CRISPR Screens: A New Frontier in Drug Discovery, Research
Contributed Commentary by Charlie Roco and Anastasia Potts, Parse Biosciences
November 17, 2023 | In 2012, Jennifer Doudna and Emmanuelle Charpentier at the University of California, Berkeley, and Feng Zhang at the Broad Institute of MIT and Harvard independently discovered that the CRISPR system could be used in human cells to target and edit DNA in a precise and programmable manner. This discovery revolutionized the field of genetic engineering and paved the way for the development of CRISPR screens.
The first CRISPR screens were performed in 2013. The results of these studies showed that CRISPR screens could be used to identify genes that are essential for a particular biological process or phenotype.
Since then, CRISPR screens have been used to study a wide range of biological processes, including cancer, immunity, and development. They have also been used to identify genes that are involved in drug resistance and to develop new drug targets. While they are still a relatively new technology, they have the potential to revolutionize our understanding of human health and disease.
To date, bulk pooled and arrayed CRISPR screening has been a valuable tool to understand gene function. Adding single cell resolution to pooled CRISPR screens pairs individual gene perturbations with rich whole transcriptome expression phenotypes. This approach has expanded the capabilities of pooled CRISPR screening to understand cell types of perturbed cells and quantify changes in gene expression, regulatory networks, signaling pathways, and other complex signatures. However, the applications and scale of these studies have been limited by the throughput and cost of droplet-based single cell RNA-seq technology.
As a result, we’ve seen limited adoption in the biotech and pharma spaces due to the need to do larger screens that are too expensive and would take too long to perform with droplet-based technologies. Now, however, the adoption has begun, as single-cell CRISPR screens take the benefits of a pooled screen and an arrayed screen and combine them, so researchers receive the benefits without the same level of historical drawbacks, such as the lack of granularity that comes with a bulk pooled screen.
One of the most promising aspects of the future CRISPR screen landscape is the ability to learn more, earlier. In the past, cost dictated that you had to narrow findings quickly, but now, better high-throughput screening creates easier identification of targets earlier in the process—and lower costs.
Because each individual cell is practically its own experiment, single-cell CRISPR screens allow researchers to get the scalability they need at a less expensive cost and serve as a powerful discovery engine. They enable researchers to pair perturbations and transcriptional profiles in millions of cells. This scale expands the applications of single cell CRISPR screening, specifically in drug discovery where cost has limited their use to targeted validation studies.
The use of pooled single cell CRISPR screens generates the opportunity to ask big questions and then let the biology tell you what's going on, opening the door to better discovery engines.
Historically over the last 30 years or so, what we’ve seen with traditional drug discovery mechanisms is that you pick a single drug target and then apply as many small molecules as possible and wait for the result. It’s quite expensive, takes a long time, and the results can be lacking in the end. It also requires that significant time be spent upfront ensuring that the quality of the drug target is high and aligning that, if researchers are interested in a particular pathway, with an understanding of what kind of a target to put in that pathway. Using pooled single cell CRISPR screens allows researchers to cast the net wider than before by letting the cell dictate how many ways you can affect change. Researchers can now let the cell itself guide their target identification rather than having to pick it in isolation because it appears to be “druggable.”
Another benefit of the greater scalability inherent in pooled single cell CRISPR screens is that researchers can access samples from a wider range of ethnicities, backgrounds, and genotypes. Then they can let the biology tell them what the best target may be. This holds tremendous benefit, as it prevents narrowing down too quickly based on a sample that may not be representative. It gives much more power to the analysis and brings researchers to a better understanding more quickly.
In the months and years ahead, we expect to see greater adoption of pooled single cell CRISPR screens in the biotech and pharma spaces. The combination of scalability with affordability should prove to make this approach the most practical for drug discovery and disease research.
Charlie Roco is co-founder and chief technology officer of Parse Biosciences, a leading provider of accessible and scalable single cell sequencing solutions. He is passionate about biology-based technology development, with over a decade of driving innovation in the field. Charlie holds a Ph.D. in Bioengineering from the University of Washington and BSE in Biological Systems Engineering from Virginia Tech. He can be reached at email@example.com.
A senior product manager at Parse Biosciences, Anastasia Potts received her BS and PhD in molecular microbiology from the University of Florida. In the past several years, she has focused on building new genomics applications and products to help researchers uncover new biology in difficult samples. At Parse, Anastasia is focused on making high-scale single-cell RNA-seq more accessible to the research community. She can be reached at firstname.lastname@example.org.