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

I would start an intensive program to characterize the response of different organs: animal organs in vitro , animal cells in culture, human cells in culture and human cells used to create OOACs. What I would try to do is launch a program of intense characterization of the organs to try to understand the extent to which the in vitro cells on plastic and OOACs in both humans and animals replicate real physiology. There is a paper I just read by a friend of mine, Jim Stevens at Eli Lilly, whose group did a weighted gene co-expression network analysis studying the comparison of in vivo rat liver, in vivo mouse liver and rat primary hepatocytes grown on a dish [ 9 ]. They took as their gold standard the rat liver in vivo , and found that the best model of the rat liver in vivo was a mouse liver in vivo , and that the rat primary hepatocytes growing quietly on a layer of collagen on a plate in the laboratory looked more like rat liver that had been exposed to an extremely toxic drug. The challenge in growing primary hepatocytes in a dish is that the trauma of being removed from a rat and grown on plastic without the right cellular neighbors and the correct media is about as drastic as the trauma of the intact rat being exposed to a highly toxic drug. I think the premise is, although it has not yet been proven universally, that OOAC does a better job of recapitulating human physiology than does biology on plastic. I think that is probably a very valid hypothesis but it has to be tested rigorously. The way to test it is by doing extensive proteomics, metabolomics and transcriptomics on not only the OOAC but the model systems you are comparing it with and decide the extent to which your in vitro models actually replicate in vivo physiology. I am involved in the DARPA Rapid Threat Assessment (RTA) program that is developing the ability to determine the mechanism of action of a drug within 30 days, rather than the typical 10 years it can take to identify some of the off-target effects. The Vanderbilt RTA group, led by Richard Caprioli, is developing analytical techniques and network analyses for proteomics, metabolomics, phosphoproteomics, transcriptomics, and end point assays with high spatiotemporal resolution. I think that our entire RTA analytics platform applied to OOAC would be absolutely the best way to fully understand physiology, pharmacology, and toxicology. The approach would be even stronger were we to suppress specific genes or apply challenge compounds as we refine and validate the mechanism of action.