As a marine engineer, Morgan Sheng's father spent months at sea, deep in the bowels of ships, keeping them running. Sheng has spent his neuroscience career plumbing the depths of the brain, elucidating the underpinnings that explain how it works.
Sheng studies how brain cells communicate and change in response to experience. He focuses on synapses, the junctions between nerve cells. Chemical messages pass across these junctions, linking brain cells into networks.
Emerging evidence shows that many common diseases of the brain may stem from miscommunication between nerve cells. Also, in neurodegenerative diseases, synapses are not working properly and are gradually lost. "By studying how synapses work and how they go wrong in illnesses, we get a window into…very human things—learning and memory, happiness and sadness," Sheng says.
Each synapse involves the axon of the "sender" nerve cell contacting the dendrites of the "receiver" nerve cell. Sheng's research focuses on a structure in the dendrites called the postsynaptic density (PSD), which helps receive chemical messages released from the sender axon. He is imaging the PSD and characterizing its component molecules, hoping to explain its structure, function, and composition. Sheng and his colleagues already have mapped the network of pathways that connect the PSD's message receptors to a cell's interior.
The PSD is key to a healthy brain. In 2007, Sheng's research group found that adding phosphate groups to part of the PSD structure (a protein called PSD-95) helps nerve cells to build stronger connections. Sheng believes that manipulating the phosphorylation of PSD-95 might boost brainpower in patients afflicted by schizophrenia, depression, or neurodegenerative disease.
A London (U.K.) native and the oldest of three boys, Sheng finished second in his class at Oxford and went to medical school. After practicing medicine for four years, he decided to transition to a more academic career. Attracted to the field of molecular genetics, Sheng wanted to get a Ph.D. to try to "bridge the gap" between physicians and basic scientists.
In graduate school at Harvard, he attended grand rounds at Massachusetts General Hospital and kept up with the medical journals, planning to return to clinical medicine. "But eventually all of that fell to the wayside, because I found that doing basic research was very interesting, and more fun than medicine. So I never went back. I enjoyed practicing medicine, but I feel like basic research is more my calling."
His work with synaptic plasticity—the ability of synapses to change their size and strength dynamically—has helped him shape a metaphor for the brain that differs from many others. "Most people talk about the brain as a machine or a computer," he says. "But the brain is much more than a computer and a machine. The brain constantly changes and adapts itself; it is amazingly malleable during childhood, and it can resculpt itself even in adulthood."
Sheng says a more apt metaphor might be a successful multinational corporation with numerous employees and many departments. "The brain, by expending a lot energy for the sake of adaptability and responsiveness…takes a lot of risk and then focuses on the things that are working," he says.
Sheng points out that not every gene is crucial for brain function. Some of them, he says, are like middle executives in a company. Loss of their functions may be relatively easy to compensate for early in development, but more difficult later on. He offers an analogy. "In later life, my father was basically a middle executive. If the company had never had him, it might do okay. But it might not be so great if they got rid of him when he was occupying the corner office."
Taking this into account, Sheng began studying phosphorylation and its effects. Different sites on proteins are phosphorylated by the addition of a phosphate (PO4) group. This process changes the shape of a protein. It can turn enzymes "on" or "off" and change protein function.
"[Studying phosphorylation] can tell you about what a protein does in ways that standard genetics approaches cannot," he says. For example, protein X could be involved in both learning and forgetting. Remove that protein (the standard genetic approach), says Sheng, "and you might completely screw up behavior, which is difficult to interpret. You might also get no effect at all, if another related protein takes over X's function." But, he says, "If you can show that one protein site is phosphorylated during learning and another site is dephosphorylated during forgetting, you learn more about the protein's function."
Sheng lives in Brookline, Massachusetts, with his wife, 11-year-old son, and 6-year-old daughter. "I don't try to edge [my children] toward science," he says. "But they probably absorb a certain scientific attitude by being around me, because I never believe anything people tell me!"
