A platform for single-molecule measurement of binding kinetics & enzyme activity.
The first molecular electronics chip has been developed, realizing a 50-year-old goal of integrating single molecules into circuits to achieve the ultimate scaling limits of Moore’s Law. Developed by Roswell Biotechnologies and a multi-disciplinary team of leading academic scientists, the chip uses single molecules as universal sensor elements in a circuit to create a programmable biosensor with real-time, single-molecule sensitivity and unlimited scalability in sensor pixel density. This innovation, appearing this week in a peer-reviewed article in the Proceedings of the National Academy of Sciences (PNAS), will power advances in diverse fields that are fundamentally based on observing molecular interactions, including drug discovery, diagnostics, DNA sequencing, and proteomics.
“Biology works by single molecules talking to each other, but our existing measurement methods cannot detect this,” said co-author Jim Tour, PhD, a Rice University chemistry professor and a pioneer in the field of molecular electronics. “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.”
A programmable semiconductor chip with a scalable sensor array design makes up the molecular electronics platform. Each array element is made up of an electrical current meter that tracks the current flowing through a precision-engineered molecular wire that has been built to span nanoelectrodes that connect it directly to the circuit. By connecting the desired probe molecule to the molecular wire through a central, designed conjugation site, the sensor is programmed. The measured current gives a direct, real-time electronic readout of the probe’s molecular interactions. To record molecular interactions data with high resolution, accuracy, and throughput, these picoamp-scale current-versus-time measurements are read out in digital form from the sensor array at a rate of 1000 frames per second.
“The goal of this work is to put biosensing on an ideal technology foundation for the future of precision medicine and personal wellness,” added Roswell co-Founder and Chief Scientific Officer Barry Merriman, PhD, the senior author of the paper. “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 new molecular electronics platform detects multi-omic molecular interactions at the single-molecule scale, in real-time. The PNAS paper presents a wide array of probe molecules, including DNA, aptamers, antibodies, and antigens, as well as the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR Cas enzyme binding its target DNA. It illustrates a wide range of applications for such probes, including the potential for rapid COVID-19 testing, drug discovery, and proteomics.
The paper also presents a molecular electronics sensor capable of reading DNA sequence. In this sensor, a DNA polymerase, the enzyme that copies DNA, is integrated into the circuit, and the result is direct electrical observation of the action of this enzyme as it copies a piece of DNA, letter by letter. Unlike other sequencing technologies that rely on indirect measures of polymerase activity, this approach achieves direct, real-time observation of a DNA polymerase enzyme incorporating nucleotides. The paper illustrates how these activity signals can be analyzed with machine learning algorithms to allow reading of 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, a co-author of the paper, 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.”
Reference: “Molecular electronics sensors on a scalable semiconductor chip: A platform for single-molecule measurement of binding kinetics and enzyme activity” by Carl W. Fuller, Pius S. Padayatti, Hadi Abderrahim, Lisa Adamiak, Nolan Alagar, Nagaraj Ananthapadmanabhan, Jihye Baek, Sarat Chinni, Chulmin Choi, Kevin J. Delaney, Rich Dubielzig, Julie Frkanec, Chris Garcia, Calvin Gardner, Daniel Gebhardt, Tim Geiser, Zachariah Gutierrez, Drew A. Hall, Andrew P. Hodges, Guangyuan Hou, Sonal Jain, Teresa Jones, Raymond Lobaton, Zsolt Majzik, Allen Marte, Prateek Mohan, Paul Mola II, Paul Mudondo, James Mullinix, Thuan Nguyen, Frederick Ollinger, Sarah Orr, Yuxuan Ouyang, Paul Pan, Namseok Park, David Porras, Keshav Prabhu, Cassandra Reese, Travers Ruel, Trevor Sauerbrey, Jaymie R. Sawyer, Prem Sinha, Jacky Tu, A. G. Venkatesh, Sushmitha VijayKumar, Le Zheng, Sungho Jin, James M. Tour, George M. Church, Paul W. Mola and Barry Merriman, 24 January 2022, Proceedings of the National Academy of Sciences.
About Roswell Biotechnologies
Roswell Biotechnologies is digitizing biology with molecular electronics to predict, prevent, and cure disease. The company has developed the world’s first molecular electronics chip, the Roswell ME Chip™, which integrates single-molecules into standard semiconductor chip technology to deliver a programmable biosensor that converges a broad range of biosensing applications and omics measurements onto one platform. The Roswell ME Platform is being commercialized for applications in drug research and discovery, molecular diagnostics, sequencing, and DNA digital data storage. Roswell Biotechnologies was founded in 2014 by industry leaders in genomic technologies and is headquartered in San Diego, California.