25th January 2022

First molecular electronics chip

A new biosensor chip – the first of its kind in the world – can observe direct electrical measurements of single-molecule interactions. This could enable faster and cheaper DNA sequencing, disease surveillance, and precision medicine on portable devices.

Roswell Biotechnologies, founded in 2014 and based in San Diego, California, is a company that aims to "digitise biology" using electronics to study, diagnose and treat diseases.

In 2019, Roswell formed a partnership with IMEC, a world-leading research and innovation hub in Belgium specialising in nanoelectronics and digital technologies. Development then began on foundry-compatible manufacturing processes for a radical new chip design. The Molecular Electronics (ME) chip – the first device of its kind in the world – has now completed testing and is detailed in a peer-reviewed study published by Proceedings of the National Academy of Sciences.

This milestone realises a 50-year-old goal of integrating single molecules into circuits. As illustrated in the video above, the chip uses individual molecules as universal sensor elements in a circuit. This creates a biosensor with real-time, single-molecule sensitivity and unlimited scalability in sensor pixel density. This will power advances in diverse fields that are fundamentally based on observing molecular interactions – including drug discovery, diagnostics, DNA sequencing, and the large-scale study of proteomes.

"Biology works by single molecules talking to each other, but our existing measurement methods cannot detect this," said co-author Jim Tour, PhD, Professor of Chemistry, Materials Science, NanoEngineering, and Computer Science at Rice University, Texas. "The sensors demonstrated in this paper for the first time let us listen in on these molecular communications, enabling a new and powerful view of biological information."

The new platform consists of a programmable semiconductor chip with a scalable sensor array architecture. Each array element consists of an electrical current meter that monitors the current flowing through a precision-engineered molecular wire, assembled to span nanoelectrodes that couple it directly into the circuit. The sensor is programmed by attaching the desired probe molecule to the molecular wire, via a central, engineered conjugation site. The observed current provides a direct, real-time electronic readout of molecular interactions of the probe.

These picoamp-scale current-versus-time measurements are read out from the sensor array in digital form, at a rate of 1,000 frames per second, to capture molecular interactions data with high resolution, precision, and throughput.

Credit: Fuller, et al. (PNAS, 2021)

"The goal of this work is to put biosensing on an ideal technology foundation, for the future of precision medicine and personal wellness," said Barry Merriman, PhD, the co-founder and Chief Scientific Officer of Roswell. "This requires not only putting biosensing on chip, but in the right way, with the right kind of sensor. We've pre-shrunk the sensor element to the molecular level to create a biosensor platform that combines an entirely new kind of real-time, single-molecule measurement with a long-term, unlimited scaling roadmap for smaller, faster and cheaper tests and instruments."

The PNAS paper presents a wide array of probe molecules – including DNA, antibodies, antigens, and aptamers (single-stranded oligonucleotides that fold into defined architectures and bind to targets such as proteins), as well as the activity of enzymes relevant to diagnostics and sequencing. This includes a CRISPR Cas enzyme binding its target DNA. The paper illustrates a wide range of applications for such probes, including the potential for drug discovery, faster COVID testing, and proteomics.

The paper also shows how DNA polymerase (the enzyme that copies DNA), can be integrated into the circuit to provide direct electrical observation of the action of this enzyme as it copies a piece of DNA, letter by letter. Older sequencing technologies have relied on indirect measures. By contrast, this new approach achieves direct, real-time observation of a DNA polymerase incorporating nucleotides. The paper illustrates how these activity signals can be analysed with machine learning algorithms to read the sequence.

"The Roswell sequencing sensor provides a new, direct view of polymerase activity, with the potential to advance sequencing technology by additional orders of magnitude in speed and cost," said Professor George Church, paper co-author, member of the National Academy of Sciences, and a Roswell Scientific Advisory Board member. "This ultra-scalable chip opens up the possibility for highly distributed sequencing for personal health or environmental monitoring, and for future ultra-high throughput applications, such as exabyte-scale DNA data storage."

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