CRISPR/Cas: The revolution has arrived!
Myron Yaster MD
When nitric oxide burst on to the medical scene in the 1990s, many of us, caught up in our daily clinical routine wondered what if any of it meant to our daily practice? We now know that it revolutionized it and our understanding of how many of the drugs we use in our daily practice actually work. We are now on the cusp of a new revolutionary wave: CRISPR/Cas. I’m sure many of you have heard of CRISPR/Cas but are wondering “What is it?” “How does it work?” “How will it change medicine and the lives of our patients?” “Are there implications for anesthesia/ICU/pain management?” I’ve been scanning the literature for an opportunity to provide you with a primer to better understand this and when I found several articles in the financial pages of the NY Times1 and Wall Street Journal announcing FDA approval of drugs developed by Vertex and CRISPR for the treatment of Sickle Cell Anemia, I grabbed the opportunity to present this to you.
In today’s PAAD I’m going to provide you with some very basic ideas of how this CRISPR/Cas works, mostly from a wonderful and easy to read review and video from Scientific American2 as well as from a Pubmed review article providing a much deeper dive.3 I would urge you to watch and listen to the Scientific American video.
I’m also hoping that CRISPR/Cas can be a featured seminar at an upcoming SPA meeting. The revolution is not only coming it is here! Myron Yaster MD
Original article and video
Tabb M, Gawrylewki A, Delviscio J. What Is CRISPR, and Why Is It So Important? This revolutionary gene-editing system has taken science by storm. Scientific American June 22, 2021
https://www.scientificamerican.com/video/what-is-crispr-and-why-is-it-so-important/
First some definitions and the basics. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. Remember, a palindrome is a word, number, phrase, or other sequence of symbols that reads the same backwards as forwards, such as noon, madam, or racecar. It turns out that palindromes are common in DNA. Some serve as backups for damage to our genetic code, while others are common in cancer mutations. With CRISPR, a group of enzymes recognize certain repeats, and break the DNA there to insert important information in the middle or remove aberrant code. These insertions are called “spacers” and in E. Coli often contain the genetic code of different viruses that have invaded in the past.
How can these spacers or an abnormal gene like the genes causing Sickle Cell Anemia, beta thalassemia, or Duchene’s Muscular Dystrophy be found from the billions of genes and sequences in DNA? Complimentary RNA targeting! Once the complementary RNA binds to the target a series of CRISPR-associated enzymes, or “Cas” enzymes attack and cut it out. For the discovery of these guide RNA molecules, Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel prize for chemistry in 2020.
Thus, the CRISPR/Cas system is designed to scan millions of lines of genetic code in DNA to search for therapeutic targets. It may make it possible to remove genes that cause problems and insert normal genes as a fix. The CRISPR/Cas system is made up of different parts, working together, to edit DNA. These parts consist of an enzyme, the Cas enzyme and the guide (targeting) RNA. Once the site has been found, the Cas-RNA complex causes the DNA to unravel. The guide RNA then lines up with the unraveled DNA. Next, the Cas enzyme cuts the DNA strand at a precise location so that the gene editing can take place. The body’s natural repair process plays a role in repairing the cut DNA. Once this process is complete, the modified genes can function with a new set of instructions.
If all of this sounds like science fiction it isn’t! I’ve only scratched the surface of this revolution and haven’t discussed the dark side which may include the use of this technology in utero to create the eugenics “fantasy” of producing supermen/women. Send your thoughts to me and I will post in a Friday review.
References
1. Kolata G. F.D.A. Approves Sickle Cell Treatments, Including One That Uses CRISPR. New York Times2023.
2. Tabb M, Gawrylewki A, Delviscio J. What Is CRISPR, and Why Is It So Important? This revolutionary gene-editing system has taken science by storm. Scientific American2021.
3. Richardson C, Kelsh RN, R JR. New advances in CRISPR/Cas-mediated precise gene-editing techniques. Dis Model Mech 2023;16(2) (In eng). DOI: 10.1242/dmm.049874.