Chapter One
GENES
Know then thyself, presume not God to scan ... -ALEXANDER POPE
* * *
Not a genetic virgin
I lost my genetic virginity in 2001 on a typically bright, still afternoon in La Jolla, California, near San Diego. I could see the heat wilting a stand of palms outside the office where I was spending my last minutes of complete ignorance about my genes - those specific combinations of genetic markers inside my cells that might reveal a proclivity for a future disease or a behavioral fl aw. For the forty - three years of my life up until that point, this information had been as hidden and secret for me as it had for nearly every human in history.
A few weeks earlier, I had given up five 9 milliliter vials of blood, less than 2 ounces, to a La Jolla start-up called Sequenom. Its scientists had teased out hundreds of my genetic markers - my As, Ts, Gs, and Cs - in a lab down the hall in this then-new, silver - metallic headquarters perched on a desert mesa close by the sea. The year 2001 was a time that today seems Jurassic, given the lightning-quick pace of genomics. Just a year earlier, President Bill Clinton had announced the completion of a rough draft of the human genome in a ceremony at the White House. The final draft would not be finished for two more years, in 2003.
I was working on a story for Wired magazine explaining this newfangled field called genomics, and I had come up with the idea of having myself tested and publicly revealing my results - something that had not yet been done by anyone. (Craig Venter had not yet revealed that the "anonymous" DNA his former company, Celera Genomics, had sequenced for the Human Genome Project was actually his own.) The idea had seemed silly at first, a gimmick. My job was to report on what scientists did, not to inject myself into the action. Yet I hoped that by having a real person take the tests, readers would connect with this highly abstract new science that involved such novel concepts to the public as nucleotides, DNA code, genes, and amino acids.
Sitting across a desk that day was Andi Braun, then Sequenom''s chief medical officer. Tall and sinewy, with a long neck, glasses, and short gray hair, the then forty-six-year-old Braun was jovial, with a light German accent, as he called up my test results on his computer. I tried to maintain a steely, reportorial facade, but my heart raced just a bit, since the tests involved a range of frightening diseases that I might have a genetic risk factor for - or not.
Braun turned his monitor so that I could see it, and I read names of genes popping up on the screen: connexin 26, implicated in hearing loss; factor-V leiden, associated with blood clots; and alpha-1 antitrypsin deficiency, linked to lung and liver disease. Beside each gene was the location of a DNA marker that scientists had linked to a risk factor for these diseases: 13q11-q12, 1q23, 14q32.1. Braun explained that these are addresses on the human genome, the "PO box numbers of life." For instance, 1q23 is the address for a gene marker that when mutant can cause vessels to shrink and impede the flow of blood; it''s on chromosome 1. (Humans have twenty-three paired chromosomes.) Thankfully, my result for this awful-sounding malady was negative.
"So, David, you will not get the varicose veins. That''s good, ja?" said Braun.
Next up was the hemochromatosis gene. This causes one''s blood to retain too much iron, which can damage the liver. As Braun explained it, somewhere in the past, an isolated human community lived in an area where food was low in iron. Those who developed a mutation that stored high levels of iron survived, and those who didn''t became anemic and died, failing to reproduce. Now that most people get plenty of iron, however, hemochromatosis is a liability. The treatment? Regular bleeding.
"You tested negative for this mutation," said Braun. "You do not have to be bled."
I was also clean for cystic fibrosis and for a genetic marker connected to lung cancer.
Then came the bad news. A line of results on Braun''s monitor showed up red and was marked "MT," for "mutant type," for a gene called ACE (for angiotensin-I converting enzyme). Many of my friends had long suspected that I was a mutant, but in this case it meant that my body makes an enzyme linked to high blood pressure. In plain English, I was a potential heart attack risk, if this marker was to be believed. Then a second red "MT" popped up on Braun''s screen: another high blood pressure mutation. My other cardiac indicators were okay, which was good news, although I remember being surprised that I had any bum genes at all. I had been told that everyone has them, since we will all die of something, but it hadn''t occurred to me that anything could be wrong with me. At the age of forty-three, I felt great - I still do at age fifty - and I came from a healthy enough family that I seldom thought about illness, disease, or death for myself.
In my Wired account of this scene in Braun''s office, I wrote that I reacted to the bad news by wanting to find out everything I could about heart disease and those rascally ACE markers. The reality is that I didn''t, in part because of my thick headedness about believing I would never get sick or die, an attitude reinforced by what a Sequenom physician standing next to Braun told me that day in San Diego.
"These mutations are probably irrelevant for you," said Matthew McGinniss.
Braun agreed. "Given your family history, it''s likely that you carry a gene that keeps these faulty ones from causing you trouble - DNA that we have not yet discovered."
I got more bad news that day: I don''t have a marker called CCR5 that prevents me from acquiring HIV, should I indulge in unsafe sex; nor do I have one that seems to shield smokers from lung cancer.
"Ja, that''s my favorite," said Braun, himself a smoker. "I wonder what Philip Morris would pay for that!"
At the time, Sequenom was exploring the idea of starting a business to test people for a string of genetic tests, something like what online genetics companies such as 23andMe and deCODEme are offering half a decade later. They even calculated a life score for me, based on genetic mutations that I have and don''t have, and came up with a crude calculation of how these might affect my life span. My score was about 14 percent higher than the norm, indicating that I would live to be ninety-one years old, although, of course, this score was based on very preliminary studies that associated genetic markers with diseases. The score also failed to take into account, as McGinniss and Braun suggested, thousands of other genes and risk factors that might kill me either before or after the age of ninety-one. And then there was that piano that might fall on my head.
In 2004, I was tested again for different markers by another genomics company, deCode Genetics, based in Reykjavik, Iceland. Founded in 1996, deCode is a world leader in hunting down genes related to diseases that range from diabetes and heart disease to restless leg syndrome, discoveries that frequently land deCode on the front pages of newspapers around the world. Its approach has been to first search for genetic associations among the three hundred thousand people of Iceland - about 40 percent of the population (60 percent of the adult population) have given deCode their consent - and then to replicate these studies in larger populations such as North America. In 2007, the company launched deCODEme, an online genetic testing site that offers anyone who wants to pay $985 results on about twenty-nine genetic markers that are linked to diseases such as obesity and cancer. DeCode is also developing drugs for stroke, heart attack, and Alzheimer''s, although as of this writing, the company was facing financial difficulties and an uncertain future.
The company was founded by Kari Stefansson, a tall, charismatic Icelander with a white, pointed beard. He first made a name for himself as a neurologist at Harvard before returning home to start his company. Stefansson is brilliant and filled with an infectious passion; he also can be rude, loud, and demanding, a combination of attributes that he undoubtedly inherited from his Viking forebearers who sailed in longboats to Iceland and settled there in the ninth century.
I had shipped several vials of blood to Iceland, where Stefansson''s geneticists cracked open my cells and extracted the DNA to test me for a new genetic marker the company had discovered that seemed to confer a higher than normal risk for stroke. On a gray, rainy summer day in Reykjavik, I arrived at deCode''s headquarters on the edge of a lava field on this volcanic island to get my results, only to be invited by Stefansson to play one-on-one basketball at a Reykjavik gym.
"This is the time of day I get exercise. You need exercise. Listen to me, I am a doctor, and I know you need exercise," he said.
"Ah, okay," I stammered, not expecting this. I realized instantly as I sized up this man - he''s 6 feet 5 inches, while I''m just over 6 feet and pathetic at basketball - that playing basketball with him would lead to my humiliation. As a journalist, I sometimes run into subjects who test my mettle, as if I need to prove my manhood to them. This might have been the case here-or possibly Stefansson just wanted a partner to play some hoops.
The game was predictably one-sided as we roared up and down a half-court, until at last I grabbed the ball and was in the air about to make a basket. It was at this moment that Stefansson decided to give me a general impression of my genetic proclivities. He was behind me, pushing, as I was about to dunk the ball into the net, when he blurted out, "I have your DNA results."
"Yeah?" I said, suspended for a moment in the air, feeling that electric rush that said this ball was going to connect.
"You are genetically defective."
I hesitated for a split second, and he jumped up high, grabbed the ball, and raced down the court, dribbling and flashing me a maniacal Viking smile.
Back in Stefansson''s office, he told me that he was just kidding on the court, although when he saw my test results, he was embarrassed to admit that I did indeed have a mutation that is associated with a higher incidence of stroke. He then explained to me what this meant, introducing me to the rapidly developing world of genetic testing, association studies, and risk factors as it had evolved even since the Sequenom experiment in 2001.
"We have established that you have a series of genetic markers that give you something like a two to seven times greater risk for developing a stroke than if you didn''t. You have this entire haplotype"-a sequence of DNA that is passed down from one generation to another with little or no change-"so you probably have three times the risk. If this turns out to be the case in the American population, you are genetically predisposed to stroke."
I was surprised, responding that no one in my family had ever had a stroke, except my maternal grandmother, in her eighties.
"The only thing you have done is to inherit a predisposition," he said. "What does that mean, eventually? It means that if you stay in a certain environment, or if you are born in a certain environment, you will develop stroke. But you are not going to develop stroke, all right? You now know that you have three times the possibility of the average individual to develop stroke. So you have a strong incentive to take measures to prevent stroke. One of them is to make sure that you don''t have high blood pressure; one of them is that you will not smoke. One of them is you will drink alcohol only moderately, because intake of large amounts of alcohol, binges, dramatically increase the probability that you will develop a stroke."
"But this genetic profile for stroke has not been tested for Americans. You''ve only tested Icelanders. Right?"
"Yes, before you can get too excited as an individual, you have to do a clinical trial in the population where you can use it, like in the American population," he said. "For some traits, ethnicity can be important. Some populations are at higher risk for some diseases."
"Those odds still make me want to go and have a drink."
"You cannot drink anymore."
That night, I met Stefansson for drinks at an Italian restaurant that served, among the usual pasta and veal, horsemeat, apparently an Icelandic specialty. After I drank enough red wine to give me a stroke for sure, Stefansson said goodnight and told me that all of that wine tonight would certainly kill me, that I would have a stroke by morning. He was kidding again, but as I walked to my hotel through the eerie lightness of the Icelandic "midnight sun," with the streets slick from dampness in the air and the distant volcanoes black and steaming, I wondered whether I should believe him.
I took a breath and decided that I felt great. I also reassured myself that I wasn''t Icelandic, so the studies might not apply to me. Later, though, other genetic tests revealed that I have a rare DNA signature in my mitochondria that does connect me with Stefansson''s Vikings. Mitochondria are structures in human cells that stay very stable over thousands of years and therefore can be used to trace a person''s roots. This particular stretch of DNA, which I will describe in detail later, is not passed down in the usual manner as a mix of one''s mother''s and father''s attributes. Rather, our mothers pass it to us in a matrilineal line. This makes sense for me, since my mother''s family, through her mother, tracks back to Scotland, where Stefansson''s Viking forebears grabbed many of the women they took with them to Iceland-including, perhaps, a long-ago ancestor of mine.
* * *
Predicting the future
Three years and another epoch or two later on the time line of genomic advances, I am back in Iceland to take more tests for the Experimental Man project. Within hours of landing, I find myself facing Kari Stefansson once again. This time he''s holding not a basketball but a needle and a syringe.
Outside, fields of black volcanic rock stretch in all directions, and the sky boils with the same gray-white clouds I remember from my last trip. But I''m not thinking about the scenery as Kari Stefansson tightens a rubber strip around my lower-right bicep and searches for a vein. He and his team need a throbbing blue vessel to poke so that they can draw out enough blood to isolate a few white blood cells and to obtain yet another complete copy of my genome.
Tapping into my blood vessel is the first step for deCode''s scientists to run my DNA through advanced machines that will eventually untangle more than one million genetic markers, or about .0001 percent of the nucleotides in my DNA. These markers are not complete genes, which are often composed of hundreds or thousands of nucleotides; they are individual letters within genes (and sometimes outside of genes) that appear in a single "base pair." DNA is made up of long, coiling strands of base pairs - written, for instance, as a pair of nucleotides that looks like this: AG or TC - that are attached to the double-helix superstructure of DNA like rungs that fit into a very long ladder. (Nucleotides are the individual As, Cs, Ts, and Gs in a genome.)
Most of the three billion base pairs in a human''s DNA, some 99 percent, are identical with every other human''s, but several million are not. That is, in one person, a specific letter in a certain base pair might be a G, and in another person, an A. These variations, called single nucleotide polymorphisms, or SNPs (pronounced "snips"), can increase one''s chances of having blond hair or red hair, or of getting cancer or not. This is one form of a mutation, defined as any change, or divergence, in the nucleotide sequence of a gene. DeCode planned to scan my genome for about a million SNPs, which is one way of checking for large numbers of genetic differences without having to scan a person''s entire three billion base pairs. Later, other companies and labs would scan me for millions more.
Like many physicians who think they can do almost anything, Kari Stefansson assumes that he can draw blood better than a trained nurse can. Earlier in the day, Stefansson jokingly dared me to let him draw my blood himself, even though he couldn''t remember the last time he had drawn blood. I agreed, a decision I now regret, as a rather nervous-looking Viking geneticist waves a very sharp needle above a swelling vein. Thankfully, the "do no harm" side of "the doctor," as his close associates call him, kicks in, and he hands the syringe to a nearby phlebotomist. The nurse rolls her eyes at her boss and me. Taking the needle, she sticks it in my arm with such expertise that I barely feel it as she drains three vials of blood. (Continues...)
Excerpted from Experimental Manby David Ewing Duncan Copyright © 2009 by David Ewing Duncan. Excerpted by permission.
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