The COVID-19 pandemic has starred in this year 2020 and is having terrible health, social and economic consequences throughout the world. Fortunately, in recent weeks we have begun to see the light at the end of the tunnel thanks to the publication of the results, very positive in terms of safety and efficacy, of the first vaccine candidates who entered phase 3 of their clinical trials. Two of them, those produced by Moderna and Pfizer / BioNTech, have already shown efficiencies of around 95%. Although there is still half a year left for this phase 3 to end, they will soon begin to be administered in the United States and Europe.
Both vaccines are based on a well-known molecule in different fields of research, but which until now has never jumped into public opinion: RNA (short for ribonucleic acid). Specifically, they use a type called messenger RNA (mRNA), with the instructions for certain cells of our immune system to produce the protein S that forms the spike of the SARS-CoV-2 coronavirus, which triggers a protective response in the person who receives the vaccine.
RNA is a molecule that can be easily degraded, mainly by the action of catalytic proteins (or enzymes) specialized in cutting it. For this reason, the vaccine RNA is administered by including an average of 10 molecules of that mRNA in protective spherical vesicles, made up of lipids (similar to those that make up cell membranes) and nano-sized (much smaller than our cells).
Unlike other types of vaccines, those based on RNA have to be kept deep-frozen until almost the moment of their administration. However, RNA is not a molecule that has become fashionable now, but has been for a long time. Specifically, during the last 3.8 billion years.
RNA, a central molecule in biology
The analysis at the molecular level of all known living beings, and specifically the comparison of their genomes, has shown great similarities between them. This showed, more than forty years ago, that the three great branches of the tree of life (bacteria, archaea and eukaryotes) come from the same ancestor.
We know that species (or, perhaps, that community of them) as “last universal common ancestor” (LUCA, acronym formed by its initials in English) and it is estimated that it could have lived about 3.7 billion years ago (Ma ), just 800 million after the Earth and Moon formed.
LUCA already had the main characteristics that appear in all current biology, and based its operation on three key molecules: DNA (genetic information file), proteins (catalytic molecules or enzymes, responsible for metabolism, and also structural), and RNA (intermediate in the flow of genetic information, which occurs in the sense DNA → RNA → Proteins).
RNA is a nucleic acid, a polymer made up of units or monomers called ribonucleotides. These can be of four types: A, C, G and U. Its most stable structure is the single chain, instead of the double helix characteristic of DNA.
However, even if it is a single chain, any RNA molecule folds back on itself when it is in solution, because its monomers tend to recognize each other following the AU, GC and GU rules. Thus, RNA ends up forming more or less complex structures, which allows it to perform various functions in cells. In fact, the RNA → Proteins step is carried out by different types of RNA:
- Genetic information, previously copied (transcribed) from DNA, is in the form of mRNA (as used in the vaccines discussed).
- Its translation into proteins is carried out in ribosomes (aggregates of ribosomal RNA, rRNA, and proteins)
- The so-called transfer RNAs (tRNAs) also participate in this information decoding process.
- Furthermore, the entire flow of genetic information is regulated by other RNA molecules.
RNA also constitutes the genome of a large number of “replicative entities” that cannot be considered authentic living beings, but that are fundamental in evolution due to their continuous interaction with the cells they parasitize: many families of viruses (including coronaviruses ), and also simpler plant pathogens called viroids.
The two sides of the coin of life
From what we have just discussed, RNA is much more than an intermediary molecule in the flow of genetic information. In fact, it can serve both as a genotype (sequence with genetic information) and as a phenotype (structural and functional molecule). In other words, RNA is so versatile as to be able to represent the two sides of the coin of life, something that is not available to DNA (it only acts as a genotype) or proteins (they only contribute to the phenotype).
In this sense, a fundamental discovery made in 1982 is that in current biology there are RNA molecules whose three-dimensional structure allows them to act as catalysts, accelerating certain biochemical reactions. Until then it was thought that catalytic functions could only be performed by enzymes of a protein nature and, by analogy, these RNA catalysts were called ribozymes. Its discoverers received the Nobel Prize in Chemistry in 1989.
We currently know of eight different types of natural ribozymes, and others have been artificially obtained through in vitro molecular evolution experiments. Furthermore, in laboratories we also use this technology to select RNA molecules called aptamers, which bind to the desired ligands with as much affinity and specificity as antibodies to their antigens.
An “RNA world” at the origin of life?
In the field of research on the origin of life, after the seminal ideas of Charles Darwin in the mid-nineteenth century and the models proposed by Alexander Oparin and John Haldane in the 1920s, the first experimental approaches were made by Stanley Miller in 1953 and Joan Oró in 1959. With this, a field called prebiotic chemistry was inaugurated, which since then has made it possible to obtain, from simple chemical compounds, monomers or basic biological molecules such as amino acids, nucleotides, sugars and simple lipids.
In this way, it has been shown that from the chemistry existing in the primitive Earth, added to the contributions made by meteorites and comets during the childhood of our planet, a prebiotic soup could be formed (an accurate metaphor that we owe to Oparin) of which biology emerged. But from these monomers to LUCA a long way had to be traveled in which chemical molecules and their interactions became increasingly complex, until systems were formed that combined the three fundamental components of living beings: a compartment based on membranes, metabolism to process matter and energy from the environment, and the replication of a genetic molecule.
Precisely in that intermediate stage we meet again with RNA, since due to its ability to act as a genotype and phenotype it is considered that it could be prior to proteins and DNA. Thus, the model known as the “RNA world” suggests that between prebiotic chemistry and LUCA there could be RNA-based protocells (called ribocytes by some scientists) that contained an RNA genome and ribozymes as metabolic catalysts, whose functions could be modulated by other biomolecules (such as peptides or various organic compounds) and even by the metals and minerals present in the medium.
The world of RNA allows us to solve a paradox that is equivalent to that of the chicken and the egg, but in a molecular version. Indeed, if we return to the scheme of the flow of biological information in all cells (DNA → RNA → Proteins) we assume that without DNA there can be no proteins. But in turn, proteins are also necessary for DNA to exist, since the replication of this nucleic acid is carried out by enzymatic proteins. So who came out before, DNA or proteins? As we have just seen, perhaps neither of those two biopolymers but RNA.
This suggestive hypothesis still has several aspects pending to be solved, but many scientists consider RNA as the starting point of Darwinian evolution on Earth … or perhaps outside it.
In 2021, some 3.8 billion years after RNA was the protagonist of the origin of life, a variant of that same molecule will decisively contribute to the survival of an animal species that has always been believed to be superior to the others, but that has been seriously threatened by a virus also based on RNA.
Carlos Briones, Senior Scientist of the CSIC and Member of the Board of Directors of the Spanish Society of Virology, Astrobiology Center (INTA-CSIC)
This article was originally published on The Conversation. Read the original.
