What is CRISPR? Drug Developers Harness The New Genome Editing Tool; But Can It Deliver Novel Drugs?

A DNA-editing tool called Crispr has been the darling of genomic researchers for the past few years, empowering scientists to make quick and cheap edits to a stretch of DNA and setting off a flurry of research, publications and business start-ups focused on harnessing the technique for disease treatment since its development in 2012. For the moment, though, the use of Crispr is still largely confined to labs and any hope that it will help physicians ensure spotless genomes--or enable drug companies to cash in on novel therapies--remains a distant dream.

The Crispr tool (which is named for an arrangement of genetic sequences known as Clustered Regularly Interspaced Short Palindromic Repeats) is a kind of biological scissors that can snip both strands of DNA at a particular point, and permits researchers to insert new genes before pasting the strands back together. Its arrival created buzz among experts in the field and commanded the attention of business leaders -- two researchers credited with its creation received the 2015 Breakthrough Prize in Life Sciences, which is backed by Mark Zuckerberg of Facebook, Sergey Brin of Google, Anne Wojcicki of 23andMe and venture capitalize Yuri Milner.

"This discovery has triggered a veritable revolution as laboratories worldwide have begun to introduce or correct mutations in cells and organisms with a level of ease and efficiency not previously possible," Jennifer Doudna, one of the prize recipients from University of California, Berkeley, wrote in an editorial published in JAMA on Tuesday. Doudna also noted that over 500 scientific papers about experiments using Crispr have been published in the past two and a half years.

This week, drug developers and researchers from companies including Bristol-Myers Squibb Co., Pfizer, Inc., Regeneron Pharmaceuticals and Novartis AG gathered at the New York Academy of Sciences in Manhattan to anticipate how Crispr and other gene-editing tools like it will lead to new drugs or, eventually, enable them to cure patients of genetic disorders. But while Crispr and its affiliates have certainly been a boon for scientists in labs, their ability to help physicians to treat patients remains obstructed by significant scientific and ethical barriers.

Though the future potential of these technologies isn't entirely clear, big bets have already been placed -- startups including Editas Medicine and Intellia Therapeutics have so far raised $80 million on the promise of treating diseases with them, according to MIT Technology Review. Earlier this year, Novartis signed a licensing deal with Intellia and Caribou Biosciences, which was founded by Doudna, to leverage the Crispr tool in its search for new drugs.

The Crispr technology has certainly streamlined laboratory experiments at these companies, and supplanted many of the former gene-probing techniques they once used. “I’m a drug discovery person. I propose new drug concepts and need to prove target and disease links,” Dharini Shah, senior scientist at Boehringer Ingelheim Pharmaceuticals, Inc., said. “All the papers and all the research suggests that it’s better – it’s faster. You can do more in a little time and generate more data. That is very key.”

Patients shouldn’t expect to have their genome edited by Crispr anytime soon, though. One of the major roadblocks to using the technique to fix genetic defects of diseases such as cancer is the potential for “off-target effects,” or mutations that may occur in other parts of the genome if the editing is not incredibly precise. Several researchers at Tuesday's day-long symposium noted this concern.

Keith Joung of Massachusetts General Hospital presented on a technique that he thinks will help scientists grasp the full extent of these unintended effects. In his talk, he described a method called GUIDE-seq that will be licensed with accompanying software by his company, and allow researchers to identify the full array of possible mistakes or errors that Crispr causes while making edits to a given genome. He said scientists were essentially working in the dark and lacked a full understanding of what was happening with each edit. “This is a significant limitation,” Jung said. “Specificity is going to be incredibly important.”

Because of this limitation, the greatest value of genome-editing techniques is likely to remain in the lab in the near future. Shah said the benefits that Crispr brings to her company’s lab is still critically important. “In that off-target talk today, they were mostly talking about how this technology would be used for therapeutics. For my application right now, this would be more of a tool to validate my disease links,” she said. “I could make some mouse models; I could make some cell lines which are modified, right now.”

Yi Yang of Novartis Institutes for Biomedical Research said in his presentation that several genome-editing tools will likely be used in combination to splice and reassemble DNA in future therapies. He spoke about his company’s efforts to study the DNA underpinnings of hemophilia B, a disorder that can be caused by up to 1,000 mutations across the genome, making it a “nightmare” from a drug discovery standpoint because there is no single target for a drug to fix.

James Inglese from the National Center for Advancing Translational Sciences at the National Institutes of Health shared his lab’s techniques for honing in on genetic causes of rare diseases such as Parkinson’s disease and standardizing procedures that will help other labs attempting to modify errors or alter the expression of problem genes. His lab works with support from patient foundations eager to investigate the origins of such disorders.

Other researchers including Lukas Dow, a biochemist at Cornell University and Evguenia Kouranova of SAGE Labs, spoke about using Crispr to more quickly engineer mice and rats for animal research. Michelle Luo, a graduate student at North Carolina State University talked about her research on applying Crispr to bacteria that live within humans known as the “microbiome,” which may someday provide a new avenue for discovering antibiotics or enable physicians to play up the beneficial effects of these microorganisms.

Even if the technical hurdles are overcome, companies that deploy Crispr for any of these purposes will also have to grapple with the ethical and security implications introduced by gene-editing technology -- such as who will have access to quick genetic fixes and how to ensure that genomic data does not fall into the wrong hands.