not
yet discovered.”
The SNPs keep rolling past, revealing more mutations, including a type-2 diabetes susceptibility,
which tells me I may want to steer clear of junk food. More bad news: I don’t have a SNP called
CCR5 that prevents me from acquiring HIV, nor one that seems to shield smokers from lung
cancer. “Ja, that’s my favorite,” says Braun, himself a smoker. “I wonder what Philip Morris would
pay for that.”
By the time I get home, I realize that all I’ve really learned is I might get heart disease, and I
could get diabetes. And I should avoid smoking and unsafe sex — as if I didn’t already know this.
Obviously, I’ll now watch my blood pressure, exercise more, and lay off the Cap’n Crunch. But
beyond this, I have no idea what to make of the message Andi Braun has divined from a trace of
my spit.
Looking for guidance, I visit Ann Walker, director of the Graduate Program for Genetic
Counseling at the University of California at Irvine. Walker explains the whats and hows, and the
pros and cons, of DNA testing to patients facing hereditary disease, pregnant couples concerned
with prenatal disorders, and anyone else contemplating genetic evaluation. It’s a tricky job
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because, as I’ve learned, genetic data is seldom clear-cut.
Take breast cancer, Walker says. A woman testing positive for BRCA1, the main breast cancer
gene, has an 85 percent chance of actually getting the cancer by age 70, a wrenching situation,
since the most effective method of prevention is a double mastectomy. What if a woman has the
operation and it turns out she’s among those 15 percent who carry the mutation but will never
get the cancer? Not surprisingly, one study, conducted in Holland, found that half of healthy
women whose mothers developed breast cancer opt not to be tested for the gene, preferring
ignorance and closer monitoring. Another example is the test for APoE, the Alzheimer’s gene. Since
the affliction has no cure, most people don’t want to know their status. But some do. A positive
result, says Walker, allows them to put their affairs in order and prepare for their own dotage.
Still, the news can be devastating. One biotech executive told me that a cousin of his committed
suicide when he tested positive for Huntington’s, having seen the disease slowly destroy his
father.
Walker pulls out a chart and asks about my family’s medical details, starting with my grandparents
and their brothers and sisters: what they suffered and died from, and when. My Texas
grandmother died at 92 after a series of strokes. My 91-year-old Missouri grandmom was headed
to a vacation in Mexico with her 88-year-old second husband when she got her death sentence —
ovarian cancer. The men died younger: my grandfathers in their late sixties, though they both
have brothers still alive and healthy in their nineties. To the mix, Walker adds my parents and their
siblings, all of whom are alive and healthy in their sixties and seventies; then my generation; and
finally our children. She looks up and smiles: “This is a pretty healthy group.”
Normally, Walker says, she would send me home. Yet I’m sitting across from her not because my
parents carry some perilous SNP, but as a healthy man who is after a forecast of future maladies.
“We have no real training yet for this,” she says, and tells me the two general rules of genetic
counseling: No one should be screened unless there is an effective treatment or readily available
counseling; and the information should not bewilder people or present them with unnecessary
trauma.
Many worry that these prime directives may be ignored by Sequenom and other startups that
need to launch products to survive. FDA testing for new drugs can take up to 10 years, and many
biotech firms feel pressure to sell something in the interim. “Most of these companies need
revenue,” says the University of Pennsylvania’s Arthur Caplan, a top bioethicist. “And the products
they’ve got now are diagnostic. Whether they are good ones, useful ones, necessary ones,
accurate ones, seems less of a concern than that they be sold.” Caplan also notes that the FDA
does not regulate these tests. “If it was a birth control test, the FDA would be all over it.”
I ask Caplan about the Gattaca scenario of genetic discrimination. Will a woman dump me if she
finds out about my ACE? Will my insurance company hike my rate? “People are denied insurance
and jobs right now,” he says, citing sickle-cell anemia, whose sufferers and carriers, mostly black,
have faced job loss and discrimination. No federal laws exist to protect us from genism, or from
insurers and employers finding out our genetic secrets. “Right now you’re likely going to be more
disadvantaged than empowered by genetic testing,” says Caplan.
After probing my genetic future, I jet to England to investigate my DNA past. Who are these
people who have bequeathed me this tainted bloodline? From my grandfather Duncan, an avid
genealogist, I already know that my paternal ancestors came from Perth in south-central
Scotland. We can trace the name back to an Anglican priest murdered in Glasgow in 1680 by a
mob of Puritans. His six sons escaped and settled in Shippensburg, Pennsylvania, where their
descendants lived until my great-great-grandfather moved west to Kansas City in the 1860s.
In an Oxford restaurant, over a lean steak and a heart-healthy merlot, I talk with geneticist Bryan
Sykes, a linebacker-sized 55-year-old with a baby face and an impish smile. He’s a molecular
biologist at the university’s Institute of Molecular Medicine and the author of the best-selling
Seven Daughters of Eve. Sykes first made headlines in 1994 when he used DNA to directly link a
5,000-year-old body discovered frozen and intact in an Austrian glacier to a 20th-century Dorset
woman named Marie Mosley. This stunning genetic connection between housewife and huntergatherer
launched Sykes’ career as a globe-trotting genetic gumshoe. In 1995, he confirmed that
bones dug up near Ekaterinburg, Russia, were the remains of Czar Nicholas II and his family, by
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comparing the body’s DNA with that of the czar’s living relatives, including Britain’s Prince Philip.
Sykes debunked explorer Thor Heyerdahl’s Kon-Tiki theory by tracing Polynesian genes to Asia and
not the Americas, and similarly put the lie to the Clan of the Cave Bear hypothesis, which held
that the Neanderthal interbred with our ancestors, the Cro-Magnon, when the two subspecies
coexisted in Europe 15,000 years ago.
Sykes explains to me that a bit of DNA called mtDNA is key to his investigations. A circular band of
genes residing separately from the 23 chromosomes of the double helix, mtDNA is passed down
solely through the maternal line. Sykes used mtDNA to discover something astounding: Nearly
every European can be traced back to just seven women living 10,000 to 45,000 years ago. In his
book, Sykes gives these seven ancestors hokey names and tells us where they most likely lived:
Ursula, in Greece (circa 43,000 BC), and Velda, in northern Spain (circa 15,000 BC), to name two
of the “seven daughters of Eve.” (Eve was the ur-mother who lived 150,000 years ago in Africa.)
Sykes has taken swab samples from the cheeks of more than 10,000 people, charging $220 to
individually determine a person’s mtDNA type. “It’s not serious genetics,” Sykes admits, “but
people like to know their roots. It makes genetics less scary and shows us that, through our
genes, we are all very closely related.” He recently expanded his tests to include non-Europeans.
The Asian daughters of Eve are named Emiko, Nene, and Yumio, and their African sisters are
Lamia, Latifa, and Ulla, among others.
Before heading to England, I had mailed Sykes a swab of my cheek cells. Over our desserts in
Oxford he finally offers up the results. “You are descended from Helena,” he pronounces. “She’s
the most common daughter of Eve, accounting for some 40 percent of Europeans.” He hands me a
colorful certificate, signed by him, that heralds my many-times-great-grandma and tells me that
she lived 20,000 years ago in the Dordogne Valley of France. More interesting is the string of
genetic letters from my mtDNA readout that indicates I’m mostly Celtic, which makes sense. But
other bits of code reveal traces of Southeast Asian DNA, and even a smidgen of Native American
and African.
This doesn’t quite have the impact of discovering that I’m likely to die of a heart attack. Nor am I
surprised about the African and Indian DNA, since my mother’s family has lived in the American
South since the 17th century. But Southeast Asian? Sykes laughs. “We are all mutts,” he says.
“There is no ethnic purity. Somewhere over the years, one of the thousands of ancestors who
contributed to your DNA had a child with someone from Southeast Asia.” He tells me a story about
a blond, blue-eyed surfer from Southern California who went to Hawaii to apply for monies
awarded only to those who could prove native Hawaiian descent. The grant-givers laughed -
??until his DNA turned up traces of Hawaiian.
The next day, in Sykes’ lab, we have one more test: running another ancestry marker in my Y
chromosome through a database of 10,000 other Ys to see which profile is closest to mine. If my
father was in the database, his Y chromosome would be identical, or possibly one small mutation
off. A cousin might deviate by one tick. Someone descended from my native county of Perth
might be two or three mutations removed, indicating that we share a common ancestor hundreds
of years ago. Sykes tells me these comparisons are used routinely in paternity cases. He has
another application. He is building up Y-chromosome profiles of surnames: men with the same last
name whose DNA confirms that they are related to common ancestors.
After entering my mtDNA code into his laptop, Sykes looks intrigued, then surprised, and suddenly
moves to the edge of his seat. Excited, he reports that the closest match is, incredibly, him —
Bryan Sykes! “This has never happened,” he says, telling me that I am a mere one mutation
removed from him, and two from the average profile of a Sykes. He has not collected DNA from
many other Duncans, he says, though it appears as if sometime in the past 400 years a Sykes
must have ventured into Perth, and then had a child with a Duncan. “That makes us not-sodistant
cousins,” he says. We check a map of Britain on his wall, and sure enough, the Sykes
family’s homeland of Yorkshire is less than 200 miles south of Perth.
The fact that Sykes and I are members of the same extended family is just a bizarre coincidence,
but it points to applications beyond simple genealogy. “I’ve been approached by the police to use
my surnames data to match up with DNA from an unknown suspect found at a crime scene,” says
Sykes. Distinctive genetic markers can be found at the roots of many family trees. “This is
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possible, to narrow down a pool of suspects to a few likely surnames. But it’s not nearly ready
yet.”
Back home in California, I’m sweating on a StairMaster at the gym, wondering about my heart. I
wrap my hands around the grips and check my pulse: 129. Normal. I pump harder and top out at
158. Also normal. I think about my visit a few days earlier — prompted by my gene scan — to
Robert Superko, a cardiologist. After performing another battery of tests, he gave me the all clear
— except for one thing. Apparently, I have yet another lame-heart gene, the atherosclerosis
susceptibility gene ATHS, a SNP that causes plaque in my cardiac bloodstream to build up if I
don’t exercise far more than average — which I do, these days, as a slightly obsessed biker and
runner. “As long as you exercise, you’ll be fine,” Superko advised, a bizarre kind of life sentence
that means that I must pedal and jog like a madman or face — what? A triple bypass?
Pumping on the StairMaster, I nudge the setting up a notch, wishing, in a way, that I either knew
for sure I was going to die on, say, February 17, 2021, or that I hadn’t been tested at all. As it is,
the knowledge that I have an ACE and ATHS deep inside me will be nagging me every time I get
short of breath.
I have two lame-heart genes, which will nag me everytime I’m short of breath. My
lifespan score is .49: I will live to the age of 88. 44 years of StairMaster to go.
The last results from my DNA workup have also come in. Andi Braun has tested me for 77 SNPs
linked to lifespan in order to assess when and how I might get sick and die. He has given me a
score of .49 on his scale. It indicates a lifespan at least 20 percent longer than that of the
average American male who, statistically speaking, dies in his 74th year. I will likely live, then, to
the age of 88. That’s 44 years of StairMaster to go.
Braun warns that this figure does not take into account the many thousands of other SNPs that
affect my life, not to mention the possibility that a piano could fall on my head.
That night, I put my 7-year-old, Alex, to bed. His eyes droop under his bright-white head of hair
as I finish reading Captain Underpants aloud. Feeling his little heart beating as he lies next to me
on his bed, I wonder what shockers await him inside his nucleotides, half of which I gave him. As I
close the book and then sing him to sleep, I wonder if he has my culprit genes. I don’t know,
because he hasn’t been scanned. For now, he and the rest of humanity are living in nearly the
same blissful ignorance as Helena did in long-ago Dordogne. But I do know one thing: Alex has my
eyebrow, the “lick of God.” I touch his flip in the dark, and touch mine. He stirs, but it’s not
enough to wake him.
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