Even in the 21st century, the essence of how the brain stores and retrieves information remains mysterious. Mark Schnitzer builds tools that literally bring these processes into focus. He designs and constructs tiny microscopes that peer deep into the brains of mice and focus on individual neurons or networks of a few hundred brain cells as they talk to each other. "The technological goal is to be able to watch what the neurons are doing as you watch what the animal is doing," Schnitzer says. Experiments of this kind may eventually help scientists fathom how networks of neurons form thoughts and create memories.
Schnitzer has built microscopic optics that are providing the first live glimpses into deep brain structures. "My motivation was very clear from the start. I wanted to develop a technique using an optical needle with the resolution of a normal light microscope to see cells in deep brain areas," he says. A visitor to his Stanford University lab can watch mice scurry around their cages with optical fibers leading from their skulls to optical equipment. These fibers—each a bit thicker than a human hair—deliver pulses of laser light that excite fluorescent dyes inside neurons in the animals' brains. The microoptics inside the fiber can see the fluorescing dye, and a computer records the action.
Schnitzer developed the core technologies for these microscopes during a four-year stint at the vaunted Bell Labs in New Jersey, where he arrived fresh from a physics Ph.D. in the 1990s. He already knew he wanted to apply fiber optics to deep brain imaging. At the time, the Internet boom was in full swing, and the facility had an active fiber optics laboratory. So he set about learning from scientists working on a much larger scale—they were transmitting light through thousands of miles of underwater glass cables. "It was a wonderful experience," Schnitzer says.
In 2002, in collaboration with the fiber optics department at Bell Labs, he fabricated a tiny lens 125 micrometers in diameter, slightly larger than the average human hair, which is about 80 micrometers in diameter. Making such a tiny working lens was an important step in his professional development, Schnitzer says, and a key step toward making the fully functioning microscope he envisioned.
The next year, Schnitzer published a paper that described the basic laser and microlens combination that composes his deep-brain microscope. This paper together with follow-up articles that detailed how the system was used to observe neurons in a live animal are now considered milestone in the field, and he has been awarded seven patents on the technology.
Schnitzer believes the next vital step in studying the brain will be massively parallel systems that can look at many brains at the same time. He is building a system to image the brains of 100 fruit flies simultaneously. The plan is to first line the flies up in rows while they are immobilized in tiny stockades. Scientists will then use a laser to drill open the thin covering of the flies' heads so the microscopes can see inside for brain imaging. "In neuroscience, we tend to be data-limited," says Schnitzer, who was a visiting scientist at HHMI's Janelia Farm Research Campus starting in 2006. But with the new system, instead of looking at the brains of one or two flies a day, one scientist will be able to monitor 100 each day. In fact, the amount of information generated will be so large—enough to fill a standard laptop hard drive in two or three minutes, at 0.5 gigabyte/second—that he has partnered with data-storage experts to figure out how best to handle so much data. These images are expected to eventually provide key insights into brain development and neurological disorders like Parkinson's disease, Schnitzer says. They could even be used to screen how new pharmaceuticals affect the brain.
Slowly, Schnitzer's imaging technologies are wending their way into the human health arena. He is collaborating with neurologists to image muscle fibers in human patients with muscular dystrophy and similar disorders. He's also designing imaging instruments to help improve the delivery of cochlear implants for the deaf.
"There's a history in biomedicine of new imaging techniques driving advances in both basic and applied science," Schnitzer says. "People get creative and devise applications well beyond what was originally intended. I'd love to see that happen here."