Making a worm do more than squirm

Scientists use a laser to manipulate nematode, learn about complicated behaviors

View a video of a laser-controlled worm

HOW THE WORM TURNS A laser system (left) controls the behavior of worms by commandeering nerve cells using light (right). Leifer et al/Nature Methods 2011

Satirist Stephen Colbert envisions his “Colbert Nation” mentally marching in lockstep with his special brand of patriotism.  But scientists have done him one better, by creating tiny worm-bots completely under their control.

Rather than comedic persuasion, these scientists are using a dot of laser light. With it they can make a worm turn left, freeze or lay an egg. The researchers report their work online January 16 in Nature Methods.

The new system, named CoLBeRT for “Controlling Locomotion and Behavior in Real Time,” doesn’t just create a mindless zombie-worm, though. It gives scientists the ability to pick apart complicated behaviors on a cell-by-cell basis.

“This system is really remarkable,” says biological physicist William Ryu of the University of Toronto, who was not involved in the research. “It’s a very important advance in pursuit of the goal of understanding behavior.”

Transparent and small, the nematode C. elegans is particularly amenable to light-based mind control. Another benefit of the worm is that researchers know the precise location of all 302 of its nerve cells. But until now, there wasn’t a good way to study each cell by itself, especially in a wriggling animal.

“This tool allows us to go in and poke and prod at those neurons in an animal as it’s moving, and see exactly what each neuron does,” says study coauthor Andrew Leifer of Harvard University. 

The system is based on the emerging field of optogenetics, in which light is used to turn cells on or off. Leifer and his colleagues genetically engineered light-responsive molecules into particular groups of cells in the worm.

Then, a computer program that the team developed figures out where in the microscope’s field of view a target cell is. Once the cell is pinpointed, the program directs lasers so that a tiny beam of light hits the cell.

“When we’re shining light on a neuron, we’re hitting that neuron and nothing else,” Leifer says.

The whole process, from finding the cell to light hitting its target, takes about 20 milliseconds. As the worm’s position changes, that information is fed back into the computer program, and the laser is adjusted. If the worm crawls too far, a motorized microscope stage brings the animal back.

One of the biggest benefits of the new method, Ryu says, is that it works in a roving animal. “The worms are not held down in any way — they’re freely moving. There aren’t many systems where you can look at such truly free organisms.”

In early tests of their technique, Leifer and his team forced worms to freeze, change directions, turn left or right, and even lay eggs. In later tests, the team focused on two nerve cells that help the worm respond to touch. Researchers knew that a gentle tickle on the head causes worms to move backward, but after too many touches, the worms grow desensitized and stop responding. By mimicking touches with light, the researchers found that a weary cell that’s been touched too many times can also tire out its partner cell that hasn’t been touched, suggesting that these cells don’t act alone.

Another group of scientists, led by Jeffrey Stirman of Georgia Tech in Atlanta, reports a similar technique for worm mind-control, also online January 16 in Nature Methods. Ryu says the two methods are similar. The CoLBeRT method appears to be a little faster, he says, but if the worm is crawling slowly, the method used by Stirman’s group may offer more precise laser targeting. “Do both papers contribute to understanding behavior at a holistic level? Yes, definitely.”

Neuroengineer Ed Boyden of MIT says the new work could allow scientists to figure out how every cell in an animal works together to generate a behavior. “The ability to
target a single cell is really important, because it allows you to understand precisely what each of these cells does.”

Laura Sanders

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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