James D. Watson was director of Cold Spring Harbor Laboratory in New York from 1968 to 1993 and is now its chancellor emeritus. He was the first director of the National Center for Human Genome Research of the National Institutes of Health from 1989 to 1992. A member of the National Academy of Sciences and the Royal Society, he has received the Presidential Medal of Freedom, the National Medal of Science, and, with Francis Crick and Maurice Wilkins, the Nobel Prize in Physiology or Medicine in 1962. In this excerpt from his book, DNA: The Story of the Genetic Revolution, we learn how Watson came to be the first person to have his DNA fully sequenced.
One day in late 2005, I received an unexpected telephone call from a biotech entrepreneur named Jonathan Rothberg. Although I had never met the man, I was vaguely aware of his accomplishments. In the early 1990s, Rothberg had founded a firm in Connecticut, a short ferry ride across the Long Island Sound from Cold Spring Harbor. Like many biotechs back then, the company, called Curagen, had enjoyed a rocket-ship ride and an absurd market valuation before gravity sent the stock crashing down to earth. By then, however, Rothberg had spun off another company named 454 Life Sciences – I had no idea what the “454” stood for – to build a novel kind of DNA sequencing instrument. And I knew he had pulled it off, because in August 2005, I’d read an article in Nature coauthored by him describing the new 454 sequencer. It was the first so-called next-generation sequencing system.
I learned later the genesis of 454: In 1999, Rothberg’s wife gave birth to a blue baby, who was immediately rushed into the hospital’s neonatal intensive care unit. As Rothberg waited anxiously for news, he pulled out from his briefcase a computing magazine with a picture of the latest high-performance microprocessor on the cover. A eureka moment of sorts ensued, in which Rothberg imagined applying the hallmarks of the computer revolution – miniaturization and parallelization – to a new DNA sequencing system that could supplant sequencing. Perhaps one day, this system could offer anxious parents the possibility of a rapid diagnosis for their sick newborns, he imagined. (The Rothbergs’ baby did fine.)
A couple of months later, Rothberg paid me a visit at Cold Spring Harbor. He was tall, slightly disheveled, with a mop of unkempt dark curly hair – not a bad description of me in my younger days. He had come with a most unusual proposition: Would I be interested in being a genomics guinea pig – to become the first person in the world to have his or her DNA sequence completely decoded? It didn’t take me long to say yes – not because I had any great desire to be the first, much less to peer into my own genome, but I did feel the exercise could be of educational use.
I consented to have my genome sequenced and share the results publicly. There was just one proviso: I had no interest in learning anything about one particular gene on chromosome 19 called APOE (apolipoprotein E). A neurogeneticist at Duke University named Allen Roses (who sadly died of a heart attack in 2016 at John F. Kennedy International Airport en route to a conference) had convincingly shown that a rare version (or allele) of this gene, dubbed APOE4, is associated with a heightened risk of Alzheimer’s disease – particularly if the individual inherits two copies of the E4 variation. One of my aunts had suffered from Alzheimer’s, and I had absolutely no desire to waste time worrying about having some genetic predisposition to such a hideous disease.
For a year or so after Rothberg’s visit, I heard nothing more about the arrangement, but in late 2006, his group contacted me again and arranged to collect a blood sample. The company’s technology had progressed considerably with a concomitant decrease in the cost of sequencing. Now Rothberg’s team had the DNA sample with which to commence “Project Jim.” In May 2007, I flew to Houston as the guest of honor for the presentation of the genome. While the actual sequencing had been carried out by 454 scientists, that process was relatively trivial compared to the herculean task facing the bioinformaticians and geneticists trying to make sense of the billions of bases of data. To that end, Rothberg had collaborated with scientists at Baylor College of Medicine, led by the geneticists Richard Gibbs and Jim Lupski, the bioethicist Amy McGuire, and a bioinformatician named David Wheeler. At the ceremony, Rothberg presented me with a portable computer hard drive containing my entire genetic code. (Note that when we say a genome has been sequenced, that doesn’t mean just once through but an average of thirty times, or 30×, to ensure every region has enough coverage to obtain some data. In a clinical setting, the density of coverage is usually even deeper, say 45×.) Someone had hastily tied a thin, superfluous red ribbon around the disk, but I can’t complain; Rothberg estimated the cost of the sequencing at about $1 million.
In truth, I was more than a little disappointed by what my DNA sequence revealed—or rather what it did not. At dinner the night before, the Baylor group had given me a preview of the highlights. Owing to a DNA variant in the gene that codes for an important enzyme called cytochrome P450, it turns out I am a slow metabolizer of certain drugs, including my blood pressure medication. I had indeed been finding that taking it tended to make me sleepy.
Armed with this genetic information, it made sense to reduce the dosage, which I have done to this day. That was actionable information. On the other hand, I was initially concerned to learn that I carried some suspicious variations in the breast cancer gene BRCA1, which could have serious health implications for my nieces if they also carried these markers. But then I heard from Mary-Claire King – who famously mapped the BRCA1 gene in 1990 and who has studied its impact in hundreds of breast cancer families – that my sequence variants were nothing more than “benign Irish polymorphisms.”
Lincoln Stein, my former colleague at Cold Spring Harbor, built a website to host my entire genome sequence – minus the aforementioned APOE gene. But we had overlooked one thing: because our DNA is inherited in blocks, much like cards sticking together when shuffling a deck, a moderately skilled geneticist could in theory infer the identity of my APOE variants just by scanning the genotypes of the adjacent genes on chromosome 19. This was pointed out publicly by a young chap named Michael Cariaso, who maintains a curated online repository of medically relevant DNA variants called SNPedia. Stein acted quickly to redact about thirty genes spanning about 1 million bases either side of the APOE gene. I apologize for any resulting inconvenience.
In 2007, only one other person had his genome completely sequenced. That individual, not surprisingly, was Craig Venter, who had initiated the project a decade earlier at Celera Genomics during the heyday of the Human Genome Project.
Venter’s colleagues got wind of Project Jim and published their results in 2007, about six months before the article describing my own genome finally appeared in Nature. A key difference, however, was that Venter’s genome was sequenced using the traditional Sanger sequencing method, whereas mine was churned out with 454’s next-generation technology. For that reason, some attached a greater significance to my rather ordinary genome. Francis Collins pronounced it “the first of the rest of us.” It appears he was right: after a short lull, the first sprinkling of human genomes rapidly turned into a hailstorm of sequences. As I write this, I estimate that up to 400,000 human genomes have been sequenced, and the cost of sequencing falls toward the semi-arbitrary goal of one thousand dollars.
Excerpt © 2017 James D. Watson, used with permission of Alfred A. Knopf, a division of Penguin Random House LLC