Formal reasoning about systems biology using theorem proving

PLoS One. 2017 Jul 3;12(7):e0180179. doi: 10.1371/journal.pone.0180179. eCollection 2017.

Abstract

System biology provides the basis to understand the behavioral properties of complex biological organisms at different levels of abstraction. Traditionally, analysing systems biology based models of various diseases have been carried out by paper-and-pencil based proofs and simulations. However, these methods cannot provide an accurate analysis, which is a serious drawback for the safety-critical domain of human medicine. In order to overcome these limitations, we propose a framework to formally analyze biological networks and pathways. In particular, we formalize the notion of reaction kinetics in higher-order logic and formally verify some of the commonly used reaction based models of biological networks using the HOL Light theorem prover. Furthermore, we have ported our earlier formalization of Zsyntax, i.e., a deductive language for reasoning about biological networks and pathways, from HOL4 to the HOL Light theorem prover to make it compatible with the above-mentioned formalization of reaction kinetics. To illustrate the usefulness of the proposed framework, we present the formal analysis of three case studies, i.e., the pathway leading to TP53 Phosphorylation, the pathway leading to the death of cancer stem cells and the tumor growth based on cancer stem cells, which is used for the prognosis and future drug designs to treat cancer patients.

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Cell Death
  • Drug Design
  • Humans
  • Kinetics
  • Models, Theoretical*
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Neoplastic Stem Cells / pathology
  • Phosphorylation
  • Prognosis
  • Systems Biology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Tumor Suppressor Protein p53

Grants and funding

The author(s) received no specific funding for this work.