Dr. Donald Ingber
Founding Director, Wyss Institute at Harvard University
Professor, Harvard Medical School & Boston Children’s Hospital
Professor at the Harvard John A. Paulson School of Engineering and Applied Sciences

What are you and your institution currently working on regarding COVID-19?

The Wyss Institute for Biologically Inspired Engineering at Harvard University is a problem-focused, technology innovation center that has developed an organizational structure designed to cross the academic-industrial interface in order to bring about near-term impact. We function independently of any department or school at the University, and we have faculty from multiple disciplines and institutions, as well as many staff who have extensive prior industrial experience.

Although none of us had worked in the coronavirus area prior to the emergence of the COVID-19 crisis, we were able to quickly refocus approaches we previously developed for other applications, and to initiate new ones, to confront the COVID-19 challenge on multiple fronts, including development of diagnostics, therapeutics, vaccines, and personal protective equipment.  Examples of recent successes include creation of inexpensive mass-produced nasopharyngeal swab replacements that are already commercially available; highly sensitive serological tests for SAR-CoV-2 that are being used at Harvard-affiliated hospitals; a materials-based COVID-19 vaccine that generates rapid and robust production of neutralizing antibodies without requiring a boost in animal models; and an FDA drug repurposing pipeline that spans from cell-based assays and human Organ Chips to animal models that is currently focused on bringing lead drugs to clinical trials in an accelerated manner.

A more thorough summary of our contributions to the COVID-19 effort has been reported recently.

 

Please, describe your work of organ, lung on a chip and pathogen capture of FcMBL as related to fighting against SARS-CoV-2?

One of the major programs that my team leads at the Wyss Institute is focused on the development of human Organ-on-a-Chip (Organ Chip) microfluidic culture. The goal is to replace animal testing and accelerate drug development, as well as advance personalized medicine. Based on this work, we had received funding from the Defense Advanced Research Projects Agency (DARPA) as part of their PREPARE program to leverage our human Organ Chips to facilitate rapid development of RNA and CRISPR-based therapeutics. Our studies confirmed that we can use these chips to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by influenza, as well as the effects of existing and novel therapeutics.

Within one day after the first article describing the SARS-CoV-2 genome was published in mid-January 2020, my team began engineering a pseudotyped SARS-CoV-2 spike virus that could be used in our BSL2 lab, with the goal of leveraging it along with computational drug repurposing pipelines we have developed at the Wyss Institute to rapidly identify existing FDA approved drugs that might be useful to combat the COVID-19 crisis. We first assessed the ability of 7 clinically approved drugs (chloroquine, arbidol, toremifene, clomiphene, amodiaquine, verapamil, and amiodarone) that were previously shown to inhibit infection by other RNA viruses (e.g., MERS, Ebola) to prevent entry of the pseudotyped SARS-CoV-2 spike virus in human Huh-7 cells.  When we administered these drugs under flow at their clinical C_max in human Airway Chips, only three of them ¾  amodiaquine, clomiphene, and toremifene ¾ significantly inhibited entry of the pseudotyped CoV-2 virus. Importantly, with additional new funding from DARPA focused specifically on COVID-19, we have recently extended this work through collaboration with Matt Frieman (University of Maryland) and Ben tenOever (Icahn Mount Sinai School of Medicine) and confirmed that amodiaquine also inhibits native SARS-CoV-2 infection both in cultured VeroE6 cells and in hamsters.  We are currently attempting to move this drug into human clinical trials in the United States.  However, this is just the first drug in our pipeline, and we hope to bring multiple other approved drugs that target either viral infection and/or host response to infection (leveraging the Organ Chip model) in the future. Our human Organ Chip capability, which is now commercially available through Emulate Inc. (Boston, MA, USA), is being integrated into our collaborators’ BSL3 labs so that host response to native SARS-CoV-2 can be studied in the future.

In parallel, we have been using a computational rational design approach to design potential new drugs that target a conserved region within the SARS-CoV-2 spike protein, which is also present in many other RNA viruses and required for viral entry.  Recent results confirm that our lead compounds are potent inhibitors of native SARS-CoV-2 infection in VeroE6 cells. Recent studies suggest that it is an even more powerful inhibitor of infection by native SARS-CoV-2, as well as by other coronaviruses and multiple influenza strains. Thus, we hope to advance these efforts with the goal of developing broad spectrum prophylactics and therapeutics that might be used to combat COVID-19 as well as future pandemics.

Another major effort in my laboratory has focused on the natural human blood opsonin, Mannose Binding Lectin (MBL), which binds to over 100 different pathogens of all classes (virus, Gram +/- bacteria, fungi, parasites) as well as pathogen-associated molecular patterns (PAMPS), such as lipopolysaccharide endotoxin. We engineered a smaller version of this lectin that contains the carbohydrate binding domain linked to the Fc portion of immunoglobulin (FcMBL). We previously demonstrated that FcMBL capture of pathogens can be used to increase the efficiency of existing diagnostic tests. We recently confirmed that FcMBL can bind to commercially available, inactivated SARS-CoV-2 and purified spike protein. This technology has been licensed to Boa Biomedical Inc., which is now exploring the potential to leverage FcMBL for both diagnostic and therapeutic applications in COVID-19.

 

Bio Sketch

Ingber is a pioneer in the field of biologically inspired engineering, and at the Wyss Institute he currently leads a multifaceted effort to create breakthrough bioinspired technologies to advance healthcare and improve sustainability. His work has led to major advances in mechanobiology, tumor angiogenesis, tissue engineering, systems biology, nanobiotechnology, and translational medicine. Through his work, Ingber also has helped break down boundaries between science, art and design. Some of Ingber’s most recent developed technologies include a dialysis-like sepsis therapeutic device that clears blood of pathogens and inflammatory toxins; an anticoagulant surface coating for medical devices that replaces the need for dangerous blood thinning drugs; a shear stress-activated nanotherapeutic that target clot-busting drugs to sites of vascular occlusion; and human Organ-on-Chips, created with microchip manufacturing methods and lined by living human cells that are being used to replace animal testing for drug development and personalized medicine. Ingber’s Organ-on-a-Chip was named Design of the Year by London Design Museum and was acquired by the Museum of Modern Art (MoMA) in New York City for its permanent design collection in 2015; it also was named one of the Top Ten Emerging Technologies of 2016 by the World Economic Forum.

Overview of The Wyss Institute at Harvard

The Wyss Institute for Biologically Inspired Engineering at Harvard University (http://wyss.harvard.edu) uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard’s Schools of Medicine, Engineering, Arts & Sciences, Design, and Education, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology. The Wyss Institute is also a Center of Excellence of the Global Virus Network that is focused on eradicating global viral threats.