Unlocking Secrets of the Brain with a worm?
June 20th 2011 20:38
In an eighth-floor laboratory overlooking the East River, Cornelia I. Bargmann watches two colleagues manipulate a microscopic roundworm. They have trapped it in a tiny groove on a clear plastic chip, with just its nose sticking into a channel. Pheromones — signaling chemicals produced by other worms — are being pumped through the channel, and the researchers have genetically engineered two neurons in the worm’s head to glow bright green if a neuron responds.
These ingenious techniques for exploring a tiny animal’s behavior are the fruit of many years’ work by Dr. Bargmann’s and other labs. Despite the roundworm’s lowliness on the scale of intellectual achievement, the study of its nervous system offers one of the most promising approaches for understanding the human brain, since it uses much the same working parts but is around a million times less complex.
Caenorhabditis elegans, as the roundworm is properly known, is a tiny, transparent animal just a millimeter long. In nature, it feeds on the bacteria that thrive in rotting plants and animals. It is a favorite laboratory organism for several reasons, including the comparative simplicity of its brain, which has just 302 neurons and 8,000 synapses, or neuron-to-neuron connections. These connections are pretty much the same from one individual to another, meaning that in all worms the brain is wired up in essentially the same way. Such a system should be considerably easier to understand than the human brain, a structure with billions of neurons, 100,000 miles of biological wiring and 100 trillion synapses.
The biologist Sydney Brenner chose the roundworm as an experimental animal in 1974 with this goal in mind. He figured that once someone provided him with the wiring diagram of how 302 neurons were connected, he could then compute the worm’s behavior.
The task of reconstructing the worm’s wiring system fell on John G. White, now at the University of Wisconsin. After more than a decade’s labor, which required examining 20,000 electron microscope cross sections of the worm’s anatomy, Dr. White worked out exactly how the 302 neurons were interconnected.
But the wiring diagram of even the worm’s brain proved too complex for Dr. Brenner’s computational approach to work. Dr. Bargmann was one of the first biologists to take Dr. White’s wiring diagram and see if it could be understood in other ways.
Cori Bargmann grew up in Athens, Ga., a small college town in the Deep South where her father taught statistics at the University of Georgia. Both her parents had been translators and met while Rolf Bargmann was working at the Nuremberg trials. Her mother, Ilse, would read to her in German the works of the Austrian animal behaviorists Konrad Lorenz and Karl von Frisch, planting the seeds of an interest in neuroscience.
“I went into science because I loved the labs,” Dr. Bargmann says. She liked the machines and instruments, the fun of building things with one’s own hands, of learning what no one else knew. An outstanding student, she chose for her Ph.D. degree to work in the M.I.T. lab of Robert A. Weinberg, a leading cancer biologist. The first mutated genes capable of causing cancer were being isolated. “It was an incredibly exciting time,” she says.
Her task was to clone a rat gene called neu. When mutated, the gene causes a tumor, but one that the rat’s immune system can attack and destroy. Several years later, the human version of neu, called HER-2, was found to be amplified in breast cancer, and its receptor protein product is the target of the artificial antibody known as Herceptin, a leading breast cancer drug.
For her postdoctoral work, Dr. Bargmann decided to work on animal behavior. The mouse is a standard organism for such studies, but she did not like hurting furry animals. “In Weinberg’s lab I would start to cry every time I had to do anything with a mouse,” she says. A nonfurry alternative was the fruit fly. She interviewed with a leading laboratory in California, but her husband at the time did not wish to move there.
That left the roundworm. There are now several hundred worm labs around the world, of which perhaps 30 or so, like Dr. Bargmann’s, focus on the worm’s nervous system. In 1987, “worms weren’t entirely respectable,” Dr. Bargmann says. But right there at M.I.T., H. Robert Horvitz had established one of the first serious worm labs in the United States. She joined his lab and read everything written on the worm, including all the back copies of the little field’s informal journal, The Worm Breeder’s Gazette.
She noticed that a particular behavior of C. elegans had been described but not well explored: it can taste waterborne chemicals and move toward those it finds attractive. Dr. White’s wiring diagram had been published the year before, in 1986. With this in hand, she told Dr. Horvitz she planned to identify which of the worm’s 302 neurons controlled its chemical-tracking behavior.
He thought the project was too ambitious, but said she could spend six months on the attempt. Each neuron in the worm’s brain is known, and is assigned a three letter name. Specific neurons can be identified under a microscope and zapped with a laser beam, allowing the neuron’s role to be deduced from whatever function the worm may seem to have lost.
Dr. Bargmann slogged her way through the task of killing each neuron one by one. Telling one neuron from another under the microscope is not easy. “It’s like knowing each grape in a bunch is different, but not quite being able to see it,” Dr. Horvitz said. “The first thing she had to do was learn the worm’s neuroanatomy, and she did so in a way only one other person has ever done.” (He was referring to John E. Sulston, who traced the lineage from the egg of all 959 cells in the adult worm’s body).
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