One of the decisive molecules turned out to be a micro-RNA—a small, single-stranded RNA with a gene-silencing function similar to the one performed by RNA interference. This molecule, dubbed lsy-6, is expressed only in the left-sided ASE neurons. It represses "right-sided" gene activity, which ordinarily would be the default case, thereby allowing left-orientation gene programs to do their work. In certain C. elegans mutants, lsy-6 is knocked out; as a result, right orientation is "de-repressed" so that all ASE neurons are right-sided.

As with the zebrafish research, Hobert can't quite follow the trail to identify the first signal in the embryo that triggers asymmetrical nerve-cell fates. But the worm findings have put on the table a mechanism that, like the processes being uncovered in the zebrafish, may be a general method adopted by higher animals.

"The discovery that there are asymmetries in invertebrate nervous systems is in itself exciting, and I predict that insights gained from these studies (i.e., of C. elegans) will be very relevant to the human story, although with some very major differences," says David C. Van Essen, a brain researcher at Washington University and a member of the HHMI Scientific Review Board. Van Essen notes that his colleagues have used functional MRI to reveal previously unknown nerve networks in human brains that allow the two hemispheres to communicate with each other more closely than had been thought. These findings fit with previous observations that the opposite side of the brain can often compensate when an important, localized function like speech is lost through a stroke or disease.

In the early 1860s, French physician Paul Broca found that a man who had become almost speechless after infection with syphilis had damage in a part of the left hemisphere now known as "Broca's area." Broca inferred, from this and other brain studies, that this left-brain structure controlled speech, as damage in the corresponding area of the right hemisphere did not affect speaking ability. This finding was the first strong evidence of lateralization of brain functions in human beings.

One hundred fifty years later, scientists are beginning to understand what genetic programs guide asymmetry and lateralization. It's a logical assumption that some genes are expressed differently in the right and left brains—as in the zebrafish and C. elegans—though studies of the brains of human adults haven't turned up any significant differences, according to Christopher A. Walsh, an HHMI investigator at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston.

Reasoning that it might be more fruitful to hunt for differences in gene expression during development when asymmetries are being established, Walsh and his colleagues obtained fetal brain tissue from an NIH-funded repository. They analyzed and compared gene activity in tissue from the left hemisphere area where language centers form and tissue from the corresponding area of the right hemisphere.

The researchers reported in Science in 2005 that 27 genes (the group has since found 13 more) were differentially expressed in the left and right hemispheres, particularly in the perisylvian regions—those around a landmark structure called the Sylvian fissure—that are specialized in the left hemisphere for language.

		Through a clever use of asymmetry, the roundworm C. elegans makes an odor-sniffing nerve cell do double duty. The AWC neuron takes two slightly different forms—AWC-ON and AWC-OFF, tuned for different scents—randomly destined for opposite sides of the worm. But since the scent-sensors can end up on either side, how does nature ensure there will always be one of each type? HHMI investigator Cornelia Bargmann at The Rockefeller University has discovered that the developing AWC cells choose up sides in a brief "chat" via cellular channels called gap junctions that form in the embryo—then vanish when their job is done. —R.S.

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