Modeling Life

Abstract

Abstract-We seek to construct physical and mathematical models of life. Such models allow us to test our understanding of how living systems function and how they respond to human imposed stimuli. One system is a genomically and chemically complete model of a minimal cell. This cell is a hypothetical bacterium with the fewest number of genes possible. Such a minimal cell provides a platform to ask about the essential features of a living cell and forms a platform to investigate ''synthetic biology.'' A second system is ''Body-on-a-Chip'' which is a microfabricated microfluidic system with cells or tissue constructs representing various organs in the body. It can be constructed from human or animal cells and used in drug discovery development. That model is a physical representation of a physiologically based pharmacokinetic model. Both the computer and the physical models provide insight into the underlying biology and provide new tools to make use of that understanding to provide benefits to society.

A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture

“…Only a few multi-compartment cell culture flow systems for the simultaneous co-culture of different tissues have been described on a miniaturised scale so far. [4][5][6][7] The majority expose tissues to laminar flow within microchannels. 3,5,8 The advantage of these multi-organ systems is an explicit adjustable fluid flow and a controllable local tissue-to-fluid ratio in the channels.…”

Physiologically relevant organs on chips

“…For example, before their use for drug screening, characterization of organs-on-chips devices, by using drugs of which the clinical efficacy and toxicity are well characterized, is required to validate the capability and limitation in predicting human responses to drugs. Another important area for further investigation is to develop mathematical models that can correlate data from organs on chips and in vivo experiments to extrapolate data obtained from organs on chips to humans, including PK–PD models [6, 7, 12]. …”

“…Shuler et al [1, 2] proposed a CCA and a microscale CCA (μCCA) of a physiologically based a pharmacokinetic–pharmacodynamic (PBPK–PD) model as an alternative to computational PBPK, cell culture, and animal models (Fig. 4A) [6, 7, 97, 98]. The microscale CCA is a physical representation of a PBPK model, in which multiple cell culture compartments, representing different organs with physiological tissue-to-tissue size ratio, are interconnected through microfluidic channels under physiologically relevant fluid flow conditions to predict the time-dependent absorption, metabolism, distribution, and elimination (ADME) of drugs in the human body and human responses to drugs.…”

“…(B) Integrated discrete multiple organ co-culture (IdMOC) system, consisting of multiple inner wells with cells from specific organs, representing physically discrete organs, within a large outer well containing the overlying medium, which interconnects the physically discrete organ cells. Reproduced from [6, 7, 100] with permission.…”

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

“…To the best of our knowledge, it represents the first and, until recently, the only dynamic microscale system supporting a physiologically based pharmacokinetic, quantitative structure-activity relationship (QSAR) and quantitative in vitro to in vivo extrapolation modelling. 56 A system proving acetaminophen sensitivity of 3D clusters of HepG2/C3A cells with four-day activity was developed by Baudoin and colleagues (Fig. 2c).…”