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Spring 2006

James Krueger, a pioneer in the biochemistry of sleep, enjoys a rare moment of rest.

For most of us, sleep is a time to rest and a chance to dream. For biochemist James Krueger, sleep offers a window into how the brain is organized, and how its trillions of cells coordinate their actions to create a perceiving, reflecting, inventing human mind.

Krueger is the founding member of a research group that has developed at Washington State University over the past 15 years. With established researchers Krueger, Lynn Churchill, and Gregory Belenky, and up-and-comers Hans Van Dongen and David Rector, the WSU sleep team is one of a few nationwide--including groups at Harvard, Stanford, and the University of Pennsylvania--that focus on fundamental questions: What makes us sleep? Why do we do it? What are the effects of not getting enough sleep? And the most basic of all: What exactly happens in the brain when we sleep?

A Sleep Switch?

Some researchers think there's a control center somewhere in the brain that emits electrical signals or chemicals that cause the rest of the brain to switch into sleep mode.

This sort of "top-down" model, of sleep being imposed on us, goes back centuries. An ancient Roman poet described sleep as a winged god that "steals o'er the greedy cares of men, and stoops and beckons from the sky, shrouding a toilsome life once more in sweet oblivion."

It's a reasonable idea, but James Krueger doesn't buy it.

Tall and genial, with the easy manner of a natural storyteller, Krueger says anyone trying to identify a single sleep control center sooner or later hits a logical snag. Say you do find a control center; then you have to ask, what controls that?

If sleep isn't imposed by some control center, what else could cause it? About 20 years ago sleep scientists began to find hints. A Russian group reported that dolphins only sleep in one half of their brain at a time. Though surprising at first, this made sense. Dolphins need to swim to the surface in order to breathe. If a dolphin ever slept in both halves of its brain at once, it would drown.

Investigators then found that sleep isn't always an all-or-nothing affair in our brains, either. Working one side of the brain harder, by exercising one side of the body, or one ear or one eye, makes the worked hemisphere undergo more and deeper sleep than the idle side.

In 1993 Krueger and visiting colleague Ferenc Obal, who died in 2004, proposed that sleep starts in individual groups of neurons called neuronal assemblies, or cortical columns. Each group contains between 10,000 and 100,000 neurons, or nerve cells, that are highly interconnected and that work together to perform a specific function. Krueger and Obal suggested that after a group is used a lot, it shifts into a sleep state. When enough groups in an animal's brain are in sleep state, the animal itself goes to sleep.

"It's a bottom-up process," says Krueger, a process that doesn't require central control. He compares it to the way ant colonies perform complex, coordinated tasks. "Colonies have behavioral properties that are whole-colony properties, and yet there's no individual ant directing that. "It's an emergent property of the whole colony."

Likewise, he and Obal theorized that sleep emerges from the activity of neuronal groups. No control center, no switch, just a sleep-wake shift depending on what the individual groups are doing.

It took Krueger a while to reach that view. He started working on the chemicals involved in sleep in 1974. Another investigator had found that injecting fluid from the nervous system of a sleeping animal into another animal made the recipient sleepy. Krueger set out to purify the substance that was causing the sleepiness.

"We were trying to isolate the sleep-promoting 'factor S,'" he says. "We thought it was a single compound. In our dreams we had ideas that we'd have the sleep hormone."

Now he chuckles at that optimism. The current list of chemicals thought to be involved in sleep regulation numbers well over a hundred.

Most belong to a class of small proteins called cytokines, which function in the immune system as well as the brain. Krueger's lab is investigating several of them, notably one called tumor necrosis factor (TNF). It 's unsettling to learn that a chemical named for its ability to kill things permeates my brain every night, but Krueger says the name is simply a holdover from its initial discovery by cancer researchers who found that it cleared up malignant skin lesions on mice overnight. "It's a miracle drug, if you're a mouse with skin cancer," says Krueger. Unfortunately, it doesn't work that way in humans-but Krueger has shown that it does appear in our blood and brain just prior to and during sleep.

"There's no other substance anywhere, of any sort, where you can correlate circulating levels with sleepiness," says Krueger. Not only that, but injecting TNF enhances sleepiness, and Hitoshi Yoshida, a visiting scientist from Japan, has found that injecting TNF into one hemisphere of a rat brain causes that hemisphere to go into a deeper sleep than the other hemisphere.

Still, Krueger has no illusions that TNF is the sleep factor. "I don't even know if phrasing the question in the sense of one being most important, or more important than another, is even a correct way to look at it," he says.

"For whatever reason, people like to have a single chemical responsible for things. Drug business drives that in part, but I think it's also somehow inherent in our minds, that we want a single gene, a single enzyme, a single neurotransmitter responsible for disease A, B, C, or D. But it ain't so.

"To think that we understand how this molecular network works is naïve. We have no idea how it works."

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