Harvard's Wyss Institute researchers are confronting the coronavirus crisis on all fronts – by rapidly developing much needed diagnostic and therapeutic inventions
By Benjamin Boettner
(BOSTON) — The burgeoning coronavirus (COVID-19) global pandemic has already killed thousands of people worldwide and is threatening the lives of many more. In an effort to limit the virus from spreading, Harvard University was among the first organizations to promote social distancing by requiring all but the most essential personnel to work remotely. However, labs that perform vital COVID-19-related research are permitted to continue their potentially life-saving work – and many of these activities are currently ongoing at the Wyss Institute for Biologically Inspired Engineering.
Essentially all medical treatment centers impacted by SARS-CoV2 (CoV2), the SARS-family virus that causes COVID-19, are overstrained or unable to confront the virus, starting from their ability to diagnose the virus’ presence in the human body, treat all infected individuals, or prevent its spread among those that have not been infected yet. Therefore, finding better solutions to diagnose, treat, and prevent the disease, is key to combating this menace and bringing this pandemic under control. Equally concerning, there are worldwide shortages on the front lines in hospitals in our region and around the world, including rapidly depleting supplies of personal protective equipment, such as N95 face masks, and nasopharyngeal swabs needed for COVID-19 diagnostic testing. Solving these challenges requires rapid responses and creative solutions.
“With our highly multi-disciplinary and translation-focused organization, we [the Wyss Institute] were able to quickly pivot, and refocus our unique engineering capabilities on much needed diagnostic, therapeutic, and vaccine solutions, and we hope to be part of the solution for many of the innumerable problems the present pandemic poses,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who also is the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). “We strive to make a major contribution to bringing this crisis under control, and are confident that what we accomplish under duress now will help prevent future epidemics.”
Meeting challenges on the front lines of patient care
Many of the Institute’s hospital partner institutions and government agencies have reached out to Institute leadership to assist in this rapidly escalating battle against COVID-19.
- Ingber’s team is working closely with collaborators at Beth Israel Deaconess Medical Center (BIDMC), other Harvard-affiliated hospitals, and generous corporate partners to develop potential solutions to the increasing shortage of nasopharyngeal swabs and N95 face masks. Senior Staff Engineers Richard Novak, Ph.D., and Adama Sesay, Ph.D., and Senior Research Scientist Pawan Jolly, Ph.D., are working diligently with our clinical partners to help devise a solution as quickly as possible.
- Wyss Institute Core Faculty member Jennifer Lewis, Sc.D. and Wyss Senior Research Scientist James Weaver, Ph.D. are co-leading the Face Shield Working Group within the Mass General Brigham health system to design and validate new face shields for front-line healthcare workers that can be quickly manufactured at a large scale. The working group includes clinicians, designers, fabricators, and academics from across the country who have held daily meetings to evaluate both 3D printed and die-cut designs. The final design is being prototyped and tested and, if successful, could be approved and ordered in record time. Lewis also is the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.
- Also working in coordination with the Mass General Brigham health system, Wyss Associate Faculty member Martin Bechthold, Ph.D., is leading an initiative in the Harvard Graduate School of Design (GSD)’s Fabrication Lab to produce visors and face-shields that are already being distributed to clinicians and health workers at Brigham and Women’s Hospital. Bechthold and his students are sifting through the many circulating designs for personal protective equipment to identify those that are most suitable for being produced, using the Fabrication Lab’s versatile 3D printers and laser cutters. Bechthold is also the Kumagai Professor of Architectural Technology and Director of the Doctor of Design Studies and Master in Design Engineering program.
- Importantly, personal protective equipment (PPE) like face masks and shields, and swabs could not only be made available to health workers and the population by fabricating them from scratch; finding ways to recycle existing PPE could significantly help overcome its lack at many places. As part of a larger engineering effort organized by SEAS, Wyss Institute Core Faculty member Kevin Kit Parker, Ph.D. in a project that is spearheaded by Postdoctoral Fellow John Zimmerman, Ph.D., in his group, is working with the United States Military Academy West Point on protocols that could enable the reliable cleaning and recycling of personal protective equipment materials. Parker is the Tarr Family Professor of Bioengineering and Applied Physics at SEAS, and closely collaborates with Colonel F. John Burpo who heads West Point’s Department of Chemistry and Life Sciences, and currently is a visiting scientist in Parker’s lab.
Diagnosing COVID-19 more quickly, easily, and broadly
With COVID-19 rapidly spreading around the planet, the efficient detection of the CoV2 virus is pivotal to isolate infected individuals as early as possible, support them in whatever way possible, and thus prevent the further uncontrolled spread of the disease. Currently, the most-performed tests are detecting snippets of the virus’ genetic material, its RNA, by amplifying them with a technique known as “polymerase chain reaction” (PCR) from nasopharyngeal swabs taken from individuals’ noses and throats.
The tests, however, have severe limitations that stand in the way of effectively deciding whether people in the wider communities are infected or not. Although PCR-based tests can detect the virus’s RNA early on in the disease, test kits are only available for a fraction of people that need to be tested, and they require trained health care workers, specialized laboratory equipment, and significant time to be performed. In addition, health care workers that are carrying out testing are especially prone to being infected by CoV2. To shorten patient-specific and community-wide response times, Wyss Institute researchers are taking different parallel approaches:
- Via one route, a team led by Wyss Core Faculty member Peng Yin,D., and Senior Staff Scientist Thomas Schaus, M.D., Ph.D., in the Institute’s Molecular Robotics Initiative are developing a disposable test that makes use of a “lateral flow device” (LFD) much like a home pregnancy test – easy to manufacture at a large scale, and able to be handled without special equipment or expertise. The team is adapting a suite of bioinspired DNA nanotechnology techniques that Yin’s lab has previously developed to enable the detection of virus RNA or protein from simple nasopharyngeal swabs with high sensitivity and accuracy. In the handheld LFD device, these tools would enable users to transform the presence of viral RNA or protein in a sample into the formation of a colored line on a simple strip of nitrocellulose paper. Yin is one of the leaders of the Wyss Institute’s Molecular Robotics Initiative and also Professor of Systems Biology at Harvard Medical School (HMS).
- Better viral RNA detection methods are also being pursued by Sherlock Biosciences Inc., a molecular diagnostics startup spun out of the Wyss Institute and Broad Institute in 2019. The company licensed the INSPECTR™ technology developed by Wyss Core Faculty member James Collins, Ph.D., and his group, including former Wyss Business Development Lead William Blake, Ph.D., who joined Sherlock Biosciences from the Wyss Institute as the company’s CTO. Collins is a co-founder of Sherlock Biosciences, and also the Termeer Professor of Medical Engineering & Sciences at the Massachusetts Institute of Technology (MIT). According to Rahul Dhanda, M.B.A., the CEO and a co-founder of Sherlock Biosciences, the company is currently working on different solutions for diagnosing COVID-19, one of which deploys the INSPECTR™ technology. INSPECTR™ consists of DNA-based sensors, which can be programmed to detect CoV2 RNA with specificity down to a single one of its nucleotide building blocks; the sensors are coupled with paper-based synthetic gene networks that produce a bioluminescent signal. The signals can be generated at room temperature, captured on instant film and read from a simple device without sophisticated equipment, and the test is currently designed to perform similarly to an off-the-shelf pregnancy test. Like the LFD approach developed in Yin’s group, INSPECTR™ technology can be readily adjusted to allow specific detection of the different continuously arising CoV2 variants, and to follow their spread through the population.
- In a different project led by Collins and spearheaded by Research Scientists Peter Nguyen, Ph.D., and Nina Donghia, and former graduate student Luis Soenksen at the Wyss Institute, the team is developing a rapid self-activating COVID-19 diagnostic face mask as a wearable diagnostic. Worn by patients or individuals at home with symptoms of the disease, the face mask could rapidly signal the presence of the virus without any need for hands-on manipulation so that patients can be quickly triaged for proper medical care, while healthcare workers and patients that are nearby are protected. Emerging from Collins’ team’s wearable diagnostic technology platform created in the Wyss Institute’s Living Cellular Devices Initiative, the approach will use highly sensitive molecular sensors that, coupled to synthetic biology networks, could enable the production of an immediately visible or fluorescent color signal in the event that CoV2 is encountered. The entire cell-free molecular machinery can be freeze-dried and integrated with the synthetic material on the interior side of face masks. Exposed to small droplets that are expelled by wearers during normal breathing, sneezing, and coughing, and the humidity of exhaled air, the reactions are re-hydrated and thus activated to produce a positive or negative signal within 1 to 3 hours.
- A method to capture CoV2 virus particles from human samples in a single step and identify them within 1 hour is being explored by Senior Staff Scientist Michael Super, Ph.D., working on Ingber’s Bioinspired Therapeutics & Diagnostics platform. The researchers are leveraging the Wyss Institute’s FcMBL pathogen capture technology to bind CoV2 virus particles, which they hope to be able to rapidly identify using mass spectrometry. FcMBL is a genetically engineered variant of the “Mannose Binding Lectin” (MBL) immune protein that binds to molecules on the surface of over 100 different pathogens, including certain viruses. Ingber’s team has confirmed that FcMBL binds to a non-infectious pseudotyped CoV2 virus that displays the CoV2 Spike protein on its surface.
- Ultrasensitive assays to detect the levels of cytokines – molecules that are secreted by certain immune cells to affect other cells – are being developed by Wyss Core Faculty member David Walt, Ph.D., to help identify effective therapeutic interventions to prevent the deadly cytokine storm that can be triggered by overproduction of immune cells in response to CoV2. The lab is also developing a serological test to ascertain individuals who are not showing any symptoms yet, but have been exposed to the novel coronavirus and have mounted an immune response. Walt is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at HMS, Professor of Pathology at Boston’s Brigham and Women’s Hospital (BWH), and Institute Professor of the Howard Hughes Medical Institute. In a related project, Walt and Wyss Research Scientist Dima Ter-Ovanesyan, Ph.D., are devising a molecular diagnostic assay for the parallel detection of CoV2-specific RNA and viral proteins, as well as patient-specific markers that can be multiplexed using the ultra-sensitive “Simoa” system previously developed by Walt’s group. Ter-Ovanesyan, in a collaboration between Walt’s group and that of Wyss Core Faculty member George Church, Ph.D., is also creating a cheap and scalable method that could enable the isolation and sequence analysis of RNA from the virus and infected cells from thousands of samples at once. This high-throughput capability could help ramp up diagnostic testing in hospital and other labs to monitor larger parts of the population. Church is also a Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard and MIT. Walt is also leading the “Diagnostic Accelerator,” a diagnostic Initiative brought to life by the Wyss Institute and the BWH that aims to speed up the time for crucial diagnostic tests to arrive in doctors’ and patients’ hands. The Diagnostic Accelerator space within the BWH’s clinical lab with its access to patient samples is now being built out as a testing ground to validate COVID-19 diagnostic tests being developed by the Wyss Institute, the Mass CPR Diagnostic Working Group, the “Mass General Brigham (MGB) Center for COVID Innovation” of which Walt is a co-Director, and by other Harvard researchers.
Advancing antiviral therapeutics on the fast track
To date there is no antiviral drug that has been proven to reduce the intensity and duration of the infection in more seriously affected patients, or protect vulnerable patients from CoV2 infection. Doctors can merely provide supportive care to their COVID-19 patients by making sure they receive enough oxygen, managing their fever, and generally supporting their immune systems to buy them time to fight the infection themselves. Research groups in academia and industry working at breakneck pace by now have compiled a list of candidate therapeutics and vaccines that could offer some help. However, given the high failure rates of candidate drugs in clinical trials, more efforts are needed to develop effective medicines for a world population that likely will vary with regards to their susceptibility and access to new therapeutic technologies.
The ongoing COVID-19 pandemic requires rapid action, and the fastest way to combat this challenge is by repurposing existing drugs that are already FDA approved for other medical applications as COVID-19 therapeutics. While clinicians around the world are attempting to do this, the approaches have been haphazard, and there is a great need to attack this problem in a systematic way.
- Ingber’s team, co-led by Senior Staff Scientist Rachelle Prantil-Baun, Ph.D. and Senior Research Scientist Girija Goyal, Ph.D., has developed a preclinical CoV2 infection model that leverages the Wyss Institute’s human Organ-on-a-Chip (Organ Chip) in vitro human emulation technology. The team engineered a CoV2 pseudovirus that is safe to use in the laboratory and expresses the key surface Spike protein, which mediates its entry into cells. They also demonstrated that it successfully infects human Lung Chips lined by highly differentiated human lung airway epithelial cells, which the team previously has shown to recapitulate human lung pathophysiology, including responses to Influenza virus infection, with high fidelity.Other members of the team, including Senior Staff Engineer Richard Novak and Senior Staff Scientist Charles Reilly, Ph.D. are respectively using network analysis algorithms and molecular dynamic simulation-enabled rational drug design approaches to identify existing FDA-approved drugs and novel compounds that can be tested in the Organ Chip-based COVID-19 therapeutic repurposing pipeline. Senior Staff Scientist Diogo Camacho, Ph.D., working in the Wyss Institute’s Predictive Biodiscovery Initiative led by Jim Collins is also applying new machine learning-enabled computational tools to confront this repurposing challenge. The team is now in active collaborations with researchers who can study the native infectious CoV2 virus in approved BSL3 biosafety laboratories, and they are working hard to rapidly identify existing FDA approved drugs and drug combinations that may be used as COVID-19 therapeutics, or as prophylactic therapies for healthcare workers or patients who are particularly vulnerable to this disease. Reilly, working with Lead Senior Staff Scientist Ken Carlson, Ph.D., is also using his molecular dynamics simulation approach to develop new broad spectrum coronavirus therapeutics targeted against a conserved region of CoV2’s surface Spike protein that would both help infected patients survive the current COVID-19 pandemic, and allow us to be prepared for infections by related coronaviruses that might emerge in the future.
- Collins’ team is also deploying computational algorithms to predict chemical structures that could inhibit different aspects of virus biology or disease pathology and be developed into therapeutics. In a collaboration with Regina Barzilay, Ph.D., a Professor at MIT’s Department of Electrical Engineering and Computer Science, his team is leveraging deep neural networks to develop therapeutic strategies that could help treat bacterial pneumonia, which can overlay pneumonia caused by the CoV2 virus and further endanger patients’ lives. In a recent study, motivated by the present dearth of antibiotics, Collins’ group successfully pioneered a deep learning approach to antibiotic discovery that led the researchers to discover new molecules with antibacterial effects towards different pathogenic strains.
- Wyss Core Faculty member George Church, Ph.D., and his graduate student Kettner Griswold are taking yet another route. One way the CoV2 virus could be fought is to harness the power of the immune system. Church and Griswold are engineering antibodies that specifically bind to the virus and could enable a potent immune attack on it. Starting from an already existing “neutralizing antibody” that binds the Spike protein of the virus responsible for the 2003 SARS epidemic, they hope to make the antibody fit the closely related CoV2 virus. Such a neutralizing agent would be akin to treatments in which patients with infectious diseases receive “blood plasma” (the liquid part of blood that holds the blood cells) from individuals that have recovered from the infection, which contains neutralizing antibodies against the pathogen. However, an engineered antibody could be manufactured in large quantities and supplied to COVID-19 patients much more quickly and easily than blood plasma.
In search of ultimate protection – a vaccine
With no vaccine currently available, but several vaccine candidates being explored around the world, Wyss Institute researchers led by Wyss Core Faculty member David Mooney, Ph.D., are developing a material that could make vaccinations more effective. Previously, Mooney’s team has developed implantable and injectable cancer vaccines that can induce the immune system to attack and destroy cancer cells.
- A key ingredient in vaccines is a fragment of the infectious agent, called an antigen, but the immune response to many antigens is weak. The bioactive materials of the Wyss’s vaccine are programmed with molecules that orchestrate the recruitment and stimulation of immune cells with presentation of the antigen. This results in robust responses that in relation to COVID-19, in theory, may enable the immune system to both kill the virus immediately in infected individuals, as well as create a memory in infected and uninfected individuals without the need of additional boosts. Given the material’s highly modular structure, one can easily plug-and-play various antigens that are being identified by researchers across the world, optimizing the response to each. This approach may yield a highly versatile platform in the fight against future epidemics and many infectious diseases. Mooney leads the Wyss Institute’s Immuno-Materials Focus Area and is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS.
Understanding how COVID-19 develops and how to control it
COVID-19 does not strike equally strong in every individual that it infects. Independent of age, some are prone to become seriously ill, while others show an astonishing level of resilience against the disease. Figuring out the biological basis for these differences could lead to new protective strategies.
- Church and Wyss Associate Faculty member Ting Wu, Ph.D., are working with “The Personal Genome Project” (PGP), an international initiative that creates public genome, health, and genetic trait data to be mined by the biomedical research community for driving scientific progress in many areas. Wu is also Professor of Genetics at HMS. Church was instrumental in founding the initiative in 2005, and has been advancing its reach with key technological advances and his emphatic stewardship. The two Wyss researchers and their teams led by Sarah Wait Zaranek, Ph.D., Curie President and PGP informatics co-Director, are now launching a project to harness the PGP platform by comparing the genomes, microbiomes, viromes, and immune systems of consenting individuals with extreme COVID-19 susceptibility and individuals that exhibit resistance. Their far-flung systems biology approach could lead to unexpected insights about the disease, and reveal key levers that could be adjusted with existing drugs to control the infection, help prioritize individuals for urgent care, as well as provide guidance as to which healthcare workers would do better on the front-lines of care.
- Besides pursuing various COVID-19-focused activities in its laboratories, the Wyss Institute is working with the broader research, hospital, and public health communities to integrate its efforts nationally. For example, Church is fastening ties with his former Postdoctoral Fellow Jay Shendure, Ph.D., Professor of Genome Sciences at the University of Washington, Seattle, who leads the “Seattle flu study,” which pivoted to COVID-19, as well as David Baker, Ph.D., Director of the Institute for Protein Design in Seattle, and Jonathan Rothberg, Ph.D., founder of life science company 4Bionics, among other companies, to develop a simple, yet different home test kit.
On the national level, Walt is a member of a COVID-19 discussion started at the National Academies’ newly formed “Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats.” The committee is strongly focusing now on the present coronavirus pandemic to find ways to help the federal government consolidate and streamline efforts across the nation but will also work long-term to develop strategies and make recommendations for future health threats.
At the international level, the Wyss Institute functions as a Center of Excellence of the Global Virus Network (GVN), with Ingber as leader and the other Wyss Faculty as key participating members. The GVN is designed to integrate surveillance and response efforts for biothreats, epidemics, and pandemics by integrating efforts of top virus research institutions from around the world. Ingber is also currently working closely with the Defense Advanced Research Projects Agency (DARPA) and Bill & Melinda Gates Foundation, as well as in active discussions with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), Biomedical Advanced Research and Development Authority (BARDA), and Public Health England, as they all try to align and coordinate efforts to meet this monumental health challenge.
“The Wyss Institute and its collaborators are taking exactly the type of comprehensive, integrated approach to addressing this pandemic that is required at local, national, and international levels,” said Walt.