Targeted Removal Of Genes Can Restore Cellular Function In Cells With Genetic De

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Targeted Removal Of Genes Can Restore Cellular Function In Cells With

Genetic Defects

http://www.medicalnewstoday.com/articles/100972.php

Gene therapy, in which a working gene is inserted into a cell to

replace a faulty or absent gene, is a promising experimental

technique for the prevention and treatment of disease.

Now a research team led by a Northwestern University physicist

reports that a counterintuitive approach also holds promise. The

targeted removal of genes -- the exact opposite of what a gene

therapist would do -- can restore cellular function in cells with

genetic defects, such as mutations.

Published online in the journal Molecular Systems Biology, the

results have ramifications for medical research as well as for

optimizing certain metabolic processes used in the production of

biofuels, such as ethanol.

After gathering extensive experimental information on the metabolic

networks of three different single-celled organisms, the researchers

built a general quantitative model that can be used to control and

restore biological function to cells impaired by a genetic defect or

by other factors that compromise gene activity. Their network-based

method does this by targeted deletion of genes, forcing the cell to

either bypass the functions affected by the defective gene or to

compensate for the lost function.

The research, led by Adilson E. Motter, assistant professor of

physics and astronomy in Northwestern's Weinberg College of Arts and

Sciences and the paper's lead author, grew out of Motter's earlier

work on the U.S. power grid -- another complex system that is very

different from biological systems but also with many similarities.

After the 2003 Northeast blackout, where a sequence of failures in

the power grid led to the largest outage in U.S. history, experts

determined that the event could have been reduced or avoided by

instigating small intentional blackouts in the system during the

initial hours of instability.

" And the same could be valid in biology, where a defective gene may

trigger a cascade of 'failures' along the cellular network, " said

Motter, whose interest and expertise lie in complex systems and

understanding how the structure and dynamics of a high-dimensional

system, such as an intracellular network or a power grid, relate to

its function.

" Our recent research shows that what is true in power networks is

also true in biological networks. Inflicting a small amount of damage

can control what otherwise would be much more significant damage. "

With the experimental information assembled, the researchers used

their computer model to simulate the organism and its function. They

started with a perfect cell and then, with a key gene deletion,

damaged the cell so that it was unable to grow or had a significantly

reduced growth rate.

Next, the researchers restored growth by deleting additional genes,

which stimulated the cell to make a different choice and use

different pathways. Interestingly, the cell's recovery was stronger

when more genes were deleted. They could even restore growth to non-

growing mutant cells; the researchers dubbed this the " Lazarus

effect. "

" Our research is based on optimizing the use of resources already

available in the cell, " said Motter. " We are exploring existing

reactions and genes in the cell that the cell would not use or use to

a lesser degree under normal conditions. This is different from

traditional gene therapy, which is based on introducing new genes

into the cell -- with its own advantages and problems because of

that. "

The team's use of predictive models is similar to how physicists use

models, for example, to determine the position of the moon tomorrow

at a specific time. Thanks to the recent wealth of available

biological information, computational scientists now are beginning to

develop quantitative models of biological systems that allow them to

predict cellular behavior.

In one in silico experiment (via computer simulation) with E. coli,

the researchers found that the deletion of one gene is lethal to the

cell but when that same gene is removed along with other genes, it is

not lethal. The gene, it turns out, is only essential in the presence

of other genes. This touches the issue, says Motter, of whether

organisms have an unconditional set of essential genes.

While Motter's team has not done actual laboratory experiments, they

have used their computational results to re-interpret and explain

specific recent experimental results. They have applied physics

methods to solve a biological problem. Their method, for example, can

identify the genes whose removal restores growth in gene-deficient

mutants of E. coli and S. cerevisiae, a type of yeast.

" From a phylogenetic viewpoint, yeast is more similar to humans than

E. coli, " said Motter, a member of the Northwestern Institute on

Complex Systems. " Of course, there is a distance between single-

celled organisms and human cells, but our results should be seen as

proof of principle. Many experimentalists are interested in our work,

and part of this interest comes from its potential for disease

treatment research. This work is a concrete application of complex

networks to solve a real problem, and, as such, also requires

substantial involvement of network theorists. "

" Needless to say, this work is built on previous research and would

not have been possible without the very significant contribution of

my collaborators, " said Motter.