‘The omicron variant of the SARS-CoV2 coronavirus has been described as “highly mutated” by numerous publications over the past few days. But what does this actually mean and does a virus having more mutations mean we should automatically be more concerned about it?
Firstly, it is important to note that I am not a virologist, I am a cancer biologist and one of the cornerstones of cancer biology and my research currently, is mutations. Simply, cancer is caused by genetic mutations, errors in human DNA which mean that the proteins made from our DNA blueprint come out mangled and dysfunctional, hyperactive or often just don’t get made at all, sending our normally well-regulated and controlled cells into a spin. Cancer evolves, often by acquiring more mutations, some which may help it grow, resist drugs or even invade other tissues (metastasize).
Viruses, along with other types of microorganisms like bacteria and fungi evolve after gaining mutations too and we know that with the SARS-CoV2 coronavirus, several ‘variants’ with different mutations have forked off the original, gaining mutations which make them more transmissible, or deadly.
But not all mutations are created equally. In cancer these range from loss of entire chromosomes meaning that the instructions of hundreds or thousands of genes are lost, to single-base substitutions where the tiniest building block of DNA (a base) is simply the wrong one out of the four that make up our whole genetic code. In cancer, a lot of mutations seem to do nothing at all. They can be in what are called “non-coding” regions of DNA, which don’t get made into proteins or if the protein is made, their effect on the shape and function of the protein can be too minimal to actually cause any problems. We call them “passenger” mutations and DNA mutations which actually do something – “drivers.”
So back to the new omicron variant of SARS-CoV2, which is an RNA virus, so uses a different type of genetic material to encode its genome than in humans. Scientists have already sequenced the omicron variant and have come up with lots of information about how this sequence is different from that of other SARS-CoV2 variants. In particular, scientists are concerned about Spike protein mutations – the protein which the SARS-CoV2 coronavirus uses to gain access into our cells, the very protein that all of the approved Covid-19 vaccines are designed to train our immune systems on.
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As the photo above shows (Credit: nference), the omicron variant has a lot more mutations in the Spike protein than any other variant described before, including delta, the current dominant variant in many parts of the world, including North America and Europe.
What the heck are these combinations of letters and numbers I keep seeing to describe mutations?
N969K, D796Y, N440K…? You may have seen these strange code-like combinations of numbers and letters used to describe mutations when people are talking about the omicron variant. The letters are a code for which amino acid, building blocks for protein, a piece of genetic code tells the cell to make and the number sandwiched between them is the location in the gene where that switch has taken place. So, for example, N440K, a mutation in the Spike protein of the omicron variant describes how a mutation at position 440 has changed amino acid N (Asparagine – the abbreviations are not always logical…) to a K, or Lysine. The name does not give any information other than the location and what the switch is.
What are the computer predictions saying right now about the mutations?
Computer predictions of what these mutations might do are a little startling, predicting potential increase in transmission and immune evasion – meaning that vaccines and treatments such as monoclonal antibodies might be less effective against omicron than they have been found to be against other variants. But the truth is, scientists ae still only at the very beginning of understanding exactly what these mutations might do.
“At this point it is too early to tell how the mutations will impact the structure and function of the spike protein and the entire virus,” said Alyson Kelvin, PhD – virologist and adjunct professor at the Vaccine and Infectious Disease Organization (VIDO) at the University of Saskatchewan in Canada. “There have been approximately 50 mutations identified in the virus with about 30 of these in the spike protein,” added Kelvin.
Not all of the mutations are new. Some have been found in other variants and from this, scientists can predict what the implications of them might be, but they also have to take into account that individual mutations might behave differently when combined with others. This also happens in cancer where sometimes a mutation in one gene known to contribute to cancer development may not alone be sufficient to start malignant growth, but when joined by several others can “tip the scales” towards unregulated and dangerous cell division.
“It is essential to keep in mind that the constellations of mutations in omicron may interact with one another and lead to different outcomes than what we understand from studying previous variants,” said Kelvin.
Computer modelling is very impressive and very advanced now – it can predict the impact of any discovered mutations on how it might affect the production, shape and activities of the protein. But biology is always full of surprises and even the most advanced computer models are not always able to take into account every variable.
To really confirm what the new mutations do, lab experiments are needed
We do this in cancer research too, often we can model what a given mutation might mean – but to really drill down on what it does, for example whether it causes the cancer to grow in the first place, makes the cancer more likely to spread, or be resistant to drugs, we have to take a look in the lab. In viruses, the principle is similar – scientists can perform experiments to see what the mutations do to the ability of the virus to do all sorts of things, including bind to and invade human cells in dishes.
“When a new virus or variant is identified such as the omicron variant, virologists and viral immunologists ask a number of questions where chiefly they are trying to determine: 1.) how sick does this virus make a person 2.) what does the illness look like after infection – what are the clinical manifestations; 3.) how fast does the virus spread or transmit between people and what routes does it spread by; 4.) does previous infection or vaccination protect against infection or illness; and finally, 5.) do the therapeutics such as antivirals or immunomodulatory drugs still work against the virus or protect against severe disease?” said Kelvin.
As is already happening in South Africa and elsewhere, epidemiologists will be looking at the number of omicron cases compared to the ‘dominant’ variant – in most countries currently this is the Delta variant. This information will also be combined with how many cases arise in vaccinated vs unvaccinated people to get a sense of how well the vaccines are performing to prevent infections of omicron.
“In the lab, virus neutralization experiments need to be conducted using antibodies collected from people who were vaccinated or previously infected with a SARS-CoV-2 virus. These studies will determine how broadly protective antibodies from vaccinated and infected people are which we can extrapolate how protected they will be in the future,” said Kelvin.
But how exactly do these experiments work? It starts with cells grown in an incubator in a specialist lab approved to work with viruses. If you have seen pictures during the pandemic of people in hazmat suits with their gloved hands in chest-freezer sized, glass sided boxes, the chances are that they were working with live viruses.
“Serum [from blood] antibodies collected from people who were vaccinated with Pfizer, Moderna, AstraZeneca or other approved vaccines, or from people previously infected, will be mixed with high concentrations of the omicron virus,” explains Kelvin.
This will give the antibodies the opportunity to bind to the Spike protein on the omicron variant. If they are able to do this, the viruses will be blocked from entering the human cells in the dish. If the viruses do enter the human cells, the cells will eventually die, showing the scientists that the antibodies have not been able to stop the viral spike protein binding to cells. If the cells continue to stay alive and remain healthy, it will tell the scientists that the antibodies have been able to block the virus from entering the cell.
“After adding the virus and antibody mixture to cells, virologists quantify the amount of cellular killing to determine how effective antibodies are at blocking the virus from infecting the cell. All together, virus neutralization assays take about 5 days. This assessment will be the fastest way to acquire experimental evidence to speculate if vaccination and previous infection will protect against infection with the new omicron variant,” said Kelvin.
Is the new omicron variant more transmissible?
It really isn’t possible to say this right now. From the computer modeling of the new mutations in omicron, there are some that indicate that it might be. But it will depend a lot on currently ongoing experiments to answer this and questions such as if vaccination is protective against infection real-world evidence is needed. South Africa, which first described the new variant is experiencing a rise in infections currently and that combined with a wealth of scientific expertise means that early answers about this will probably come from the country in the coming weeks. At a later stage, studies on laboratory animals will also be completed to determine what clinical symptoms and effects omicron has, how transmissible the virus is and also how effective current vaccines and drugs to treat Covid-19 are, but these will take months to complete.
If omicron does spread and we need new vaccines to effectively protect against it, are we back to square one?
“Having a platform in place for designing and manufacturing COVID-19 vaccines at a large scale for human use as well as the pipelines in place for evaluating these vaccines preclinically, in human clinical trials, and by regulatory health authorities will be a huge advantage for any modifications that vaccine manufactures may make in the future,” said Kelvin.
“It is not surprising that we continue to detect new SARS-CoV-2 variants considering it is an RNA virus which has continued to infect new hosts and replicate over the past two years. The omicron variant has been detected in at least 13 countries and is most likely present in other countries as well. A global vaccine equity strategy along with having continued public health measures in place are urgently needed to stop the chain of transmission and the emergence of new variants,” said Kelvin.
As Science Magazine journalist Kai Kupferschmidt perfectly put it yesterday, “Imagine you’re doing a puzzle not knowing what the final picture will be and all you have are a few pieces. In the beginning every new piece can change your mind…” The sequencing of the omicron variant is just a handful of pieces of a 1000 piece puzzle, the computer modeling of the implications of each of the new mutations found is another few pieces. Finding out what each mutation does is another piece per mutation. The puzzle will grow quickly over the coming weeks and we will get an idea of what it looks like, but it won’t be finished for months or even years.