Is this mouse really autistic? His symptoms may come closer to mimicking the human disease than most mouse models of mental illness, because the gene involved has such a powerful effect. That is unusual. Disorders like depression and schizophrenia are each linked to hundreds of genes. No one gene is likely to make much difference.
But genes are only one part of the story. Other clues to human mental health can be found in the neural circuits of mouse brains. By tracing the wiring that connects one brain region to the next, researchers hope to develop more precisely targeted medications. Many vintage psychiatric drugs, such as Valium, Ritalin, and antipsychotics, were stumbled upon rather than tailor-made to solve a problem. As a result, they are too broad: They affect more than one type of receptor, on more than one kind of nerve cell, in more than one part of the brain. Many patients decide the cure is not worth the many side effects.
A few corridors away from Chesler’s office at Jackson Lab is neuroscientist Zhong-wei Zhang, a man on the hunt for the impaired circuits that might give rise to autism. He wants to know what causes social messages to stall in an animal’s brain. On his bench, 50 pounds of microscope magnifies a translucent shaving of mouse brain. A hair of a diode feeds electrical pulses into one side of a single cell; an electrode on the other side records that cell’s response. If it is shorting out like a bad lamp, Zhang could add a drug to the liquid in which the brain slice floats. Better now? Worse? “The brain as tissue is very normal—it’s like a piece of tofu,” Zhang says. “But the complexity is because it has such a large number of components interacting.”
Those interactions are his key interest. Even when each component of a brain works well, if the connections between regions are missing a crucial protein or chemical messenger, autism could result. Under the giant microscope, Zhang tests the connections like an electrician, navigating by a spiral-bound atlas of the mouse brain. Each slice in the atlas is a Swiss cheese of discrete little regions. And mouse brains are relatively simple. The human brain is vastly more complex, not to mention far less accessible to scalpel-wielding researchers.
With mice, Zhang never has to worry about supply running low. He can always order more brains. Mice are champion breeders, capable of producing 10 to 15 offspring a litter and about one litter every month. There is just one snag: Many psychiatric diseases in humans may well result from circuitry found only in humans.
Mice may be the best models we have of psychiatric disorders, but best does not mean great, or even decent. Gerald Dawson, founder and chief scientific officer of P1Vital, a pharmaceutical consulting firm in the United Kingdom, had his heart broken by the mouse mismatch. In the late 1990s, when he was working at a British division of the pharmaceutical giant Merck, mice ruled the world of drug discovery. You would create a mouse model of attention deficit/hyperactivity disorder (ADHD) or depression and dose the rodent with molecules carefully designed to close one cell receptor or open another.
So when Dawson set out to eliminate the drowsiness from anxiety drugs, he naturally turned to mice. The class of drugs he wanted
to modify, benzodiazepines such as Valium, Xanax, Ativan, and Klonopin, target the GABAa system. To grossly simplify, that system’s mandate is to put the brakes on nerve firing: It slows things down. So GABAa drugs help address problems like anxiety attacks and seizures. As with most neurotransmitters, the GABAa system is so evolutionarily ancient that it has diversified to serve many purposes. Hence the brain has six different GABAa receptor types, presumably to perform six different jobs. Dawson had a suspicion that the sleepiness side effect originated from just one of those six receptors. If he could determine which one, corporate chemists could design a molecule that would avoid activating it. He began to make mice.
One by one, he manipulated the receptor genes, breeding a new line of mice each time. With each new strain, he would administer the equivalent of a tiny Valium. If the animals grew drowsy, he knew he had not yet knocked out the right receptor. Knocking out receptor 1 made little difference. Receptor 3 proved too hard to knock out. Receptor 5 seemed to account for the amnesia that people (and mice) experience when they take anxiety drugs. Targeting receptor 2, Dawson identified a chemical that reduced a mouse’s startle response—a measure of anxiety—without impairing its ability to balance atop a rotating rod. Success!
Or so he thought. “When these compounds went into humans, they turned out to be just as sedating as the original drugs,” Dawson sighs. “It happens very rarely that a researcher gets to go through the whole process with a chemical, from mouse to man.” Normally the many steps are farmed out hither and yon, and no one feels the pride of parenting a new drug. He came so close. He got to test the drug on people. “And they fell asleep.”
Dawson blames the mice. “There’s not enough predictability in animal research. A lot of pharma companies are getting out.” Dawson moved on too. His company offers drug companies a new animal model for testing their drugs: humans. He will assemble a group of people to voluntarily try an existing drug for a new application before a pharmaceutical company embarks on a bigger, more costly human trial.
In a way, his shift hearkens to the backroom reality of drug testing. “I’ve tried lots of things: scopolamine, benzodiazepines, antipsychotics,” Dawson says. “We take lots of existing drugs too, to see if they have other applications. That’s very common.” He chuckles at the blockbuster success of the anti-narcoleptic drug modafinil, better known as Provigil. It is now widely taken off-label to boost alertness and acuity. “Modafinil has $2.4 billion in sales a year,” Dawson says. “There is not that much narcolepsy around.” The journal Nature reported recently that modafinil and other “cognitive enhancers” are in particular demand on the “ivory market” of academia.
But for all Dawson’s frustration with mice, the rodents did yield a couple of interesting drug leads. That receptor 5 implicated in the amnesia side effect? An experimental chemical that blocked its action created temporary geniuses: Mice on it were whizzes in the Morris water maze. A drug company is testing the compound to treat people with Down syndrome. And in the process of trying to eliminate drowsiness, Dawson and his team homed in on one of the chemical switches that cause mammals to go to sleep. Ambien locks onto that switch, associated with receptor 1, and sends you off to slumber.