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Turning Science Fiction into Science Reality with Crisscross Nanotechnology

Using DNA to build a physical platform that transforms molecular diagnostics

Turning Science Fiction into Science Reality with Crisscross Nanotechnology
Caption: Dionis Minev (left) and Anastasia Ershova (right) are developing the Crisscross Nanoseed Detection technology at the Wyss Institute. Credit: Wyss Institute.

Despite the current widespread availability of tests that can diagnose COVID-19, diagnostics is an industry that is ripe for improvement: diagnostic errors and other inefficiencies cost the U.S. economy $750 billion each year, even without a pandemic to deal with. The Wyss Institute’s Crisscross Nanoseed Detection is an enzyme-free DNA nanotechnology that can be used for rapid, ultrasensitive, and low-cost detection of infectious disease biomarkers in a wide variety of point-of-care settings, allowing diseases to be identified and treated earlier to save money, time, and lives.

A vision that started with Wyss Core Faculty member William Shih, Ph.D. led to the development of the Crisscross Nanoseed method by Wyss Institute Postdoctoral Fellow Dionis Minev, Ph.D., along with Chris Wintersinger, a graduate student at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Anastasia Ershova, a graduate student at the Harvard Graduate School of Arts and Sciences. Wintersinger and Ershova are both mentored by Shih, who is also a professor at HMS and the Dana-Farber Cancer Institute.

Using this method, the team can initiate the self-assembly of micron-scale DNA ribbons from single strands of DNA (referred to as “slats”). A nanoseed structure forms upon the detection of a specific biomarker present in a drop of blood (or other body fluid). Following this seeding event, a ribbon is rapidly grown through the base pairing of complementary sequences of single-stranded DNA slats, which amplifies the detection signal. The resulting ribbons extend over several micrometers and can be easily visualized using quantitative (e.g., fluorescence) or qualitative (e.g., lateral flow) methods.

Their approach has great potential for solving many diagnostic, therapeutic, and fabrication challenges due to the extraordinary specificity with which the micron-scale structures are assembled, and their easy detection with available laboratory techniques.

“I took a synthetic biology class with William Shih and it just fascinated me,” said Minev. “How he was so engaged and interested in recruiting students, but also working with people very closely. That was the first time I got an in-depth look at DNA nanotechnology and I learned about all the different things you can do with it.”

Minev started to work with Shih on the project in 2015 and, after earning his Ph.D. in 2020, stayed on at the Wyss to work on the Crisscross Nanoseed Detection project.

In 2018, Ershova met Shih at a retreat in New Hampshire. “I found him so inspiring. I thought, ‘I have to rotate into this lab, this seems like so much fun,’” she said.

Turning Science Fiction into Science Reality with Crisscross Nanotechnology
This diagram (top left) illustrates how Crisscross Nanoseed Detection creates a “seed” structure (green) initiates an all-or-nothing assembly process at the nanoscale. The seed’s exposes binding sites in the form of protruding single strands that can be detected by DNA “slats” (grey) weaving themselves into a continuously elongating nanoribbon that can become several micrometers long. The TEM images show a single tiny seed structure with a ribbon assembled on it (top right) at high magnification, and multiple elongated seed structures (bottom). Wyss Institute at Harvard University

Minev and Ershova have been working together to apply the Crisscross Nanoseed technology to diagnostics since 2019. The interdisciplinary environment at the Wyss Institute has brought Minev’s engineering background and Ershova’s work in biology and computation together, resulting in a team that tackles problems from all angles to carry out groundbreaking research.

“Our partnership makes it inherently better to make decisions – we come to agreement quickly,” said Minev. “It always benefits to have two minds thinking about the problem.”

Their approach to science is mirrored in their dedication to translating, de-risking, and commercializing the Crisscross Nanoseed Detection technology. Minev and Ershova have participated in the Activate Bio (now Nucleate Bio) program and are currently enrolled in MIT’s I-Corps program. In 2021, Ershova was recruited into the 50 Years Industries’ inaugural cohort of its 50/50: PhD to VC Program, which supports scientists in their quest to commercialize their research via tech startups.

Having successfully completed the Wyss’ Validation Project program in 2020 and 2021, the Crisscross Nanoseed Detection team generated enough data to demonstrate a proof-of-concept and are continuing to de-risk their technology.

“It took a really long time to build [the technology] from the high-level concept that William Shih pitched at the beginning. Now we have something where we can start working on applications and potentially spin out,” said Minev.

“Iterating through design cycles week after week, it has been an amazing experience to team with Dionis, Chris, and Anastasia to power through a series of important technical milestones,“ said Shih.

Looking to the future, Minev and Ershova would ultimately like to achieve their mission of building a diagnostic platform that is accessible and has the potential to outperform existing technologies in terms of speed, scope and cost.

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