Twenty years ago, Professor Na Ji (PhD in Chemistry ‘05) went through what she calls the grad student version of a mid-life crisis. “I just got a bit bored. You publish a few papers, but then it’s like, ‘What’s next?’” So she started picking up biology textbooks – molecular, developmental, and finally neurobiology. “They talk about current, voltage–they speak the language of physicists. Very quantitative. I basically decided that I want to become a neurobiologist.” Her renowned Physics advisor, Yuen-Ron Shen(link is external), connected her with the head of the neurobiology program, Mu-ming Poo(link is external), who told her that she was not too old to switch her research to neurobiology, given the long graduate and post-graduate training that is typical for the field. Through a series of accidental connections, she was introduced to Eric Betzig (Nobel Prize(link is external) in Chemistry ‘14), who just started a lab at Janelia Research Campus(link is external) of the Howard Hughes Medical Institute. Although he was a microscopist and not a biologist, neuroscience was a major focus at Janelia, and Professor Ji realized that the optics training acquired from her PhD gave her a unique opportunity to use microscopy as a gateway into the neuroscience community.
Professor Na Ji
“If you take a cell out of the brain and stick it on a slide, you can get a really good look at it. But that does not tell you how the brain works - you need to look at the cells in the brain itself.” These cells, called neurons, receive electrical and chemical signals from many other neurons. Our mental activity emerges from the interaction of neurons within neural circuits of staggering complexity, where the computations involved include those carried out by an individual neuron integrating its many inputs, and those performed by the coordinated activity of many neurons within neural circuits. To get a handle on this complexity, one of our most promising avenues is through the development of new tools.
On this point, Professor Ji likes to quote(link is external) Sydney Brenner (Nobel Prize 2002(link is external)), founder of the Berkeley Molecular Sciences Institute: "Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order."
Over the last twenty years, such tools have included new microscopes and fluorescent sensors. These have transformed biological imaging from static snapshots to dynamic movies inside living organisms. In neuroscience, they have proven particularly powerful, because structure and function are deeply intertwined.
However, given the enormity of the task of understanding the brain, much more was (and is) needed. For example, when light passes through the brain, it gets distorted by the brain tissue, similar to the way the atmosphere blurs the telescopic image of a star. This makes it difficult or impossible to see synaptic connections between neurons that are only a few hundred nanometers in size. In addition, the most popular microscopy method in neuroscience, two-photon excited fluorescence microscopy(link is external) uses near-infrared laser light that penetrates farther into opaque brain tissue than visible light to visualize neural structure and activity. However, because it acquires images one pixel at a time, it has limited speed: 30 frames per second (30 Hz) can be achieved by standard microscopes, but they are too slow to capture the electrical signal that goes by in a millisecond, which needs to be imaged at a thousand frames per second (1 kHz). Inspired by concepts from astrophysics and optical physics, and supported by the Brain Initiative (launched(link is external) 2013) and Weill Neurohub(link is external), Professor Ji has addressed these challenges with a suite of microscopy tools that can image the brain at higher resolution, greater depth, and faster time scales.
Adaptive Optics (AO) has helped astronomers get clearer images by correcting for the blurring caused by Earth’s atmosphere. Indeed, ground-based AO-equipped telescopes can now see distant stars and planets almost as sharply as if the telescopes were in space. But AO methods developed for astronomy are for clear skies and are not immediately applicable to tissues that are not see-through. The Ji lab has invented new AO approaches that improve the quality of microscopic images in opaque biological tissues. “It’s like putting prescription glasses on the microscope, compensating for the distortion.” This allows synapses to be visualized deep inside living animals.
The Ji lab has also used Bessel beam(link is external), a thin, pencil-like beam that doesn’t spread out as it travels, to image an entire slab with the brain simultaneously. Using infinity mirrors(link is external), two angled mirrors that allow two-photon excited fluorescence microscopy to acquire millions of pixels per second, her lab has also improved its imaging speed to thousands of frames per second. Now(link is external) we can see how the brain functions by tracking the rapid chemical and electrical signals in neural circuits. It has also allowed the Ji lab to watch blood cells zipping(link is external) through vessels in the brain at microsecond resolution.