A key step in the origin of many pandemics occurs when an animal-borne virus infects humans and then evolves to spread more efficiently from person to person.
For that reason, scientists and doctors keep closely monitoring viruses that could jump from animals to humans, such as emerging strains of avian flu and bat coronaviruses, as well as those such as hantavirus and Ebola that have already crossed into humans but, for now, spread poorly among people.
In just a few months, the researchers recreated in a test tube the evolutionary path the coronavirus followed during the COVID-19 pandemic – from the original Wuhan strain to the emergence of the highly contagious Omicron variants.
This achievement resulted from a new collaboration among the laboratories of Prof. Gideon Schreiber of the Weizmann Institute of Science, Dr. Jirí Zahradník of the First Faculty of Medicine, Charles University in Prague, and the BIOCEV Center.
The findings, published in Nature Communications under the title “Stringent selection drives convergence toward omicron-like SARS-CoV-2 receptor-binding motifs,” raise hopes that in the future, scientists could predict how viruses are likely to evolve and under what conditions new waves of infection could emerge.
Weak selection pressure leads to multiple viral variants
The experiment simulating this scenario, conducted at Weizmann, was led by Aviv Shoshany from Schreiber’s team. Under weak selection pressure, by contrast, many viral variants survive, and advantageous mutations become enriched without taking over completely. This scenario was simulated by Ruojin Tian, Dr. Miguel Padilla-Blanco, and Dr. Martin Mokrejš from Zahradník’s group in Czechia.
Zahradník, who previously did his postdoctoral work in Schreiber’s lab, focused on weak selection, while the Weizmann lab staff focused on stronger selection. “We found that if you begin with Omicron, even if it’s weak, it’s stable and remains there. We worked on only a section of protein in the virus, and most of the mutations were in that segment.”
“It took only a few months to make our discovery, but we spent more than two years preparing a journal article for publication, because we had to conduct many tests, including mathematical calculations,” Schreiber recalled. “It was unbelievable. Billions of people were infected, but for all, there was the same result – we found the essence of the evolution of the virus. There aren’t many cases like that.”
In August 2021, Schreiber and colleagues published the results of an in vitro evolution experiment that identified a pair of mutations in the coronavirus’s binding site that make the virus highly contagious by improving its ability to bind to receptors in the human respiratory tract.
About three months later, the Omicron variant was first identified in South Africa; when researchers sequenced it, they found the same pair of mutations. That was the moment Schreiber realized that the in vitro evolution method developed in his lab could potentially predict major turning points in the course of pandemics.
Schreiber, who earned his degrees at the Hebrew University of Jerusalem and did post-doctoral work at Cambridge University, told The Jerusalem Post in an interview that evolution proceeds through mutations and natural selection. To survive and spread, viruses replicate at high speed, which can often lead to genetic errors that accumulate, producing new variants. In the new study, the researchers replicated the gene encoding the coronavirus binding site using a deliberately error-prone mechanism, thereby simulating in “fast forward” the appearance of mutations.
Using genetically engineered baker’s yeast cells, they exposed millions of resulting variants to human receptors and, imitating natural selection, retained only those that still bound successfully. By repeating cycles of mutation and selection over and over, the scientists reconstructed the evolution of the virus-human interaction over the course of a whole pandemic.
At the starting line of this evolutionary race in a test tube were the original Wuhan strain and several variants that emerged during the pandemic – including Alpha, Beta, and Omicron. The researchers studied how their binding sites evolved under two scenarios – strong selection pressure and weak selection pressure. Strong selection pressure is a situation in which only a small number of viruses survive each evolutionary stage, allowing advantageous mutations to rapidly become dominant.
“No matter which viral variant we started with, under strong selection pressure, a variant remarkably similar to Omicron and its sub-variants emerged early on and rapidly took over the entire population,” Schreiber said. “The exact same trajectory was observed during the coronavirus pandemic, which has not undergone another major shift since Omicron appeared and became dominant at the end of 2021.
“Some future pandemics that spill over from animals to humans may follow a similar path – accelerated evolution culminating in the dominance of a viral variant that is highly contagious and specifically adapted to bind to human receptors,” Schreiber predicted.
The evolutionary pathway leading to Omicron dominance was not viewed under weak selection pressure – and computer simulations revealed why, he continued. During the mutation process, several mutations can sometimes arise simultaneously. If one mutation gives a new viral variant a survival advantage and helps it dominate the population, other mutations – those that are neutral or even detrimental – can “hitchhike” alongside it and spread as well. The simulations showed that under strong selection pressure, advantageous mutations become dominant before the hitchhikers get a chance to accumulate. Under weak selection pressure, however, beneficial mutations drag many additional mutations with them, diminishing their own dissemination advantage.
“To survive in their bodies, the virus had repeatedly to fight their residual immune activity and repeatedly infect receptors in the respiratory tract,” Schreiber explained. “Those are precisely the conditions of strong selection pressure, and our study shows they are essential for the emergence of Omicron – further supporting the hypothesis that it originated in immunocompromised people. Interestingly, when we started the selection from Omicron, both strong and weak selection pressures were sufficient to maintain the Omicron sequences, explaining why this variant persists in the general population. This highlights how important it is to properly treat immunosuppressive conditions such as AIDS before the next global pandemic strikes, and to protect immunocompromised individuals from infection and chronic disease.”
He concedes that today, the coronavirus arouses much less interest here and abroad compared to four years ago. “People forgot, because of new crises, but next time, I hope we’ll be better prepared to cope with pandemics. We have very good tools now to understand how they advance.”
