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      Looking to the future of organs-on-chips: interview with Professor John Wikswo

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          Abstract

          John Wikswo talks to Francesca Lake, Managing Editor: John is the founding Director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE). He is also the Gordon A Cain University Professor; a B learned Professor of Living State Physics; and a Professor of Biomedical Engineering, Molecular Physiology and Biophysics, and Physics. John earned his PhD in physics at Stanford University (CA, USA). After serving as a Research Fellow in Cardiology at Stanford, he joined the Department of Physics and Astronomy at Vanderbilt University (TN, USA), where he went on to make the first measurement of the magnetic field of an isolated nerve. He founded VIIBRE at Vanderbilt in 2001 in order to foster and enhance interdisciplinary research in the biophysical sciences, bioengineering and medicine. VIIBRE efforts have led to the development of devices integral to organ-on-chip research. He is focusing on the neurovascular unit-on-a-chip, heart-on-a-chip, a missing organ microformulator, and microfluidic pumps and valves to control and analyze organs-on-chips.

          Most cited references6

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          The relevance and potential roles of microphysiological systems in biology and medicine.

          Microphysiological systems (MPS), consisting of interacting organs-on-chips or tissue-engineered, 3D organ constructs that use human cells, present an opportunity to bring new tools to biology, medicine, pharmacology, physiology, and toxicology. This issue of Experimental Biology and Medicine describes the ongoing development of MPS that can serve as in-vitro models for bone and cartilage, brain, gastrointestinal tract, lung, liver, microvasculature, reproductive tract, skeletal muscle, and skin. Related topics addressed here are the interconnection of organs-on-chips to support physiologically based pharmacokinetics and drug discovery and screening, and the microscale technologies that regulate stem cell differentiation. The initial motivation for creating MPS was to increase the speed, efficiency, and safety of pharmaceutical development and testing, paying particular regard to the fact that neither monolayer monocultures of immortal or primary cell lines nor animal studies can adequately recapitulate the dynamics of drug-organ, drug-drug, and drug-organ-organ interactions in humans. Other applications include studies of the effect of environmental toxins on humans, identification, characterization, and neutralization of chemical and biological weapons, controlled studies of the microbiome and infectious disease that cannot be conducted in humans, controlled differentiation of induced pluripotent stem cells into specific adult cellular phenotypes, and studies of the dynamics of metabolism and signaling within and between human organs. The technical challenges are being addressed by many investigators, and in the process, it seems highly likely that significant progress will be made toward providing more physiologically realistic alternatives to monolayer monocultures or whole animal studies. The effectiveness of this effort will be determined in part by how easy the constructs are to use, how well they function, how accurately they recapitulate and report human pharmacology and toxicology, whether they can be generated in large numbers to enable parallel studies, and if their use can be standardized consistent with the practices of regulatory science.
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            Metabolic consequences of interleukin-6 challenge in developing neurons and astroglia

            Background Maternal immune activation and subsequent interleukin-6 (IL-6) induction disrupt normal brain development and predispose the offspring to developing autism and schizophrenia. While several proteins have been identified as having some link to these developmental disorders, their prevalence is still small and their causative role, if any, is not well understood. However, understanding the metabolic consequences of environmental predisposing factors could shed light on disorders such as autism and schizophrenia. Methods To gain a better understanding of the metabolic consequences of IL-6 exposure on developing central nervous system (CNS) cells, we separately exposed developing neuron and astroglia cultures to IL-6 for 2 hours while collecting effluent from our gravity-fed microfluidic chambers. By coupling microfluidic technologies to ultra-performance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS), we were able to characterize the metabolic response of these CNS cells to a narrow window of IL-6 exposure. Results Our results revealed that 1) the use of this technology, due to its superb media volume:cell volume ratio, is ideally suited for analysis of cell-type-specific exometabolome signatures; 2) developing neurons have low secretory activity at baseline, while astroglia show strong metabolic activity; 3) both neurons and astroglia respond to IL-6 exposure in a cell type-specific fashion; 4) the astroglial response to IL-6 stimulation is predominantly characterized by increased levels of metabolites, while neurons mostly depress their metabolic activity; and 5) disturbances in glycerophospholipid metabolism and tryptophan/kynurenine metabolite secretion are two putative mechanisms by which IL-6 affects the developing nervous system. Conclusions Our findings are potentially critical for understanding the mechanism by which IL-6 disrupts brain function, and they provide information about the molecular cascade that links maternal immune activation to developmental brain disorders. Electronic supplementary material The online version of this article (doi:10.1186/s12974-014-0183-6) contains supplementary material, which is available to authorized users.
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              Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes

              The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.
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                Author and article information

                Journal
                Future Sci OA
                Future Sci OA
                FSO
                Future Science OA
                Future Science Ltd (London, UK )
                2056-5623
                June 2017
                20 January 2017
                : 3
                : 2
                : FSO163
                Affiliations
                [1 ]Vanderbilt University, Nashville, TN 37235–1807, USA
                Author notes
                *Author for correspondence: john.wikswo@ 123456vanderbilt.edu
                Article
                10.4155/fsoa-2016-0085
                5481807
                f6cd92bf-46e9-4efe-8fc5-d528751241df
                © John P Wikswo

                This work is licensed under a Creative Commons Attribution 4.0 License

                History
                : 27 September 2016
                : 16 November 2016
                Categories
                Interview

                bioengineering,body-on-a-chip,drug development,microfluidics,organ-on-a-chip,systems biology,toxicology

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