In leukemia cells, the CRISPR-based method surveyed about 200 potential drug targets in proteins and successfully identified the 6 already known (red spikes)—most of which are at the focus of existing drug development efforts—and found an additional 19 targets (prominent grey spikes) never before recognized. The spikes indicate the degree to which blocking specific receptors will cause cancer cells to die.
Cold Spring Harbor, NY — Imagine having a complete catalog of the best drug targets to hit in a particularly deadly form of cancer. Imagine having a master catalog of such targets for all the major cancer types and subtypes. Scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Nature Biotechnology a method of compiling just such a catalog, using the revolutionary gene-editing technology called CRISPR.
CRISPR enables biologists to manipulate the genetic material of cells with unprecedented precision and ease—letter by DNA letter. CSHL Assistant Professor Chris Vakoc, M.D., Ph.D., and Junwei Shi, a Ph.D. student investigator in his lab, have figured out how to harness CRISPR’s elegant power to the task that preoccupies their lab and so many others across the world: finding binding pockets inside cancer cells that when blocked prevent the cells from proliferating and cause them to die.
Fascinated with CRISPR, Ph.D. student Shi spent much of the last year devising a way to use it to rapidly and accurately identify the best leukemia drug targets. The concept is not difficult to explain. It begins with the notion that genes provide cells with the code to build proteins—the molecules that do all the work in cells and support the tissues of our bodily organs.
Since completion of the full human genome sequence over a dozen years ago, scientists have been amassing databases that document or predict how specific stretches of DNA letters in the genome encode specific segments of proteins, called domains. Among the domains of greatest interest to drug developers are those that form pocket-like features on the surface of proteins that other molecules can fit into, as keys fit into locks. Drugs are keys that fit into binding-pocket locks, sometimes for the purpose of blocking access to the lock, and other times to initiate a cascade of signaling inside the cell.
CRISPR is a wonderful tool of discovery, since it can be used to change the DNA letters that “spell out” particular binding pockets. If you want to know if a cancer cell depends upon a particular pocket, you mutate it—change its DNA code, causing the pocket to take on an unnatural shape. You mimic the action of an effective drug targeting that particular pocket.
The research described in this story was supported by the National Institutes of Health; Burroughs-Wellcome Fund Career Award for Medical Scientists, Alex’s Lemonade Stand Foundation ‘A’ Award; National Cancer Center Support Grant Development Funds; Simons Center for Quantitative Biology.