title: Systems biology for organotypic cell cultures.
abstract: Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, "organotypic" cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomic data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data.
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Grego
authors.affiliation: Texas A&M University, College Station, TX, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Dougherty
authors.affiliation: Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Alexander
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Auerbach
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Berridge
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Bittner
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Casey
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Cooley
authors.affiliation: HemoShear Therapeutics, Charlottesville, VA, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Dash
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fennell
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Hawkins
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
authors.affiliation: Johns Hopkins University, Center for Alternatives to Animal Testing, Baltimore, MD, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Kleensang
authors.affiliation: IPQ Analytics, Kennett Square, PA, USA.
authors.forename: Michael N J
authors.initials: MNJ
authors.lastname: Liebman
authors.affiliation: Phillip Morris International R&D, Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maull
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Paragas
authors.affiliation: Defense Threat Reduction Agency, Ft. Belvoir, VA, USA.
authors.forename: Guilin Gary
authors.initials: GG
authors.lastname: Qiao
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Sreenivasa
authors.initials: S
authors.lastname: Ramaiahgari
authors.affiliation: RTI International, Research Triangle Park, NC, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Sumner
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.|ScitoVation, Research Triangle Park, NC, USA.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yoon
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D003198:Computer Simulation; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D056656:Lab-On-A-Chip Devices; D018570:Risk Assessment; D049490:Systems Biology
chemical_list: D015386:Hazardous Substances
keywords: 3D models; engineered cell cultures; multiscale modeling; systems pharmacology; systems toxicology