How CRISPR is revolutionizing our study of complex diseases, like Alzheimer’s

Contributed by Jean Paul Chadarevian & Amanda McQuade

Dr. Emmanuelle Charpentier and Dr. Jennifer A. Doudna make history as the first all-female team to be awarded the Nobel Prize in Chemistry for their pioneering discovery of CRISPR-Cas9, a highly specific and efficient genome editing technology.

Emmanuelle Charpentier and Jennifer A. Doudna (Photo by [Peter Barreras]/Invision/AP)

Charpentier, Director at the Max Planck Institute for Infection Biology in Berlin, and Doudna, biochemist at the UC Berkeley, first described the CRISPR-Cas9 system in their 2012 publication in Science. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, was first observed in the bacterial immune system.

Like us, bacteria are prone to viral infections; however, as single-celled organisms, they lack the complex systems of immune cells that flow through our bodies and keep us safe. In humans, our immune cells have “memory cells” that allow us to more quickly fight diseases we have seen before. Bacteria have instead evolved an immune response that copies segments of viral genetic information and stores them within the bacteria’s own DNA using CRISPR. These segments are then transcribed into looped fragments of RNA that couple with digestive enzymes like Cas9 to allow a bacterium to recognize a repeat infection and quickly destroy the pathogen. Dr. Charpentier and Dr. Doudna isolated the two components of this “genetic-scissor” and were the first to recognize its capability to be utilized by researchers to make individual nucleotide changes in the DNA of any organism with great specificity.

Since their landmark publication in 2012, scientists around the globe continue to find innovative ways to employ CRISPR-Cas9 technology. Here at UCI, CRISPR-Cas9 technology has become an integral part of our daily scientific research. In the Stem Cell Research Center, the CRISPR Core now provides faculty investigators custom gene-editing services using CRISPR-Cas9. Core co-Manager Jean Paul Chadarevian has utilized advancements in this technology to genetically modify stem cell lines for various investigators to express fluorescent reporters, silence genes of interest, and model genetic variations of multiple genetic disorders.

In the induced pluripotent stem cell (iPSC) Core led by Mathew Blurton-Jones at the UCI Alzheimer’s Disease Research Center, CRISPR-modified human cell lines are being used to investigate how Alzheimer’s risk factors influence human microglia. Most recently, doctoral candidate Amanda McQuade’s manuscript, “Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease,” was accepted for publication in Nature Communications. Her findings highlight that individual genetic changes in immune cells can drastically alter the ability of these cells to fight disease and suggests activation of the immune system in the early stages of disease may be beneficial for patients.

From the investigation of risk genes in various diseases, to the discovery of novel biomarkers, and even to the development of cell-based therapeutics, CRISPR-Cas9 is being used in research labs and biotech companies alike to revolutionize our science. It is a readily available, highly specific, and cost-effective technology that has unquestionably changed what is possible in the investigation and potential treatment of devasting illness, like Alzheimer’s disease.

Goran K. Hansson, the secretary-general of the Royal Swedish Academy of Sciences, has gone as far as to say this discovery is, “about rewriting the code of life.” While Dr. Doudna has shared that this research began with sheer curiosity about bacterial immune functions, it is clear that Doudna and Charpentier have revolutionized the ways we do science and are certainly deserving of this prestigious award.

 


 

Jean Paul Chadarevian MS

Jean Paul Chadarevian is a graduate student in the department of Neurobiology and Behavior working with Dr. Mathew Blurton-Jones. He is the founding co-Manager of the UCI CRISPR Core at the Stem Cell Research Center. His ongoing work utilizes CRISPR to model Autoimmune lymphoproliferative syndrome in chimeric animal models and engineer human-derived stem cell lines to deliver target-specific therapeutics in vivo.

 

Amanda McQuade MS

Amanda McQuade is a graduate student in the department of Neurobiology and Behavior working with Dr. Mathew Blurton-Jones. Her graduate work focuses on using CRISPR to study risk mutations for Alzheimer’s disease in human cell models and chimeric animal models. Her ongoing studies highlight the critical need for more research into immune function in neurodegenerative disease. McQuade is currently acting as a Co-Chair of the trainee program on Research and education within UCI MIND, ReMIND, which focuses on community outreach and trainee education.