The two teams are also trying to discover genes that are essential in specific contexts. Moffat likens this to a daisy: The core represents genes that are always necessary, while the petals represent those that are important, say, when cells are growing or reproducing, or in one type of cell but not another. CRISPR makes it easy to analyze both the core and the petals. “Anything we can detect in a dish, like whether a cell is square or red, we can find the genes that underlie that,” says Sabatini. “And if you're interested in cancer, you can say: Give me the genes that each type of cancer, and only that type of cancer, cares about.”
Cancer is foremost on his mind. His team has already catalogued the essential genes in four cancer-cell lines, taken from patients with leukemia and lymphoma. Meanwhile, Moffat analyzed cell lines grown from cancers of the brain, colon, skin, and cervix.
Their goal was to find genes that are expendable in healthy cells but crucial in specific types of tumors. These genes represent the box of tricks that cancers use to thrive in the body. They also represent weaknesses that scientists can exploit to destroy cancer cells without harming normal ones. For example, Moffat predicted that some of the colon-cancer cells he studied would be vulnerable to a drug called metformin, while another group would succumb to linezolid—and he was right on both counts.
“We’ve known for many years that the molecular drivers of tumors vary from cancer to cancer and even patient to patient, but we have previously lacked the tools to tackle these differences in a systematic way,” says Feng Zhang from MIT, one of the pioneers of CRISPR. “[These groups] show that CRISPR-based tools are up to the job.”
“My only fear is that we won't find a huge number of genes that differentiate cancer cells and non-cancer cells, and the ones we find won't be druggable,” says Sabatini. “But we need the answer. And if those genes are there, we can find them. It'll just take industrializing this approach, with not just tens of cell lines but hundreds.”
Such work is already underway. Scientists at the Broad Institute and the Dana-Farber Cancer Institute have launched Project Achilles—an initiative that will use CRISPR to search for specific weaknesses in over 500 cancer-cell lines.
“This is a great demonstration of the impact of CRIPSR,” says Aviv Regev at the Broad Institute. “It’s truly better than the tools we had before; it lets us ask crisp questions and get precise answers.” It’s also increasingly versatile, she says. Although scientists initially used it to delete genes, they can now use it to switch genes on, or to gently turn their activity down a notch.
But even CRISPR has its limits. Sabatini says that it’s not great for studying regions of the genome that have been copied many times over. According to few upcoming papers, when CRISPR targets these amplified regions, it cuts all the copies and induces a generic toxic response in the affected cell. “Almost all human cancer lines have amplifications,” says Sabatini, “so if you want to know what the genes there are doing, you can't do it through CRISPR.” Or, at least, not yet.