An Israeli-Czech collaboration has succeeded in recreating in vitro the evolutionary trajectory of the coronavirus, from the Wuhan strain to Omicron, offering a possible tool for early identification of particularly contagious variants.
Many of the modern pandemics have started when an animal virus infected humans, then evolved to improve its ability to spread from person to person. Therefore, scientists and medical professionals are anxiously monitoring viruses that could potentially jump from animals to people – such as new strains of bird flu and bat coronavirus – as well as those that have already jumped from animals but are currently having difficulty spreading between people, such as anthrax and Ebola. In a new study, a collaboration between the laboratories of Prof. Gideon Schreiber from the Weizmann Institute of Science and Dr. Jiří Zahardnik from Charles University in Prague, the researchers were able to simulate in vitro, within a few months, the evolutionary path that the coronavirus underwent throughout the entire pandemic – from the Wuhan strain to the spread of the particularly contagious omicron. The studyHis findings are now being published. in the scientific journal Nature Communications. It is hopeful that in the event of a future pandemic, it will be possible to predict in advance how the virus will change and in what situations renewed waves of infection will erupt.
August 2021 Results have been published. of an in vitro evolution experiment conducted by Prof. Schreiber and his colleagues, in which a pair of mutations were identified in the binding site of the coronavirus to a receptor in the human respiratory tract, which makes it highly contagious. About three months later, the omicron virus was first discovered in South Africa, and when it was sequenced, exactly the same pair of mutations were found. This was the moment when Prof. Schreiber realized that the in vitro evolution method that had been refined in his lab could be used to predict turning points in the course of epidemics.
Evolution progresses through mutations and natural selection. To survive and spread, viruses replicate themselves rapidly, accumulating genetic errors and producing new variants. In the new study, scientists replicated the coronavirus binding site gene in a mechanism that is prone to frequent errors, thus simulating the emergence of mutations in “high speed.” Using genetically engineered yeast cells, they presented the millions of different variants that were obtained to human receptors, and, similar to natural selection, selected only those that still bound to the receptors. The scientists repeated the mutation and selection over and over, thus re-evolving the relationship between virus and human throughout an entire pandemic.
"No matter which version of the virus we started with, under strong selection pressure a variant that closely resembles Micron emerged early on and quickly took over the entire population."
Strong and weak mucous pressure
The starting line of the in vitro evolutionary race was set for the original Wuhan strain and several variants that emerged throughout the pandemic, such as alpha, beta, and omicron. The scientists examined how their binding site changes in two scenarios: strong selection pressure and weak selection pressure. Strong pressure is a situation in which only a few viruses survive each stage of evolution, and therefore mutations that confer an advantage quickly become dominant. The evolutionary experiment that simulated it was carried out at the Weizmann Institute, led by Aviv Shoshani from Prof. Schreiber's group. Under weak pressure, on the other hand, a variety of versions of the virus survive and beneficial mutations are enriched but do not take over. This situation was simulated by Rujin Tian, Dr. Miguel Padilla-Blanco, and Dr. Martin Mukris from Dr. Zahardnik's group in the Czech Republic.
“No matter which version of the virus we started with, under strong selection pressure, a variant very similar to Omicron emerged early on and quickly took over the entire population,” explains Prof. Schreiber. “The exact same trajectory was observed in the coronavirus pandemic, which has not undergone another turn since Omicron emerged and took over in late 2021. In fact, we were able to accurately simulate the trajectory of the coronavirus evolution among billions of people over three years, in laboratory experiments that lasted a few months.”
"Some of the next pandemics that will jump from animals to humans may develop along a similar path – accelerated evolution that ends with a version of the virus that is specifically adapted to bind to human receptors and is highly contagious taking over," predicts Prof. Schreiber. "We examined the possibility that this could happen with the SARS virus (SARS-CoV-1), which had a limited outbreak in the early 2000s. When we evolved it in vitro under high selection pressure, a version that binds very efficiently to receptors in the respiratory tract quickly took over. The good news is that thanks to the similarity to the coronavirus pandemic, we probably have partial immunity."
The Omicron Mystery
The evolutionary path that ultimately led to Omicron taking over was not observed under weak selection pressure, and computer simulations have revealed why. In the process of mutation, several mutations sometimes appear together. If one of them gives the new version of the virus a survival advantage and helps it take over the population, other mutations that are not beneficial and may even be harmful can ‘hijack’ and spread with it. The simulations showed that under strong selection pressure, the beneficial mutations are enough to take over before hitchhikers accumulate. In contrast, when selection pressure is weak, the beneficial mutations drag many other mutations with them, and their advantage is compromised.
To this day, the origin of omicron remains a mystery, as it is genetically very different from other coronavirus variants. Since the virus is quickly cleared by the immune system in healthy people, it does not have enough time to accumulate many mutations, so it has been hypothesized that omicron originated in immunosuppressed individuals, in whom the disease lasted for many months. "To survive in their bodies, the virus has to fight time and time again against the remnants of their immune activity and successfully infect the receptors in the respiratory tract," explains Prof. Schreiber. "These are conditions of high selection pressure, and our study shows that they are essential for the creation of omicron - which further strengthens the hypothesis that it originated in immunosuppressed individuals. This emphasizes how important it is to treat immunosuppressive diseases, such as AIDS, well before the next global pandemic breaks out, as well as to protect immunosuppressed individuals from infection and chronic morbidity."
To bind or to evade
Three key factors determine whether a virus will survive in humans – its infectivity, its structural stability and its ability to evade the immune system – but the balance of power between them was unknown. “In our evolution experiment, we selected at each stage the variants that bound most strongly to the human receptor, and under strong selection pressure we also required that they remain stable at high temperatures,” says Prof. Schreiber. “Although they were not required to deal with the immune system at all, most of the mutations characteristic of the microbe still appeared. This shows that the evolution of the coronavirus was mainly focused on improving its infectivity. However, we identified using databases that, as the population became vaccinated, the virus began to accumulate ‘compromise’ mutations – those that balance the ability to infect and evade the immune system.”
"The in vitro evolution method we have perfected can be applied in the future to other viruses of concern," he emphasizes. "We can isolate a viral protein and study how it is expected to change in different scenarios. The experiment we presented makes it possible to identify in advance dangerous variants that are going to take over, and allows us to focus our efforts on trying to prevent the conditions in which they take over and prepare for them in time."
The study also included Adam Hrushka, Aditi Koner and Dr. Katrina Baksova from Charles University in Prague, Czech Republic, and Dr. Eyal Zoller from the Institute's Department of Biomolecular Sciences.
Short FAQ
What were the researchers able to do in the study?
The researchers simulated the evolution of the coronavirus binding site in vitro, and reconstructed a pathway that led to the emergence of a variant very similar to micron.
Why is the research important?
It offers a way to examine in advance how viruses might change under different conditions, thereby helping to prepare for future pandemics.
What is strong selection pressure?
This is a situation where only a few variants of a virus manage to survive at any given stage. Under such conditions, mutations that confer an advantage can quickly take over.
What does it have to do with the Umicore?
The study showed that under conditions of strong selection pressure, an Omicron-like variant quickly emerged, a result that reinforces the hypothesis that Omicron evolved in an environment where the virus was required to adapt repeatedly.
Can the method also be used for other viruses?
According to the researchers, the in vitro evolution method could also be applied to other viruses of concern.
More of the topic in Hayadan:
