Blogging the Human Genome: Was the Human Genome Project a failure?

According to his published DNA sequence, James Watson should be blind, deaf, and have a tiny head. Why doesn’t he?

Blogging the Human Genome Entry 16

Illustration by Andrew Morgan

There are many things you might know about James Watson. That he co-discovered the double helix structure of DNA. That he was the first head of the Human Genome Project. That he kicked up a real shitstorm in 2007 for making nasty comments about the intelligence of Africans. That he has a tongue so sharp that one science historian called him “the Caligula of biology,” someone “given license to say anything that came to his mind and expect to be taken seriously.”

You might not know that—according to his DNA sequence, published in Nature in 2008—Watson by all rights should have been blind, deaf, photophobic, prematurely decrepit, and possibly mentally retarded.

In the middle of chromosome 10 sits the ercc6 gene, which plays various roles in basic cell processes like DNA repair. When ercc6 fails, you get Cockayne syndrome, which leads to a stunted frame, accelerated aging, tiny-headedness (microcephaly), extreme sensitivity to sunlight (even a few minutes outdoors can sear the skin), and in some cases, mental handicaps. This devastating disorder is recessive, thankfully—you need two bum copies of ercc6 to get Cockayne. Well, James Watson’s published DNA sequence says he has two bum copies. Yet he’s neither dwarfish, nor mentally deficient, nor microcephalic, and although he has aged lately, it’s nothing abnormal for an 84-year-old. Watson also supposedly has two recessive mutations that should have disabled a gene on chromosome 11, giving him Usher syndrome, which causes a Helen Keller–like deafness-blindness double whammy. If you haven’t guessed, Watson is neither deaf nor blind.

There are a few possible explanations for this discrepancy between genes and reality. Most likely, the scientists who sequenced Watson worked too quickly and screwed up: He probably has just one bad copy of those genes, not two, and for some reason no one double-checked this before publishing. (This does not instill a lot of confidence in this sort of quick-and-dirty genetic testing.) The other possibility, while quite slim, is perhaps more disturbing, because it highlights our essential ignorance: Maybe Watson has the bum DNA after all but somehow dodged the disease. With many ailments, in fact, people can have a clear genetic signature for it and yet escape genetic destruction. Scientists call this state incomplete penetrance, and they often have no idea how people escape. As a result, predicting who will and won’t get a disease becomes more or less impossible.

Such escapes might warm the hearts of people (usually nonscientists) who fear that genes rigidly dictate our destinies. And it does underscore the importance of the environment in triggering some genetic diseases. But the inability to trace DNA to actual diseases has serious consequences. As does the opposite problem—not being able to trace diseases back to DNA. Scientists know from twin studies and other work, for instance, that many common ailments like heart disease and diabetes have strong genetic components. Yet when they trawl through people’s DNA and look for flaws, these victims often don’t have many mutations in common. Much of the so-called culprit DNA for common diseases is missing.

There are many possible reasons for this, and The Violinist’s Thumb examines some of them in greater detail. But one possibility is that rare genetic mutations cause most of the problems. That is, even though two people might have similar bodily symptoms—fluctuating blood sugar, joint pain, high cholesterol—they might not have the same molecular, genetic flaws. That seems especially likely when a gene works in tandem with dozens of other genes to carry out some multistep process, and so a flaw in any one gene could crash the whole system. In that case, something that medicine currently classifies as a disease, singular, might actually be many diseases, plural, masked by common symptoms. Some scientists paraphrase Tolstoy to make this point: Perhaps all healthy people are alike, but all sick people are sick in their own way.

So how can scientists make headway? One promising approach was highlighted in a recent paper about, among other things, sneezing. Nature hardwired the sneeze reflex into our brains long ago, but sneezing can get cross-wired with other ancient brain systems, sometimes in comical ways. Certain inheritable conditions can leave people achoo-ing uncontrollably—up to 43 times in a row in one case—after looking into the sun, eating too much, or having an orgasm. These poor folk simply cannot hold back, and end up snobbering on their lovers or dirty dishes. The sunlight-sneeze link, called the photic sneeze reflex, isn’t even that uncommon, affecting around one-quarter of all people, according to some studies.

Despite the prevalence of PSR, only in 2010 did scientists tease out any genetic contributions to it, including a stretch on chromosome 2. How did they did so? Nine of the paper’s 10 authors worked for 23andMe, the pop genetic-testing service, and they drew on nearly 10,000 people’s DNA, a dataset vastly bigger than in most conventional medical studies. PSR is of course less serious than heart disease or diabetes (unless you’re a fighter pilot). But what’s exciting about the work was the approach. Geneticists are finally gathering enough data, and finally have enough computer horsepower, to riffle through the DNA of thousands of average Joes and Josephines at once. Now that the low-hanging fruit of human genetics has been picked, in fact, geneticists will likely have to turn to the masses more and more to make progress on complicated diseases.

In the decade since the Human Genome Project wrapped up, scientists have had a surprising amount of difficulty transforming genetic knowledge into medical treatments, and this fact has led some geneticists, Craig Venter included, to mumble that the HGP has—kinda, sorta, so far—flopped. I don’t see it that way. We know now that medical insights won’t just pop out, Matrix-style, from streams of genetic data: Devising cures will take work, lots of money, and perhaps some Copernican conceptual shifts about how genes and environment and culture work together. But even if we never cure a single disease, the Human Genome Project and other ventures will have been worth it.

The know-how and trickle-down effects from these projects has reinvigorated, if not revolutionized, virtually every other field of biology. We now have precise molecular clocks for tracking evolution, and know that humans harbor huge stretches of viral DNA. We can now trace the global migration patterns of our ancestors—including our liaisons with Neanderthals—and can unmask how close we came to extinction. Medical cures get the hype—that’s what most people mean when they speak of the impending “genetic revolution”—but genetics has really become history by other means.

In fact, the most profound change that genetics brings about might not be scientific at all. It might be mental and even spiritual enrichment: a more expansive sense of who we humans are, existentially, and where we came from, and how we fit with other life on earth. After delving deep, deep, deep into all aspects of human DNA, and uncovering so many stories about our past, that’s the genetic revolution I’m most excited about.