What is CRISPR? | MD Anderson Cancer Center


There are over 6 billion letters, or nucleotides, of DNA in the genome. These contain all the information needed to create an individual organism. Certain sequences of DNA, called genes, contain instructions for making proteins that determine everything about how we look and how we function. We expect there to be some differences in these sequences that result in differences in individual people, but sometimes these instructions have significant mutations or changes that can lead to serious diseases like cancer.

Imagine having to find out which changes in which sequences in this long chain of 6 billion letters are important for the targeted treatment of diseases. And once you’ve identified some of those important genes, how do you fix those mutations?

A groundbreaking discovery of a system called CRISPR in 2012 has sparked a revolution in biomedical breakthroughs over the past decade. Scientists can use it to target, edit, modify and regulate genes and place any desired enzyme or protein anywhere in the genome. This allows them to find new treatment targets and understand how different genes affect cells in ways that were previously impossible.

But how do we apply CRISPR to understand cancer? We spoke to Traver Hart, Ph.D., Associate Professor of Bioinformatics and Computational Biology, to learn more about CRISPR and how it could be used to advance cancer care.

What is CRISPR?

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. That’s a mouthful, so scientists just refer to it as CRISPR. These are repeated sequences in the genetic code first found in bacteria and later found to be part of a novel bacterial adaptive immune system against phages, viruses that attack bacteria.

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This system combines the CRISPR DNA sequences and a set of Cass (“CRISPR howsocialized”) proteins to identify and destroy invading viral DNA. It also embeds a sample of that viral DNA between those CRISPR sequences so it can easily recognize and attack the same virus in the future. Thanks to this unexpected discovery in E. coli Bacteria scientists can now use this method and apply it in human cells in a similar way.

How does CRISPR work?

The main part of the CRISPR system is Cas endonuclease, the Cas protein that cuts DNA strands. These Cas proteins can be programmed to find a 17- to 24-letter sequence by appending a guide RNA that uniquely matches the specific DNA target. It is comparable to a key that fits a lock. Researchers have at their disposal a large library of guide RNAs that may correspond to specific parts of different genes in the human genome.

Once CRISPR is added to a cell, it seeks out and binds to that matching target sequence in the DNA, and the attached Cas protein is activated to do what scientists have asked it to do. Some Cas proteins – like Cas9 – can cut or break DNA. This is the original protein found in bacteria. Others have been engineered to turn a gene on or off without having to cut it. This allows researchers to find out more about what happens when cells produce too much (up-regulation) or too little (down-regulation) of a given protein and how this can affect a cell’s outcome.

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How do we use CRISPR to study cancer in human cells?

In the past few decades, studies have been performed on yeast cells and other model organisms that allow scientists to efficiently edit the genome. The discovery of CRISPR was instrumental in changing that.

Thanks to CRISPR, we can edit the genome directly in human cells with unprecedented ease.

Once CRISPR cuts the target DNA, it is repaired or replaced with a different sequence. Scientists use this method to turn off human genes in cancer cells and identify which of these genes are essential for tumor cells to grow without harming normal cells. This allows us to nominate gene candidates for drug targets that can be highly tumor specific. My lab is trying to find better ways to kill tumor cells by turning off multiple genes at once with another Cas protein called Cas12a. This gives us a better insight into how different genes and proteins in tumor cells work together to promote cancer progression.

A recent study by Yohei Yoshihama, Ph.D., and Ronald Depinho, MD, used CRISPR to probe cancer cells and identify a protein called JMJD1C as a candidate target in castration-resistant prostate cancer. Another study by Chao Wang, Ph.D. and Junjie Chen, Ph.D., used CRISPR to screen growing human cancer cells in mouse models and discovered a protein called KIRREL that has been shown to be important in tumor suppression.

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Can CRISPR fix genes in humans?

While the idea of ​​being able to fix “bad” genes to cure disease is a worthy pursuit, science is not yet at the point where it can safely and effectively do so. Researchers are studying how CRISPR can be used to correct the genetic defects that cause beta thalassemia and sickle cell anemia, diseases that affect the amount of hemoglobin in the body and result in patients needing constant blood transfusions. If approved, this type of therapy called Exa-Cell would become the first CRISPR-based medical treatment, which is incredibly exciting.

What’s next for CRISPR?

The possibilities for the information that can be gleaned from the use of CRISPR systems are endless, and after just 10 years, scientists have only scratched the surface. Newer Cas proteins and other enzymes are being studied, and there are still questions about how to make CRISPR more specific so it doesn’t inadvertently have unintended targets.

Here at MD Anderson, our use of CRISPR continues to advance our understanding of how cancer cells work and help uncover many avenues to tailor treatments specifically to specific tumors that we hope will one day achieve our goal of ending cancer.

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