Abstract

Fitting iPSCs, 3D Cell Culture, Tissue Chips and Microphysiological Systems into the Grand Scheme of Biology, Medicine, Pharmacology, and Toxicology

John Wikswo, A.B. Learned Professor of Living State Physics; Founding Director, Vanderbilt Institute for Integrative Biosystems, Vanderbilt University

As the engineering supporting body-on-chip (BoC) studies advances and begins to penetrate both science and industry, we need to explore three separate multidimensional spaces – one that spans BoC components, one that covers the analytical techniques to characterize BoC performance and drug response, and a third that spans the fields of application.  The component technologies being brought together include induced pluripotent stem cells (iPSCs), 3D cell culture (which is beginning to involve vascularization), tissue-chip bioreactors that enable the recreation to tissue-like microenvironments, and the hardware required to operate coupled microphysiological systems in a manner that recapitulates human physiology and its response to drugs and toxins. The second, analytical space is only now coming to the fore. To date, most tissue-chip studies have reported morphological features, the expression of small sets of genes, or the secretion of a few, organ-specific compounds. A much more comprehensive battery of techniques is already in regular use in the pharmaceutical industry, including genomics, proteomics, and transcriptomics. Metabolomics is rapidly moving into prominence as the instrumentation improves and the databases expand. What is needed, though, are comprehensive comparisons between in vitro and in vivo studies, as has been recently demonstrated with a weighted gene coexpression network analysis that compare rat liver in vivo with both mouse liver in vitro and rat primary hepatocytes growing in a dish, which showed that a mouse liver was a better model of the rat liver than the primary rat hepatocytes in a dish, which more closely resembled a rat liver exposed to a significant toxic load. The BoC community needs to compare, for example, a mouse with a mouse-on-a-chip to confirm that the appropriate physiology is being recapitulated. The final space spans biology, medicine, pharmacology, physiology and toxicology. BoCs offer, for the first time, the ability to recreate in vitro and in parallel, with an ever-dropping cost, the effects of organ-organ interactions. Nowhere will this be more important than in studies of absorption, distribution, metabolism, and excretion - toxicity (ADME-Tox), where one may need skin, lung, or gut to absorb a drug or toxin, liver and kidney to metabolize and excrete drug metabolites and toxins, adipose and muscle tissue to store metabolites and toxins, and a means to characterize in depth the underlying processes and how they affect the chosen target organs. BoCs will thereby contribute not only to toxicology, but our fundamental understanding of cellular biology and systems physiology, thereby advancing both pharmacology and medicine. Given that we will never create a perfect microHuman BoC, we can use these three spaces to guide the compromises we make as we create useful models, even toy models, of human physiology.