The Homunculus Metaphor Revisited In Drug Discovery: Body-on-a-Chip

The16th century alchemical and 19th century science fiction revival of a miniature human being in a test tube is undergoing a radical upgrade. Microfluidics,  complex organoid cultures, and nanodetection of phenotypic and genomic outputs are turning the metaphor into a reality to be seriously reckoned with in drug R&D. Here are recent highlights from the (mostly) open access literature, which should bring drug hunters up to speed

The basic idea started with the arrangement of cells into coordinated 3D cultures, tissue-like organoids, of different cell phenotypes sharing interconnections to mimic the exchange of ions and metabolites found in real organs. An example of such an early incarnation would entail clustering different cells representative of the liver asinus to function as a liver-on-a-chip. The obvious next step in the evolution towards a "body-on-a-chip" would then array emulations of, for example, liver, gut and pancreas on the same chip and so forth, culminating in a modern incarnation of the homunculus.

Speculations of this sort were far-fetched as early as 6 or 7 years ago when perspectives on the field were articulated by enthusiastic adopters. The review by Huh, Hamilton and Ingber at the Wyss Institute provides one of the better starting points from a special issue on 3D cell biology appearing in 2011 (Ref. 1). Early insights from Uwe Marx and colleagues at the University of Berlin (Ref. 2) and from Michael Shuler's group at Cornell (Ref. 3), extending the paradigm into the realm of on-chip toxicology and PK/PD, proved equally inspiring and controversial. Predictably, critical skeptics offered considerable pushback, doubting that technical hurdles would ever be surmounted to provide a relevant or practicable mimic of an intact organism.

Cut the narrative to late 2017, and the critics appear to be in full retreat. Not only have regulatory and funding agencies (Refs. 4-5) embraced the concept, but it is now increasingly adopted as a drug research platform by both pharma and academia. Over two dozen organ systems are represented in on-chip systems. Recently published comprehensive reviews cover the state of the art in broad strokes. Kimura et al. focus on the transition from organ to body-on-a-chip for drug discovery (Ref. 6 and the graphic shown below), while Bovard et al. address related approaches for toxicological assessment and early stage development (Ref. 7). Platform biomaterials, cells, microscale technologies and fabrication methods are covered by Ahadian et al. (Ref. 8).

A noteworthy compilation of 10 open access articles covering the gamut of applications from drug discovery and microfluidic biomimicry to gateways for on-chip personalized medicine appeared as a May 2017 (volume 3, issue 2) eCollection in Future Science (Ref. 9). These provide the foundation of integration concepts for multi-organ chips. For readers interested in more hands-on approaches ready for the drug discovery laboratory, there are also several standout publications to be recommended either as "ready to use" or as templates for furthering on-chip assay advances.

The work from Charles Baroud's laboratory, on innovations with droplet microfluidics, is a standout on establishing how to connect 3D cell cultures on a chip to multiscale cytometry in a shift towards quantitative studies under dynamic conditions (Ref. 10). In addition to advanced imaging, the read-outs from on-chip studies also accommodate cell viability assays, ELISA for secreted proteins, detection of intracellular expression, RT-PCR, BrdU and actin staining. On-chip work requires prototyping, especially regarding cell spheroid selection. Ivanov and Grabowska provide a solution using exploratory spheroid arrays. These afford a set up for subsequent chip design based on results from single-cell analysis of morphology and biomarker expression in 3D (Ref 11). Returning to the fray, Wang et al. from Shuler's group, provide a recipe for a pumpless system with the ability to build multi-organ configurations that are of low cost, high reliability, and self-contained, complete with built in physiological function monitoring (Ref. 12).

Will the upgraded "homunculus" metaphor prove successful as a platform in the quest for new therapeutics? The science indicates that it will; so do reports in a sampling from the marketplace press (Refs. 13a-g).

References:

1. From 3D cell culture to organs-on-chips, Huh et al., Trends Cell Biol. 2011 (O/A), http://bit.ly/2AV0S40
2. ‘Human-on-a-chip’ developments: a translational cutting-edge alternative to systemic safety assessment and efficiency evaluation of substances in laboratory animals and man?, Marx et al, ATLA 2012 (O/A), http://bit.ly/2jLO6cW
3. A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip, Sung et al., Lab Chip 2010 (not O/A), http://rsc.li/2AMLYw8
4. FDA researchers to evaluate ‘Organs-on-Chips’ technology, FDA web site with links to article and infographic (O/A), http://bit.ly/2Auxvo5
5. About tissue chips, NIH, NCATS, web site on initiatives and projects 2017 (O/A), http://bit.ly/2nrK8eK; major projects are cited here: http://bit.ly/2A123P5
6. Organ/body-on-a-chip based on microfluidic technology for drug discovery, Kimura et al., Drug Metab. Pharmacokineti. 2017 (O/A), http://bit.ly/2zO9XY7
7. Organs-on-a-chip: A new paradigm for toxicological assessment and preclinical drug development, Bovard et al., Toxicol. Res. Appl. 2017 (O/A), http://bit.ly/2ihBQR2
8. Organ-on-a-chip platforms: A convergence of advanced materials, cells, and microscale technologies, Ahadian et al., Adv. Healthcare Materials 2017 (not O/A but available from researchgate.com), http://bit.ly/2zMImqc; http://bit.ly/2jOmLGX
9. Looking to the future of organs-on-chip, multiple authors, Future Science 2017 (O/A), http://bit.ly/2AvzmXO
10. Multiscale cytometry and regulation of 3D cell cultures on a chip, Sart et al., Nature Comm. 2017 (O/A), http://go.nature.com/2AV0ZN0
11. Spheroid arrays for high-throughput single-cell analysis of spatial patterns and biomarker expression in 3D, Ivanov and Grabowska, Sci. Rept. 2017 (O/A), http://go.nature.com/2jbMB8E
12. Self-contained, low-cost body-on-a-chip systems for drug development, Wang et al., Exp. Biol. Med. 2017 (O/A), http://bit.ly/2AqfJlM
13. a) Organs on chips, PharmaVoice, http://bit.ly/2iiaE4E; b) Organs on chips, The Scientist, http://bit.ly/2AtY36Q; c) Organ-on-a-chip technology trumpeted as future of drug discovery, GEN, http://bit.ly/2AqkDiP; d) Organs-on-chips market, Ozsheba blog, http://bit.ly/2AWwztK; e) Organoids Promise Big Boost to Medical Care, NBC News MACH, http://nbcnews.to/2xc4Qiy; f) Organs-on-chips: applications, challenges, and the future, Technology Networks, http://bit.ly/2wD6HxW; g) Scientists mimic human organs on microscopic ‘Chips’ that enable drug testing, Pfizer news blog, http://on.pfizer.com/2nrCUap.

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