Nanoscale Biosensors For Personalized Medicine

Kumiko. This is not only a lovely female's name, but also the designation of a traditional woodworking art. Originally from Japan, Nako Nakatsuka, assistant professor at EPFL, is well acquainted with this technique. 'Simple but precisely defined wooden elements are assembled into complex patterns based on their shape, without the need for nails or screws', the art-loving chemist explains. Through this modular assembly, new structures emerge with new functions-such as a lampshade.

When Nako Nakatsuka and her team design novel biosensors, their approach mirrors the craft of a Kumiko master. They work with familiar, simple, well-defined building blocks-short, single-stranded DNA sequences known as aptamers. As in Kumiko, the design allows no room for error. Aptamers bind with extraordinary specificity guided by their shape, to capture even very small target molecules such as neurotransmitters like serotonin or dopamine. 'These biomarkers play a crucial role in brain disorders such as Parkinson's and Alzheimer's disease, making aptamers a promising tool for advancing diagnostics and therapies', says Nakatsuka.

Form follows function

'When the negatively charged DNA aptamer binds its target molecule, it undergoes a 3-D structural transformation, which also shifts how electrical charges are arranged ,' explains Nakatsuka, 'When paired with devices that can detect these charge changes, the aptamer can act as a biological sensor element by generating a measurable electrical signal upon binding the specific target molecule.'

The signal is measured using a nanopipette - a tiny glass cannula in which the aptamers are fixed. Together, the aptamer and nanopipette form the biosensor. This sensor is positioned in an electrochemical measuring setup. When a biological sample enters the nanoscale opening of the nanopipette, the aptamers bind to the target molecules, generate an electrical signal and provide information about the quantity of the target molecule.

Measuring dopamine for Parkinson's disease patients

Based on the mentioned concept, Nakatsuka and her team developed a biosensor in 2023 that can detect dopamine in picomolar concentrations ( Stuber et al. 2023 ) - a breakthrough because, unlike glucose (e.g., in blood sugar measurements), detecting neurotransmitters in serum is extremely difficult due to their low concentration in a complex matrix.

The sensor is currently being improved for robustness and upscaled in anticipation of quantifying dopamine using samples from Parkinson's disease patients. 'Parkinson's disease leads to a decrease of dopamine in the brain, which causes symptoms such as the tremor,' remarks Nakatsuka. 'Our biosensor is not a cure for Parkinson's disease, but if we can use it to test whether blood dopamine is a good proxy for brain dopamine, we could eventually develop a monitoring system for Parkinson's patients, empowering them to track their dopamine levels and fine-tune their medication in real time. Better patient care through personalized medicine. That is our goal.'

Challenge as an opportunity

To get closer to this goal, Nako Nakatsuka has spent almost a decade characterizing the binding of aptamers to the target molecule. 'Aptamers offer remarkable advantages: unlike antibodies, they can be rapidly synthesized and tailored in the laboratory, enabling them to bind even the smallest target molecules with precision. After the hype of the 1990s, however, many researchers doubted their potential - largely because we lacked a basic understanding of how aptamers interacted with their targets. So aptamers had a poor reputation.'

Nakatsuka, who has always been a determined person, accustomed to endurance as a triathlete, did not give up. For her, challenges are not obstacles but opportunities. As a young woman, she ventured alone from Japan to New York to earn her bachelor's degree at Fordham University. It was a bit of a culture shock, as she recalls, but also a chance. She met Prof. Ipsita A. Banerjee, who encouraged and challenged her. 'Her group was doing tissue engineering research to self-heal torn tissues. At the time, I was hobbling around on crutches thanks to a tendon injury. That was when I first realized that chemistry could have a very practical impact.'

Kumiko style: from design to product

With her first publications in hand, she moved to California for her doctoral studies and continued as a postdoctoral researcher at ETH Zurich. She immersed herself in neuroscience and aptamer research and learned in multidisciplinary research groups that chemical expertise can be applied to different disciplines and technologies. 'In aptamer research, I finally noticed that there was a gap between the people who designed the aptamers, those who built the biosensors, and those who brought them to clinical application.' What if everything came from a single source, as is customary with Kumiko?

Now, as a professor at EPFL, Nakatsuka pursues this holistic approach with her own multidisciplinary team-guiding projects from design all the way to application. Her research advances on multiple fronts: the range of detectable biomarkers is expanding beyond small molecules to protein targets linked to Alzheimer's disease ( Schlotter et al. 2024 ) ; a recently awarded ERC grant will support the development of a novel technology to map chemicals at the nanoscale; and a patent is already in progress for a novel aptamer architecture for detecting small molecules.

It's people who make a difference

In honor of all her efforts to advance in the field of aptamer-based biosensors, Nako Nakatsuka is receiving this year's Ruzicka Prize 2025. 'Receiving the Ruzicka Prize is a great honor, and I am proud of my multidisciplinary team,' Nakatsuka states happily. 'It's not the research itself that makes a difference - it's the people you work with.'

That's why diversity in science is so important to her. The same goes for good scientific outreach and teaching. 'The influence that teachers have on a person's life is often underestimated. To this day, I am still grateful to my high school chemistry teacher who sparked my fascination with the subject. Every milestone I have achieved is related to people who believed in me and gave me opportunities. So, I would like to pay that forward.'