All about Messenger RNA Medicines

The two first Covid-19 vaccines to release successful Phase III data are both mRNA vaccines. This is a relatively new but promising medical biotechnology. In the next two blogs we’ll explain the basic biology behind it, break down the initial clinical data on the Pfizer and Moderna vaccines, and provide several classroom resources.

mRNA

RNA is an essential part of life’s genetic toolkit. Its best-known role is as the intermediary that transfers information stored in the genome out of the nucleus and into a cell’s cytoplasm where it’s then used as a template to build proteins. Like DNA, RNA molecules are a chain of nucleotide subunits. Each RNA subunit consists of a ribose sugar, a phosphate group, and a unique nitrogenous base. Unlike DNA, RNA is usually single-stranded and has an extra hydroxyl group on its sugar which makes the molecule less stable. Most cells also have a host of RNA degrading enzymes. As a result, RNA is constantly being produced, used, degraded, and remade in our cells.  Thus, RNA is far more ephemeral than DNA.

There are several types of RNA including transfer RNA (tRNA), ribosomal RNA (rRNA), and messenger RNA (mRNA). mRNAs carry complimentary genetic codes copied from DNA during transcription to ribosomes and provide the blueprint for making proteins during translation. Their structure reflects this primary function. mRNA molecules have a primary coding region flanked by two untranslated regions that help with stability and translation. Each molecule also has a 5’ prime cap and a poly-A tail that also provide protection and that help the mRNA leave the nucleus and attached to a ribosome.

Plociam, CC BY-SA 3.0 http://creativecommons.org/licenses/by-sa/3.0/, via Wikimedia Commons

In the body, mRNA is synthesized from DNA on an as needed basis. However, mRNA can also be created synthetically. Scientists creating synthetic mRNA must decide on the exact protein they want to code for and also carefully design the 5’ cap, poly-A tail, and UTR regions.

mRNA Medicine

Pfree2014, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia

The exciting possibilities of using mRNA to treat diseases have been tantalizing scientists since the molecule was first discovered in the early ’60s. By creating and delivering mRNA to a patient, cells could become their own drug factories and temporarily produce any type of protein. For example, one promising use of mRNA medicine is to help a patient’s body target cancerous cells by prompting them to create a class of protein markers called neoepitopes. Another treatment proposed using mRNA to promote healing following open-heart surgery by having nearby blood vessels produce a growth hormone.

The technology had several alluring features. Because the nucleotide code of mRNA is easy to change such genetic instructions could be quickly updated when conditions changed or could even be personalized for an individual. Another promising advantage – by using a person’s cells to do the important but complex job of protein production, mRNA manufacturing would skip many of the challenges and lags of mass-producing medical-grade proteins. Finally, the treatment would be easy to confine and manage because any mRNA introduced into the cell would be degraded within a few days.

However, mRNA medicine also faced significant challenges. The first was mRNA’s reactivity and particularly its extreme instability outside of a cell. This made storage and delivery of the molecule at best unreliable and at worst completely unrealistic. Another challenge was getting the mRNAs into the targeted cells. Finally, developers struggled with the cell and body rejecting the mRNAs and triggering an unintended immune response.

Luckily, scientists have discovered several ways to overcome these challenges! One important innovation is packaging mRNA molecules in lipid nanoparticles which provides essential protection when outside of the cells and enables the mRNA to pass across the cell membrane into the cell. Another breakthrough was replacing the original mRNA nucleoside (guanine, adenine, cytosine, and uracil) with closely related analogs that could still code for proteins, but which did not as easily trigger a cells immune response. Such inventions represent years of dedicated research but were luckily in place by 2020 when the call went out for a Covid-19 vaccine that could be produced quickly and at a very large scale. 

“With an mRNA vaccine, you sit at your computer and design what that piece of RNA is going to look like, and then you have a machine that can make that RNA for you relatively easily… In some ways, we’re lucky in 2020 that this very powerful technology was ready for prime time, because it could be a really big advantage.” Dr. Paula Cannon, associate professor at the Keck School of Medicine.

RESOURCES

Ready to bring current events into your classroom, provide science-based information about this important but charged topic, and review key concepts like molecular biology’s central dogma? Here are some resources. And keep watching our blog as we continue to follow the development and testing of vaccines.