Drug safety tests often focus on "physiological safety", meaning their possible effect on patients. Weizmann Institute of Science scientists propose a new type of test: evolutionary safety
How many mutations should I, or members of my species, have in order for our chances of survival to improve? There is no single answer to this question, but it can be thought of in terms of the inherent tension between innovation and conservatism. If we prefer a fast mutation rate, meaning more mistakes in copying the genome from parent to offspring, they will occasionally yield positive results for us that will allow us to better adapt to the environment, but the price we pay for this will be a large load of changes. On the other hand, if we prefer a conservative approach with a slow mutation rate, we will ensure the continuation of the existing situation - but we will prevent the development of new traits that may improve the lineage's chances of survival.
Many researchers are busy with this question, but so far it has not come up in relation to a new medical approach of treatments that increase the mutation rate of viruses or bacteria to the point of their elimination. Surprisingly, the person who did it was a tweeter on Twitter, who is not a scientist but endowed with common sense. The tweeter responded to encouraging news that was published in the peak days of the Corona epidemic: the Merck company has developed a drug, called molnopirvir and won FDA approval on a fast track for emergency situations, which confuses the SARS-CoV-2 virus and accelerates its rate of mutations to death. The tweeter responded to this with a logical explanation: of course, the acceleration of mutations is usually fatal for the virus, but occasionally it may benefit from changes in the genome that will yield upgraded features for it, and then we humans will encounter more dangerous corona strains - and pay a heavy price for evolutionary innovation.
Prof. Chili pepper from the Department of Molecular Genetics at the Weizmann Institute of Science read the tweet and wondered: Is it possible that there is a serious failure in the drug that escaped the notice of those who developed and approved it? Prof. Pepper explains: "As far as I know, this is the first drug ever developed to attack the virus with the help of accelerating mutations as a central mechanism of action - and thus may change the course of the spread of a deadly epidemic. Since drug safety tests usually focus on their effects on the patients themselves, that is, on the 'physiological safety' of the drug, it seems that there is a need to develop a method that will enable a new type of safety test related to the entire population: 'evolutionary safety'. Such a test will also be relevant to drugs that were developed before molnopirvir and which increase the mutation rate of viruses or bacteria, but do so as an unplanned side effect of their action."
""We call on the regulatory bodies and the pharmaceutical companies to integrate the issue of evolutionary safety in the process of developing and approving medical treatments"
And so began the search for ways to face the challenge of evolutionary safety, in collaboration with PhD student Gabriela Lubinska from Prof. Pepper's lab and Prof. Martin Novak from the Department of Evolutionary Biology and the Department of Mathematics at Harvard University. The researchers examined three possible pathways for testing evolutionary safety. The first route is to integrate it as part of the clinical trials. This is an in-depth way that is expected to clearly identify the mutual effects between the cause of the disease and the patient's body - but may be too complex to perform, partly due to the need to follow the multiple branches of the lineage of viruses or bacteria. At the same time, due to the limited scope of the experimental group of medical treatment recipients, it will probably reflect only a small part of all the mutations and is even expected to miss those that led to the extinction of the causative agent of the disease and therefore did not survive in the bodies of the patients. A second route to test the evolutionary safety can be carried out in the laboratory, and is expected to show a more complete picture of the array of mutations, including those that are created following different types of treatment, such as varying doses of a drug.
A third track, which the researchers focused on, is a theoretical test using a mathematical model, which can present a broad picture of the lineage of viruses or bacteria and how they respond to medical treatment. The researchers began formulating the computational template that would allow scanning the tens of thousands of possible mutations in the genome of the corona virus. They sought to assess the chances of three situations materializing: a mutation that is good for the virus and dangerous for humans, such as one that develops improved infectivity or resistance to existing drugs, a mutation that is destructive to the virus and good for us, or cases where it does not cause a significant change in the virus's genome.
In the article thatRecently published in the scientific journal PLOS Biology, the researchers conclude that Merck's medicine registers a double achievement - it both saves corona patients and benefits humanity. The secret is in the numbers. The researchers concluded that as far as evolutionary safety is concerned, the amount of mutations that are good for the virus but bad for us is of limited importance. If medical treatment increases the amount of mutations in the genome of the virus or bacteria but decreases their population more quickly - the evolutionary risk posed by it is low. Along with this, it should be taken into account that evolutionary safety is also largely influenced by the strength of the patient's immune system and the date of treatment initiation.
"We call on the regulatory bodies and pharmaceutical companies to integrate the issue of evolutionary safety into the process of developing and approving medical treatments," the researchers conclude. "A better understanding of the healing mechanism based on mutation acceleration and its consequences will make it a valuable ally in the fight to eradicate diseases. It will make it possible to better anticipate the formation of new strains and to plan medicines that will ensure both the recovery of the patient and the safety of the entire population."
