3S - Systematic, systemic, and systems biology and toxicology

Abstract

A biological system is more than the sum of its parts - it accomplishes many functions via synergy. Deconstructing the system down to the molecular mechanism level necessitates the complement of reconstructing functions on all levels, i.e., in our conceptualization of biology and its perturbations, our experimental models and computer modelling. Toxicology contains the somewhat arbitrary subclass "systemic toxicities"; however, there is no relevant toxic insult or general disease that is not systemic. At least inflammation and repair are involved that require coordinated signaling mechanisms across the organism. However, the more body components involved, the greater the challenge to reca-pitulate such toxicities using non-animal models. Here, the shortcomings of current systemic testing and the development of alternative approaches are summarized. We argue that we need a systematic approach to integrating existing knowledge as exemplified by systematic reviews and other evidence-based approaches. Such knowledge can guide us in modelling these systems using bioengineering and virtual computer models, i.e., via systems biology or systems toxicology approaches. Experimental multi-organ-on-chip and microphysiological systems (MPS) provide a more physiological view of the organism, facilitating more comprehensive coverage of systemic toxicities, i.e., the perturbation on organism level, without using substitute organisms (animals). The next challenge is to establish disease models, i.e., micropathophysiological systems (MPPS), to expand their utility to encompass biomedicine. Combining computational and experimental systems approaches and the chal-lenges of validating them are discussed. The suggested 3S approach promises to leverage 21st century technology and systematic thinking to achieve a paradigm change in studying systemic effects.

Emerging Role of Organ‐on‐a‐Chip Technologies in Quantitative Clinical Pharmacology Evaluation

“…To realize the full potential of these emerging technologies, collaboration across various stakeholders in this multidisciplinary setting is essential. Several public‐private partnerships in the development and application of various microphysiological systems to evaluate the efficacy, safety, and toxicity of therapies have already been established …”

“…Several public-private partnerships in the development and application of various microphysiological systems to evaluate the efficacy, safety, and toxicity of therapies have already been established. [25][26][27][28] Physiology and disease Microphysiological systems represent advancement over conventional technologies by leveraging the recent advances in microfluidics, microfabrication, and cell biology to better mimic and control the physiological microenvironments. As such, they are more suitable for investigating complex organ-level physiology, tissue architecture, and functions than traditional 2-D cell culture models.…”

Predicting toxicity of chemicals: software beats animal testing

“…They analysed fish acute lethality (LC 50 ) values for 44 compounds (for which at least 10 data entries existed) that were extracted from the ECOTOX database, yielding 4,654 test records showing variability of test results exceeding several orders of magnitude. There is no indication that reproducibility is better for systemic toxicities (Smirnova et al., ): a concordance of 57% was found comparing 121 replicate rodent carcinogenicity assays (Gottmann et al., ). Our own analysis (Luechtefeld et al., ) of 28‐day vs 90‐day no observed adverse effect levels (NOAELs) showed no correlation.…”

“…While both assays were about 90% reproducible, based on 655 chemicals, the two species were only 77% predictable of each other (Luechtefeld et al., ). That is still better than mice and rats in cancer bioassays predicting each other in only 53% of cases (Basketter et al., ; Smirnova et al., ) or various species predicting each other's results in reproductive toxicity studies by about 60% (Hurtt et al., ; Bailey et al., ). Species concordance (310 chemicals) for non‐neoplastic pathology between mouse and rat was 68% (Wang and Gray, ).…”

New European Union statistics on laboratory animal use – what really counts!

“…The recent advances in organoids, organ-on-chip and microphysiological systems is a major hope for advancing animal replacement (Marx et al, 2016(Marx et al, , 2020Smirnova et al, 2018). Francis Collins, Director of the U.S. National Institutes of Health testified in US Congress already in 2016 "I predict that 10 years from now, safety testing for newly developed drugs…will be largely carried out using human biochips…This approach…will mostly replace animal testing for drug toxicity and environmental sensing, giving results that are more accurate, at lower cost and with higher throughput."…”