Two genes help an embryo pick sides.

The growing human embryo quickly learns to tell left from right. That's vital, since the outward bilateral symmetry of a human body isn't matched internally. The heart, stomach, and spleen reside on the left, while the liver prefers the right. Even paired organs such as the lungs exhibit some asymmetry; the right lung has three lobes, while the left has two.

To understand how this left-right aids arises, scientists have sought the mutated genes responsible for the rare cases in which the internal organs of people, or mice, are flipped left to right or positioned randomly on either side of the body They've now found two such genes.

"These are the first demonstrations of single-gene defects that lead to naturally occurring left-right patterning abnormalities in human and mouse," writes Deepak Srivastava of the University of Texas Southwestern Medical Center at Dallas in the November Nature Genetics

Brett Casey of the Baylor College of Medicine in Houston, who describes one of the new genes, grew fascinated with left-right asymmetry many years ago when he performed an autopsy on an infant whose internal organs, particularly the heart, were askew. At the autopsy, a colleague told Casey about a large family in which newborn boys frequently had similar problems.

After studying the family's history, Casey concluded that a mutated gene must exist on the X chromosome. In 1993, he narrowed its location to a small region of the chromosome. In the November Nature Genetics, Casey and his colleagues identify the gene and describe mutations found in the original family and in other people with left-right developmental anomalies.

The newfound gene encodes a protein called ZIC3, whose amino acid sequence suggests that it binds to DNA and regulates gene activity. The investigators do not yet know how ZIC3 contributes to formation of left-right asymmetry, but they think its gene acts early in the process.

The discovery of the gene may help unearth additional genes that create the bilateral axis. Mutations in ZIC3's gene account for only a small percentage of people with abnormal left-right asymmetry.

"There are obviously too many genes involved in this complicated cascade to think that any one will be the dominant player," says Casey.

By studying two strains of mice in which some animals are born normal, some with their internal organs inverted completely, and some with organs in random positions, researchers have found a second gene that seems to play a role in left-right asymmetry.

"We think this gene may be involved in the initial determination of left-right asymmetry," says Martina Brueckner of the Yale University School of Medicine.

The gene, described in the Oct. 30 Nature, encodes a dynein, a protein that forms huge complexes which can serve as molecular motors. Dynein complexes usually interact with long intracellular rods called microtubules, transporting cargo along them or bending them.

Since microtubules have distinguishable ends and dyneins always move toward the same end, the microtubules may act as one-way streets that establish an original left-right asymmetry.

"You've got to have something asymmetric to create new asymmetry. You can't create it out of nothing," Brueckner notes. "We're assuming that the original asymmetric molecule is the microtubule and that the dynein takes that asymmetry and converts it into cellular asymmetry."

Determining how that conversion takes place is next on the agenda, she adds.