DNA is the book of life. Its also the book of death. In the future well all be read cover tocover. Heres what its like to take the worlds first top-to-bottom gene scan.By David Ewing DuncanI FEEL NAKED. EXPOSED. As if my skin, bone, muscle tissue, cells have all been peeled back,down to a tidy swirl of DNA. Its the basic stuff of life, the billions of nucleotides that keep mebreathing, walking, craving, and just being. Eight hours ago, I gave a few cells, swabbed frominside my cheek, to a team of geneticists. Theyve spent the day extracting DNA and checking itfor dozens of hidden diseases. Eventually, I will be tested for hundreds more. They include, as Iwill 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 scoresof biotech startups incubating in the canyons north of San Diego. Im waiting to find out if I havea genetic proclivity for cancer, cardiac disease, deafness, Alzheimers, or schizophrenia.This, Im told, is the first time a healthy human has ever been screened for the full gamut ofgenetic-disease markers. Everyone has errors in his or her DNA, glitches that may trigger a heartspasm or cause a brain tumor. Im here to learn mine.Waiting, I wonder if I carry some sort of Pandora gene, a hereditary predisposition to peek intoplaces I shouldnt. Morbid curiosity is an occupational hazard for a writer, I suppose, but Ivenever been bothered by it before. Yet now I find myself growing nervous and slightly flushed. Ican feel my pulse rising, a cardiovascular response that I will soon discover has, for me, direimplications.In the coming days, Ill seek a second opinion, of sorts. Curious about where my genes come from,Ill travel to Oxford and visit an ancestral geneticist who has agreed to examine my DNA for linksback to progenitors whose mutations have been passed on to me. He will reveal the seeds of myindividuality 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 everyonesgenome will be deposited on a chip or stored on a gene card tucked into a wallet. Physicians willforecast illnesses and prescribe preventive drugs custom-fitted to a patients DNA, rather thanthe one-size-fits-all pharmaceuticals that people take today. Gene cards might also be used tofind that best-suited career, or a DNA-compatible mate, or, more darkly, to deny someone jobs,dates, and meds because their nucleotides dont measure up.Its a scenario Andrew Niccol imagined in his 1997 film, Gattaca, where embryos in a not-toodistantfuture are bioengineered for perfection, and where genism discrimination based on onesDNA condemns the lesser-gened to scrubbing toilets.The Gattaca-like engineering of defect-free embryos is at least 20 or 30 years away, butSequenom and others plan to take DNA testing to the masses in just a year or two. The prize: aprojected $5 billion market for personalized medicine by 2006, and billions, possibly hundreds ofbillions, more for those companies that can translate the errors in my genome and yours intocustom pharmaceuticals.4/16/13 Wired 10.11: DNA as Destinywww.wired.com/wired/archive/10.11/dna_pr.html 2/6Sitting across from me is the man responsible for my gene scan: Andi Braun, chief medical officerat Sequenom. Tall and sinewy, with a long neck, glasses, and short gray hair, Braun, 46, is bothjovial and German. Genetic tests are already publicly available for Huntingtons disease and cysticfibrosis, but Braun points out that these illnesses are relatively rare. We are targeting diseasesthat impact millions, he says in a deep Bavarian accent, envisioning a day when genetic kits thatcan assay the whole range of human misery will be available at Wal-Mart, as easy to use as ahome pregnancy test.But a kit wont tell me if Ill definitely get a disease, just if I have a bum gene. What Sequenomand others are working toward is pinning down the probability that, for example, a colon cancergene will actually trigger a tumor. To know this, Braun must analyze the DNA of thousands ofpeople and tally how many have the colon cancer gene, how many actually get the disease, andhow many dont. Once this data is gathered and crunched, Braun will be able to tell you, forinstance, that if you have the defective DNA, you have a 40 percent chance, or maybe a 75percent chance, by age 50, or 90. Environmental factors such as eating right or wrong andsmoking also weigh in. Its a little like predicting the weather, says Charles Cantor, thecompanys cofounder and chief scientific officer.Braun tells me that, for now, his tests offer only a rough sketch of my genetic future. We cantyet test for everything, and some of the information is only partially understood, he says. Itsmore of a peek through a rudimentary eyeglass than a Hubble Space Telescope. Yet I will be ableto 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 apart of this story, too. Heres where I squirm, because as a father I pass on not only theingredients of life to my children but the secret codes of their demise just as I have passed onmy blue eyes and a flip in my left brow that my grandmother called a little lick from God. DNA isnot only the book of life, it is also the book of death, says Braun: Were all going to die, ja?Strictly speaking, Braun is not looking for entire genes, the long strings of nucleotides thatinstruct the body to grow a tooth or create white blood cells to attack an incoming virus. Hesafter single nucleotide polymorphisms, or SNPs (pronounced snips), the tiny genetic variationsthat 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. Eachstep 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 athousand SNPs diverging to make us distinct. For instance, you might have a CG that makes yoususceptible to diabetes, and I might have a CC, which makes it far less likely I will get thisdisease.This is all fairly well-known: Genetics 101. Whats new is how startups like Sequenom haveindustrialized the SNP identification process. Andi Braun and Charles Cantor are finding thousandsof 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 fractionare tightly linked with common ailments. These disease-causing SNPs are fueling a biotechbonanza; the hope is that after finding them, the discoverers can design wonder drugs. In thecrowded SNP field, Sequenom vies with Iceland-based deCode Genetics, American companies suchas Millennium Pharmaceuticals, Orchid BioSciences, and Celera Genomics, as well as multinationalslike Eli Lilly and Roche Diagnostics. Its the Oklahoma Land Grab right now, says Toni Schuh,Sequenoms CEO.The sun sets outside Brauns office as my results arrive, splayed across his computer screen liketarot cards. Im 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 explainsthat these are addresses on the human genome, the PO box numbers of life. For instance, 1q23 isthe address for a mutant gene that causes vessels to shrink and impede the flow of blood itson chromosome 1. Thankfully, my result is negative. So, David, you will not get the varicose4/16/13 Wired 10.11: DNA as Destinywww.wired.com/wired/archive/10.11/dna_pr.html 3/6veins. Thats 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 homepregnancy tests.Next up is the hemochromatosis gene. This causes ones blood to retain too much iron, which candamage the liver. As Braun explains it, somewhere in the past, an isolated human community livedin an area where the food was poor in iron. Those who developed a mutation that stores highlevels of iron survived, and those who didnt became anemic and died, failing to reproduce.However, in these iron-rich times, hemochromatosis is a liability. Todays treatment? Regularbleeding. You tested negative for this mutation, says Braun. You do not have to be bled.Im also clean for cystic fibrosis and for a SNP connected to lung cancer.Then comes the bad news. A line of results on Brauns monitor shows up red and is marked MT,for mutant type. My bodys programming code is faulty. Theres a glitch in my system. Named ACE(for angiotensin-I converting enzyme), this SNP means my body makes an enzyme that keeps myblood pressure spiked. In plain English, Im a heart attack risk.My face drains of color as the news sinks in. Im not only defective, but down the road, everytime I get anxious about my condition, Ill know that I have a much higher chance of droppingdead. I shouldnt be surprised, since Im 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 ratherridiculous assumption that I would come out of this with a clean genetic bill of health. I almostnever get sick, and, at age 44, I seldom think about my physical limitations, or death. Thisattitude is buttressed by a family largely untouched by disease. The women routinely thrive intotheir late eighties and nineties. One great-aunt lived to age 101; she used to bake me cupcakesin 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, Im glimpsing my ownfuture; my own mortality. Im 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 MatthewMcGinniss, a Sequenom geneticist standing at Brauns side.One gene seems to shield smokers from lung cancer. Thats my favorite, says thedoctor, 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 thescreen another high blood pressure mutation. My other cardiac indicators are OK, which isrelatively good news, though Im hardly listening now. Im already planning a full-scale assault tolearn everything I can about fighting heart disease until McGinniss delivers an unexpectedpronouncement. These mutations are probably irrelevant, he says. Braun agrees: Its likely thatyou carry a gene that keeps these faulty ones from causing you trouble DNA that we have notyet 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 dont have a SNP calledCCR5 that prevents me from acquiring HIV, nor one that seems to shield smokers from lungcancer. Ja, thats my favorite, says Braun, himself a smoker. I wonder what Philip Morris wouldpay for that.By the time I get home, I realize that all Ive really learned is I might get heart disease, and Icould get diabetes. And I should avoid smoking and unsafe sex as if I didnt already know this.Obviously, Ill now watch my blood pressure, exercise more, and lay off the Capn Crunch. Butbeyond this, I have no idea what to make of the message Andi Braun has divined from a trace ofmy spit.Looking for guidance, I visit Ann Walker, director of the Graduate Program for GeneticCounseling at the University of California at Irvine. Walker explains the whats and hows, and thepros and cons, of DNA testing to patients facing hereditary disease, pregnant couples concernedwith prenatal disorders, and anyone else contemplating genetic evaluation. Its a tricky job4/16/13 Wired 10.11: DNA as Destinywww.wired.com/wired/archive/10.11/dna_pr.html 4/6because, as Ive learned, genetic data is seldom clear-cut.Take breast cancer, Walker says. A woman testing positive for BRCA1, the main breast cancergene, 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 theoperation and it turns out shes among those 15 percent who carry the mutation but will neverget the cancer? Not surprisingly, one study, conducted in Holland, found that half of healthywomen whose mothers developed breast cancer opt not to be tested for the gene, preferringignorance and closer monitoring. Another example is the test for APoE, the Alzheimers gene. Sincethe affliction has no cure, most people dont want to know their status. But some do. A positiveresult, 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 committedsuicide when he tested positive for Huntingtons, having seen the disease slowly destroy hisfather.Walker pulls out a chart and asks about my familys medical details, starting with my grandparentsand their brothers and sisters: what they suffered and died from, and when. My Texasgrandmother died at 92 after a series of strokes. My 91-year-old Missouri grandmom was headedto 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 bothhave brothers still alive and healthy in their nineties. To the mix, Walker adds my parents and theirsiblings, all of whom are alive and healthy in their sixties and seventies; then my generation; andfinally our children. She looks up and smiles: This is a pretty healthy group.Normally, Walker says, she would send me home. Yet Im sitting across from her not because myparents 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 geneticcounseling: No one should be screened unless there is an effective treatment or readily availablecounseling; and the information should not bewilder people or present them with unnecessarytrauma.Many worry that these prime directives may be ignored by Sequenom and other startups thatneed to launch products to survive. FDA testing for new drugs can take up to 10 years, and manybiotech firms feel pressure to sell something in the interim. Most of these companies needrevenue, says the University of Pennsylvanias Arthur Caplan, a top bioethicist. And the productstheyve 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 FDAdoes 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 shefinds out about my ACE? Will my insurance company hike my rate? People are denied insuranceand 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 frominsurers and employers finding out our genetic secrets. Right now youre likely going to be moredisadvantaged than empowered by genetic testing, says Caplan.After probing my genetic future, I jet to England to investigate my DNA past. Who are thesepeople who have bequeathed me this tainted bloodline? From my grandfather Duncan, an avidgenealogist, I already know that my paternal ancestors came from Perth in south-centralScotland. We can trace the name back to an Anglican priest murdered in Glasgow in 1680 by amob of Puritans. His six sons escaped and settled in Shippensburg, Pennsylvania, where theirdescendants 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 BryanSykes, a linebacker-sized 55-year-old with a baby face and an impish smile. Hes a molecularbiologist at the universitys Institute of Molecular Medicine and the author of the best-sellingSeven Daughters of Eve. Sykes first made headlines in 1994 when he used DNA to directly link a5,000-year-old body discovered frozen and intact in an Austrian glacier to a 20th-century Dorsetwoman named Marie Mosley. This stunning genetic connection between housewife and huntergathererlaunched Sykes career as a globe-trotting genetic gumshoe. In 1995, he confirmed thatbones dug up near Ekaterinburg, Russia, were the remains of Czar Nicholas II and his family, by4/16/13 Wired 10.11: DNA as Destinywww.wired.com/wired/archive/10.11/dna_pr.html 5/6comparing the bodys DNA with that of the czars living relatives, including Britains Prince Philip.Sykes debunked explorer Thor Heyerdahls Kon-Tiki theory by tracing Polynesian genes to Asia andnot the Americas, and similarly put the lie to the Clan of the Cave Bear hypothesis, which heldthat the Neanderthal interbred with our ancestors, the Cro-Magnon, when the two subspeciescoexisted 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 ofgenes residing separately from the 23 chromosomes of the double helix, mtDNA is passed downsolely through the maternal line. Sykes used mtDNA to discover something astounding: Nearlyevery European can be traced back to just seven women living 10,000 to 45,000 years ago. In hisbook, 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 twoof 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 toindividually determine a persons mtDNA type. Its not serious genetics, Sykes admits, butpeople like to know their roots. It makes genetics less scary and shows us that, through ourgenes, 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 areLamia, Latifa, and Ulla, among others.Before heading to England, I had mailed Sykes a swab of my cheek cells. Over our desserts inOxford he finally offers up the results. You are descended from Helena, he pronounces. Shesthe most common daughter of Eve, accounting for some 40 percent of Europeans. He hands me acolorful certificate, signed by him, that heralds my many-times-great-grandma and tells me thatshe lived 20,000 years ago in the Dordogne Valley of France. More interesting is the string ofgenetic letters from my mtDNA readout that indicates Im mostly Celtic, which makes sense. Butother bits of code reveal traces of Southeast Asian DNA, and even a smidgen of Native Americanand African.This doesnt quite have the impact of discovering that Im likely to die of a heart attack. Nor am Isurprised about the African and Indian DNA, since my mothers family has lived in the AmericanSouth 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 whocontributed to your DNA had a child with someone from Southeast Asia. He tells me a story abouta blond, blue-eyed surfer from Southern California who went to Hawaii to apply for moniesawarded 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 Ychromosome through a database of 10,000 other Ys to see which profile is closest to mine. If myfather was in the database, his Y chromosome would be identical, or possibly one small mutationoff. A cousin might deviate by one tick. Someone descended from my native county of Perthmight be two or three mutations removed, indicating that we share a common ancestor hundredsof years ago. Sykes tells me these comparisons are used routinely in paternity cases. He hasanother application. He is building up Y-chromosome profiles of surnames: men with the same lastname whose DNA confirms that they are related to common ancestors.After entering my mtDNA code into his laptop, Sykes looks intrigued, then surprised, and suddenlymoves 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 mutationremoved from him, and two from the average profile of a Sykes. He has not collected DNA frommany other Duncans, he says, though it appears as if sometime in the past 400 years a Sykesmust have ventured into Perth, and then had a child with a Duncan. That makes us not-sodistantcousins, he says. We check a map of Britain on his wall, and sure enough, the Sykesfamilys 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. Ive been approached by the police to usemy surnames data to match up with DNA from an unknown suspect found at a crime scene, saysSykes. Distinctive genetic markers can be found at the roots of many family trees. This is4/16/13 Wired 10.11: DNA as Destinywww.wired.com/wired/archive/10.11/dna_pr.html 6/6possible, to narrow down a pool of suspects to a few likely surnames. But its not nearly readyyet.Back home in California, Im sweating on a StairMaster at the gym, wondering about my heart. Iwrap my hands around the grips and check my pulse: 129. Normal. I pump harder and top out at158. Also normal. I think about my visit a few days earlier prompted by my gene scan toRobert 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 atherosclerosissusceptibility gene ATHS, a SNP that causes plaque in my cardiac bloodstream to build up if Idont exercise far more than average which I do, these days, as a slightly obsessed biker andrunner. As long as you exercise, youll be fine, Superko advised, a bizarre kind of life sentencethat 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 knewfor sure I was going to die on, say, February 17, 2021, or that I hadnt 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 getshort of breath.I have two lame-heart genes, which will nag me everytime Im short of breath. Mylifespan 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 SNPslinked to lifespan in order to assess when and how I might get sick and die. He has given me ascore of .49 on his scale. It indicates a lifespan at least 20 percent longer than that of theaverage American male who, statistically speaking, dies in his 74th year. I will likely live, then, tothe age of 88. Thats 44 years of StairMaster to go.Braun warns that this figure does not take into account the many thousands of other SNPs thataffect 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 hairas I finish reading Captain Underpants aloud. Feeling his little heart beating as he lies next to meon his bed, I wonder what shockers await him inside his nucleotides, half of which I gave him. As Iclose the book and then sing him to sleep, I wonder if he has my culprit genes. I dont know,because he hasnt been scanned. For now, he and the rest of humanity are living in nearly thesame blissful ignorance as Helena did in long-ago Dordogne. But I do know one thing: Alex has myeyebrow, the lick of God. I touch his flip in the dark, and touch mine. He stirs, but its notenough to wake him.FOR MORE INFORMATION ON THIS TOPIC CLICK HERE
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