Accidents in the power supply system and in a living cell: what do they have in common?

Gene therapy, which involves embedding a missing gene or replacing a pathological version of a gene with its normal variant, is a promising experimental approach to the prevention and treatment of various diseases.

Scientists at Northwestern University (Evanston, Illinois), working under the guidance of Dr. Adilson E. Motter, argue that the opposite approach – targeted removal of genes – can restore the normal functioning of cells with genetic defects.

The authors collected a large amount of experimental information about the metabolic systems of three different unicellular organisms, the processing of which allowed them to create a general quantitative model that allows them to virtually control the biological functions of cells disrupted as a result of a genetic defect or the effects of factors negatively affecting gene activity. The systematic approach they propose is based on targeted gene removal, which forces the cell either to avoid a function, the implementation of which depends on a defective gene, or to compensate for its loss.

The premise of the study was Motter's earlier work on the U.S. energy system, another complex system that is very different and at the same time in many ways similar to biological systems.

After the power system accident in the northeastern United States in 2003, when a series of consecutive outages led to the longest power failure in the history of the United States, experts found that such accidents can be avoided or at least reduce the economic losses associated with them by deliberately shutting down individual components of the system when the first signs of instability appear.

Motter argues that this principle also applies to biological systems in which a single defective gene can trigger a cascade of malfunctions of cell components. The results of the study also suggest that a small intentional damage can prevent much more significant losses.

The researchers used a computer model developed by them to simulate the functioning of a single-celled organism. They started working with an ideal cell, from the genome of which one of the key genes was removed, which significantly slowed down or completely stopped the growth of the cell.

The subsequent removal of additional genes stimulated the cell to use alternative mechanisms of vital activity and restore the ability to grow. An interesting fact is that the more genes scientists removed, the higher the level of cell repair was.

The diagram shows how the removal of genes can be used to redirect the reactions occurring in the cell, bypassing the disturbed mechanisms.
The letters A to G denote proteins encoded by the a-g genes, respectively, and R1-R5 are enzyme–catalyzed reactions conjugated by biochemical compounds (red and pink arrows).

According to the authors, the described effect is based on the optimization of resources that are insufficiently or not used at all by the cell under normal conditions. This method is fundamentally different from traditional gene therapy, which involves embedding new genes into the cell – an approach that has both advantages and disadvantages.

During one of the "in silico" experiments with E. coli, scientists found that the removal of one gene is detrimental to the cell, while its removal simultaneously with a number of other genes does not kill the bacterium. Thus, this gene is critical only in the presence of other genes. Motter emphasizes that the results undermine the traditional notion that every organism contains a mandatory set of vital genes.

Of course, there is a huge evolutionary gap between unicellular organisms and human cells, but the results obtained by the authors are proof of the principle. Many specialists have become interested in this work, which is partly due to the possibility of using such methods to treat various diseases.

Article by Adilson E Motter et al. Predicting synthetic rescues in metabolic networks is published in the electronic version of the journal Molecular Systems Biology.

Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of Northwestern University

01.04.2008