Tyler Jacks, PhD
CRISPR is a revolutionary new gene-editing technology that has taken the medical research community by storm.
Although researchers have been exploring gene editing for more than 40 years, scientists say the CRISPR technology offers game-changing methods for anticancer research as well as a host of other applications. CRISPR, which is an acronym for clustered regularly interspaced short palindromic repeats, is also referred to as the CRISPR-Cas9 system. It consists of repeating sequences of genetic code, interrupted by spaces or spacer sequences. The technology allows for rapid and precise editing or alteration of a cell or organism’s genome, inactivating or repairing genes as needed by changing the DNA sequences.
The system is “borrowed” from a biological phenomenon in bacteria, whereby bacteria can defend themselves against invading viruses using an enzyme called Cas9 and a piece of RNA called a guide RNA, or gRNA. The gRNA finds the target sequence and binds to it.
The Cas9 enzyme, which has been compared to a pair of extremely sharp scissors, follows the gRNA and makes a cut across the two DNA strands. Once the cut is made, the cell tries to repair itself, but it is at this point that scientists can step in and alter the sequence of the gene that can, in turn, change the function of the encoded protein.
The technology has quickly become the “newest and most widely used gene-editing technique,” according to a National Institutes of Health (NIH) committee that recently examined a number of developments in the broader field.1
CRISPR “has rapidly led to breakthroughs in the editing of genomes of many organisms, including plants, nematodes, flies, fish, monkeys, and human cells,” the panel said.1
Changing the Landscape
According to researchers, CRISPR and functional genomics have changed the cancer research landscape. Researchers have been working on genome engineering since the 1970s but the techniques were inefficient or too difficult to use. “The reason [CRISPR] is exciting is that we have not had the ability to so precisely and so simply manipulate the genomes of cells, mammalian cells in particular, before this time,” Tyler Jacks, PhD, said in an interview with OncLive
. “It’s remarkably powerful and beautiful in its simplicity. It’s just such a simple, straightforward system to use, and that is why it’s so popular— because an eighth-grader could do it.”
Jacks is a Daniel K. Ludwig Scholar and investigtor at the Ludwig Center at MIT, and his laboratory has pioneered the use of CRISPR to construct in vivo models of human cancers. “We can think of older genome engineering technologies as similar to having to rewire your computer each time you want to run a new piece of software, whereas the CRISPR technology is like software for the genome. We can program it easily, using these little bits of RNA,” Jennifer Doudna, PhD, explained in a TED Talk late last year.2
Doudna is a professor of Chemistry and of Molecular and Cell Biology at the Department of Chemistry and Chemical Engineering of the University of California, Berkeley, and also is a pioneer in CRISPR technology.
CRISPR was named as one of the Top 10 breakthrough technologies in 2014 and 2016 by MIT Technology Review, and it won the Science Magazine’s Breakthrough Award in 2015, after being runner up in 2012 and 2013.3,4
“It’s swept the field, which is pretty remarkable because the first breakthrough paper was only published in the summer of 2012,” Jacks said. “The last I counted, there had been something like 5000 papers since then, using the technology, which is pretty phenomenal.”
The ability to make such precise alterations may have been exciting on its own; however, CRISPR has an even greater advantage: more than one gene can be altered at the same time. Considering that most genetic disorders, including cancer, are caused by more than one damaged gene, the ability for multiple manipulations increases CRISPR’s potential utility.
Tumors require at least 3 to 6 mutations for them to become malignant, starting with a mutation that allows them to activate and sustain continuous proliferation.5