Conjectures on near-balanced biological networks

Formalize and prove the conjectures that (1) interaction graphs that are nearly balanced (i.e., close to sign-consistent/orthant-monotone structure) tend to exhibit more regular dynamical behavior and confer biological advantage compared to graphs that are far from monotone, and (2) real biological networks are substantially closer to being balanced than random networks of comparable size and with the same distribution of positive and negative edges. Provide precise mathematical definitions of "nearly balanced" and appropriate comparison baselines, and establish the conjectures rigorously.

Background

The paper develops a connection between signed interaction graphs and monotone dynamics, showing that balanced (sign-consistent) graphs correspond to orthant-monotone systems with strong qualitative predictability and robustness. It then presents empirical evidence that intracellular regulatory networks (e.g., yeast and E. coli) are far more balanced than random graphs, motivating conjectures about the prevalence and dynamical benefits of near-monotone structure.

The authors explicitly state two conjectural claims: that near-balanced networks may be biologically advantageous by yielding more regular dynamics, and that real networks are closer to balanced than matched random networks. They note the absence of precise mathematical formulation or proofs and call for work to make these ideas rigorous, including definitions of "distance to monotonicity" and statistical baselines.

References

Of course, there is no a priori reason for a system to have a balanced interaction graph. Yet we speculate that: (1) systems that are "nearly balanced" may be, statistically, more biologically advantageous than those that are far from monotone, in the sense that they tend to exhibit more regular dynamical behavior; and (2) real biological networks may lie much closer to being balanced than random networks with the same numbers of vertices and the same distribution of positive and negative edges. To the best of our knowledge, there is no precise mathematical formulation, let alone a proof, of these conjectures.

Dynamic response phenotypes and model discrimination in systems and synthetic biology (2512.24945 - Sontag, 31 Dec 2025) in Biological networks, balancing, and monotonicity (subsection); following discussion of balancing and coherence