When Charles Darwin returned to England in 1836 after his five-year voyage on the Beagle, he was 27 years old and on the cusp of one of the most brilliant careers in the history of science. He was also a bit of a wreck. He began complaining of "constant attacks"—heart palpitations, trembling, shortness of breath, and "swimming in the head." When offered a secretaryship at the Geological Society of London, he declined, explaining that "anything that flurries me completely knocks me up afterward." Two years later the once-intrepid traveler moved to his country home in Kent and became a legendary recluse, leaving only when absolutely necessary and then traveling in a carriage with darkened windows. On one rare trip in 1861, a brief speech in front of the Linnean Society prompted a 24-hour vomiting episode.
Darwin never learned the true nature of his malady. Physicians of the time diagnosed it as anything from "dyspepsia with aggravated character" to "suppressed gout"; their successors might have attributed it to a weak nervous system or a conflicted superego. But according to a team of researchers led by Xavier Estivill, a molecular geneticist at Barcelona's Medical and Molecular Genetics Center, Darwin's agoraphobia may have had a more specific origin. In a study published in the journal Cell last summer, Estivill contended that nearly every social phobia and panic disorder is rooted in a single stretch of about 60 genes.
Anxiety disorders first caught Estivill's attention 14 years ago through the work of physician Antoni Bulbena. While working at the Hospital del Mar in Barcelona, Bulbena made an odd observation: Patients who were double-jointed complained of nervous disorders far more often than others—fully 16 times as often, a follow-up study showed. Intrigued by the coincidence, Estivill traveled to a small Catalonian village near Barcelona, collected DNA samples from families known to have both conditions, and began combing through the samples for common characteristics.
Such comparative research usually entails a genome-wide analysis—an onerous process of lining up corresponding segments of DNA and looking for shared sequences. But Estivill, on a hunch, took a shortcut: He first examined the blood and then the sperm cells of 10 of the patients for genetic abnormalities that might contribute to the association. It was on the 15th chromosome that he found what he was looking for: Eighty-seven percent of the double-jointed and 90 percent of the anxiety-afflicted villagers carried a duplicated region spanning the length of about 60 genes. When Estivill repeated the study in a group of unrelated Catalonians, the association was even stronger: Ninety-seven percent of those diagnosed with an anxiety disorder carried the duplication compared with 7 percent in the general population. "It was astounding," he says. "You just don't expect that much of a relationship between a single region and a complex disorder that's supposed to be the result of many genes."
If Estivill's numbers hold up, says University of Oxford molecular biologist Jonathan Flint, they will demonstrate the most specific genetic association ever reported for a psychiatric disorder. "It's got a lot of people excited," Flint says. Like many of his colleagues, however, Flint still has nagging doubts. During the past year alone, he notes, an average of one study a day has been published purporting a genetic link to some psychiatric illness or other. Granted, no other study has produced statistics so compelling, but if the link was so obvious, why had no one found it before?
The answer, Estivill says, is that the duplication isn't being passed along according to standard patterns of heredity. Most other genetic disorders are caused by a hereditary mutation at a specific location on a specific chromosome. Cystic fibrosis, for instance, is caused by a mutated gene that codes for a faulty protein that makes the mucus in the lungs too viscous. Such genes might be dominant or recessive, but once they appear in the DNA, they are passed down through the generations virtually unchanged.
Estivill's duplication doesn't work that way. Not only does its position change along the chromosome, but its sequence is sometimes inverted or otherwise rearranged. Stranger still, those changes sometimes occur from cell to cell in the same individual, not just between parents and offspring. The reason, Estivill suggests, is that the duplication itself isn't being passed along. Rather, it's the tendency to duplicate that's inherited.
There are two ways such a pattern of inheritance could occur, he says. The enzymes that repair or copy DNA could be faulty and more prone to making doubling errors. Or the problem could have a more novel origin. The 60-gene duplication area is surrounded by smaller repeated sequences known as duplicons. Such duplicons are usually just junk DNA, but under certain circumstances they could cause trouble. "If the smaller repeats are very close copies of each other, they could throw off the copying machinery—trick it into making it see something twice and make a double copy of a nearby region," Estivill says. "It's impossible at this point to say exactly how this is happening. You've got to keep in mind that this is something no one has ever seen before."
In essence, Estivill is proposing an entirely new mechanism of genetic disease. "It's not an unreasonable explanation, given his observations," says Brad Schmidt, a psychologist at Ohio State University's Anxiety and Stress Disorders Clinic who has been looking for anxiety-related genes for nearly a decade. "I have a hard time believing something that looks as complex as panic disorder and phobias could really be that simple, but then the history of science is full of cases that looked very complex from one angle and turned out to be very simple when viewed another way. We've assumed that because drugs like Xanax and Paxil are so effective, all sorts of combinations of genetic variants of their receptors must play a role. But that line of thinking might be right up there with assuming that an aspirin deficiency causes arthritis."
If Estivill is right, such chromosomal rearrangements could lie behind many other hereditary disorders—schizophrenia, obsessive-compulsive disorder, and depression among them. Or for that matter, patterns like the duplication could cause any illness—from asthma to heart disease—that has been blamed on the effects of many genes working in concert. So far, attempts to unravel the genetic basis of complex conditions have been embarrassingly unsuccessful, Flint admits. "When attempts to find particular combinations of genes fail, the common wisdom just assumes they are even more complex than anyone thought. A mechanism like Estivill's could potentially explain quite a lot."
Since isolating the duplication region, Estivill has gone a step further, pinpointing his patients' anxieties to a double dose of at least one neuroreceptor coded for by one or more genes. "We can't be certain. We haven't identified all the genes in the region," he says. "But this one is a type thought to play a central role in the brain regions activated by fear." Mice that Estivill has bred with an extra copy of one gene scare more quickly and run away faster when faced with rats, bright lights, and other mouse horrors.
Such discoveries may well lead to treatments for anxiety disorders, but an outright cure would be going too far. Unlike hemophilia, Huntington's disease, and other hereditary illnesses, a certain amount of anxiety is good for people. "It's part of a highly evolved and adaptive defense mechanism and protects us from getting too close to cliff edges or hungry lions, just as the immune system protects us from bacteria," says Randolph Nesse, an evolutionary psychiatrist at the University of Michigan. Panic attacks are less a problem of maladaptation, Nesse says, than a case of too much of a good thing.
Even Darwin recognized that his suffering had some benefits. Before he died, he admitted that "ill-health, though it has annihilated years of my life, has saved me from the distraction of society and its amusements." Without panic disorder to focus his passions and spare him from interruptions, some researchers have suggested, Darwin might never have written On the Origin of Species.
For more about psychiatric genetics, see Jonathan Flint's Web page: www.well.ox.ac.uk/flint; to learn about clinical aspects of anxiety disorders and Brad Schmidt's work, see anxiety.psy.ohio-state.edu; and for more on the evolutionary perspective from Randolph Nesse, see www-personal.umich.edu/~nesse/Articles/Fear&Fitness-Ethol&Sociobiol-1994.PDF.