Science lab spotlight

‘Watch, perturb, and map’

A multifaceted approach to studying the human brain and condition

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An expanded piece of mouse brain shows the fine wiring of the brain. The neurons are expressing fluorescent proteins.
Courtesy of the Synthetic Neurobiology Group

For Ed Boyden ’99, leader of the Synthetic Neurobiology Group, the ultimate puzzle can be summed up in one succinct phrase, he said in his interview with The Tech: “addressing the problems of the human condition through science.” It is only fitting that the lab’s work involves the creation and dissemination of the tools to study the fundamental mechanisms of brain function and applying these findings to treating disorders.

At a young age, Boyden became fascinated by the nature of suffering and happiness, and his perpetual curiosity drove him to becoming one of the world’s top biological innovators. However, the course that led him to the brain was rather nonlinear. Upon getting an early start to his college education, Boyden delved into a research project on the chemical origins of life and the derivation of DNA from inorganic precursors. He then transferred from his previous institution to MIT at age 16, initially applying his Course 6 and 8 education to a quantum computing project. Eventually, he landed on the brain, perhaps the most intricate yet revealing lens into the human psyche and behaviors. From then on, Boyden framed his outlook on the brain with engineering, philosophy, and science.

Boyden described his arrival to neuroscience as “great timing,” as his previous experiences in other fields equipped him with the unique ability to approach problems technologically. The evolution of his career is directly reflected in the lab’s work and makeup, which Boyden deemed “omnidisciplinary.” The Synthetic Neurobiology Group consists of 50 full­time contributors, including a professional neurosurgeon, a former professional photographer with a background in art, biologists, chemists, physicists, electrical engineers, computer scientists, and more; this leads Boyden to conjecture that it may be one of the largest neuroscience groups in academia.

“Watch, perturb, and map” is the mantra of this avant­-garde group of thinkers. In order to obtain the most comprehensive picture of the brain, the vast team of scientists is focusing on integrating three technologies: fluorescent voltage indicators to watch the brain­­, optogenetics to perturb the brain­­, and expansion microscopy to map the brain. Fluorescent voltage indicators, which the lab developed and announced last year, are molecules that glow when put into active brain cells. They are primarily used to image neural activity, or, in other words, watch the brain, by measuring membrane potentials.

Perturbation of the brain is achieved through optogenetics. Like fluorescent voltage indicators, optogenetic molecules are put into brain cells. But, mechanistically, they are more directly controllable. These molecules convert electricity to light, so when light is shined upon the brain, the brain cells containing these molecules are electrically activated. This command over the brain is key in understanding behaviors, as activating brain cells helps determine how they, as Boyden put it, “trigger behaviors or pathological states,” while deactivating them aids in establishing their uses and necessities. The implications of optogenetics are versatile, as the activation of a certain set of cells may have the capacity to, for example, trigger memories or combat disease progression. The technology has popularized immensely, and the Boyden lab has given it to thousands of research groups across the globe.

Finally, the brain is mapped through expansion microscopy. In 2015, the lab patented this technique, which allows for tissues to be imaged with nanoscale precision. Instead of relying on optical magnification, by which cost, imaging speed, and hardware complexity limitations arise, expansion microscopy involves physically and evenly magnifying specimen. This process is driven by the infusion of the tissue with what Boyden coined a “baby-diaper-like” chemical, which swells upon exposure to water and evenly expands the sample. The resulting tissue is essentially transparent, as it is primarily composed of water, and the expansion is so precise that, within the brain, for example, even the most minute of connections can be visualized. Since the magnification is physical, a variety of cheap, scalable, or high­-throughput optical tools (such as lattice ­sheet microscopy or the aforementioned imaging techniques) can be paired with expansion microscopy, which, according to Boyden, has allowed the lab to image brain circuits “a thousand times faster than the competition, with this number growing soon.”

These three technologies have many applications to areas unrelated to the brain. For instance, two years ago, the lab published a paper on the implications of expansion microscopy on early cancer breast cancer detection. Typically, detecting cancer early is hindered by the small scale of the disease ­driven biological changes, but expansion microscopy can amplify these small, early changes into those that are visible. Since pathologists disagree roughly half of the time about the diagnosis of breast cancer biopsies, Boyden and his team devised a machine learning algorithm to classify expansion­ microscopy­ enlarged ­biopsies with a high degree of accuracy.

Though Ed Boyden’s work centers on the brain, the technologies his group pioneers are multidisciplinary at their core. Whether the lab is pursuing new diagnostic possibilities by applying their methods in a translational context, investigating the augmentation of brain function in the face of disability, or gaining a better understanding of our emotion, cognition, and motion as humans, it is clear that the trajectory of the work is forward, moving across boundaries and borders, imbued with an interminable zest to grasp the human condition and its infinite complexities.