CRISPR-Chip from the Cover of Nature BME in June 2019 to a product in June 2020

CRISPR-Chip: a CRISPR-powered Transistor that links biology to computers.

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By Kiana Aran PhD, Amanda Zimmer, Zack Raborn, and Francie Barron PhD. 

Right now, you’re likely to be reading this on a screen. It could be on a phone, tablet, or a computer, but the technology and electrical systems powering them are almost all the same. They are all built on electrical signals running through circuits with messages that differ depending on what you want to do. Something very similar is also happening in your body. Signals to and from your brain are making your eyes scan over these letters, converting them into words, and adding different meanings to them depending on the words coming before and after. These signals, known as cell messaging, are electrical at the core and were discovered well over a hundred years ago. Despite all biological signaling being electrical in nature, the “leading” technology today in Life Science and Genomics is all optical rather than electrical. PCR was invented in 1983, 37 years ago, and ELISA was invented in 1971, 49 years ago. The pandemic has taught us that we cannot solve 21st century problems with 20th century technology. Optical systems require extensive sample prep, amplification, expensive reagents, and long sample to answer times in form of frozen-in-time indirect visual estimates of what you want to measure. The simple answer to why optics is the most commonly used technology in the industry, is that it’s too complex to link computers directly up to the live signals of biology. But what if it wasn’t? 

In the spring of last year we published the paper “Detection of unamplified target genes via CRISPR–Cas9 immobilized on a graphene field-effect transistor” to illustrate how we’ve combined graphene-based Biology-gated Transistors with CRISPR-dCas9 molecules to scan genomes for genetic sequences of interest. We called this transistor technology “CRISPR-Chip”. Upon the successful detection of Duchenne’s muscular dystrophy in a minimally purified DNA sample for a proof-of-concept, the technology became coined the “World’s First DNA Search Engine”. CRISPR-Chip is an advanced, yet beautifully elegant combination which bring together three Nobel Prize-winning revolutionary technologies, CRISPR, Graphene and Transistors. Each of these technologies have made a significant impact in our lives independently and their combination brings a promises of revolutionizing thousands of markets and applications by providing the backbone for faster & more accurate diagnostics, safer gene editing, and even improvements to the safety of our food – just to name a few. 

Following the success of the paper, in October of 2019, Nanosens (the company I formed surrounding the invention of CRISPR-Chip) merged with Cardea to make CRISPR-Chip a part of Cardea’s Tech+Bio Infrastructure to bring CRISPR-Chip out of the lab and into the real world. Adding CRISPR-Chip to the Cardea catalog of “Tech+Bio modules” enables CRISPR-Chip products to be developed quickly and at scale so that this technology can have the meaningful real-world impact I have always envisioned. Tech+Bio modules include handheld readers, automated liquid handlers, cloud computing, machine learning & artificial intelligence, true multiplexing technology, and more. These modules, including CRISPR-Chip, are combined and modified into customized solutions for Cardea’s Innovation Partners. Examples of some of these endless possibilities include applications for detecting and combating diseases in humans and plants, improved environmental monitoring, biohazard safety, and precision quality control tools for genome editing. CRISPR-Chip technology & the Tech+Bio Infrastructure it is built upon is exclusively available through the Cardea Innovation Partnership Program.

I want to congratulate Dr. Jennifer Doudna and Dr. Emmanuelle Charpentier for being awarded the Nobel Prize in Chemistry 2020 for their pioneer work in CRISPR. The award was well deserved and has truly brought CRISPR into the spotlight. Beyond the prize, documentaries such as “Human Nature” and the TV show “Unnatural Selection” have certainly helped solidify CRISPR as so commonplace that you are as likely to find it being discussed in the lab as at the dinner table. 

CRISPR technology has already made many promises, but few have yet to be delivered upon because there is still much to be worked out in how to use it properly. Having the power to alter DNA at will is exciting in its potential, but also carries with it a huge responsibility. Before getting ahead of ourselves and believing that we can solve all of life’s problems with CRISPR, we need to put effective safeguards in place. In our previous “behind the paper”, we stated that “CRISPR-Chip can be used to improve the efficiency and safety of CRISPR gene editing. In vitro, validation studies are often required to maximize CRISPR efficiency. However, these studies mostly assess the CRISPR molecule efficiency at the immediate vicinity of the target. Off-target CRISPR activities, as it can cut or edit in unintended places in the genome, is a real problem we have to minimize at all cost as we move toward CRISPR for therapeutic use.” Since then, we’ve been actively working with one of our Innovation Partners, CRISPR QC, on pioneering streamlined and automated CRISPR quality control testing. We have recently launched CRISPR-BIND. As the first of a three-generation product line, CRISPR-BIND is an automated liquid handling system built upon CRISPR-Chip technology and other Tech+Bio modules, to measure the strength of binding interactions between gRNA and CRISPR-Cas complexes. This allows researchers to identify the most optimal guides and Cas complexes for each CRISPR experiment and effectively reduces the risk of human errors or false positives.

CRISPR QC’s solutions are first-of-their-kind products that help prevent poor editing efficiency and mitigate the risks of off-target effects. This will accelerate CRISPR research, reduce associated costs, and improve both editing accuracy and safety. Later product generations will offer even more capabilities, such as determining binding interactions of amplicons and whole genomic unamplified DNA as well as kinetic characterization of both guide RNA’s and genomic DNA. 

Biology is made up of a multitude of highly complex systems within systems that work together to determine our reality; our health, our diet, our physical traits, our diseases, but also other aspects we may not think about such as cosmetics and the health of our pets. The invention of CRISPR-Chip has enabled us to sit down with companies and discuss how to solve some of humankind’s biggest problems. By enabling our partners to convert streams of real-time biological data from these systems to digital information, we can discuss how to create a broad range of products and applications that will impact and forever transform our everyday lives from healthcare, agriculture, food and water safety, to biosafety and the environment.

Kiana Aran

Professor , Keck Graduate Institute

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