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Thinking Small: A New Tool for Decoding the Brain’s Chemical Signals


Chemist Nako Nakatsuka is developing tiny sensors that could revolutionize our ability to monitor and understand all kinds of health problems, including brain disease.

From remembering song lyrics to pouring a cup of coffee, every impulse in the brain starts on a tiny scale, with an electrical signal firing between brain cells across a synapse only 50 nanometers wide—2,000 times thinner than a sheet of paper. That signal directs the flow of brain chemicals such as serotonin, norepinephrine, and dopamine, which trigger the next electrical signal, and so on.

Physicians use sophisticated tools, such as electroencephalograms, or EEGs, to diagnose and monitor brain disorders, but they see only the electrical impulses, which is a bit like hearing two people talking but not understanding what they are saying, says Nako Nakatsuka, Ph.D., a chemist at ETH Zürich in Switzerland. “It’s like a very muffled conversation.”

Scientists have struggled to identify those complex chemical interactions at the time they occur. Often, that requires extracting liquid from the brain and putting it through tedious purification techniques in the lab, a process that can take days.

“I wanted to be able to insert a sensor close to where these interactions happen and monitor this chemical flux in real time,” says Nakatsuka, a 2012 Fordham College at Rose Hill graduate who has spent the past several years developing a chemical biosensor to do just that. The technology she created consists of a glass pipette tapering to just 10 nanometers at its tip, able to get in close proximity to synapses and monitor chemicals at the source. “We’re using nanotechnology to approach the dimensions at which the chemistry happens,” Nakatsuka says.

The invention earned her a spot this year on MIT Technology Review’s list of “35 Innovators Under 35” (out of over 500 nominations). More importantly, it could revolutionize the study of diseases such as Alzheimer’s and Parkinson’s by allowing neuroscientists to truly understand, for the first time, chemical interactions inside the brain as they occur.

Into the World of Bionanotechnology

Nakatsuka spent her formative years attending an all-girls school in Japan, where she was just as interested in art and athletics as she was in science.

“I was able to grow into myself and be confident in the things I liked and pursued without issues such as body image or imposter syndrome,” she says. “No one ever told me, ‘You can’t do that because you are a girl.’” Inspired by hands-on chemistry experiments in high school, she decided to pursue the subject at Fordham, where she also ran competitively on the cross country and track and field team.

An unexpected connection between sports and science led to her interest in nanotechnology. She was taking a course in organic chemistry, and professor Ipsita Banerjee, Ph.D., was her lab instructor. “I was ranting to her about how I had no idea how this stuff was applicable to real life,” remembers Nakatsuka, who at the time had torn a ligament and tendon in her ankle while running, and was on crutches and wearing a walking boot. Banerjee told her about her research in tissue engineering. “She said, ‘Imagine if you could heal yourself by using biocomposites you created in a lab that could mimic the tissue in your body, rather than getting surgery and being out of commission for a year.’”

Nakatsuka was fascinated by the idea. She joined Banerjee’s lab the following fall and plunged into the world of bionanotechnology, a highly interdisciplinary field focused on developing biomolecular composites for biomedical applications in tissue engineering, biosensors, and drug delivery. “She was my scientific savior at a time when I was pretty lost and didn’t know how to focus my energy,” Nakatsuka says. “She really put in a lot of time and effort in developing my potential as a scientist.”

At the time, Fordham lacked much of the equipment necessary for Banerjee’s nanotechnology research, so she would drive her students to Queens College, part of the City University of New York, where a colleague allowed them to use the equipment in his lab. Initially, Banerjee was worried that Nakatsuka’s sports schedule would keep her from the necessary work. Instead, she found her to be an incredibly dedicated researcher. “It didn’t matter if she had exams, or had a meet somewhere, I could rely on her,” Banerjee says. The two developed a tight bond, with the professor sometimes dropping Nakatsuka back at her dorm at 3 a.m. after a night of experiments in the lab and animated conversations about science over breakfast at an all-night diner.

“Since we don’t have a graduate program, I expect graduate-level work from my research students,” Banerjee says. Nakatsuka rose to the challenge, becoming lead author on a review paper on tissue engineering, and co-authoring seven other peer-reviewed papers with Banerjee during her time at Fordham.

Catching the Brain’s Chemical Signals

While presenting one of their papers at an American Chemical Society national meeting in San Diego, Banerjee and Nakatsuka met with Paul Weiss, Ph.D., a UCLA professor and nanotechnology pioneer whose research group combines science, engineering, and medicine. The ability to make a practical difference appealed to Nakatsuka, who joined Weiss’ group as a doctoral candidate after graduating from Fordham.

“It fascinated me to think about using chemistry and biology to do something I was passionate about, and contribute to society,” she says. While there, she began working with aptamers, short single strands of DNA that are specifically designed to attach themselves onto a chemical target.

Nakatsuka was intrigued by the ability these aptamers have to change their shape when latching onto their prey. “It is like when the fingers of a baseball glove come down to capture a ball,” she explains. “They structure switch.”

Nakatsuka began using that property to create a sensor that could detect the presence of a specific chemical in the body. Existing biosensors have struggled to differentiate similar molecules from one another accurately, especially when the desired chemical is in short supply.

“It’s like trying to find and capture one fish in a sea of similar-looking fish that exist in much higher amounts,” Nakatsuka says. Collaborating with nanoscientists and engineers, she created an ingenious probe with a tiny pore at one end that was covered in aptamers designed to capture a specific neurochemical such as serotonin, along with several electrodes. When serotonin was present, the aptamers would switch their structure to make the nanoscale opening more porous, and alter the electrical flow that could be measured by scientists in real time. By calibrating the sensor in advance, they could even tell how much serotonin was present in a given sample.

Toward a Better Understanding of Brain and Body Health

After designing the sensor and earning a Ph.D. at UCLA, Nakatsuka moved to ETH Zürich, a scientific institute with a specialized Laboratory of Biosensors and Bioelectronics, for a postdoctoral fellowship in 2018. She’s now a senior scientist there, working with a team of neuroscientists to train the sensors to detect neurochemicals that could provide new insights into Alzheimer’s and Parkinson’s, for example, by quantifying neurochemicals in the brain and blood associated with those diseases.

“What’s exciting to me is that there are neuroscience groups that have been focused on one question for a long time—for example, understanding how dopamine is regulated in brain development, or how serotonin is regulated in anxiety and depression,” Nakatsuka says. By distributing her kits to these scientists, she says, she can provide new tools to generate data and answer some of those questions in a much quicker and easier way.

While Nakatsuka’s sensors are currently being used only in the laboratory, she hopes that eventually they could be used in the body, inserted like an acupuncture needle to monitor brain chemistry in patients. They could have applications beyond neuroscience, as well, providing an ability to detect chemicals anywhere in the body—for example, monitoring iron in anemic patients or stress biomarkers for people with anxiety disorders. She envisions people wearing a Band-Aid-like device with the nanopores integrated inside that could withdraw small amounts of blood with a tiny needle to provide ongoing monitoring. “That’s more of an engineering challenge,” she says. “But it’s really not crazy to imagine implementing it in a way that is practical and applicable for daily use.”

From such tiny beginnings, Nakatsuka’s nanosensors have big potential, giving scientists new ways to understand and monitor diseases throughout the body. “Now I often hear, ‘Are you going to commercialize this? When are you going to go on the market?’” she says. “To be honest, I never thought about it, but now it’s something I want to start looking into to see how I might make a larger impact.”

—Michael Blanding is a journalist and the author of three books, including North by Shakespeare: A Rogue Scholar’s Quest for the Truth Behind the Bard’s Work (Hachette, 2021).


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