Why RNA?

Hey it’s Nestor writing from Aarhus and yes, I will be talking about RNA (again) but this time, instead of a perspective about building nanorobots with it, a bit more biological, related to the current world pandemic. Why do he hear so much about RNA vaccines? We will try to go through that in this post.

To make sure it is understood and for the critic reader, a little scientific mistake has been introduced in this blog post, hopefully you will be able to find, let me know in the comments!

We have lately heard a lot about RNA in Corona vaccines. Covid-19 mRNA vaccines give instructions for our cells to make a harmless piece of the famous Spike protein, which is found on the surface of the virus that causes COVID-19, it binds to the receptors in the surface of our cells and is essential for viral infection.

Most traditional vaccines consist of either killed or weakened forms of a virus or bacterium. These particles induce an immune response that allows the body to fight off the actual pathogen later on when a potential infection occurs. On the other hand, RNA vaccines deliver genetic information that allows the body’s own cells to produce a viral protein. Synthetic messenger RNA that encodes a viral protein can borrow this machinery to produce many copies of the protein. These proteins stimulate the immune system to produce a response, without posing any risk of infection. What is this based on?… Let’s take a look at the flow of information in molecular biology (fig. 1).

Figure 1. The genetic information is stored in the DNA, transcribed into RNA and translated into proteins (illustrated here the infamous spike protein) Dashed arrows indicate unusual processes.

In the usual flow of information, the DNA sequence encodes the information and gets replicated for the sake of biological inheritance. Segments of this information are copied into RNA, the molecule that acts as a messenger, getting the information contained in the DNA out of the nucleus (in eukaryotic cells), where it finds its way into a ribosome, which is in charge of translating the information into a protein structure. There are also some uncommon paths in which the RNA gets reverse transcribed into DNA or it self-replicates [1].

But, if DNA is the molecule that stores the genetic information, then why is RNA being used to produce this specific set of vaccines? Why not DNA?

As for many accepted rules in any discipline, there are exceptions to it. The above stated dogma is not really true for all the living organisms and a good example of this are actually some viruses. Some viruses use RNA as means of genetic information storage, some of the most familiar ones are the common cold, influenza, dengue, hepatitis C and E, retroviruses (HIV) and surprise, Covid-19.

All known cellular organisms use DNA genomes for storage of genetic information. RNA genomes, although they probably preceded DNA as the original information carriers (this hypothesis is known as the RNA world [2]), are now found only in host-dependent cellular parasites (RNA viruses for example). The reason for this is that DNA is more stable than RNA, and owing to the proofreading and repair mechanisms that have evolved, DNA is replicated with much greater fidelity, whereas the enzymes that replicate viral RNA genomes, such as RNA-dependent RNA polymerase and reverse transcriptase in retroviruses lack the proof-reading activity that DNA polymerases often have [3].

Viruses, that depend on high rates of mutations for each replication cycle to evolve and overcome the host defense mechanisms, may consider RNA as a better option to contain their genetic information. RNA viruses are the most common intracellular parasite found and have a higher mutation rate than DNA viruses, making vaccine development a bit harder towards them [4].

Rates of evolution and mutation have been calculated from available sequencing data for many genes and different organisms, it is estimated that the mutation rate (frequency of new mutations over time) of the human genome (that counts around 3 billion base pairs) could be less than 10-9 nucleotide substitutions per site per generation, one can say we do not suffer many mutations as individuals. Now, RNA viral genomes have mutation about a million times higher. The mutation rate of HIV is estimated to be between 10-2-10-3 substitutions per site per year [5]. The case of coronaviruses is slightly different, as their RNA-dependent RNA polymerase have the proofreading ability, showing a mutation rate slightly lower than HIV (10-3 substitutions per site per year [6]).

Mutations can occur in any part of the genome, they can be neutral, beneficial or deleterious, in the case of Covid-19, when mutations occur in the spike protein, new variants that bind to our ACE 2 cellular receptors in a different way can be generated. For example, the more infectious variant GD614 appeared due to a single amino acid mutation in the spike protein and in a matter of months took over basically the entire world (fig. 2), [7]. Researchers are now working hard trying to solve many questions related to coronavirus mutations, but as of now, no one has found a variant that evades immune systems, vaccines or other kinds of antibody therapies.

Figure 2. Global frequency of the D614G coronavirus variant. Source [7].

We have seen that RNA viruses evolve faster and we have learned to counterattack using the same molecule to effectively train our immune system, a molecule that is not just a messenger but a both-ways major role player.

Could you notice the lapse in the post? We read your comments, stay tuned for more! 🙂

List of references

1. Crick FH. (1958) On protein synthesis. Symp Soc Exp Biol 12:138-63.

2. Gilbert W. (1986) Origin of life: The RNA world. Nature 319:618-618.

3. Gorbalenya AE, Enjuanes L, Ziebuhr J and Snijder EJ (2006) Nidovirales: Evolving the largest RNA virus genome. Virus Research 117:17-37.

4. D A Steinhauer et al. (1987) Rapid Evolution of RNA Viruses. Annual Review of Microbiology 41:409-431.

5. Peck KM et al. (2018) Complexities of Viral Mutation Rates. Journal of Virology 92:e01031-17.

6. Zhao Z et al. (2004) Moderate mutation rate in the SARS coronavirus genome and its implications. BMC Evolutionary Biology 4:21.

7. Korber B et al. (2020) Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182:812-827.e19.

3 comments

  1. Interesting article by you’ll get very few readers because most people today don’t want to think that hard. What I understand is the MRNA is relatively new and this is the first population-wide usage. That should be a concern to people. Time will tell..

    Like

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