Mathematical Model Resolves Decade-Old Debate On Regulation Of Protein Production By MicroRNAs In Cells
An international team of mathematicians has proposed a new solution to understanding a biological puzzle that has confounded molecular biologists.
They have applied a mathematical model to work out the functioning of small molecules known as microRNAs – components of the body akin to the electronics in modern airplanes.
For a long time molecular biologists thought that the major role of RNA in living cells was to serve as a copy of a gene and a template for producing proteins, major cell building blocks. This belief had been changed at the end of 90s when it was found that myriads of RNA molecules are involved in regulating speeds of practically all molecular mechanisms in a cell. These abundant molecules are essential in regulating the speed of protein production – a vital function in bodily processes, including development, differentiation and cancer.
The problem to date has been that scientists have differed over interpretations of how the production of the major building blocks of a cell, proteins, is controlled by microRNAs.
Basically, there were different and sometimes conflicting theories about ways in which microRNAs regulate protein production since the results varied depending on only slightly changed experimental conditions.
Professor Alexander Gorban, who holds a Chair in Applied Mathematics at University of Leicester, said: “The old metaphor of an elephant and blind scientists trying to describe it will be always relevant to science. However, often we use it only as a metaphor, as a generic statement. In this project the elephant’s metaphor can be applied literally as a working principle.
“Different biological labs or slightly changed experimental conditions meant that results were different for investigators.
“Quite dramatically, there has been a series of reports in top-ranked journals with contradictory results supporting one or another mechanism. Furthermore, researchers are puzzled by the fact that the same couple of protein and microRNA demonstrate different mechanisms of regulation in different biological labs or in slightly changed experimental conditions.”
The mathematical model constructed by Professor Gorban from University of Leicester and Andrei Zinovyev from Institut Curie in Paris in collaboration with biologists Nadya Morozova and Annick Harel-Bellan from CNRS in France showed that there might be one simple mechanism which manifests itself differently in different conditions. Their findings are due to be published in the RNA Journal.
Professor Gorban said: “We have shown that what appeared to be very different mechanisms are in fact manifestations of one relatively simple biochemical reaction, but taking place in various contexts.
“Our model proposes that microRNA performs many actions simultaneously to the protein development, basically acting to get the job done (regulating the speed of protein production) in a stable and efficient way, given whatever conditions the experiment is occurring in.
“If this model is accepted, we would be able to take active steps in determining what the main mechanism of microRNA action is, as the model suggests experiments to verify the hypothesis. This in turn should lead to a resolution of a decade long debate to understand the means in which these very important molecules actually work.”
Pat Heslop-Harrison, Professor of Cell Biology at the University of Leicester, said: “The discovery of miRNA and its regulatory role has completely changed our view of how genes in cells are controlled.
“Understanding all the ways the regulation is happening and interpreting experimental evidence has proved a huge challenge. In this important new paper, Alexander, Andrei, Nadya and colleagues overview the characteristic features of no less than nine different mechanisms, and then generate a unifying model of the whole system integrating the nine mechanisms.
“The multifunctional model gives dynamic predictions of gene control; it can now be tested to understand significance of the various mechanisms coexisiting under different conditions. It will be exciting to link this back the huge range of functions and responses of organisms and understanding miRNA control mechanisms is a systematic and predictive way.”
Molecular biologists had previously thought that the major role of RNA in living cells is to serve as a copy of a gene and a template for producing proteins, the major cell building blocks. This belief was changed at the end of 90s when it was found that myriads of RNA molecules are involved in regulating speeds of practically all molecular mechanisms in cell.
In particular, it was found that there is a class of short RNA molecules which are actively involved in regulating the speed of protein production itself. Since these molecules are very short compared to others (their sequence contains only about 25 genetic “letters”), they were called microRNAs. Recent research showed that practically any protein production can be, and is, controlled by microRNAs. Some researchers say that the role of microRNAs in human cells can be compared to the role of electronics in the modern airplanes. The omnipresent involvement of microRNAs in regulating protein production makes cells of higher organisms more stable, more functional and more efficient compared to the microbes’ cells where there are no microRNAs.
MicroRNAs rather slow down protein production than enhance it, but globally this allows more coordinated and equilibrated protein synthesis for various cell’s purposes. How exactly microRNAs achieve protein production reduction was a subject of active scientific research for the last decade. Biologists have described nine distinct mechanisms of microRNA action which appeared to be very different one from another. This has led to a hot debate on what is the “main” mechanism of microRNA action?
Professor Gorban added: “MicroRNA’s function is to reduce protein production. It seems that it does not matter for a cell how this is achieved, but it should be done stably and efficiently in various conditions. So evolution ‘invented’ a biochemical mechanism in which a microRNA acts simultaneously at many steps of protein production. But an observer sees only that effect of microRNA which affects the most sensitive place of a protein production in current condition and will completely ignore the others.”
If this point of view is accepted by the scientific community, a very hot debate on “which mechanism of microRNA action is the most important?” will become more constructive and less speculative. The model suggests a series of new experiments in order to verify the unifying hypothesis. It advises to biologists which data should be collected to univocally identify the most “visible” (but not the most “important”!) mechanism of microRNA action in their experimental conditions.
The research is due to be published in RNA, Vol. 18, No. 9, September 1st, 2012. Published in Advance July 31, 2012, doi: 10.1261/rna.032284.112
Two relevant preprints are also available online: http://arxiv.org/abs/1202.1243 , http://arxiv.org/abs/1204.5941. The general theory of the sensitive places (“dominant systems”) of the complex reaction networks was developed recently by Gorban, Zinovyev and Radulescu (A. N. Gorban, O. Radulescu, A. Y. Zinovyev, Asymptotology of chemical reaction networks, Chemical Engineering Science 65 (2010) 2310).
Professor Gorban is Chair in Applied Mathematics, at University of Leicester, UK and Chief Scientist (on leave), at the Institute of Computational Modeling, Russian Academy of Sciences, Russia. He is best known for his work on physical and chemical kinetics and data analysis as well as more for his work on how humans adapt to hard living conditions.
University of Leicester