Creative Minds: Applying CRISPR Technology to Cancer Drug Resistance

Posted on December 10, 2015 by Dr. Francis Collins

Patrick Hsu

As a child, Patrick Hsu once settled a disagreement with his mother over antibacterial wipes by testing them in controlled experiments in the kitchen. When the family moved to Palo Alto, CA, instead of trying out for the football team or asking to borrow the family car like other high school kids might have done, Hsu went knocking on doors of scientists at Stanford University. He found his way into a neuroscience lab, where he gained experience with the fundamental tools of biology and a fascination for understanding how the brain works. But Hsu would soon become impatient with the tools that were available to ask some of the big questions he wanted to study.

As a Salk Helmsley Fellow and principal investigator at the Salk Institute for Biological Studies, La Jolla, CA, Hsu now works at the intersection of bioengineering, genomics, and neuroscience with a DNA editing tool called CRISPR/Cas9 that is revolutionizing the way scientists can ask and answer those big questions. (This blog has previously featured several examples of how this technology is revolutionizing biomedical research.) Hsu has received a 2015 NIH Director’s Early Independence award to adapt CRISPR/Cas9 technology so its use can be extended to that other critically important information-containing nucleic acid—RNA.Specifically, Hsu aims to develop ways to use this new tool to examine the role of a certain type of RNA in cancer drug resistance.

As scientists have pinpointed the underlying genetic causes of more and more diseases, the highly specific, DNA-editing power provided by CRISPR/Cas9 has made it possible to envision a future in which those inherited conditions might one day be corrected with extreme precision. Often compared to a molecular scalpel, the CRISPR/Cas9 machinery can be readily programmed to cut the genome in just the right spot by attaching a short stretch of RNA to guide the way [1]. This enables researchers to cut and paste genes into the genome with incredible ease, vastly accelerating the pace of biological discovery and raising hopes for a new generation of treatments and cures.

Hsu found himself at the forefront of this revolution in gene editing as a graduate student and postdoc at the Broad Institute and Harvard University, Cambridge, MA. He was an instrumental member of a team led by NIH grantee Feng Zhang that showed how CRISPR/Cas9, originally derived by studying the way bacteria defend themselves against viruses [2], could be adapted for use in human and mouse cells [3]. He also began to explore the use of CRISPR/Cas9 technology in gene therapy, first at Broad and then at Editas Medicine, Cambridge, MA, which is among the biotech firms now working to translate gene editing technologies into new therapeutics. For his many contributions to the development and application of CRISPR/Cas9 technology, the 23-year-old Hsu was named one of Forbes magazine’s 30 Scientists Under 30 for 2015 [4].

Hsu now hopes to adapt CRISPR/Cas9 tools so they can be used to manipulate RNA just as skillfully as one can manipulate DNA. To understand how this might be important and useful, consider that all of the cells in your body are essentially identical at the genetic level. The reason that these cells look and function differently in different types of tissues and organs mainly stems from differences in which genes are switched on inside those cells—that is, which genes are being expressed, or transcribed into RNA.

Many RNA molecules serve as templates for the production of proteins—they’re called messenger RNAs (mRNAs). However, some other RNA molecules, dubbed noncoding RNAs (ncRNAs), aren’t directly involved in protein production and can influence gene expression in ways that scientists are still working hard to understand. Hsu thinks the new RNA-editing approaches that he is developing may serve to accelerate such efforts.

To test this idea out, Hsu plans to use his CRISPR/Cas9 RNA editing system to study the role of ncRNAs in the development of resistance to cancer therapies, specifically targeted therapies for melanoma. Drugs aimed at particular genetic mutations have produced remarkable results in some people with this deadly form of skin cancer, but, all too often, their tumors eventually stop responding to the drugs. So, Hsu plans to search for ncRNAs associated with the development of drug resistance in melanoma, and then use his new RNA-editing tools in lab experiments aimed at precisely elucidating their functions. Such information could prove valuable for efforts to design new and better drugs for melanoma, as well as many other types of cancer.

While Hsu’s current work is centered on cancer, he has never lost his curiosity about the brain, motivated by his own hunger for learning and by a family history of Alzheimer’s disease. So, he’s also eager to apply new RNA-editing tools for exploring questions about how the brain’s neurons can function so differently, despite having the same underlying genome.

Who knows where Hsu’s scientific creativity will take him after that? After all, this is a young man who is already living what he says is every scientist’s dream: “To lead an independent research group, develop your own ideas, and drive them to reality.”

References:

[1] Development and applications of CRISPR-Cas9 for genome engineering. Hsu PD, Lander ES, Zhang F. Cell. 2014 Jun 5;157(6):1262-1278.

[2] A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. Science. 2012 Aug 17;337(6096):816-21.

[3] Multiplex genome engineering using CRISPR/Cas9 systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Feb 15;339(6121):819-23.

[4] 30 under 30: Young scientists who are changing the world. Hedgecock S, Herper M. Forbes. 2015 Jan 5.

Links:

Patrick David Hsu (Salk Institute, La Jolla, CA)

Hsu NIH Project Information (NIH RePORTER)

NIH Director’s Early Independence Award

NIH Support: Common Fund