Pivoting to confront the COVID-19 challenge using Organ Chip technology

A human lung Airway Chip is used to rapidly repurpose existing drugs for viral pandemics

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The COVID-19 pandemic has changed all of our lives, both at home and at work.  In my laboratory, we were more prepared for this challenge than most as we had been funded by NIH and DARPA beginning over three years ago to explore whether our human organ-on-a-chip (Organ Chip) microfluidic culture technology could be leveraged to accelerate drug development if confronted with a future viral pandemic.  At that time, however, our focus was on influenza viruses given their central role in past pandemics. Thus, over the past few years we developed a human Airway Chip and showed that it is indeed very useful to study both initial infection of the bronchial epithelium and the host response to infection including contributions of endothelium, immune cells, and associated production of inflammatory molecules that can contribute to the ‘cytokine storm’ we hear so much about today in the context of COVID-19.  Having developed this high fidelity in vitro model of the human lung response to influenza virus infection, we also explored whether we could use it to repurpose existing drugs as antiviral agents.  This led to the discovery that the anticoagulant drug, nafamostat, had direct antiviral activities, and more importantly, it could double the therapeutic time window of the first-line antiviral therapeutic, oseltamivir (Tamiflu), from 48 to 96 hours.  And then in January 2020, SARS-CoV-2 came into our lives.

Two of my research fellows who were trained as virologists, Longlong Si and Haiqing Bai, immediately jumped into action upon reading the first publication describing the SARS-CoV-2 gene sequence on January 12, 2020. One day later, they set about engineering pseudovirus particles expressing the SARS-CoV-2 spike protein (CoV-2pp) so that we immediately could begin to carry out studies in our lab as we do not have a BSL3 facility required to work with the native infectious virus. Based on the desperate situation we saw around us and their prior experience in the field, we selected eight existing drugs that had been previously shown to show inhibitory activity against other infectious viruses (e.g., SARS-CoV, MERS-CoV, Ebola) and started testing them in a conventional culture assay using a Huh-7 cell line that is commonly used in the virology field. Within a few weeks, we found that all of these drugs, which included hydroxychloroquine and chloroquine, effectively inhibited entry of CoV-2pp in these cells when added in the low micromolar range.  But when we then tested these same drugs in the more physiologically relevant human Airway Chip by perfusing them through the vascular channel at a clinically relevant dose (Cmax reported in humans), both hydroxychloroquine and chloroquine were found to be totally inactive (which was later confirmed in COVID-19 clinical trials), and only 3 showed any activity, with the related antimalarial drug, amodiaquine, being most potent.

Based on these preliminary findings and the urgent need for therapeutics to confront SARS-CoV-2 in the spring of 2020, we were able to obtain additional funding from DARPA to build a rapid drug repurposing pipeline by combining our Airway Chip model with high throughput in vitro screens using native SARS-CoV-2 virus in Matt Frieman’s BSL3 lab at University of Maryland School of Medicine, and with a COVID-19 small animal model developed by Ben tenOever at Icahn School of Medicine at Mt. Sinai.  When amodiaquine was moved through this pipeline, we found that it potently inhibited infection by native SARS-CoV-2 in VeroE6 cells and human ACE2 expressing A549 cells in vitro. Importantly, it also prevented SARS-CoV-2 infection when administered before or after virus inoculation in the animal model, and it very effectively prevented animal-to-animal transmission of virus.  As this drug is very inexpensive and widely available in Africa, a bioRxiv preprint describing an earlier version of this work published in April 2020 (1) caught the attention of Medicines Malaria Ventures (MMV), Witwatersrand University, and Shin Poong Pharmaceutical, which initiated a clinical trial for COVID-19 in the fall of 2020.  Drugs for Neglected Diseases initiative (DNDi) also introduced amodiaquine into their ANTICOV trial that is being organized across 19 sites in 13 countries in Africa a few months later.

We believe that this work provides an excellent example of how microfluidic human Organ Chips can help to accelerate the drug discovery and development, as well as expedite the delivery of new therapeutics to the clinic.   Organ Chips may be particularly useful for future pandemics; however, to confront this challenge, it is critical that we get this technology into BSL3 laboratories that can carry out studies on host responses as well as initial infection using highly infectious viruses.  Luckily, this is beginning to happen around the world. 

Our paper: A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics.   Longlong Si, Haiqing Bai, Melissa Rodas, Wuji Cao, Crystal Yuri Oh, Amanda Jiang, Rasmus Moller, Daisy Hoagland, Kohei Oishi, Shu Horiuchi, Skyler Uhl, Daniel Blanco-Melo, Randy A. Albrecht, Wen-Chun Liu, Tristan Jordan, Benjamin E. Nilsson-Payant, Ilona Golynker, Justin Frere, James Logue, Robert Haupt, Marisa McGrath, Stuart Weston, Tian Zhang, Roberto Plebani, Mercy Soong, Atiq Nurani, Seong Min Kim, Danni Y. Zhu, Kambez H. Benam, Girija Goyal, Sarah E. Gilpin, Rachelle Prantil-Baun, Steven P Gygi, Rani K. Powers, Kenneth E. Carlson, Matthew Frieman, Benjamin R. tenOever, and Donald E. Ingber. Nature Biomedical Engineering (2021). https://rdcu.be/cjS8a


  1. Si L, Bai H, Rodas M, Cao W, Oh CY, Jiang A, Nurani A, Zhu DY, Goyal G, Gilpin S, Prantil-Baun R,  Ingber DE. Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. bioRxiv2020.04.13.039917; doi: https://doi.org/10.1101/2020.04.13.039917

Donald E. Ingber,MD,PhD

Founding Director & Professor, Wyss Institute for Biologically Inspired Engineering at Harvard University