Rationale. Problem: because of multiscale complexity, conceptual, mechanism-based, in vitro-to-in vivo mapping models are hard to falsify and can be flawed in ways that may not be obvious until challenged experimentally, which can be costly. When the results of such experiments are equivocal or not supportive, the information needed to revise mechanistic hypotheses may be lacking. Translation of in vitro phenomena to in vivo counterparts requires a mapping model. Currently, mechanism-agnostic correlation models are common. When translation is based on hypotheses about underlying mechanisms, the mapping model is almost always conceptual, often described in prose, supported by diagrams and, occasionally, mathematical models. Solution: explicitly instantiate mechanistic mapping models in silico and explore their feasibility. We envision concrete, computational, observable-in-action, experimentally challengeable mapping models that will evolve to become executable knowledge embodiments showing what does and does not translate under specific conditions.
The concept is illustrated in a recent paper (PMID: 20406856), “Tracing multiscale mechanisms of drug disposition in normal and diseased livers.” We used, improved, and revalidated a multiscale in silico liver (ISL). An ISL is an example of a new class of computational models. We posited that changes in micromechanistic details from normal to diseased ISLs may have disease-causing, hepatic counterparts. Together, the ISL and in silico methods represent an important step toward unraveling the complex influences of disease on drug disposition. We demonstrated translating—morphing—a validated “normal” ISL into a “diseased” ISL. Although ISLs are abstract software constructs, that transformation stands as a concrete, mechanistic hypothesis about what does and does not translate from one to the other. The methods, which are new and novel, are designed to be extensible to whole organisms and, eventually, patients. Being able to transform one validated ISL into another is important: it is evidence that the approach can be used to explore and challenge ideas about translation, making translational research more concrete.
We envision “translational models” showing how, for example, in silico micromechanistic details are morphed between analogues of in vitro rat and human hepatocyte cultures, and in time between in vitro computational analogues and human analogues. The morphing process will show what must be added and what is lost in translation. A long-range goal for such morphings will be to provide an easily understood, mechanistic interpretation of how cause-effect relationships resulting from an experimental intervention in a wet-lab model are believed to manifest (or not) in a human analogue. The expectation is that those relationships will have real world counterparts.
Plan. An essential precondition for achieving the above vision is to have two different, biologically related models (e.g., in vitro & in vivo) that have independently achieved validation targets. We will focus on the above-cited ISLs and improved versions of in silico hepatocyte (ISH) cultures (PMID: 21768275): we will focus on translation of phenomena measured in hepatocyte cultures to corresponding, location dependent phenomena within hepatic lobules in rat and human livers. We have designed the models so that hepatocytes can be exchanged: ISHs that have achieved validation targets under different culture conditions (ongoing during year one) can be plugged into an ISL (after its hepatocytes are removed). The iterative refinement needed to reestablish whole-liver validation targets (including intralobular zonation) will provide a concrete theory of mechanistic attributes gained and lost in translation.
Criteria and metrics for success. 1) Instantiation of quasi-autonomous ISH objects and documentation (a conference paper, e.g., the Winter Simulation Conference) that they can be transferred from one context (a simulated culture) to another (a simulated lobule) while retaining all the mechanistic features validated in vitro. 2) Produce a draft manuscript that demonstrates that an ISL with these new hepatocytes can also achieve whole liver phenomena, such as zonation of enzyme induction. Produce a draft manuscript by year’s end for submission within the following four months.
Approximate cost and brief justification. Achieving 1 & 2 above will require several hundred cycles of iterative refinement (1 postdoc @ $48K working full time with Dr. Hunt) of in silico components (described in PMID: 20406856). Simulation, publication, and meeting costs bring the total to $58K.
Collaborators. Jackie Maher, UCSF Liver Center
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