This is the third article in an in-depth series on the impact of CRISPR/Cas9 genome editing technology on basic and clinical research, the biotechnology industry, and the world at large. The first installment, on the development of the CRISPR toolkit, can be found here. The previous installment, on CRISPR in basic biology, can be found here.
NEW YORK (GenomeWeb) – Amidst attention-grabbing headlines of research on the ability to edit mutations causing genetic disease and of panels to discuss human gene editing, CRISPR/Cas9 is quietly spurring a revolution in another area of biomedical science: the traditional drug discovery process.
At last week's CRISPR conference, co-hosted by the Wellcome Trust Sanger Institute and AstraZeneca and held at the Sanger's Hinxton, UK campus, that revolution was on full display.
CRISPR/Cas9 enables things researchers had only dreamed of, but it also improves their ability to do the things they've already been doing, Jacob Corn, professor at the University of California, Berkeley and scientific director of the Innovative Genomics Institute, told GenomeWeb. "It's business as usual, but better, faster, cleaner, nicer" he said.
Martin Main, director of reagents and assay development at AstraZeneca, said the company is applying CRISPR to its core business "in as many areas as we can," from target identification and validation to lead optimization to translating clinical findings into better models of disease.
"CRISPR is important as it can help us to identify new targets, for example through genome-wide CRISPR screens," he said. "Also, by using CRISPR to develop cellular or animal models, we'll be able to better understand how our compounds affect human biology before they enter the clinic."
If the technology can help lower project attrition at multiple stages of the drug discovery process, as AstraZeneca believes, it could save untold amounts of time and money.
At the conference, AstraZeneca scientist Barry Rosen, also a scientist in the reagents and assay development division, described two case studies in which the company had used CRISPR/Cas9: to validate a drug target and to develop an in vitro model of disease.
And as CRISPR science develops, more uses for the technology, such as arrayed screens, could be put into practice very soon.
Main said that AstraZeneca has long used RNAi whole-genome knockdown screens for target identification, one of the methods that can be improved using CRISPR. "CRISPR knockout provides complete ablation of the target protein, whereas with RNAi, there are always concerns that protein knock-down is not complete or that there are off-target effects," he said.
As CRISPR has exploded into the scene, AstraZeneca has been particularly aggressive in securing access to the technology. It has CRISPR-driven partnerships with both the Sanger Institute and IGI, as well as Thermo Fisher Scientific, the Broad Institute, and the Whitehead Institute. But it's far from the only pharma giant to get into the CRISPR game.
Novartis is developing CRISPR/Cas9 as a research tool at its Novartis Institutes for BioMedical Research and has invested heavily in Berkeley, California-based Caribou Biosciences, a company co-founded by UC-Berkeley professor and CRISPR pioneer Jennifer Doudna that is concentrating on developing the technology as a gene editing platform. Novartis has also joined Caribou to fund Cambridge, Massachusetts-based Intellia Therapeutics, which is developing CRISPR-based in vivo and ex vivo therapies.
GlaxoSmithKline, through its independent capital arm, SR One; Celgene; and Vertex Pharmaceuticals have aligned themselves with Basel, Switzerland-based CRISPR Therapeutics, co-founded by CRISPR pioneer and Emmanuelle Charpentier of the Max Planck Institute for Infection Biology. Vertex's deal, announced in October, explicitly includes licensing rights for CRISPR/Cas9. SR One and Celgene have invested in CRISPR Therapeutics, but if they gained any IP rights, they weren't disclosed.
AstraZeneca's Main pointed to two case studies presented at last week's conference as indicative of the firm's application of CRISPR.
The first example was classic target validation, driven by a hypothesis that a specific kinase played an important role in macrophage function. "There are three isoforms of the kinase, and we wanted to understand which isoform was mediating the biological effect," Main said. Scientists made different edits in induced pluripotent stem cells that were differentiated to create three kinds of macrophages, each expressing a different kinase isoform. "We were then able to run functional experiments and validate that one of the kinase isoforms plays an important role in human macrophage biology," Main said. "From there, we can start a conventional drug discovery project."
He added that the ability to combine CRISPR with other recent advances in technology, such as iPSCs and next-generation sequencing, is "very exciting," saying that the company has established a range of in vitro models with iPSC-derived cells.
"The ability to differentiate iPS cells into a number of human cell types is very exciting, and we have established a range of in vitro models with iPS derived cells. In this era of genomics, we have vast amounts of genome sequencing data, and now with CRISPR, we have the ability to use that information, to reconstitute the genomic setting in our cellular models," he said.
The second case study from AstraZeneca is an example of the ability of CRISPR to improve models of disease.
In analyzing blood samples from patients in a clinical trial for an EGFR inhibitor, AstraZeneca scientists identified a specific mutation in some patients that showed progression of disease, a cysteine to serine point mutation that was contributing to resistance to the drug. "It helped us to rationalize why we were getting resistance," Main said. But they didn't stop there. Using CRISPR allowed them to recreate a cellular model with that same mutation and use it in the next phase of drug discovery to find drugs that were effective in patients with that mutation.
Berkeley's Corn explained why this matters. "Before, if you wanted to make a cellular model, you had to go out and find a patient that had that mutation and make iPS cells from them. That's tough, especially if there are a whole bunch of different mutations. Now, once you observe it computationally, you can make it rather than having to go out and find it. The ability to make patient mutations that have been observed in large datasets on the individual lab scale is totally transformative," he said.
And it's not just cellular models of disease that can benefit from CRISPR, he said. "What would you consider safety testing in non-human primates?" he said. "Instead of just asking 'How safe is my drug in this particular [non-human primate] model?' you could ask, 'How efficacious is it when [non-human primates] have the exact same mutation as human patients do?'"
On a more speculative note, CRISPR can also help create new therapies, he said, such as cell and gene therapies, and AstraZeneca as well as others, such as Bayer and Juno Therapeutics, are pursuing those as well. But there are things nobody's tried before that could help the more traditional drug discovery process.
Avowedly "bullish" on CRISPR, he said he thinks scientists in drug development are just beginning to unleash CRISPR in creative ways, such as for safety screens, toxicology screens, drug metabolism screens, and anywhere one could use a mammalian cell.
Beyond gene editing, CRISPR interference and CRISPR activation are areas where Main and Corn see possibilities. "The ability to dial up the expression of a specific endogenous gene is not something that we [had] before," Main said. "The only other way is to overexpress genes [using DNA on a plasmid] and get a very artificial increase in protein."
CRISPR could even help improve the production of biologics grown in other organisms, such as humanized mice used to make antibodies. "Those are really transformative, they allow you to make human antibodies," he said. "Maybe you could humanize other animals that allow you to make more antibodies."
"I'm confident even in [the] traditional therapeutic space, from small molecules to large molecules, we will see developments form people that blow apart the ways people have done things," Corn said."[People] see the new tool and they have all these creative ideas."