  An important goal of medical research is to develop methods to recover the
loss of cellular function due to mutations and other defects. Many approaches
based on gene therapy aim to repair the defective gene or to insert genes with
compensatory function. Here, we propose an alternative, network-based strategy
that aims to restore biological function by forcing the cell to either bypass
the functions affected by the defective gene, or to compensate for the lost
function. Focusing on the metabolism of single-cell organisms, we
computationally study mutants that lack an essential enzyme, and thus are
unable to grow or have a significantly reduced growth rate. We show that
several of these mutants can be turned into viable organisms through additional
gene deletions that restore their growth rate. In a rather counterintuitive
fashion, this is achieved via additional damage to the metabolic network. Using
flux balance-based approaches, we identify a number of synthetically viable
gene pairs, in which the removal of one enzyme-encoding gene results in a
nonviable phenotype, while the deletion of a second enzyme-encoding gene
rescues the organism. The systematic network-based identification of
compensatory rescue effects may open new avenues for genetic interventions.
