Over the past 18 months, we have discussed the nucleic acids RNA and DNA in the context of the COVID-19 pandemic and, as part of that discussion, we have covered a great deal on mRNA vaccines. These are the vaccines manufactured by Pfizer/BioNTech and Moderna that use messenger RNA (mRNA) as the genetic payload, carrying a recipe for body cells to make the spike protein, the protein that SARS-CoV2 (the virus that causes COVID-19) projects from its coat that enable the viral particles to attach to a protein on the surface of various body cells, called ACE-2 (or the ACE-2 receptor). What is remarkable and disruptive (in a positive way) about mRNA as the business end of a vaccine is that it is so easily programable. In contrast with more traditional vaccines, such as the inactivated whole virus vaccines —examples being Sinovac and Sinopharm COVID-19 vaccines made in China— which have to be cultivated anew to make them different, for instance to improve their efficacy against new variants, mRNA vaccines can be reprogramed, simply by changing the sequence of the mRNA strip, which amounts to a change of recipe. So it is more of a software change than a hardware change. Importantly, since the hardware is the same, mRNA vaccines can be reprogrammed, not only to tweak COVID-19 vaccines to respond to variants, but also to create other mRNA vaccines against completely different infectious agents. This means a need for a much shorter amount of time needed for safety testing compared with older vaccine technologies and also that the same factories can be used over and over again to make vaccines against different diseases. Putting all of this together, we can expect not only extremely effective vaccines in the years to come, but also short timelines for making and testing them, such as a year, or several months, in contrast with previous timelines of a decade of more.
While the vaccine technology alone is a game changing advance, vaccines are just one example of the application of RNA technology, which is on track to be deployed against an increasing number of medical conditions, including some of particular interest to new parents and parents to be who may be concerned about hereditary conditions. In this context, one entire category of RNA technology is expanding exponentially and is appropriate to discuss in a series of blog posts, since the year that the COVID-19 pandemic hit us, 2020, was also a year when the Nobel Prize in Chemistry was awarded for a very important innovation that makes use of RNA. That innovation is called CRISPR genome editing (or CRISPR gene editing) and the Nobel Prize for inventing this editing system, based on a discovery of the workings of a kind of bacterial immunity system, was awarded in December 2021 to two scientists, Jennifer Doudna and Emmanuelle Charpentier.
While Doudna and Charpentier made their discoveries less than a decade ago, they, and also scientific rivals in the field, have founded a bunch of small companies, each of which is developing CRISPR technology toward different, particular clinical applications, creating all sorts of improvements along the way. We will get more into the particulars in future posts, so here we are going just an overview on what CRISPR is and why it can become a game changer for your health, or for the health of your child or other family member. Before delving into what CRISPR is, however, let’s do a quick overview on RNA and DNA and what these molecules do in your cells.
DNA and RNA are both nucleic acids — long molecules, or polymers, made of units, called nucleotides which carry information based on how their sequence from one end of the molecule to the other. In all known living organisms, DNA serves for long-term storage of genetic information —the genes are made of DNA— whereas RNA has a diverse role of functions. RNA can be used in many different ways, including as mRNA, which is like a paste it note, carrying a message short term from DNA, a message that is translated into the sequence of amino acid building blocks that comprise a protein. But, as I just wrote, RNA has a variety of functions, including functioning as enzymes, molecules that help with various processes, including delivering proteins to where they need to go along a molecule of DNA.
The term CRISPR is an acronym for a term that I won’t throw at you, because you don’t need to memorize it. What the acronym refers to though are various genetic sequences within bacterial DNA, and also within the DNA of archaea (Earth life consists of three domains: Bacteria, Archaea, and Eukaryotes and we belong to the latter) that enable the recognition that a microorganism is being infected with a virus. This recognition enables a protein, called a CRISPR-associated (CAS) protein to come into play and cut up the DNA of the invader. There are various types of CAS proteins and they get to where they need to go because of special molecules of RNA produced to guide them.
What Doudna and Charpentier figured out, and why they won the Nobel Prize, is that CRISPR-CAS systems could be hijacked and re-purposed for the sake of cutting out particular sequences of DNA from any organism, including humans, and, with further innovations, to change, or edit, DNA sequences. This has the potential for major improvements to gene therapies, it’s happening in different ways for different diseases, and so we’ll get into it more in upcoming posts, and the key to the whole thing is RNA, because RNA is what brings the CAS proteins where they need to go, and the RNA can be programmed to go to any DNA sequence.