The year that RNA came into the world’s mouths A year of the pandemic

Ribonucleic Acid – RNA in Portuguese acronym and RNA in English acronym. These words and acronyms have long since entered the vocabulary of scientists. But it seems that it wasn’t until 2020, when the current pandemic set in, that they definitely became part of the vocabulary of all of us. However, this wasn’t the genetic material of SARS-CoV-2 – the virus that causes Covid-19 – and the nucleic acid that was looked for in the diagnostic PCR tests.

If anyone knows ribonucleic acid well, it’s Cecília Arraiano. The scientist at the Institute for Chemical and Biological Technology (ITQB) of the Universidade Nova de Lisboa has been studying it since the 1980s. It all started with my doctorate in the USA and has been leading a group at ITQB since 1990 investigating the role of RNA maturation and RNA degradation in the regulation of gene expression. Your connection to this connection is so strong that at the European Academy of Microbiology you have already referred to it as “Madame Ribonucleases”. Ribonucleases are proteins that break down and control ribonucleic acid levels and the great specialty of your laboratory.

RNAs are molecules that can carry out or modify instructions derived from the genetic code of DNA. To clarify what exactly the NRA is and what its role is, Cecília Arraiano says that she will use the same explanation that she gives to her students. And the clarification starts with the DNA. “DNA is like the architect’s plan to build a house, and the plan is the genetic material,” he says. “Then there are the civil engineers, the electrical engineers and the builders who will carry out the architect’s plan. The RNAs are the ones that do it. “These engineers and builders can even change the plan – just like us humans when we build houses.

Many of these RNAs are involved in the production of proteins (that is, the structural part of the house, like the bricks). “Proteins can be used to make up the skeleton of the house or to serve some functions, but they have to be made from these RNAs first.” There are other RNAs that are not involved in the production of proteins but have a regulatory function. “It’s like these executors were saying, ‘It’s very hot today and we’re going to work at a certain time or cut the working hours [na construção da casa]’. They are regular, ”the scientist metaphorically expressed. “They have a very important function and in certain living things they can even pull out bits of DNA to say, ‘This won’t stay on the plane, let’s get it out.’ RNAs are the executors of genetic inheritance. They are hugely important in the execution of what DNA is made of. “

Cecília Arraiano DR

Over the years, the importance of these executors has faded. The biochemist Jacques Monod (1910-1976) suggested the existence of the messenger RNA molecule, meaning that these executors could code for one or more proteins. Then, about 20 years ago, RNA regulators that did not encode proteins were identified. “”[O RNA] has experienced a huge boom, ”emphasizes Cecília Arraiano. Proof of this were the NRA-themed Nobel Prizes. Let’s look at some of them.

In 1989, Sidney Altman and Thomas Cech received the Nobel Prize in Chemistry for the discovery that RNAs can perform chemical reactions without the need for proteins. These RNAs are called ribozymes. In 2006, Craig Mello and Andrew Fire received the Nobel Prize in Medicine for their discovery that RNA that does not encode proteins can silence the expression of the message of other RNAs called “interfering RNA”.

The 2009 Nobel Prize in Chemistry went to Venkatraman Ramakrishnan, Thomas Steitz (1940-2018) and Ada Yonath for discovering the structure and function of the ribosome – the molecular machine that creates proteins. When the messenger RNA tells you the code to make it, it’s the ribosomes that trigger the production of proteins.

Last year, Emmanuelle Charpentier and Jennifer Doudna received the Nobel Prize in Chemistry for developing the genome editing method CRISPR / Cas9. What is the connection with the RNA? The scientists found a virus-fighting system in bacteria that uses small non-coding RNAs to cause a specific ribonuclease (Cas9) to cut DNA at a specific location. From this learning it was then possible to apply this knowledge in modifying and correcting the genomes of higher beings. “There was a revolution based on RNA,” notes Cecília Arraiano. The uses are numerous, from agriculture to medicine.

“The new technologies, namely RNA and DNA sequencing, have shown that there is more RNA in all beings than previously thought,” adds the scientist. And he recalls that dark DNA material used to be even referred to as segments of DNA that seemed to have no function, and that they are now known to produce multiple RNA regulators. “Technology has contributed to its growing importance, and it is already known that many small RNAs are specific for certain diseases and can diagnose certain diseases.”

The genetic material of SARS-CoV-2

And when we refer to the SARS-CoV-2 RNA, what are we talking about? It is the genetic material of this coronavirus. In contrast to us or other viruses, SARS-CoV-2 does not contain any DNA and its RNA is stored in the virus capsule. When the coronavirus lands in the host’s cells, it injects its RNA into those cells that recognize the RNA as theirs. The virus is thus able to insert into the cells its genetic material, which contains instructions for making some proteins. When the RNA enters, the ribosomes (such molecular machines) then translate several proteins of the virus, which are either part of a new capsule of the coronavirus or are important for its replication.

All of this happens on a small scale. The smallest known RNA virus is that of human hepatitis D and has 1.7 kilobases (one kilobase corresponds to a thousand “letters”). The largest RNA viruses are coronaviruses, which are between 26 and 32 kilobases. SARS-CoV-2 has 29.9 kilobases, ie approximately 30,000 “letters” (the human genome has three billion pairs of letters).

RNA was also used in the development of some vaccines against Covid-10, in particular messenger RNA – the molecule that transfers the information contained in DNA about the production of proteins to the place of their manufacture in cells. Moderna or BioNtech-Pfizer vaccines use this technology and have created a synthetic version of a piece of the messenger RNA of this coronavirus. “”[Nas vacinas] They send an RNA into the cells that does not produce the entire virus, but only a small amount, ”describes Cecília Arraiano and points out that the spike protein that is responsible for the entry of SARS-CoV-2 into human cells was attacked above all.

Regarding the effectiveness of these vaccines against the most worrying variants of SARS-CoV-2 (such as those originally identified in South Africa, Brazil and the UK), the researcher emphasizes that “the little bit” that the vaccines became vaccines against not significantly changed in these variants. In addition to the RNA with the virus in the vaccine, the vaccines also contain adjuvants that support the reaction of our immune system.

Science in Public

Ribonucleic acid entered Cecília Arraiano’s life and laboratories around the world a long time ago. “It was more public this year,” notes the researcher. “Because of this pandemic that affects us all, everyone is already saying ‘this RNA virus’.” And he also remembers that DNA and then proteins had already been included in the common vocabulary. “Only now has RNA come for the worst of reasons.”

This had been planned for some time. The scientist even remembers a selection made by Science magazine nearly 20 years ago with the most promising discoveries. First, small RNA regulators that do not produce proteins have been discovered, and fourth, sequencing of the human genome. “It has already been seen that an atlas is less important than the ability to model and regulate.” Even so, for Cecília Arraiano, one of the most recent words that inevitably appeared in public was also “vaccine”. “This shows the importance of science. It is the scientists who save us when a pandemic breaks out. “

And what have been the biggest contributions for you when you look at the science developed in Portugal? Cecília Arraiano highlights some works that were selected for Covid-19 in a competition by the Foundation for Science and Technology (FCT). Within this set, he highlights a project to diagnose Covid-19 through saliva under the direction of Catarina Pimentel from ITQB. Although slightly less reliable than PCR testing, this type of test can help you follow up cases in schools or airports in a short amount of time. And they’re cheaper.

The most important thing for the progress of our society is that science is in public

Cecilia Arraiano

It also points to an investigation into how the virus got to Portugal by the National Health Institute Dr. Ricardo Jorge in collaboration with the Gulbenkian Institute of Science. Or ongoing work at ITQB on methods to better understand how the virus attacks cells with the help of computer models. “This is important for new vaccine development and for serological testing,” he says.

After Cecília Arraiano, “Madame Ribonucleases”, explains to us the importance of a nucleic acid, she leaves a message that she believes is crucial: “The most important thing for the progress of our society is that science is in the public eye. Only then can the public put pressure on politicians to drive scientific progress. “2020 will have been the year the NRA finally entered the world’s mouth.

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