Venturing Inside the Genome: Feng Zhang on the Promise of CRISPR

 

Few acronyms roll off the tongue as easily as CRISPR — and that’s a good thing, since the name of this gene-editing tool is spoken a lot. It gives researchers an unprecedented ability to turn genes on and off, as well as insert new genes into DNA strands. Behind the catchy name and the near-deafening buzz surrounding the technology, CRISPR also has the potential to help scientists understand sections of the human genome whose roles are still unknown.

For their October 3 seminar, the KSJ fellows took a field trip to one of the institutions pioneering the use of CRISPR in biomedical research, the Broad Institute of MIT and Harvard, just across Main Street from campus. Over pizza and beer in a conference room hung with heavy yellow fabric (“We’re still working on getting this room un-mustarded,” said Lee McGuire, Broad’s chief communications officer), the fellows learned about CRISPR from three members of the Feng Zhang Laboratory.

Vanessa Verdine, a research associate, began the presentations with a “CRISPR Crash Course” detailing, among other things, what the name stands for (clustered regularly interspaced short palindromic repeats), where it comes from (bacterial genomes, a system used to adapt and gain resistance to intruders), and how a number of genes often accompany CRISPR sequences in bacterial DNA; they are known as CRISPR-associated, or “Cas,” genes.

Verdine said that one technique the Zhang lab has been investigating is the use of the Cas 9 protein to “knock out” certain sequences of the genome by making precise cuts in spots along a DNA or RNA strand. In a process called screening, Cas9 can be tuned to knock out a number of genes that researchers suspect are responsible for biological functions. As the DNA replicates, the biologists can monitor how the knockout screen affected an organism’s biology. “Cas9 is just a small slice of CRISPR,” said Verdine. “There are still lots of useful proteins yet to be discovered.”

Julia Joung, an MIT graduate student and researcher in the Zhang lab, presented another application of Cas9: identifying the roles of non-coding sections of the human genome. “These DNA and RNA sections were long considered to be junk, since they do not code proteins that are used in the body,” she said. “But they do other things in the cell.” Using Cas9 to screen and compare sections of long non-coding RNAs or lncRNA (pronounced link RNA), Joung and her team were able to discover that certain sequences help cancerous skin cells resist a common drug treatment. The study was recently published in Nature.

After the presentations, the lab’s director, Feng Zhang — core institute member at Broad, investigator at the McGovern Institute for Brain Research at MIT, and MIT professor of neuroscience and biological engineering — fielded questions from the fellows about the work’s potential.

“There’s so much we don’t know … and so much we don’t know that we don’t know,” he replied. “The genome is so vast, and each thing in the genome might influence many others, so the permutations are in the millions. We could find gene circuits that work together … circuits that influence immunity to disease, circadian rhythm ….”