With all the transformations that 2020 has forced society (and the globe at large) to undergo and endure, remarkably the scientific field has been one that was able to over-accomplish in the midst of these challenges, and still deliver various feats of notable significance. I found it exhilarating to review the various colossal advancements and breakthroughs the scientific field was able to enact (at a distance) throughout the course of the year. Even a global pandemic could not stifle scientific progress and instead, swift advancements were made to specifically restore global health through a variety of avenues: elucidating the pathogenesis of Covid-19, achieving breakthroughs in sequencing and of course, incredible accomplishments for the vaccine developments. The pandemic has proven to be a clarifying force in exposing the strength and resilience of human achievement in a myriad of ways, especially in medical sciences in terms of newly uncovered biological models to newly-elucidated pathways and phenomenons to novel machines, tools and technologies.
A fascinating article published in Nature (Landhuis, 2016) previously has reported that the scientific literature publication field experiences 8–9% growth in the volume of reported publications every single year for the past couple of decades. For instance, reports account that more than 1 million papers for the biomedical sciences field are inputted into the PubMed database every year, roughly amounting to 2 papers/minute. The task of absorbing and digesting literature from relevant health-science fields to further research efforts is too massive an undertaking, and most consider it implausible to even attempt to integrate and keep track of knowledge that is constantly churning and producing, in order to pull and recall at a moment’s need. Yet, it’s intuitively understandable that it’s critical to keep up with the current state of knowledge to accelerate and innovate health research or drug discovery or clinical translation efforts according to recent evidence findings to achieve improved public health. Although one may argue that, one’s area of inquiry and research within the scientific field will usually be narrow and specialized in subject content, it’s still valuable to consider a broader, systems-level approach to exploring human pathophysiology to expedite the rate of innovation in healthcare. Although this may sound extremely intuitive to apply in theory, in actuality, achieving a systems-level understanding of human pathophysiology has been relatively difficult to undertake in the past due to various limitations. To provide an example, classical toxicology testing usually involves conducting various types of different preclinical animal tests to investigate chemical-induced toxic effects by examining an array of different apical toxicity endpoints in an isolated manner. This entails that researchers are assessing chemical-induced toxicity effects through simply identifying various endpoints such as cancer, or skin allergies, or liver function etc. Although this approach is relatively uncomplicated, investigating these events in a stand-alone manner provides simply an end result and omits information conducive to deeper analysis or assessments (i.e. underlying pathways of toxicity, bilateral influences, etc.) Information that can help overcome these knowledge gaps and provide deeper understandings may stem through intaking knowledge from technological advancements that have been made recently as well as novel algorithms and visualization programs, data structures, and novel biological models such as organoids or organ-on-a-dish. This allows researchers to pivot and instead examine a more holistic and system-wide approach to examining human health.
Need for New Framework
With this massive volume of information, the construction of an all-encompassing knowledge management framework to integrate this overwhelming volume of information still is needed. The ideal framework would be one that provides a sequential overview of an impact of a stressor (such as radiation or toxic chemicals) at multiple levels of organization (i.e. cell, tissue, organ levels etc.) and culminates in a final outcome of interest (i.e. cancer). This pathways-based approach would also be quite informative if one could conglomerate and aggregate various pathways together to achieve a systems-level overview, such as through examining how the pathways affect one another or the types of changes and cell-types that are involved in one type of cancer versus another, and so on. Amazingly, this framework exists and not in fiction but in reality. The framework was created out of a need for the toxicity-testing field for the limitations previously discussed by the Organisation for Economic Co-operation and Development (OECD) in 2012. The framework is known as the ‘adverse outcomes pathway,’ and aims to collect and organize evidence in the form of measurable and linked biological changes across multiple levels of biological organization.
Framework Design
The pathway initiates with a molecular initiating event (MIE) which refers to the interaction of a stressor with a bio-molecule in the organism. For instance, upon the administration of chemicals/drugs in the body, the MIE can refer to the resultant attachment of a compound to the cell receptor. The MIE can then be linked to various intermediate key-events (KE’s) occurring at different (molecular, cellular, organ, organism and population) levels of organization. In the pathway, the KE’s must be measurable and essential check-points, such that if the KE is prevented, then the progression to subsequent KE’s in the pathway will not occur. The KE’s then culminate with a final adverse outcome (AO).
The final deliverable of this knowledge synthesis effort is a final adverse-outcomes pathway. This pathway is viewable on a transparent, cross-collaborative platform provided by the OECD. The most intriguing and informative aspect of this effort is that these pathways are not stand alone. Various pathways, created by different research groups and industries across the globe can be all visualized within a merged-and linked view. This is important because this means that the impact of a stressor such as a chemical can be visualized across various levels of organization and culminate in various adverse-outcomes (each potentially developed by various research groups), which cumulatively offer the capability to visualize the body’s dynamic inner workings and facilitate improved knowledge synthesis like never before!
Innovation in Knowledge Synthesis
Within the present-day medical-sciences research realm, current medical research relies heavily on animal models which limits the implementation of current innovations and technology models. As of late, a main priority of the research-sciences realm has also been to pivot from excessive and inhumane animal testing and overly simplistic cell models through implementing the 3 R’s (Replacement, Refinement and Reduction) in research efforts. Adopting the adverse-outcomes-pathway framework would allow for the attainment of this goal as well as facilitate the inclusion of novel data findings such as various -omics (genomics, proteomics, metabolomics, etc) research, computational modelling, human-specific in vitro models, clinical studies, etc. to develop a comprehensive understanding within a systems-level human biology framework with multiscale pathways.
The framework is especially unique such that it helps to facilitate improved collaboration especially in cases where research groups that possess knowledge of different parts of a pathway can collaborate to create a cohesive-network pathway. In addition, the framework also allows for researchers to view previously-created pathways and modify the events in order to fit another subject’s topic, as well as update the framework based upon the consideration of future emergent knowledge. This strategy enables researchers to visualize diseases and conditions as the resultant outcome of the input of various extrinsic stressors (i.e. chemical exposure, radiation exposure, etc.) intermingling and interacting with intrinsic changes or events (i.e. genetic and epigenetic changes) and receive a more coherent picture of the body’s inner workings.
After Development of Framework
Just as this transitional process of applying the AOP is beginning to take root in the field of chemical toxicity, this effort is also extremely applicable to applications within the medical research field as well as environmental research: In medical sciences, the adverse outcome could constitute an increased risk of disease pathology in organ/organ system or tissue in an individual or subset of the population In environmental or wild-life assessments, the adverse outcome could include markers of population sustainability or demographic changes, etc.
The framework can be used to support regulatory decision making as the mechanistic toxicological knowledge can more readily support safety assessment decisions as well as inference/extrapolation efforts. By extrapolating from KE measurements conducted at low levels of biological organization, this can help facilitate the framework’s predictive toxicology capabilities to forecast the effect of chemicals on biological systems or the likelihood of certain adverse events occurring at higher levels of the organization and in turn, help guide regulatory protection goals and overall decision making. Through constructing the pathways, the framework also offers the ability to identify research gaps within the knowledge-management framework and guide novel research activities to elucidate these gaps.
Conclusion
The framework is scientifically-based and transparent in its creation and apart from the glaring drawbacks of this effort, namely the immense time resources that such a project entails, the adverse outcomes pathway remains a noteworthy and innovative approach. The pathway can help to collect mechanistic knowledge from various sources in order to support various applications ranging from chemical safety assessment to decision making within the biomedical health field or environmental assessments and I am excited to see the increasing development and use of AOPs within the scientific and regulatory community within the near future, and the knowledge that will stem from these efforts.
References
Ankley, G. T., Bennett, R. S., Erickson, R. J., Hoff, D. J., Hornung, M. W., Johnson, R. D., Mount, D. R., Nichols, J. W., Russom, C. L., Schmieder, P. K., Serrrano, J. A., Tietge, J. E., & Villeneuve, D. L. (2010). Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. In Environmental Toxicology and Chemistry (Vol. 29, Issue 3, pp. 730–741). Wiley Blackwell. https://doi.org/10.1002/etc.34
Coady, K., Browne, P., Embry, M., Hill, T., Leinala, E., Steeger, T., Maślankiewicz, L., & Hutchinson, T. (2019). When Are Adverse Outcome Pathways and Associated Assays “Fit for Purpose” for Regulatory Decision-Making and Management of Chemicals? Integrated Environmental Assessment and Management, 15(4), 633–647. https://doi.org/10.1002/ieam.4153
Halappanavar, S., Van Den Brule, S., Nymark, P., Gaté, L., Seidel, C., Valentino, S., Zhernovkov, V., Høgh Danielsen, P., De Vizcaya, A., Wolff, H., Stöger, T., Boyadziev, A., Poulsen, S. S., Sørli, J. B., & Vogel, U. (2020). Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale. In Particle and Fibre Toxicology (Vol. 17, Issue 1, p. 16). BioMed Central Ltd. https://doi.org/10.1186/s12989-020-00344-4
Landhuis, E. (2016). Scientific literature: Information overload. Nature, 535(7612), 457–458. https://doi.org/10.1038/nj7612-457a
Langley, G., Austin, C. P., Balapure, A. K., Birnbaum, L. S., Bucher, J. R., Fentem, J., Fitzpatrick, S. C., Fowle, J. R., Kavlock, R. J., Kitano, H., Lidbury, B. A., Muotri, A. R., Peng, S. Q., Sakharov, D., Seidle, T., Trez, T., Tonevitsky, A., van de Stolpe, A., Whelan, M., & Willett, C. (2015). Lessons from toxicology: Developing a 21st-century paradigm for medical research. Environmental Health Perspectives, 123(11), A268–A272. https://doi.org/10.1289/ehp.1510345
Madden, J. C., Rogiers, V., & Vinken, M. (2014). Application of in silico and in vitro methods in the development of adverse outcome pathway constructs in wildlife. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1656), 20130584. https://doi.org/10.1098/rstb.2013.0584
OECD. (2013). Adverse Outcome Pathways, Molecular Screening and Toxicogenomics. http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm