Like many college freshman interested in biology, Kang Shen set his sights on becoming a doctor. Fresh out of high school, he enrolled in an accelerated program at Tongji Medical University in China that combined undergraduate and medical school with a year of research.
That single year at the bench compelled him to go halfway around the world to become a scientist. "I found myself thinking this is what I want to do. I want to be a researcher, and the best environment for research is in the U.S.," says Shen, who studied the effects of herbal ingredients on calcium channels in cardiac muscle cells during his year of research.
"I see my scientific career as comprised of two transformations," says Shen, who traveled to Duke University to study for a Ph.D in cell biology and neuroscience. "One from medicine to research; the other from China to the U.S. And I made them both simply for the pure joy of doing research."
Shen found his research path right away, as he made that transition from medical student to graduate student. The research that interested him involved an enzyme in brain cells that is important for learning and memory. One form of the enzyme was active close to the synapse, the communication junction between neurons.
"That got me really excited about thinking about synapses and how neurons form them," Shen says. Neurons in the central nervous system send out long projections called axons in an effort to form synapses with specific neurons. Although much is understood about how axons travel to the appropriate location, little is known about how they pick their partners from the many neurons present in the same area. "It is an essential question," Shen says.
Shen began looking for a lab where he could answer that question. "I was really searching for an experimental system that would allow me to focus on finding the molecular mechanisms that determine which neurons ultimately form synapses." He began a postdoctoral fellowship in the lab of HHMI investigator Cornelia Bargmann, who has pioneered studies of the development and function of the olfactory system in the nematode worm Caenorhabditis elegans. Shen says C. elegans is the perfect model system because its nervous system is composed of just 302 neurons that form unvarying connections with other neurons, and its genetics are well described. Better yet, the worm's translucent body allows researchers to see synapses directly when proteins that congregate there are tagged with a fluorescent label.
While in Bargmann's lab, Shen discovered how the HSNL neuron in nematodes—which helps regulate egg-laying—chooses its sole synaptic partner. He found that the two partner neurons did not find one another on their own. Instead, guidepost cells positioned near the site of the eventual synapse guided HSNL, which formed its synapse in response to the interaction between the SYG-1 protein residing on its cell surface and the SYG-2 protein dotting the surface of the guidepost cells. "This interaction is the nature of the secret handshake," Shen says.
This was a reasonable explanation for how this single neuron established a connection in the worm's simple nervous system. However, the discovery created a problem for Shen, who hoped his research would help explain how synapses are formed in humans, who have roughly 25,000 genes and 100 trillion synapses. "When I was interviewing for faculty positions and presenting my research, people kept asking me, 'How could there be enough of these types of proteins to account for all synaptic pairs?'" Shen says. "I didn't really have an answer. They were right, it was a problem."
Shen, now at Stanford University, has focused on studying how neurons build synaptic connections. His group uses genetic screens to collect mutants likely involved in the development of synapses, which has helped him make inroads into that problem. His lab has discovered that a diverse array of mechanisms modulate synaptic connectivity and prompt the formation of specific synapses. One solution to the greater complexity faced by developing neurons in higher organisms, such as humans, is the existence of a combination of positive and negative signals that guide synapse formation, Shen says. His lab has found some positive signals that encourage synapse formation and some negative signals that ward off neurons trying to establish an inappropriate connection.
"Having negative and positive signals solves the problem of not having enough genes to go around—a combinatorial mechanism significantly increases the diversity of the signals" that can direct the formation of a synapse, Shen says.
His lab is focusing on further understanding those signals and searching for others in the nematode as well as in mice and other vertebrates. His team is exploring whether several mouse proteins—Nephrin and NEPH1, -2, and -3, which are similar to SYG-1 and SYG-2—trigger synapse formation by interacting with each other. In addition, the lab is collaborating with HHMI investigator Richard Axel at Columbia University to see if the same mouse proteins play a role in development of the olfactory system.
"Building a synapse requires many proteins to localize at the right place at the right time," Shen says. "I speculate that ultimately the question of synaptic formation is going to be solved by studying a variety of different synapses."
Synapses aren't uniform entities—for example, those driving muscle contractions are enormous compared with others in the brain. In addition, some synapses can rearrange themselves while others are static. The genetic screens Shen's lab uses to collect mutations have uncovered a worm mutant that is related to aging—the synapses develop normally but fall apart as they age. "Aging humans tend to lose synaptic functions before neurons are lost," Shen says, noting that the synapses of nematodes are remarkably similar to those in human brains.
"Neuroscience has really exploded over the last decade as many new tools are now available to address questions that have been around for decades," Shen says. "It is a very exciting time to be a neurobiologist."