The story so far: In March 1953, James Watson, the co-discoverer of the structure of DNA, received a note from Harriett Ephrussi-Taylor, a friend from the National Centre for Scientific Research in France. The note, titled “Top Secret”, contained news of a potential discovery that had enormous implications for molecular biology, virology, and immunology.
The note read, “Burnet swears, from work in his lab, that flu virus has principally, possibly exclusively, RNA. Suspects same for Polioviruses.”
Why is DNA preferred over RNA?
Most organisms prefer DNA over RNA, its chemical cousin, to store genetic information. As life evolved from single-celled organisms to increasingly complex forms, the amount of genetic data that had to be transferred to subsequent generations became correspondingly higher. So organisms needed to make sure that the mechanism for copying the genetic material was that much more robust.
In particular, organisms needed the ability to correct any inadvertent errors in the copying mechanism. The enzymes responsible for copying DNA, collectively known as DNA polymerases, possess this error-correction property, known in technical parlance as ‘proofreading’. This proofreading ability allowed the total DNA of higher organisms, known as the genome, to be longer and more complex.
On the other hand, the RNA counterparts to DNA polymerases, known as RNA polymerases, do not possess the ability to proofread. As a result, when RNA is the genetic material, the genomes typically tend to be shorter. Longer genomes would contain proportionately higher mistakes, and such genomes would be eliminated by natural selection.
Coronaviruses beautifully illustrate this point since their genomes are typically three- or four times the size of those of other RNA viruses. They can afford the longer genomes due to the presence of a unique protein, in addition to the RNA polymerase, that performs the proofreading function.
RNA polymerases are also capable of recombination, a process that allows them to stitch together multiple pieces of different viral RNAs. This way, if one viral RNA contains a mutation at location X and another contains a mutation at location Y, recombination can create a virus containing both X and Y by sewing the two regions of the viral RNA containing those mutations. This is how, for example, the XBB variant of SARS-CoV-2 is the product of the BA.184.108.40.206 and BA.220.127.116.11.1.1 variants.
What is the advantage of RNA?
At the time Watson received the note from Ephrussi-Taylor, scientists widely held the view that DNA was the genetic material of all life forms. Frank Burnet’s discovery was groundbreaking because he showed, for the first time, that certain viruses existed that had RNA as their genetic material.
The discovery was important because, if you asked a common person today to name any 10 viruses, most of them are likely to be RNA viruses. The most popular disease-causing viruses bear RNA, not DNA, including the causative agents of COVID-19, AIDS, polio, influenza, dengue, chikungunya, Ebola, Zika, Hepatitis C, rabies, Marburg, yellow fever, and Japanese encephalitis.
Except for HIV, which is responsible for AIDS, all of these viruses contain an error-prone RNA polymerase. HIV uses a slightly different mechanism to replicate, but the enzyme responsible shares the error-prone nature of its siblings.
The better known DNA viruses included members of the pox family (smallpox and chickenpox) and Hepatitis B.
At the heart of the domination of RNA viruses over human disease lies the error-prone nature of their polymerases. This singular property allows the virus to acquire multiple adaptations that serve as tools in the viral arsenal.
Foremost, the RNA polymerase enables these viruses to exist in a form that scientists refer to as a quasi-species. This means that a given virus can exist in multiple variant forms simultaneously in each host. Such an existence directly results from these viruses’ error-prone replication.
What are the consequences of RNA as genetic material?
Some of these viral variants will be non-infectious due to mistakes in the genome, and the host immune system will eliminate another significant fraction. However, such diversity also allows the creation of an odd variant that possesses a survival advantage against a vaccine or a drug. Such variants will undergo further natural selection, and the virus will continue to proliferate.
This is why multiple variants of SARS-CoV-2 continue to circulate to this day. It is also why developing highly effective vaccines against RNA viruses remains challenging.
A second, indirect consequence of the low-fidelity replication process is the small size of the viral genome. This allows RNA viruses to have very short generation times. In a very short period after infection, the host’s virus population becomes enormous.
This high viral output, together with the diversity, overwhelms the immune system.
The third consequence of the nature of viral replication is that the viruses can ‘jump’ across species, a process termed zoonosis. This is because the high error rate and the short generation time enable the virus to adapt to newer conditions much faster, allowing the infection to spread easily among newer hosts.
This is why up to 89% of all human infectious RNA viruses are considered to be a result of zoonotic transmissions.
Why is viral surveillance important?
These remarkable properties have collectively made sure RNA viruses represent the largest group of pathogenic organisms that cause new diseases.
Every year, two or three new RNA viruses that can infect humans are discovered. While this number is by itself enough cause for worry, it is also a worthless underestimate due to the lack of adequate surveillance in tropical and sub-tropical countries. Viral surveillance and monitoring must be stepped up in these regions to arrive at more accurate numbers.
Viruses are primitive forms of life. Scientists have advanced multiple theories about how life may have originated on earth. They range from turbulent atmospheric conditions creating primitive forms of the cellular blocks to the idea that life evolved outside earth and was brought here on a meteorite.
However, all those theories agree that once life begins, the ability to accurately transmit genetic information is absolutely necessary for it to continue.
It is therefore incredible that RNA viruses thrive whilst making a mockery of something so vital to the existence of everything else.
- Since life forms evolved and became multi-cellular, organisms needed to make sure that the mechanism for copying the genetic material was more robust and hence preferred DNA.
- The most popular disease-causing viruses bear RNA, not DNA, including the causative agents of COVID-19, AIDS, polio, influenza, etc. due to its hit-or-miss strategy of replication.
- This genetic structure gives viruses the ability to create odd variants that possess a survival advantage against a vaccine or a drug.
Dr. Arun Panchapakesan is a scientist working for the Y.R. Gaitonde Medical Educational and Research Foundation, Chennai.