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Loren Looger is motivated by the audacity of his plan: to redesign the way we think.
The purely practical applications that follow, says Baker, can be handled by others. For the past few years, he has run the calculations necessary to predict protein shape with help from the computers of laypeople around the world. The distributed computing network is called Rosetta@home and has more than 200,000 members from all walks of life. Now, Baker and his colleagues at UW have devised a multiplayer game for them called Foldit. Players score points for folding amino acid sequences into the most stable shapes. Later this year, the Foldit team plans to introduce a design element to allow players to create brand new proteins. The design game aims to turn people all over the world into competitive molecular engineers. “I imagine a 12-year-old in Indonesia who can visualize proteins in his head and build a cure for HIV,” Baker says.
Like Baker, Loren Looger, a group leader at Janelia Farm, likes to build. At the moment, Looger thinks of his lab as a one-stop tool shop for his colleagues at Janelia—making new molecules to assist their research. “People want sensors for all the hot neurotransmitters—serotonin, GABA, glutamate, dopamine,” he says. “We also make brighter fluorescent proteins, and fluorescent proteins that can switch colors. Those are useful for different modes of imaging.”
According to Looger, whose training is in math, synthetic chemistry, and computer science, making sensors and fluorescent proteins isn't exactly easy, but “it's pretty obvious what needs to be done.” In a year or so, after he's taken care of his colleagues' pressing needs, Looger plans to turn his prowess in manipulating molecules to the wiring of neurons. “We'll start to swing the pendulum back toward crazier things, like getting inside neurons and whole-scale rewiring,” he says. “There's that idiom that you don't really understand a system until you can redesign how it works.”
In his drive to test his understanding of how neurons function, Looger will change the sequence of amino acids in neuronal proteins, basically reengineering the proteins that control the way neurons communicate. “That work is mainly driven by curiosity … the sheer audacity of trying to redesign the way we think,” he says.
Down the hall from Loren Looger's office at Janelia Farm, Dmitri Chklovskii is looking for simple engineering principles in the dizzying structure of neural networks.
Chklovskii is investigating a century-old tenet called “the wiring economy principle.” The idea was formulated by Santiago Ramón y Cajal, a Spaniard who won the 1906 Nobel Prize in Physiology or Medicine for his work on the structure of the nervous system.
Ramón y Cajal believed that evolution would act to reduce the length of connections between neurons to conserve energy and materials. The same principle is a key part of microchip design: fitting transistors close together on chips allows engineers to reduce the distance electrons must travel along wires, thereby increasing processing speed. In addition, says Chklovskii, “wires are mostly what take up the room on a computer chip. If you don't optimize their length, you can't fit a significant circuit on a chip of a limited size.”
Testing the wiring economy principle on the scale of a whole brain in fact involves borrowing the tools of a microchip engineer: tracing every nerve connection in an organism's nervous system, then feeding the connection data into a computer and comparing its “optimal” layout with the reality of what's there.
Photo: Barbara Ries