In Feng Zhang’s laboratory at MIT’s McGovern Institute for Brain Research and the Broad Institute, members “share a sense of excitement and urgency,” says Omar Abudayyeh ’12, a sixth-year MD/PhD student in the Harvard-MIT Program in Health Sciences and Technology (pictured above, left, with Zhang). That’s because they are propelled by a common purpose: expanding the toolkit for manipulating genes in eukaryotic cells, and engineering genes in order to understand, treat, and cure some of our most intractable diseases and disorders.
“What Feng instills in us is the desire to do science at the edge, to push the needle,” says Abudayyeh.
The Zhang lab’s RNA approach avoids the cancer hazards associated with DNA editing.
The group’s most recent research accomplishes just that. They have devised a gene editing tool called REPAIR that can make precision fixes in human RNA. “It’s exciting because there are thousands of diseases caused by genetic mutations,” says Abudayyeh, who is co-first author, along with fellow graduate students Jonathan Gootenberg ’13 and David Cox, of an October 25, 2017, article in Science describing this work. “REPAIR revolutionizes how we can do genome editing, and makes it possible to correct problems, even down to a single letter of genetic information.”
The acronym stands for “RNA Editing for Programmable A to I Replacement”—referring to the tool’s ability to change a single RNA letter, or nucleic acid base, to another. A is adenosine, and I is inosine (which cells read as G, or guanosine). Single-letter mutations from G to A—the kind REPAIR targets— have been identified in such devastating human diseases as Duchenne muscular dystrophy and Parkinson’s.
This work springboards from prior discoveries by Zhang, the Patricia and James Poitras (1963) Professor in Neuroscience at the McGovern Institute, a core institute member of the Broad Institute, and an associate professor in the departments of brain and cognitive sciences and biological engineering. Since opening his lab at MIT and Broad in January 2011, the 36-year-old Zhang has been pioneering the development of CRISPR genome editing tools, technologies based on naturally occurring enzymes derived from bacterial immune systems, which can precisely snip the DNA of mammalian cells.
“REPAIR revolutionizes how we can do genome editing, and makes it possible to correct problems, even down to a single letter of genetic information.”
REPAIR introduces new domains of medical treatment.
In the long slog to make personalized medicine a reality, CRISPR technology represents a potential superhighway. CRISPR systems have made it possible both to diagnose infections and diseases in people with incredible speed, and to inactivate genes associated with many diseases. With REPAIR, CRISPR-based genetic engineering takes another leap forward. Says Zhang, “The REPAIR system brings all the machinery necessary to generate changes at the RNA level into a cell, fixing genetic sequences and producing the correct proteins.”
It’s a tool that lifts a burden for biomedical researchers. “REPAIR eliminates problems that have inhibited therapeutic possibilities until now,” explains Abudayyeh. “When you edit DNA to make a correction, you worry that if the edit goes off target, it might create a mutation that accidentally turns a gene on, a mistake that gets replicated in the genome, potentially making cells cancerous.”
But because RNA itself doesn’t naturally replicate, cells subject to REPAIR’s RNA fixes don’t pass on changes to the next generation of cells, and engineered genes can revert to their original form. “We have a technology that’s like a small molecule drug: when it’s taken, it has an effect, and when you stop taking it, the effects stop,” says Abudayyeh.
This technology breaks open new domains of medical treatment. Certain kinds of liver diseases and anemias, unyielding to current therapies, are likely susceptible to REPAIR. “And it will be great for illnesses that are temporal,” says Abudayyeh. “Imagine taking something to alleviate a migraine flare, or defend against an RNA-based virus infection, like influenza.”
Excerpted from “To the Letter” in the spring Spectrum. Read the full article.