Growing Left, Growing Right - How a Body Breaks Symmetry One day in 1788, students at the Hunterian School of Medicine in London were opening a cadaver when they discovered something startling. The dead man's anatomy was a mirror image of normal. His liver was on his left side instead of the right. His heart had beaten on his right side, not his left. The students had never seen anything like it, and they rushed to find their teacher, the Scottish physician Matthew Baillie, who was just as stunned as they were. "It is so extraordinary as scarcely to have been seen by any of the most celebrated anatomists," he later wrote. His report was the first detailed description of the condition, which came to be known as situs inversus and is thought to occur in about 1 in 20,000 people. Baillie argued that if doctors could figure out how this strange condition came to be, they might come to understand how our bodies normally tell the right side from the left. Over two centuries later, the mystery of left and right still captivates scientists. "I know what it is, you know what it is, but how does the embryo learn what it is?" asked Dominic P. Norris, a developmental biologist at the University of Cambridge in England. Now Dr. Norris and other scientists are beginning to answer that question. They have pinpointed some of the steps by which embryos" organs develop on the left or right. And their research may do more than simply solve an old puzzle. Mutations that cause situs inversus can lead to a number of serious disorders, including congenital heart defects. Deciphering the effects of mutated genes could lead to diagnoses and treatments for those conditions. "Understanding how you put this axis together has a lot of implications for understanding congenital heart disease," said Rebecca Burdine, a molecular biologist at Princeton. Our bodies start out symmetrical, the left side a perfect reflection of the right. "Visible signs of left-right asymmetry in the human body are apparent around six weeks," said Sudipto Roy of the Institute of Molecular and Cell Biology in Singapore, an author of a review of left-right asymmetry that was published last week in the journal Open Biology. The heart shows the first visible asymmetry. Starting out as a simple tube, it loops to the left. The heart then starts to grow different structures on each side, producing the chambers and vessels required to pump blood. Meanwhile, other organs start moving. The stomach and liver each move clockwise away from the midline of the embryo. The large intestines sprout an appendix on the right. The right lung grows three lobes, the left only two. But these visible changes arise long after the embryo has developed differences on its left and right. Experiments have revealed that the early embryo produces different proteins on each side while it still looks symmetrical. Biologists have pinpointed a single spot where this symmetry breaking starts: a tiny pit called the node, on the embryo's midline. The interior of the node is lined with hundreds of tiny hairs, called cilia, which whirl round and round at a rate of 10 times a second. These whirling cilia are tilted, pointing away from the head. The tilt is essential to their ability to divide the body into left and right. Recently Kathryn V. Anderson and her colleagues at Memorial Sloan-Kettering Cancer Center disabled genes required to tip the cilia in the node. As they report in the journal Development, that mutation led to some mouse embryos" developing a mirror-image anatomy. The tilt of the cilia is so important because the embryo is bathed in a thin film of fluid; if they were upright, they would push the fluid in all directions, creating no flow at all. "It's like a blender," Dr. Norris said. It just goes round and round. Tilted, they all push the fluid in one direction, from right to left. When scientists reversed that flow in mouse embryos, it resulted in reversed organs. It takes only a very weak flow to the left side to start an embryo on its proper development: Last year, scientists at Osaka University in Japan reported that the whirling of just two cilia were enough to get the job done. And that raises another question: "What on earth are we doing with all those cilia if we don't need them?" as Dr. Norris put it. We don't know. Once the fluid starts flowing, it takes only three or four hours for the left and right sides to be determined. Scientists have only a patchy understanding of the steps in between. In the first step, the fluid flows across the node until it reaches the left side of the rim. The rim is ringed by cilia that do not spin. Somehow, they respond to the flow. They may physically bend, or the flow may deliver some protein to them. "We don't know the nitty-gritty," Dr. Norris said. We don't know the actual mechanics in these cells of what is happening.