Processes 2018, 6,56
Example I.1: The well-known Hodgkin and Huxley model is a Mechanistic Explanation.
It is an incomplete how-possibly story that provides preliminary insights into mechanisms
responsible for generating and propagating action potentials along axons [13]. The authors
make clear that their account is merely an explanatory model, not an actual explanation.
“ ... certain features of our equations were capable of a physical interpretation but the success of the
equations is no evidence in favour of the mechanism of permeability change that we tentatively had in
mind when formulating them.”
Example I.2: Russmann et al. [14] offer a three-step Mechanistic Explanation of how
hepatocyte death may be caused by drug-induced liver injury. 1) The initial injury results in
direct cell stress possibly including mitochondrial impairment. 2) Death receptor-mediated
pathways are triggered leading to mitochondrial permeability transition. 3) The result is
apoptotic or necrotic cell death.
Example I.3: Bassler et al. [15] sought Mechanistic Explanations for unanticipated clinical
side effects and efficacy limitations of integrin αIIbβ3 antagonists. They posited a three-stage
Mechanistic Explanation involving paradoxical platelet activation by αIIbβ3 antagonists:
a ligand-bound conformation change; receptor clustering; and pre-stimulation of platelets.
5.1.2. II—Analogous-Mechanism Model
It is common to encounter a mechanism-oriented explanation of a biological phenomenon that is
framed as a mechanism analogy based on engineering principles, continuum mechanics, chemistry,
electronics, computer science and so forth. When the analogical explanation meets the definition
of mechanism, it can be accurately identified as an Analogous-Mechanism Model of Explanation
(simply Analogous-Mechanism Model hereafter). It too is supported by diagrammatic depictions
and often includes mathematical descriptions. Like I, it is still cartoonish. There are more cause
and effect than in I. Although the mechanism’s phenomenon is expected to be biomimetic, features
of mechanism’s components, their spatial arrangement, and/or temporal aspects are typically not
biomimetic. The following are examples.
Example II.1: The three-element Hill muscle model for estimation of muscle force
generation [16] is an idealized Analogous-Mechanism Model (Figure 2b). Such models
do not have direct biological counterparts and any contextual location is hypothetical.
However, measurements of the idealized mechanism during operation—if it were made
real, concrete—are expected to adequately match measurements of the target phenomenon
qualitatively and quantitatively.
Example II.2: Some therapeutic proteins such as trastuzumab, which is a monoclonal
antibody, bind to pharmacological targets on cells. Efficacy is disrupted when the
therapeutic protein binds instead to soluble targets shed from cells. Li et al. [17] describe
a minimal physiologically based pharmacokinetic Analogous-mechanism Model intended
to represent key features of a plausible mechanism hypothesized to be responsible for
reduced efficacy. A computational description of their model in operation was used to
simulate efficacy changes.
Example II.3: A demographic collapse of freshwater fish species, such as brown trout,
can occur when rates of environmental change exceed the population’s capacity to adapt.
Ayllón et al. [18] describe a spatially explicit, multi-attribute, eco-genetic individual-based
Analogous-mechanism Model that was used to study possible trout dynamics under three
scenarios: (1) climate change-induced warming, (2) warming plus flow reduction resulting
from climate and land use change and (3) a baseline of no environmental change.
189
Example I.1: The well-known Hodgkin and Huxley model is a Mechanistic Explanation.
It is an incomplete how-possibly story that provides preliminary insights into mechanisms
responsible for generating and propagating action potentials along axons [13]. The authors
make clear that their account is merely an explanatory model, not an actual explanation.
“ ... certain features of our equations were capable of a physical interpretation but the success of the
equations is no evidence in favour of the mechanism of permeability change that we tentatively had in
mind when formulating them.”
Example I.2: Russmann et al. [14] offer a three-step Mechanistic Explanation of how
hepatocyte death may be caused by drug-induced liver injury. 1) The initial injury results in
direct cell stress possibly including mitochondrial impairment. 2) Death receptor-mediated
pathways are triggered leading to mitochondrial permeability transition. 3) The result is
apoptotic or necrotic cell death.
Example I.3: Bassler et al. [15] sought Mechanistic Explanations for unanticipated clinical
side effects and efficacy limitations of integrin αIIbβ3 antagonists. They posited a three-stage
Mechanistic Explanation involving paradoxical platelet activation by αIIbβ3 antagonists:
a ligand-bound conformation change; receptor clustering; and pre-stimulation of platelets.
5.1.2. II—Analogous-Mechanism Model
It is common to encounter a mechanism-oriented explanation of a biological phenomenon that is
framed as a mechanism analogy based on engineering principles, continuum mechanics, chemistry,
electronics, computer science and so forth. When the analogical explanation meets the definition
of mechanism, it can be accurately identified as an Analogous-Mechanism Model of Explanation
(simply Analogous-Mechanism Model hereafter). It too is supported by diagrammatic depictions
and often includes mathematical descriptions. Like I, it is still cartoonish. There are more cause
and effect than in I. Although the mechanism’s phenomenon is expected to be biomimetic, features
of mechanism’s components, their spatial arrangement, and/or temporal aspects are typically not
biomimetic. The following are examples.
Example II.1: The three-element Hill muscle model for estimation of muscle force
generation [16] is an idealized Analogous-Mechanism Model (Figure 2b). Such models
do not have direct biological counterparts and any contextual location is hypothetical.
However, measurements of the idealized mechanism during operation—if it were made
real, concrete—are expected to adequately match measurements of the target phenomenon
qualitatively and quantitatively.
Example II.2: Some therapeutic proteins such as trastuzumab, which is a monoclonal
antibody, bind to pharmacological targets on cells. Efficacy is disrupted when the
therapeutic protein binds instead to soluble targets shed from cells. Li et al. [17] describe
a minimal physiologically based pharmacokinetic Analogous-mechanism Model intended
to represent key features of a plausible mechanism hypothesized to be responsible for
reduced efficacy. A computational description of their model in operation was used to
simulate efficacy changes.
Example II.3: A demographic collapse of freshwater fish species, such as brown trout,
can occur when rates of environmental change exceed the population’s capacity to adapt.
Ayllón et al. [18] describe a spatially explicit, multi-attribute, eco-genetic individual-based
Analogous-mechanism Model that was used to study possible trout dynamics under three
scenarios: (1) climate change-induced warming, (2) warming plus flow reduction resulting
from climate and land use change and (3) a baseline of no environmental change.
189