Systems Therapeutics: Updated Diagram

Background

Two reports have been posted on Systems Therapeutics on this website, first, “Systems Therapeutics: A Diagram and Four Categories” in April 2015 (1), and second, “Systems Therapeutics: Variabilities” in May 2016 (2). The purpose of the underlying systems therapeutics diagram is to provide a high-level framework to facilitate discussions on how pharmacologic processes and pathophysiologic processes interact to produce a therapeutic response.

In essence, the systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, each starting at the molecular level, through the cellular and tissue/organ levels, and finally the clinical level, culminating in therapeutic response. The pivotal interactions between the pharmacologic and pathophysiologic processes, at each of the four biologic levels, determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as was outlined in the May 2015 post. In addition, each of these two processes, pharmacologic and pathophysiologic processes, have their inherent variabilities, as was outlined in the May 2016 post, which also suggested that variability on the pathophysiologic process side might be an important determinant of patient therapeutic response characteristics, including response variability and responder rate, in addition to variability on the pharmacologic process side, although it is unclear where the source of such variability might reside, including potentially at different levels.

Updated Diagram

The current report presents an updated systems therapeutics diagram, see below (click here for a larger graph), that includes the following modifications of the diagram presented in the May 2016 post:

systems-therapeutics-sep-2016

  • On the pharmacologic processes side, the following systems components have changed names: “Pharmacologic Agent” has replaced “Drug” and “Drug Concentration”, and “Pharmacologic Response Element” has replaced “Pharmacologic Target”. The rationale is to use more neutral and descriptive terms, with an emphasis on an agent acting on an element in a pharmacologic pathway, resulting in a response. Here, the pharmacologic agent, and its concentration or exposure, is the undisputed fundamental driver of pharmacologic processes, including interpatient variability. Another change involves adding at the clinical level “Clinical Effect” as the last systems component on the pharmacologic processes side, corresponding to “Disease Manifestation” on the pathophysiologic processes side. The descriptors for the transitions from one systems component to another on the pharmacologic processes side, e., signal transduction, pharmacodynamics and translation, remain unchanged.
  • On the pathophysiologic processes side, the following systems components have changed names: “Intrinsic Operator” has replaced “Environmental” and “Factor”, and “Etiologic Causative Factor” has replaced “Etiologic Factor”. The main rationale is to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, with an emphasis on an etiologic factor in a disease network being driven by a hypothetical operator, eventually leading to manifestation of a disease. It is noted that this construct, incorporating a hypothetical systems component at the beginning of pathophysiologic processes, is intended in part to lump together different entities thought to influence “Etiologic Causative Factor” (as addressed in the May 2016 post, including etiome and network medicine), and in part to serve as a hypothetical driver of pathophysiologic processes, including interpatient variability. Whether this simple hypothesis survives the test of time is obviously unclear, but for now this “Intrinsic Operator” serves a role as an integral systems component. The descriptors for the transitions from one system component to another on the pathophysiologic process side, e., disease initiation, pathogenesis and progression, remain unchanged.

Comments

The systems therapeutics diagram, first introduced in the April 2015 post (1) has been modified twice, first in the May 2016 post (2), and now in the present report. Both modification have principally involved the system components at the beginning of the pharmacologic and pathophysiologic processes, how they are depicted and named.

This updated framework, highlighting how these parallel processes – pharmacologic and pathophysiologic – contribute to patient therapeutic response characteristics, also helps focus on areas where future basic research efforts are sorely needed, such as initiating disease process mechanisms and variability in disease process drivers.

It is our hope that those interested in this general subject will find the updated systems therapeutics diagram useful as an aid in thinking about the various determinants, known and unknown, of patient therapeutic response to approved drugs, while recognizing our limited understanding in this area at this time.

References

  1. Therapeutics Research Institute: Systems Therapeutics: A Diagram and Four Categories, May 2015. http://tri-institute.org/niDFW
  2. Therapeutics Research Institute: Systems Therapeutics: Variabilities, May 2016. http://tri-institute.org/TyQij