One day in 1788,students at the Hunterian School of Medicine in London were opening a cadaver when they discovered something startling. The dead mans 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 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.
Biologists have pinpointed a single spot where this symmetry breaking starts: a tiny pit called the node,on the embryos 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. Its like a blender, 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.
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 dont know the nitty-gritty, Norris said. We dont know the actual mechanics in these cells of what is happening.
Regardless of those details,the cilia on the rim of the node respond to the flowpossibly by releasing calcium atoms that then spread to surrounding cells. Those cells respond by spewing out a protein called Nodal,which spreads through the left side of the embryo,in turn spurring other cells to spew out Nodal of their own in a kind of feedback loop that leaves the left side loaded with Nodal and the right with almost none. Nodal begets Nodal,and then were off, Norris said.
The reversal is relatively safe because all the organs line up with one another. You look at yourself in the mirror,and you look perfectly normal, Norris said. You dont stop looking like a human being just because you see yourself backward. The real danger,it appears,is in incomplete reversals. Most worrisome are cases in which the heart is affected.
In other cases,the heart grows correctly on the left side of the body,but the structures inside the heartthe valves and chambersgrow on the wrong side. These disorders may not be immediately fatal,but they can become dangerous later in life,requiring complex surgery to rearrange the heart.
Rebecca Burdine,a molecular biologist at Princeton hopes that research on left-right disorders will lead to genetic tests that can predict the risk of these hidden heart defects. She even sees an application to attempts to rebuild damaged hearts with stem cells. Its going to be more than just making the right cells, she said,adding that they would need to be placed in the proper three-dimensional structure and given the correct signals on where to go. And one of those signals, she said,is the left-right signal.