MUTATED VIRUSES which survive and thrive are called variants. In the case of SARS–CoV-2, the virus that causes covid-19, these started to spread in earnest in November 2020, with the appearance of the Alpha variant, first spotted in Britain. The Delta variant, which is the dominant global strain, was first detected in India in late 2020. The latest, Omicron, was first identified in South Africa in November 2021.
There is much still to find out about Omicron. Although the early evidence suggests that this variant spreads very fast indeed, more work is needed before anyone knows whether it will displace Delta. Omicron has roughly 30 mutations on the spike protein, the structure that studs the surface of the virus and enables it to lock on to and insert its genome into human cells. Around 20 more mutations operate on other parts of the virus: some of them may also be dangerous. How do mutations increase transmissibility?
Viruses, like all organisms, have life-cycles. Theirs are parasitic, beginning when a parent virus infects another creature and hijacks its cells to make copies of itself. In the case of SARS–CoV-2, this happens when it latches onto an enzyme called ACE2 that sits in the membrane of some human cells. SARS–CoV-2 then slips its genome through into the cell. This cellular invasion is helped by the spike protein. Some parts of the structure of the virus are better able to withstand mutations: the spike is the most tolerant to changes.
The mutable nature of viruses is rooted in the randomness inherent in the process of producing copies of any object, making errors unavoidable. As host cells churn out copies of SARS–CoV-2, errors occur. The vast majority of viruses do not survive these errors in replication. But some do, and may even thrive as a result of the changes, outcompeting ancestral viruses and spreading more efficiently through their host population. New variants must hold some advantage over old ones if they are to become the dominant form of the virus. That advantage could be won in many different ways, but for a respiratory disease like covid-19, one of the most important factors is transmissibility, how easily the virus passes from one person to another.
One of the first mutations to increase transmissibility was referred to as N501Y, sometimes known as “Nelly”, one of eight mutations that characterised the spike protein of the Alpha variant and which is also found in Omicron. The “501” means that the change is happening to the 501st amino acid in a chain of 1,273 that comprise the spike. The order and composition of these amino acids is dictated by a matching genome sequence, so that “501” refers to both the position on the genome and the position on the amino acid chain. “N” is short for asparagine, which in N501Y is swapped out for “Y”, which is tyrosine.
Since different amino acids have slightly different chemical properties, this swap affects the structure of the spike protein. This is because the way electrical charge is distributed across it changes. That alters the shape of the protein slightly, as areas of positive electrical charge attract areas of negative charge. Thanks to these dynamics, N501Y allows a crucial part of the spike to twist around by about 20 degrees, letting it find a more snug fit with the ACE2 receptor. Better binding occurs as a consequence, which means that any copy of the variant which enters the body is more likely to find its target and start replicating. This increases transmissibility. Other mutations perform a similar trick, freeing up different parts of the spike in different ways so that it may bind more effectively to ACE2.
Changes to the shape of the spike protein are not the only way to increase transmissibility. Ravindra Gupta, a molecular virologist at Cambridge University, and his colleagues have argued that Delta’s increased transmissibility was down, in part, to a mutation at site 681. This is the point on the spike where, after it has bound to ACE2, the protein is cleft in two. Dr Gupta says that, among other things, P681R, helped by two shape-modifying mutations elsewhere, makes it easier for the virus to inject its genome into host cells.
Still other mutations make the virus more transmissible by helping it evade the antibodies that the immune system throws at it in order to protect the body from infection. Just as a spike protein may be shifted by a set of mutations to bind better to ACE2, so too can other mutations in return make it harder for antibodies to bind to spike. If so, they will be less effective in stopping an infection.
One reason scientists worry about Omicron is that it appears to possess all three kinds of mutations—as well as many more that are still not understood. Only further data will show to what extent their fears are borne out.■
To keep up with our latest coverage on the spread of the Omicron variant go to economist.com/omicron