During China's Cultural Revolution, Yishi Jin lived in a small village in the northern part of the country, where farm life piqued her curiosity about the natural world. Four years after the revolution ended, she went to Beijing University, where she found biology professors so glad to teach again that they lavished attention on their students. In 1985, the China–United States Biochemistry and Molecular Biology Examination and Administration (CUSBEA) selected Jin as one of the top 60 biology graduates in China, enabling her to pursue a Ph.D. in the United States. Since finishing graduate school, Jin has remained in this country, using her gift for science to understand how nerve cells interconnect.
A nerve cell communicates with another nerve cell when the tip of its long "arm," or axon, releases sacs of chemicals into a small gap between the two cells. When these chemicals bind to receptor proteins on the second cell, they transmit information. The specialized membrane at the end of the axon (the presynaptic membrane), the gap, and the membrane that receives the message (the postsynaptic membrane) are called a synapse, which is what Jin studies. "Synapses have a very organized arrangement with particular types of vesicles and numbers of subcellular structures that are arranged in a very tiny space," Jin says. "The question is how all the components can come together in one place, be arranged in an orderly fashion, and then get stabilized." Determining how synapses form and are maintained in experimental organisms should enlarge our understanding of diseases such as autism and schizophrenia, Jin adds, because synaptic abnormalities have been implicated in several psychiatric conditions and synaptic proteins have been conserved during evolution.
Looking for a model organism, Jin turned to a minute worm called Caenorhabditis elegans, a free-living nematode found ubiquitously in soil. C. elegans is the only organism in which every nerve cell's development and connectivity are known; therefore, scientists can precisely identify the developmental consequences of any genetic mutation.
By screening thousands of mutant worms, Jin found several whose synapses were disrupted. By cloning the responsible genes, she discovered an enzyme named regulator of presynaptic morphology, or RPM-1. This large protein sits at the periphery of the presynaptic terminal, and it turned out to be a ubiquitin ligase. These enzymes attach a small protein called ubiquitin to a target protein, which is then put into the cell's garbage cans to terminate the signaling cascade it triggers. Jin's group revealed that RPM-1 tags a signaling molecule called MAP kinase, which initiates a variety of cellular events. "The key questions of our continued interest are what is MAP kinase doing at the synapse and why does RPM-1 need to terminate its activity?" Jin says.
Through genetic screening, Jin hopes to find all the proteins involved in RPM-1 function. She will then determine how these proteins interact in space and time as a synapse develops. "This will involve developing more time-resolvable methodologies to allow us to turn something on and off whenever we want to," she says.
Jin's interest in synapse development eventually led her to study nervous system repair in adult organisms because nerves that are damaged in, say, a car accident, have to form new synapses to regain function. With the help of physicists from Stanford University, her group at the University of California, Santa Cruz (where she was on the faculty from 1996 to 2006) developed a way to sever a single nerve axon in the worm with a laser beam. To better mimic the consequences of traumatic nerve damage, which harms adjacent tissue as well, she is now modifying this type of surgery. She and her collaborators found that nerve axons begin to regrow just 12–24 hours after being severed, and she's now looking for the genes that promote axonal growth and synapse formation. "We hope such information will aid the development of drug targets to stimulate nerve growth and stabilize a synapse," Jin says.
Such targets are likely to be suggested by the worm, Jin points out. "Often I have no clue where to go, but genetics has always led me to find players that have not been discovered, and that leads me to rethink a process and go from there," she says. "It takes curiosity and persistence and not thinking that a problem is as simple as you'd like it to be."
