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vivo microenvironment6. The chips contain tiny channels lined with extracellular matrix, which can be populated with almost any cell type. Cell media is flowed through the channels, creating the mechanical shear stress present in all tissues. These complex systems behave like real tissue in many aspects, and can even represent elements of organ functionality. The Lung-Chip, for example, can simulate breathing processes, with airflow across a surface of cells and blood flow beneath, allowing for gaseous exchange. This provides a realistic sys- tem for modelling effects of interest, such as prop- erties of inhaled compounds. Organs-on-Chips can also contain immune cells and blood components, enabling interactions that influence disease and compound behaviour to be replicated. Establishing compound safety in relevant tissue


is a major application of our Organs-on-Chips. If a toxic response is seen in an animal model, we may not know whether it is generally toxic, or a species- specific effect. This limit in translatability between different animal species and humans creates a crit- ical and difficult decision-making stage in drug dis- covery. In order to bridge the gap between animal in vivo and human in vitro systems, we have creat- ed rat Liver-Chips and dog Liver-Chips, and are currently working to confirm that they give an equivalent toxicity response to their in vivo coun- terparts. Once we establish this, we will be able to compare data across human, dog, and rat Liver- Chips to determine whether toxic responses in ani- mals are species specific. Advancing this technology even further, we are starting to investigate multi-organ systems. These


CRISPR (clustered regularly interspaced palindromic repeats) gene editing tool


can be used, for example, to model complex dis- ease processes and allow us to rapidly assess the functional outcome of targeting in a human-rele- vant system. We are currently developing a model of type 2 diabetes using a Liver-Chip coupled to a Pancreas-Chip7. Preliminary results show that when the Liver-Chip is insulin-resistant, it can feed back to the pancreas affecting insulin release, as is the case in type 2 diabetes. Once the system is fully tested, we will be able to use this as a diabetes model for target validation. AstraZeneca is committed to the adoption and


application of Organs-on-Chips technology, and recently announced a partnership with Emulate Bio, a leading producer and founded by pioneers of the technology, to embed Organ-Chips within our drug safety laboratories and eventually across our entire pipeline.


Humanised miniature organs Cardiovascular disease is a priority therapy area for AstraZeneca, so translatable heart models are important for our early science prediction. Mechanical and electrical forces in a beating heart are difficult to realistically simulate in vitro. We recently published a proof-of-principle paper in which we developed a humanised heart model that mimics the complexity of heart function8. By ‘decellularising’ a rat heart to leave a scaf-


fold, we were able to recreate a realistic model of a functional heart by repopulating it with human iPSC-derived heart cells. The model had features such as vasculature, valve function and the ability to beat. Accurately predicting cardiac drug effects


20


Drug Discovery World Summer 2018


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