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The Impact of Functional Genomics in Drug Discovery

A drug capsule filled with small beads, with cells in the background.
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What is functional genomics?

Functional genomics involves “applying targeted genetic manipulations at scale to understand biological mechanisms,”  Dr. Benjamin Haley, a professor at the University of Montreal told Technology Networks.


This scale enables researchers to deconvolute the link between genotype and phenotype in disease, revealing genes of interest. Unlike genome sequencing and genome-wide association studies, functional genomics approaches enable researchers to define molecular outcomes to better understand how specific genes may contribute to disease.


“The functional genomics field has gone through several waves of evolution, starting with circulating DNA expression screens, RNA interference (RNAi), transposon/retroviral insertion screening and the introduction of CRISPR,” Haley said. “More recently, the ability to pair large-scale gene manipulation with single-cell technologies has sparked another revolution in the field, since users can screen hundreds of perturbations in parallel with unbiased transcriptome, proteome or chromatin-based readouts.”

Why is functional genomics useful in drug discovery?

“Functional genomics can be considered a biological accelerant, enabling users to efficiently narrow down to a specific target or genetic pathway of interest,” Haley explained. “It is also teaching us more about existing drugs.”


Functional genomics is particularly useful for heterogenous disease, like cancer. Researchers have analyzed gene expression profiles of breast cancer to identify potential drug targets, selecting genes for which RNAi knockdown suppressed cell proliferation for further study.


This led to the identification and characterization of more than a dozen cancer-specific functional genes, which can assist in the development of novel therapeutics that are highly selective for cancer cells.

“Innovative applications of CRISPR, namely CRISPR base and prime editing, have given us a deeper look at the biologically relevant domains within proteins, sometimes down to the individual amino acids, which represent unique therapeutic targeting opportunities,” noted Haley.


CRISPR base editing screens have also been used by researchers to map the genetic landscape of drug resistance in cancer. Coelho et al. identified potential mechanisms of resistance to 10 oncology drugs, honing in on 4 classes of proteins that modulate drug sensitivity and could be targeted with inhibitors to overcome resistance.

What challenges are there in this approach?

“I believe that the biggest challenge relates towards applying functional genomics tools in more complex biological systems, whether it be organoids or in vivo models,” said Haley. As the systems used for drug discovery become more complex, they become harder to scale, necessitating screening technologies that are more specific and robust.


“CRISPR is likely here to stay for a while as the lead functional genomics technology,” opined Haley, “but the field is still in the process of optimizing its various forms and understanding how best to apply each.”


At the Society for Laboratory Automation and Screening 2025, Haley will discuss the potential of using Cas12a, a close cousin of the widely used Cas9 enzyme, for single-cell and in vivo studies. He will explore the unique capabilities of Cas12a, focusing on its use for developing compact screening libraries or libraries that enable the user to selectively disrupt more than one gene at a time in each cell, which is highly informative for understanding gene interactions.