Towards a disease digital twin: Howard T. Odum's legacy for cancer biology and medicine

• Howard T. Odum’s legacy offers a new systemic research approach to complex diseases. • Stock-flow diagrams offer a new tool to represent complex disease dynamics. • Emergy algebra can serve as the basis for computational simulators of diseases. • Diseases are systems governed by feedback networks shaping their progression. • Systems Thinking energy language is a novel interdisciplinary tool for biomedicine. Complex systems – such as ecosystems – display non-linear, self-organizing behaviors that go beyond simple cause-effect relationships among individual components: the presence of feedback networks enables responses and adaptations that can only be understood by "zooming out" to wider perspectives. In this regard, moving from general systems theory and thermodynamics, H.T. Odum made lasting contributions in developing a quantitative approach for understanding the nature of these fundamental relationships and the dynamical representation of their emergent properties. Among all the realms in which his work was source of novel and influential ideas (e.g., ecology, energy, economics), a new possibility, still underexplored, appears applying the energy system language to study complex biomedical systems. In this framework, complex diseases such incurable cancers and as self-immune diseases arise as systemic features, manifesting the malfunctioning of regulatory control processes and the interactions/crosstalk between cells and their micro-environment. We provide a conceptualization of how Odum’s heritage can help to address the complexity of these malignant, complex ecosystem, laying the foundation for an analytical, dynamical representation of a Disease Digital-Twin , focusing on the evolutionary scenarios for classes of diseases, at different hierarchical and timescales. Finally, we discuss how using data coming from innovative experimental techniques (small Tumor Ecosystems) provides powerful tools for developing a holistic framework for patients’ treatment and general individual health care. "An alteration induced in a stable system configuration may gives rise to systemic competition between stocks, and consequent proliferation of one to the expenses of the others. This leads to the destruction of the remnants of the system. When this happens in human, we call it cancer". Howard T. Odum