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May 18, 2020

From New York to Luxembourg, via Namibia, Iceland and Bhutan, the new SARS CoV-2 coronavirus has turned the modern world into a crisis zone. An unprecedented global effort is underway to understand the elusive pathogen and find effective therapies.

An intriguing approach to treating COVID-19, the disease caused by the novel coronavirus, was recently suggested by Arizona State University faculty members Jeff Jensen of the Center for Evolution and Medicine and Michael Lynch of the Biodesign Center for Mechanisms of Evolution.

This graph shows a series of cycles of viral replication for a hypothetical viral population in a patient – with four representative viral genomes displayed at each time point. At the time of infection, no mutation is present. Over time, mutations accumulate, and if natural selection fails to remove these harmful mutations, each generation can become less fit than the last. In this way, the most suitable genome carries more and more deleterious mutations over time. This phenomenon, known as Muller’s ratchet, puts the viral population on a one-way street to extinction. Graphic courtesy of Shireen Dooling
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The strategy they describe for overcoming SARS CoV-2 is rooted in the theory of evolution. The basic idea is simple: if a particular drug could sufficiently increase the mutation rate of the virus, it might be possible to attribute so many harmful genetic errors to the pathogen that a patient’s viral population would collapses.

The phenomenon, known as mutational fusion, was first described by Lynch three decades ago in the context of preventing the extinction of small or threatened populations.

In the new research, the goal is rather to encourage the extinction of large viral populations, by a ruinous accumulation of viral mutations. (The concept is similar to a phenomenon described later known as lethal mutagenesis.)

“This is a great example of well-established principles of the theory of evolution being reused to solve important practical problems,” said Lynch.

In addition to providing a promising candidate for the treatment of SARS CoV-2, mutational fusion could offer a new model for the treatment of a wide range of infectious diseases. The method is particularly interesting because it has the potential to deal a fatal blow to infectious agents, causing damage to their genomes so extensive that they are unable to develop resistance to antivirals or antibiotics.

Lynch and Jensen recently described the strategy in the journal Heredity.

In previous proof-of-concept research, Jensen, his postdoctoral associate Claudia Bank, now a faculty member at the University of Bern, Switzerland, and their colleagues at the University of Massachusetts medical school demonstrated that the drug favipiravir, if administered in a sufficiently high dosage, could indeed induce mutational fusion in laboratory populations of influenza A virus.

New killer on the block

As of May 14, 2020, the number of confirmed cases of COVID-19 exceeded 4.5 million worldwide. Over 300,000 have died and the numbers almost certainly represent a significant undercount.

The success of SARS CoV-2 in invading human cells and spreading rapidly throughout the world population is due to the fact that the virus has probably undergone specific mutations, allowing it to to jumpThese species-straddling pathogens are called zoonotics. of certain species reservoirs to man.

Genetic mutations are nature’s ultimate double-edged sword. They provide the raw material for evolution to act and explain the astonishing diversity observed across species, including humans. Through natural selection, mutations conferring an adaptive advantage in nature’s great game can become established in a population and be passed on to offspring through generations.

Most genetic mutations, however, are deleterious and represent a dizzying array of illnesses, from mild to fatal. Over the course of successive generations, natural selection can act on these errors, increasing the probability of ultimate fixation for beneficial mutations and decreasing the probability for those which are deleterious, due to the biological formFitness is a measure of an organism’s ability to reach adulthood and successfully contribute to the next generation of offspring. organisms that carry these harmful mutations.

While harmful mutations can wreak havoc in the individuals who acquire them, over time populations tend to eliminate the majority of harmful mutations. In sexually reproducing organisms, this purging process is facilitated by the recombination of genetic elements provided to the offspring of two genetically distinct parents.

Ratchet of doom

Although evolution works to remove deleterious mutations from the population through purifying selection, there are limits to this cleansing process. If the total number of the population falls below a certain threshold, the purifying selection cannot keep pace with the accumulation of bad mutations.

teacher portrait

Michael Lynch heads the Biodesign Center for Mechanisms of Evolution and is a professor in the ASU School of Life Sciences.

“This is because the efficiency of selection is reduced in small populations, due to the increased noise in the process of transmission across generations,” Lynch said.

In this case, the biological fitness of the remaining population will be continuously degraded, placing the organism on a one-way street to extinction.

For example, a population initially carrying no harmful mutations will eventually degrade into a population with all members carrying at least 1 bad mutation, later 2, then 3 and so on. These populations become increasingly sick over time, further reducing the size of the population, in a snowball effect.

This irreversible mechanism, long recognized by evolutionary biologists, is known as the Muller’s ratchet, for the one-way ratchet-like accumulation of harmful mutations in a population. This process is traditionally thought to be the result of genetic drift, a random evolutionary process, but under high mutation rate regimes these “clicks of the click” can be caused by the mutation itself.

Hacking the viral genome

Typically, single-stranded RNA viruses have a 100 to 1000-fold higher mutation rate per replication than humans per human generation. Coronaviruses like SARS CoV-2, however, are unique among RNA viruses because they have a replay domain used to reduce the build-up of mutations.

The strategy described seeks to target this replay device with drug therapy, damaging its functionality. If the virus could be induced to pick up deleterious mutations at an accelerated rate, Muller’s ratchet could begin to click, eventually reducing the ability of the population to the point of no return: mutational collapse.

teacher portrait

Jeff Jensen is a population geneticist and professor at the Biodesign Center for Mechanisms of Evolution, the Center for Evolution and Medicine, and the School of Life Sciences at ASU.

“In practice, a key question here is how much the mutation rate must be increased to achieve this effect,” Jensen said, “because one certainly does not want to run the risk of an insufficient increase in the rate which can generating adaptive mutations without generating a sufficient deleterious mutational load to ensure quenching. “

If a viral invader like SARS CoV-2 were to be treated with a sufficient dose of a drug that stimulates the mutations, the result would be to cover the entire viral genome with mutations, which could make it very difficult for the resistance of the virus to evolve.

The drug favipiravir is one such candidate for the improvement of mutations, which has already shown promise in this regard in a number of RNA viruses, including Ebola, yellow fever, chikungunya, enterovirus and the notovirus.

In previous work on the influenza A virus, Jensen and colleagues accurately predicted the subtle dynamics of mutational fusion due to favipiravir, which involved a linear rate of accumulation of mutations leading to a fatal transition point, at – beyond which harmful mutations quickly accumulated before the collapse of the viral population.

Recently, another drug, remdesivir, showed promise against a clinical isolate of SARS-CoV-2. Like favipiravir, the treatment appears to disrupt the virus’s genetic proofreading system. As Lynch notes, “Anything we could do to mess the proofreader would increase the mutation rate by about 20 times.”

Such therapies could be used in conjunction with other drugs targeting different aspects of viral assembly or replication, further increasing the likelihood of achieving efficient fusion. However, much more work is needed – both experimental and theoretical – to determine whether the strategy can be safely and effectively applied to treat COVID-19, or be used as a general antiviral strategy in future unknown pandemics.

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