Systems Therapeutics Category Zero

Musings About Disease Origination

Reposted from Medium 2024

“These are my principles and if you don’t like them, well, I’ve got others.

Groucho Marx

Summary

Systems therapeutics has previously been described in detail, illustrating how pharmacologic processes interact with pathophysiologic processes to produce a clinical therapeutic response. At its center is a systems therapeutics diagram illustrating the four fundamental biologic levels of interaction between these processes, which then determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissues/organ level) and Category IV (at the clinical level). Systems therapeutics Category Zero (0) refers to an interaction between pharmacologic and pathophysiologic processes at the front end of these processes — at the origin level — involving a pharmacologic agent and an initiator of disease origination. The objective of this paper is to consider a general hypothesis regarding disease origination, to outline the underlying rationale, and to discuss the two fundamental systems components involved, intrinsic operator and etiologic causative factor.

Introduction

Systems therapeutics defines how pharmacologic processes interact with pathophysiologic processes to produce a clinical therapeutic response. The systems therapeutics diagram shows two rows of four parallel systems components for pharmacologic processes and pathophysiologic processes, representing the four fundamental biologic levels of interaction between these two processes — at the molecular, cellular, tissue/organ, and clinical or whole body levels — which then define four systems therapeutics categories, i.e., Categories I, II, III and IV, respectively (Bjornsson 2023a).

During the construction of the systems therapeutics diagram two hypothetical systems components were introduced at the front end of pathophysiologic processes (Bjornsson 2023a). First, the systems component intrinsic operator was introduced as the initiator of the pathophysiologic processes, corresponding to the pharmacologic agent of the pharmacologic processes, in part to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, and in part to stimulate discussions on this front. These two front end systems components, an intrinsic operator and a pharmacologic agent — at the origin level — comprise the systems therapeutics Category Zero (0). The intrinsic operator represents an initiator or driver, acting on the second systems component, etiologic causative factor, which represents the seeds of the disease, and thus, determines the specific disease expression. In contrast, their counterparts on the pharmacologic processes side, the pharmacologic agent, i.e., a drug, and the pharmacologic response element, e.g., a receptor, are generally recognized and accepted.

As background for the present report, two recently published reports discussed where to place clinical disease modifiers (Bjornsson 2023b) and clinical disease categories (Bjornsson 2023c) within the systems therapeutics scheme, both of which may influence disease development and progression, while it is generally thought that these modifying factors are not directly involved in the disease origination processes.

Objective

The objective of this paper is to consider a general hypothesis regarding disease origination, to outline the underlying rationale, and to account for the two fundamental systems components initiating and determining specific disease expression. This involves the two systems components already mentioned, intrinsic operator and etiologic causative factor, and the systems processes disease preindication1 and disease initiation2, connecting the two components at the front end of the pathophysiologic processes. Refer to Chart 1, lower left hand corner. Together, these two processes and two systems components then constitute disease origination mechanisms.

Chart 1. The systems therapeutics diagram, with the addition of Category Zero/Origin Level, on the left hand side (modified from Bjornsson 2023a).

Any general hypothesis regarding disease origination thus developed, supported by experimental data and fully understood, could eventually suggest what kind of pharmacologic agents might counteract the disease origination mechanisms. It could also aid in the development of approaches to modeling and simulation of the pathophysiologic processes, and thus, coupled with pharmacologic processes, of the overall systems therapeutics processes.

Rationale

The present focus on Category Zero and its pathophysiologic processes extends logically from the systems therapeutics diagram, first posted in its current version in 2016 (Bjornsson 2023a). The impetus behind this report principally involves three general considerations:

a) Age of disease onset. While different diseases manifest clinically at different age ranges, one typically assumes the underlying etiologic causative mechanisms have been in place for some time, perhaps years or decades — even from the earliest signs of life. For example, the age of onset for schizophrenia is typically in early adulthood, in late teens to mid-30s, while the age of onset for Alzheimer’s disease is typically in late adulthood, in the 60s or later. On the other hand, inborn errors of metabolism, e.g., phenylketonuria, typically occur in very early childhood, often starting at a few months of age, while acute lymphocytic leukemia typically starts in early childhood, usually in the 2–5 years age range. A commonly stated explanation to account for the differently delayed onset of diseases involves the theory that varying durations of time are required for the pathophysiologic processes to progress before a disease becomes clinically manifest, from a few months to a few decades. Thus, only short durations of time are required for inborn enzymatic deficiencies to result in catastrophic accumulation of metabolites, while more subtle disease mechanisms might take years to decades for diseases to become clinically manifest. The first tenet of the present general hypothesis of disease origination is that the blueprints for the disease origination systems components and processes have been in place since the differentiation of the principal cell types of the different organs or organ systems, but only brought into existence at a later date.

b) Central role of principal cell types. Disease initiation events are generally assumed to take place in the principal cell types of the different organs/organ systems, i.e., the cells responsible for an organ’s biochemical and physiologic characteristics. Therefore, this further assumes that both the intrinsic operator and the etiologic causative factors originate and reside in these cells, and that the intrinsic operator initiates and maintains the disease origination process. Regarding the different cell types, it is of interest to note that there are currently ongoing extensive efforts to develop catalogues of the different human cell types (e.g., Human Cell Atlas and Human Cell Tree Map) as well as published articles relevant to their role on medicine (e.g., Rood et al. 2022). Two generic features are worth emphasizing, i) a typical organ/organ system based disease occurs only in one organ/organ system while the same genome exists in all organs/organ system, and ii) each organ/organ systems has only a limited number of disease expressions. These features suggest organ-specific mechanisms, and thus principal cell type specific mechanisms, as far as the intrinsic operator and the etiologic causative factor are concerned, and their interactions viathe disease preindication process. The second tenet of the present general disease origination hypothesis is that it applies to diseases in general, that its causative mechanisms reside in the principal cell types of the respective organ/organ system, and that it is independent of classic disease categories and disease modifiers, although these can influence disease development and progression.

c) Variability in clinical therapeutic drug response. Considering currently approved drugs, there are very few examples of drugs acting directly at the etiologic mechanistic cause of the disease (Category I), when one excludes treatments of infectious diseases and replacement therapies. As previously outlined with examples (Bjornsson 2023a), approved drugs work at different biologic levels, and can be categorized by the biologic levels of the pivotal interactions between pharmacologic processes and pathophysiologic processes, with most drugs interacting at the biochemical level (Category II) and the physiologic level (Category III), while others are at the clinical symptomatic level (Category IV). Thus, a meaningful clinical therapeutic response can be accomplished by interactions between the pharmacologic and pathophysiologic processes at different biologic levels. Yet there is considerable range in the average patient responder rate for different pharmacologic classes (Spear et al. 2001), as well as a significant interpatient response variability among patients within a given pharmacologic class. It is suggested that this overall variability in clinical therapeutic response can be attributed to variabilities in both pharmacologic processes and pathophysiologic processes, the former due to variabilities in pharmacokinetic and pharmacodynamic processes, the latter due to variabilities in disease originating and disease development and progression processes. The third tenet of the present general hypothesis of disease origination is the promise of being able to minimize the sources of key variabilities in both pharmacologic and pathophysiologic processes, thus achieving the highest possible clinical responder rate and the lowest interpatient response variability, with a promise of disease prevention or regression, through pharmacologic intervention at the origin level — at Category Zero.

General Hypothesis of Disease Origination

The disease origination hypothesis being considered involves an intrinsic operator and an etiologic causative factor, their interaction through a disease preindication process, and the subsequent connection of the etiologic causative factor to pathogenic pathways through a disease initiation process. Together, these two processes and the two systems components constitute disease origination. Refer to Chart 2, which shows the pathophysiologic processes divided into an early disease origination phase and a later disease development and progression phase. Below we will focus on the systems components intrinsic operator and etiologic causative factor.

Chart 2. Pathophysiologic processes showing disease origination, comprising intrinsic operator and etiologic causative factor, and disease preindication and disease initiation processes. Subsequent disease development and progression involves pathogenic pathway, pathophysiologic process and disease manifestation, and pathogenesis and progression processes.

Intrinsic Operator

The term intrinsic operator represents the front-end systems component of the pathophysiologic processes. It was introduced on the systems therapeutics diagram in 2016, in part to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, and in part to stimulate discussions on disease origination, as has been mentioned above.

The intrinsic operator is envisioned as an endogenous intracellular entity, not external or circulating, residing in the diseased organ’s principal cell type(s), although its production or activity could be modulated by an extracellular entity. It could be a macromolecular protein or a product derived from a larger intracellular compound. The prototypical candidate for an intrinsic operator involves a transcription factor or a transcription factor-like molecule. Transcription factors are proteins that control the rate of gene expression, they are involved in most cellular functions, and they are thus found in all living organisms. There is an extensive literature on transcription factors and related coactivators, coregulators and nuclear receptors, and how they bind to a given gene’s DNA sequence to elicit the formation of a normal or abnormal gene product (e.g., Boija et al. 2018; Lonard et al. 2012).

One of the attractive attributes of transcription(-like) factors (and attendant molecular machinery) as intrinsic operators is that it could help explain the age of disease onset differences. Their activity, post-differentiation, would be based in the principal cell type(s) of the organ/organ system to be affected by disease. This suggests that an intrinsic operator becomes active at a certain point in time, early or late, depending on the disease in question, initiating a disease preindication process.

Etiologic Causative Factor

The etiologic causative factor was initially envisioned as a singular biomolecular entity, representing the molecular abnormality or malfunction characterizing the disease under consideration, such as a specific genetic mutation or protein abnormality.

The analogous systems component for the etiologic causative factor on the pharmacologic side of the systems therapeutics diagram is the pharmacologic response element (e.g., a receptor); such a construct — a drug and a drug target — has been accepted for a century. In contrast, on the pathophysiologic side of the systems therapeutics diagram there is currently limited information about the identity of such causative entities and mechanisms, except examples of genes expressing abnormal proteins (e.g., enzymes). The concept of an etiologic causative factor can be broadened to potentially include a network or an assembly, including the primary etiologic causative factor, which then becomes an etiologic causative network. The prototypical candidate for a primary etiologic causative factor involves a disease-specific gene whose expression is stimulated by a specific disease associated intrinsic operator. Such a network is more in line with disease causation mechanisms discussed in the network medicine literature (e.g., Chan & Loscalzo 2012; Silverman et al. 2020), and does allow for a more general disease origination paradigm.

The etiologic causative factor/network contains the seeds of a disease, and after being interacted on by the intrinsic operator via a disease preindication process, leads to disease development and progression via a disease initiation process. Thus, the interaction of the intrinsic operator and the etiologic causative factor/network results in a directiveness3 towards a specific disease evolution, whose overall rate and variability is primarily determined by the initiating and driving factor, the intrinsic operator, and also influenced by the components of the etiologic causative factor/network.

One of the attractive attributes of an etiologic causative factor/network as leading to pathogenic pathways through a disease initiation process, is that its specific components need not always be identical, yet leading to the same disease expression and manifestation. This is reminiscent of the system theory concept of equifinality.

Conclusion

A general hypothesis has been considered for disease origination. Obviously, it’s a long road from musings involving an untested hypothesis to even a plausible hypothesis, necessitating extensive research over an untold number of decades. In addition to state-of-the-art cellular, biologic and bioinformatics research technologies, this effort is also likely to benefit from the study of the natural history of diseases.

In the systems therapeutics diagram the systems components responsible for disease origination have been referred to as intrinsic operator and etiologic causative factor. As has been mentioned above, the hypothetical intrinsic operator was initially introduced in part to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, and in part to stimulate discussions about disease origination. The etiologic causative factor/network has been envisioned as involving a primary abnormal biomolecular entity in a network, representing the molecular abnormality or malfunction characterizing the disease under consideration. Thus, the intrinsic operator represents the initiator or driver of the pathophysiological processes, and the etiologic causative factor/network contains the seeds of the disease, determining the specific disease expression.

We hope these systems components of the pathophysiologic processes of the systems therapeutics construct will eventually be as well understood as the interaction between a pharmacologic agent and a pharmacologic response element, and that such an understanding will help lead to the discovery and development of novel Category Zero pharmacologic agents.

References

Bjornsson TD. Systems Therapeutics: Framework, Diagram, Categories, Definitions, Examplestri-institute.org. January, 2023a.

Bjornsson TD. Systems Therapeutics and Disease ModifiersMedium, July 9, 2023b.

Bjornsson TD. Systems Therapeutics and Disease CategoriesMedium, July 22, 2023c.

Boija A, Klein IA, Sabari BR, Dall’Agnese A, Coffey EL, et al. Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains. Cell, 175: 1842–1855, 2018.

Chan SY, Loscalzo J. The emerging paradigm of network medicine in the study of human disease. Circ Res, 111(3): 359–374, 2012.

Human Cell Atlas, https://www.humancellatlas.org (last accessed in March 2024)

Human Cell Tree Map, https://humancelltreemap.mis.mpg.de (last accessed in March 2024)

Lonard DM, O’Malley BW. Nuclear receptor coregulators: modulators of pathology and therapeutic targets (2012). Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nat Rev Endocrinol., 8(10): 598–604, 2012.

Rood JE, Maartens A, Hupalowska A, Teichmann SA, Regev A. Impact of the Human Cell Atlas on Medicine, Nature Medicine, 28(12):2486–2496, 2022

Silverman E, Harald H, Schmidt HW, Anastasiadou E, Altucci L, et al. Molecular networks in Network Medicine: Development and applications. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, vol. 12(6), 2020.

Spear BB, Heath-Chiozzi M, Huff J. Clinical applications of pharmacogenetics. TRENDS Mol Med, 7:201–204, 2001.

Footnotes

1 This term is based on preindication (noun), meaning an event that is experienced as indicating important things to come.

2 This term is based on initiation (noun), meaning the action of the beginning of something.

3 This term is based on directiveness (noun) or directivity (noun, synonym), meaning the character of being determined in direction of development.