Mainstream media has been abuzz about CRISPR, a new tool that biologists can use to change the human genome (our DNA blueprint), but what really is CRISPR, and what kind of impact will it have on cancer research?
CRISPR (pronounced “crisper”) is an acronym for clustered, regularly-interspersed short palindromic repeats. Bacteria have used the CRISPR system for millions of years to defend themselves against viruses: after an infection, bacteria copy a part of the virus’ DNA into its own genome. The next time it is infected, the bacteria are ready to cut up and destroy any new, invading viruses since it already has a “memory” of the infection. This is similar to how vaccinations work in humans: we can think of CRISPR as a type of bacterial immune system. Over the course of about a decade, geneticists took the bacterial CRISPR system and engineered it to work in human cells. CRISPR is now a programmable pair of genetic scissors that can make any change in any cell’s DNA.
So what? Why is CRISPR being touted as such a breakthrough?
One of the best ways to study what a gene does is to cut it out of the DNA. This means that the gene has been deleted from the DNA. Scientists can then do different tests, called assays, on cells to see if their behaviour has changed, if at all, as a result of losing the gene. Historically, accomplishing this has been exceedingly difficult and CRISPR is a vast improvement from previous strategies.
Prior to CRISPR, researchers turned to a technique called RNA interference (RNAi) in order to reduce, but not completely delete, the effect of a gene- often resulting in “messy” or inconclusive results. To completely delete a gene, a different technique that involves using proteins to cut DNA (nucleases) must be used. Older systems using zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENS) can be also engineered to delete genes. However, they are extremely expensive and time consuming to create- so much so that they simply aren’t practical to use in everyday research.
What sets CRISPR aside, is that it allows researchers to make changes to the genome, in addition to deletions – something old techniques just could not do. In this way, CRISPR is similar to Johannes Gutenberg’s invention of the printing press- researchers could always cut DNA, but now anyone can cut and edit it quickly, effectively, and at a minimal cost.
Unsurprisingly, CRISPR has, and will continue to have, a MASSIVE effect on cancer research: the power of deleting and editing DNA will write the story of CRISPR moving forward. One area of study that has always been challenging to study is cancer initiation, i.e. what specific genetic changes occur that cause normal cells to become cancerous? Over the years, research revealed numerous changes in normal cells routinely associated with early disease growth and spread. However, since cancers are often identified at later stages where cells are already heavily mutated, it has been very hard to determine exactly what role each cell change plays. Now, we can use CRISPR to drastically improve laboratory cancer models by mimicking these specific changes and methodically studying their individual or combined effects, ultimately leading to improved early detection and treatment. In addition, researchers can further investigate how cancer progresses by recreating the cell changes responsible for disease growth. This has led to a better understanding of what causes cancers to become aggressive- an area previously difficult to study.
Now, we can also look at the big picture- the REALLY big picture. Since CRISPR is so cheap, simple and effective, scientists can systematically delete thousands of genes at a time and study their effects using a type of experiment called a screen. Dr. Jason Moffat at the University of Toronto and his team have designed a CRISPR screen that has uncovered genes responsible for cancer cell growth in brain, colon and skin cancers. Each and every gene identified is a new weakness discovered- weaknesses that can be exploited by becoming a target for future drug development and cancer therapies.
Other research groups have designed CRISPR screens to understand how and why cancer cells become resistant to drugs and provide clues to solving this resistance. Interestingly, performing a screen isn’t a new idea- this strategy builds on concepts that have been around for decades, and accomplished long before CRISPR hit the scene. What is absolutely staggering is that Dr. Moffat’s study was able to discover 4 times more essential cancer genes than previous strategies, such as RNAi. This highlights the true potential of CRISPR.
CRISPR is simply a tool, and right now it is the brightest, best and shiniest tool in the molecular biologist’s and geneticist’s tool kit. It can be used in both large and small scale experiments to understand the fundamentals of cancer biology. CRISPR will soon stop making headlines and become similar to an architect’s ruler- always present, invaluable, but invisible. Yet the data that it produces will shape generations to come.
This article was written by Mike Pryszlak. Mike is currently completing the third year of his PhD at the University of Toronto. He studies how normal stem cell genes are changed in cancer stem cells. To learn more about Mike and his research check out our members page.
References and further reading:
Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., Sun, S., et al. (2015). High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163, 1515–1526.