New DNA Technology Based on CRISPR Could Revolutionize Medical Diagnostics

Lead author, Karl Barber with a PICASSO microarray. Credit: Karl Barber, Schmidt Science Fellows

Scientists have repurposed CRISPR genetic engineering technology to identify antibodies in patient blood samples in a move that could inspire a new class of medical diagnostics among numerous other applications.

The technology involves customizable sets of proteins attached to a variant of Cas9, the protein at the heart of CRISPR, which will bind to DNA but not cut it like genetic modification. When these Cas9-fused proteins are applied to a microchip containing thousands of unique DNA molecules, each protein in the mixture will self-assemble at the position on the chip that contains the corresponding DNA sequence. The researchers have named this technique ‘PICASSO’, short for peptide immobilization through Cas9-mediated self-organization. Then, by applying a blood sample to the PICASSO microarray, it is possible to identify the proteins on the microchip that are recognized by the patient’s antibodies.

The team led by Dr. Stephen Elledge of Harvard Medical School and Brigham and Women’s Hospital, Boston, published the study online today (Aug. 13, 2021) in Molecular Cell. The first author of the article, Dr. Karl Barber, is a 2018 Schmidt Science Fellow, and much of the work developing the technology takes place during his Fellowship Research Placement in the lab of corresponding author Dr. Elledge.

dr. Describing PICASSO, Barber said, “Imagine you want to paint an image on a canvas, but instead of painting in a normal way, you mix all your paint together, splash it onto the canvas and the perfect image is created. With our new technique, you place DNA molecules at defined locations on a surface and each protein from a mixture will then assemble itself into its corresponding DNA sequence, like an automated paint-by-number kit. DNA template allows you to quickly identify antibodies in clinical samples that recognize the proteins you are interested in.”

The research team has shown that the technology assembles thousands of different proteins, suggesting it could be easily adapted as a broad-spectrum medical diagnostic tool. In the paper, they used the technique to detect antibodies that bind to proteins derived from pathogens, including SARS-CoV-2, from the blood of recovering COVID-19 patients.

dr. Barber said: “In this work, we demonstrated the application of PICASSO to protein studies, creating a tool that we believe can be rapidly adapted for medical diagnostics. Our protein self-assembly technique could also be used for the development of new biomaterials.” and biosensors, simply by attaching DNA targets to a scaffold and allowing Cas9-linked proteins to bind.”

Group leader, Dr. Elledge, commented: “One of the most exciting aspects of this work is the demonstration of how CRISPR can be applied in an entirely new environment. Previously, CRISPR was mainly used for gene editing and the detection of DNA or RNA. PICASSO brings the power of CRISPR to a new field of protein studies, and the molecular self-assembly strategy we demonstrate can help develop new research and diagnostic tools.”

dr. Megan Kenna, executive director of Schmidt Science Fellows, said: “This technology has the potential to be used as a medical diagnostic tool that could one day provide doctors with a way to quickly determine the diagnosis and the best course of treatment for each individual. patient.”

“The way Karl and the research team brought basic biology and molecular engineering together to make this important discovery demonstrates why the interdisciplinarity at the heart of our Fellowship is so crucial to the advancement of science.”

The research was supported by Schmidt Science Fellows, the Jane Coffin Childs Memorial Fund for Medical Research, National Science Foundation and the Howard Hughes Medical Institute.

Reference: “CRISPR-based peptide library display and programmable microarray self-assembly for rapid quantitative protein binding assays” by Barber et al., Aug. 13, 2021, Molecular Cell.
DOI: 10.1016/j.molcel.2021.07.027

About Schmidt Science Fellows

An initiative of Schmidt Futures delivered in conjunction with the Rhodes Trust, the Schmidt Science Fellows program brings together the brightest minds who have earned a PhD in science, mathematics, engineering or computer science, and places them in a postdoctoral fellowship in a field other than their existing expertise. Fellows are supported with a stipend of USD$100,000 per year for a minimum of one and a maximum of two years.

Schmidt Science Fellows has a vision of a world where interdisciplinary science flourishes indefinitely, accelerating discoveries that benefit the world, and driving innovations that improve the quality of life for all. Realizing this vision requires a network of individuals and organizations working together to advance interdisciplinary science.