Researchers from the University of Haifa and the University of California have developed a revolutionary method that integrates biotechnological and computational tools to accurately monitor the adaptive mutations in viruses such as AIDS, SARS and polio.
In a study published in the prestigious journal Nature, the researchers have demonstrated how the method they have developed successfully monitors the evolution of harmful poliovirus mutations, how fitted are five specific harmful mutations from among hundreds of mutations, and identified the specific protein of the viral genome these mutations effect.
“In practice, this method is the development of a new tool in biomedicine. It works as a “microscope” that, for the first time, enables researchers to monitor the evolution of potentially harmful mutations under laboratory conditions. This will allow us to develop medical treatment, sometimes long before the harmful mutation spreads among people,” said Dr. Leonid Brodsky from the Tauber Bioinformatics Research Center at the University, who was one of the research partners.
The genome of viruses with RNA as their genetic material, ranging from AIDS, SARS and polio to West Nile virus, measles and influenza, evolves rapidly and adapts itself to the human immune system by accumulating multiple mutations. In cases of rare radical mutations, these changes can enable an insect-adapted virus to adapt to humans, which is how humans become infected after being bitten by mosquitoes as in the case of the West Nile virus.
The study of evolutionary courses of aggressive mutations is critical to the protection of humanity from harmful epidemics, such as the polio epidemic that was recently in the news again in Israel. This endeavor however, has been fraught with difficulty. Present technology frequently “errs” when “reading” virus genomes, and one cannot distinguish between true genome mutations and errors. A no less significant problem is that present technology cannot identify and distinguish between harmless mutations that endanger humanity and neutral mutations.
That is, until the current study by Prof. Raul Andino and Dr. Ashley Acevedo from the University of California, San Francisco, and Dr. Leonid Brodsky, from the University of Haifa. These scientists have developed the aforementioned “microscope”, that provides a solution to solving these problems. The development is based on an innovative and groundbreaking technology developed at the University of California: an innovative method called CirSeq for “reading” the genome that enables the distinction between those errors introduced by the instrumental measurements, and true mutations. The second part of the development is based on an innovative computational method developed by Dr. Brodsky at the Tauber Bioinformatics Research Center at the University of Haifa, which is capable of detecting rare mutations potentially harmful to humanity.
In this new study, using this new development the three scientists monitored the poliovirus by taking one million mutated viral genomes from a culture of human cells infected with the poliovirus, and placing them under the innovative “microscope”. CirSeq, with its enhanced technological capabilities, was able to identify which mutations were “neutral (not beneficial to the virus), and therefore did not make it harmful — and which mutations were beneficial to the virus and gave it an advantage in spreading inside human cells in comparison with other sub-populations (strains) of the same virus.
In practice, this new technology has made it possible to measure the mutation rate for each position of virus genome. However, even after reaching this stage, there were still hundreds of potentially harmful virus genome mutations.
Measurements do not clearly determine the exact margin of error that describes the range of possible rates for a given mutation — which can be larger or smaller than the value measured by the instrument.
Due to the high number of possibly aggressive mutations on the one hand — as mentioned, hundreds of mutations — and the uncertainty regarding how harmful they really were on the other, it could not be determined which mutations research efforts should be invested in.
It was at this stage that Dr. Brodsky’s development was implemented. Using statistical and mathematical methods, he was able to calculate the margin of error in mutation rates and demonstrate which mutations have a small margin of error and which have a large margin of error. Thus, he could effectively identify for researchers those mutations most likely to be harmful.
In this way the researchers performing this current study were able to identify five specifically harmful mutations. Further examination has indicated that all five of these mutations were associated with a virus protein, which is known to neutralize human cell defense. This discovery shows that accurate detection of mutation fitness in many virus genome positions opens a prediction perspective for researches: what mutations are advantageous for the virus, and, thus, how an anti-viral drug could be developed in response.
In effect, these researchers have demonstrated for the first time that the evolution of potentially harmful strains of viruses can be identified under laboratory conditions long before they evolve in nature and become harmful to people.
“Until now we had no way of knowing how many new and harmful strains there were because we had no way of identifying them. Initial identification of harmful strains was often only after people became ill with the virus. Now, with this new research system, we may possibly be prepared in advance with appropriate care,” Dr. Brodsky noted.