Wednesday, April 22nd, 2020

Time	Event
8:52a	Researchers identify cells likely targeted by Covid-19 virus Researchers at MIT; the Ragon Institute of MGH, MIT, and Harvard; and the Broad Institute of MIT and Harvard; along with colleagues from around the world have identified specific types of cells that appear to be targets of the coronavirus that is causing the Covid-19 pandemic. Using existing data on the RNA found in different types of cells, the researchers were able to search for cells that express the two proteins that help the SARS-CoV-19 virus enter human cells. They found subsets of cells in the lung, the nasal passages, and the intestine that express RNA for both of these proteins much more than other cells. The researchers hope that their findings will help guide scientists who are working on developing new drug treatments or testing existing drugs that could be repurposed for treating Covid-19. “Our goal is to get information out to the community and to share data as soon as is humanly possible, so that we can help accelerate ongoing efforts in the scientific and medical communities,” says Alex K. Shalek, the Pfizer-Laubach Career Development Associate Professor of Chemistry, a core member of MIT’s Institute for Medical Engineering and Science (IMES), an extramural member of the Koch Institute for Integrative Cancer Research, an associate member of the Ragon Institute, and an institute member at the Broad Institute. Shalek and Jose Ordovas-Montanes, a former MIT postdoc who now runs his own lab at Boston Children’s Hospital, are the senior authors of the study, which appears today in Cell. The paper’s lead authors are MIT graduate students Carly Ziegler, Samuel Allon, and Sarah Nyquist; and Ian Mbano, a researcher at the Africa Health Research Institute in Durban, South Africa. Digging into data Not long after the SARS-CoV-2 outbreak began, scientists discovered that the viral “spike” protein binds to a receptor on human cells known as angiotensin-converting enzyme 2 (ACE2). Another human protein, an enzyme called TMPRSS2, helps to activate the coronavirus spike protein, to allow for cell entry. The combined binding and activation allows the virus to get into host cells. “As soon as we realized that the role of these proteins had been biochemically confirmed, we started looking to see where those genes were in our existing datasets,” Ordovas-Montanes says. “We were really in a good position to start to investigate which are the cells that this virus might actually target.” Shalek’s lab, and many other labs around the world, have performed large-scale studies of tens of thousands of human, nonhuman primate, and mouse cells, in which they use single-cell RNA sequencing technology to determine which genes are turned on in a given cell type. Since last year, Nyquist has been building a database with partners at the Broad Institute to store a huge collection of these datasets in one place, allowing researchers to study potential roles for particular cells in a variety of infectious diseases. Much of the data came from labs that belong to the Human Cell Atlas project, whose goal is to catalog the distinctive patterns of gene activity for every cell type in the human body. The datasets that the MIT team used for this study included hundreds of cell types from the lungs, nasal passages, and intestine. The researchers chose those organs for the Covid-19 study because previous evidence had indicated that the virus can infect each of them. They then compared their results to cell types from unaffected organs. “Because we have this incredible repository of information, we were able to begin to look at what would be likely target cells for infection,” Shalek says. “Even though these datasets weren’t designed specifically to study Covid, it’s hopefully given us a jump start on identifying some of the things that might be relevant there.” In the nasal passages, the researchers found that goblet secretory cells, which produce mucus, express RNAs for both of the proteins that SARS-CoV-2 uses to infect cells. In the lungs, they found the RNAs for these proteins mainly in cells called type II pneumocytes. These cells line the alveoli (air sacs) of the lungs and are responsible for keeping them open. In the intestine, they found that cells called absorptive enterocytes, which are responsible for the absorption of some nutrients, express the RNAs for these two proteins more than any other intestinal cell type. “This may not be the full story, but it definitely paints a much more precise picture than where the field stood before,” Ordovas-Montanes says. “Now we can say with some level of confidence that these receptors are expressed on these specific cells in these tissues.” Fighting infection In their data, the researchers also saw a surprising phenomenon — expression of the ACE2 gene appeared to be correlated with activation of genes that are known to be turned on by interferon, a protein that the body produces in response to viral infection. To explore this further, the researchers performed new experiments in which they treated cells that line the airway with interferon, and they discovered that the treatment did indeed turn on the ACE2 gene. Interferon helps to fight off infection by interfering with viral replication and helping to activate immune cells. It also turns on a distinctive set of genes that help cells fight off infection. Previous studies have suggested that ACE2 plays a role in helping lung cells to tolerate damage, but this is the first time that ACE2 has been connected with the interferon response. The finding suggests that coronaviruses may have evolved to take advantage of host cells’ natural defenses, hijacking some proteins for their own use. “This isn’t the only example of that,” Ordovas-Montanes says. “There are other examples of coronaviruses and other viruses that actually target interferon-stimulated genes as ways of getting into cells. In a way, it’s the most reliable response of the host.” Because interferon has so many beneficial effects against viral infection, it is sometimes used to treat infections such as hepatitis B and hepatitis C. The findings of the MIT team suggest that interferon’s potential role in fighting Covid-19 may be complex. On one hand, it can stimulate genes that fight off infection or help cells survive damage, but on the other hand, it may provide extra targets that help the virus infect more cells. “It’s hard to make any broad conclusions about the role of interferon against this virus. The only way we’ll begin to understand that is through carefully controlled clinical trials,” Shalek says. “What we are trying to do is put information out there, because there are so many rapid clinical responses that people are making. We’re trying to make them aware of things that might be relevant.” Shalek now hopes to work with collaborators to profile tissue models that incorporate the cells identified in this study. Such models could be used to test existing antiviral drugs and predict how they might affect SARS-CoV-2 infection. The MIT team and their collaborators have made all the data they used in this study available to other labs who want to use it. Much of the data used in this study was generated in collaboration with researchers around the world, who were very willing to share it, Shalek says. “There’s been an incredible outpouring of information from the scientific community with a number of different parties interested in contributing to the battle against Covid in any way possible,” he says. “It’s been incredible to see a large number of labs from around the world come together to try and collaboratively tackle this.” The research was funded by the Searle Scholars Program, the Beckman Young Investigator Program, the Pew-Stewart Scholars Program for Cancer Research, a Sloan Fellowship in Chemistry, the National Institutes of Health, the Aeras Foundation, the Bill and Melinda Gates Foundation, the Richard and Susan Smith Family Foundation, the National Institute of General Medical Sciences, the UMass Center for Clinical and Translational Science Project Pilot Program, and the Office of the Assistant Secretary of Defense for Health Affairs. 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3:15p	MIT’s Love Lab developing a Covid-19 vaccine to potentially reach billions After cities shut down and citizens were urged to stay home to slow the spread of Covid-19, scientists in major cities like Boston were suddenly far removed from their labs. At MIT, on-campus research was ramped down, reduced to only the most critical activities. That includes important work to better understand the virus and help stop the spread. In the lab of Professor J. Christopher Love at MIT’s Koch Institute for Iterative Cancer Research, a small team was cleared to return to the lab to continue their mission: generating and testing preclinical materials to push new vaccines for Covid-19 to reach the stage of conducting human trials on a much faster timeline than the many years that vaccine development typically takes. “It was like a blitz at the beginning to see if something would work,” says Neil Dalvie, a graduate research assistant who’s part of the Love Lab’s onsite team, together with Andrew Biedermann, Laura Crowell, and Sergio Rodriguez, also graduate research assistants. Everyone else from the lab coordinated from home, via Zoom, phone, and email. Dalvie says it’s not the most efficient way to work. Having team members working remotely slows the whole process down, right when the need for speedy development has become most crucial. But the Love Lab got it done. “We obtained preclinical material in a month,” Dalvie says. Now, that material’s ability to provoke an immune response is being tested in animal models with two lab partners to get to the next stage of development (a process that typically takes six weeks). Timing matters, with the U.S. Centers for Disease Control and Prevention already reporting more than 45,000 U.S. Covid-related deaths. Researchers all over the world are working toward developing the first vaccines for Covid-19, but the Love Lab knows they can’t just think about how fast they can make small amounts of the medicine, or how effective it will be at neutralizing the virus. The lab partners with the Gates Foundation, which has estimated that reducing the rate of infection worldwide will likely require billions of doses of Covid-19 vaccine. To reach that need, the Love Lab knows achieving such a goal will require thinking about manufacturing, too. Currently, the U.S. Department of Health and Human Services is supporting Janssen Pharmaceuticals (a branch of Johnson & Johnson) in the development of 300 million vaccine doses, a fraction of the billions of doses that might be necessary. To address the gap, the Love Lab has thought constantly about how the solutions they are pursuing might scale in cost-effective ways. They have invoked a strategy they previously developed under a Grand Challenge for ultra-low cost vaccines to accelerate the readiness of preclinical materials for manufacturing as they advanced the first vaccine candidate toward animal and human trials. “To reach the widest number of people, we need to be very intentional about incorporating in aspects of the manufacturability of a vaccine, even at the early stages of discovery,” says Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering. With this first vaccine candidate, his lab has furthered what they aim to be a new paradigm for vaccine development, by continuing to enhance the manufacturing process in parallel to the animal testing taking place. This approach could shorten the time required to transfer their processes to manufacturers who are simultaneously working to prepare to produce those materials in large quantities when ready. By overlapping these stages of development, the whole process becomes streamlined, as manufacturers learn to work with materials, becoming better-prepared to produce vaccines at the scale needed once trials are completed. While this kind of platforming of the drug development process is common for the development of certain cancer drugs like monoclonal antibodies, Love says that’s not the case for developing vaccines. “This is not a common approach in vaccine manufacturing,” he says, explaining that normally, “Every vaccine is manufactured by its own unique process.” For years, the Love Lab has sought to change this perspective, and now they’re putting theories they’ve developed in the lab to the test in real-time. Crowell says more typically, a team would focus on showing they can validate a potential new drug, often just at small scales, before ever thinking about how to produce the drug on a larger scale. There was no time for that serial approach when it came to a Covid-19 vaccine. Manufacturing has had to factor into every development decision. Rodriguez says the Love Lab’s streamlining begins with applying knowledge gained from designing past processes and investigating how a given protein molecule could fit into an existing process. From there, the process is refined and enhanced, with simple tweaks to the sequence that improve the vaccine material’s quality and manufacturability. For the current vaccine the Love Lab is testing, the team looked at the similar structure of the coronavirus SARS-CoV-1 as a starting point. “We can look at similar molecules to give us a ballpark or a benchmark for starting a production process to just try to find something that works for a first run,” Rodriguez says. They have also worked to improve production of the vaccine in parallel. “As we undertook our first production runs, we also developed faster methods to tailor our cell culture media formulation for Covid vaccine production to improve productivity and quality,” Biedermann said. “We wanted to show that we can produce these vaccine candidates quickly and at concentrations relevant for commercial manufacturing.” What the Love Lab is developing is called a subunit vaccine, which works by using just a small part of a protein from the virus to train the immune system to recognize the whole virus and stop it from infecting cells. Such vaccines often work by invoking antibodies that can bind and neutralize the virus and give the body a fighting chance to destroy the virus. Dalvie says the advantages of producing a subunit vaccine are that it’s easy to make, safe, and, if the right protein is chosen “wisely,” an appropriate protective immune response can be provoked. The team’s work has provided a fast solution to a first potential vaccine for further testing that also buys time while the team enhances the process and develops more robust vaccines that may produce a stronger immune response. Currently, immunogenicity and formulation studies are underway for the Love Lab’s first vaccine candidate, but they continue to work on others. “This is a case where we may need multiple solutions to realize vaccines for many people,” Love says. Another aspect of manufacturing that the Love Lab considers is cost. It’s important to produce an affordable vaccine if the expectation is for it to be widely dispersed, potentially inoculating two-thirds of the population. “Many of the vaccines in development now are likely going to be effective, but some of them may not be affordable in many parts of the world,” Love says. “A vaccine could be more broadly available at affordable costs — potentially all over the world,” Dalvie says. “If we have also considered our ability to manufacture it.” (Comment on this)
4:15p	Maria Zuber on climate change: “Breakthroughs will happen” Climate change is a very personal issue to Maria Zuber, MIT’s vice president for research. A native of eastern Pennsylvania, she watched her grandfathers, both coal miners, battle black-lung disease. “The burning of anthracite coal drove my community and was a central part of my childhood,” says Zuber. “Yet it’s been known since the 1800s that combustion of fossil fuels puts CO2 into the atmosphere, and that the effects can be damaging.”  Today, the catastrophic effects of climate change are showing up even faster than models predicted, she observes. “If you just look at it that way, it’s easy to despair.”  Yet Zuber, also the E. A. Griswold Professor of Geophysics, remains optimistic. “People are looking at those effects based on what we know now, but I think about the actions that will be taken when we have technological breakthroughs and an improved understanding of the climate system,” she explains. “Those breakthroughs will happen — we just don’t know exactly when.”  Zuber identifies three areas of MIT-based research that show particular promise for climate action: battery technology, renewable energy, and fusion.  Battery power “Batteries are key to combating climate change because in the deployment of renewable energy, one of the greatest challenges is intermittency,” she explains. “We need to store the power of wind and sun so we can use them when the sun isn’t shining and the wind isn’t blowing. We need better battery capacity, efficiency, and design, and we need batteries that are made out of common-earth materials as opposed to rare ones.” At the third in a series of climate action-focused symposia sponsored by the Institute this academic year, Yet-Ming Chiang ’80, ScD ’85, the Kyocera Professor of Ceramics in MIT’s Department of Materials Science and Engineering, provided examples of this effort. Chiang is a cofounder of Form Energy, one of the portfolio companies of The Engine, an MIT-based innovation hub for startups focused on technology with potential for changing the world. Chiang described research and development of batteries based on materials such as sulfur and zinc, which are cheaper and more abundant than the lithium commonly used today.  Solar and wind While superior battery technology is still in our future, Zuber is already encouraged by the increased use of renewable energy. “Solar and wind energy are really penetrating into society, and a lot of new jobs are being created as a result,” she says. “Just renewables won’t solve all the problems, though. We also have to move toward decarbonizing other parts of the energy system where we haven’t made as much progress. But you can really see the tide starting to turn.” Zuber cites the work of Vladimir Bulović, the Fariborz Maseeh Chair in Emerging Technology and founding faculty director of MIT.nano, who works to create next-generation, lightweight, flexible photovoltaics that could dramatically improve solar energy systems. “We have a lot going on in solar energy,” she says. Fusion On the topic of fusion, Zuber’s enthusiasm is boundless. “Fusion is the process that powers the sun, and we need to bring that process down to Earth,” she explains. “The fuel is hydrogen, a component of water, so it’s practically free and virtually inexhaustible.” The greatest obstacle to working with fusion is designing a device that creates more energy than it uses for power. “This is a really difficult challenge,” she admits. “But fusion could be an important contributor to limiting the change in our climate. It doesn’t put CO2 in the atmosphere, and there’s no radioactive fuel waste involved.”  Zuber highlights the Institute’s collaboration with Commonwealth Fusion Systems (CFS), a startup spun out of MIT’s Plasma Science and Fusion Center. MIT’s role in CFS was conceived by researchers led by center director Dennis Whyte, the Hitachi America Professor of Engineering and cofounder of CFS.  “People never took fusion seriously, but they seem to be taking it seriously now,” says Zuber. “We have considerable investment in CFS. The fact that the private sector is also investing heavily in fusion energy indicates optimism that the technology has matured to the point where it’s a reasonable longer-term investment.” Outside engagement In addition to research, Zuber described the Institute’s successful collaboration with other organizations and governments. In one example, MIT joined forces with two local organizations, Boston Medical Center and the Post Office Square Redevelopment Corporation, in a 2016 power-purchase agreement that resulted in the construction of a 650-acre, 60-megawatt solar farm on the site of a former tobacco farm in North Carolina. The power generated by the solar farm replaces power previously supplied by a coal-fired plant. “We have also convened investment firms, fossil fuel companies, climate-scenario producers, environmental advocates, and NGOs, along with academics like ourselves, to explore the role of corporate disclosures with regard to climate change,” she says. “Companies are taking major risks if they don’t consider the financial consequences of global warming.”  Continued engagement with outside organizations and populations is key. “Climate change affects everybody on Earth, and MIT can’t solve a global problem alone,” Zuber points out. “A solution that might work here in Cambridge might not work in India or Africa, so we’ve sought out partners from different areas of the developing world. We need to consider those perspectives in energy solutions.” Hope for the planet Much of Zuber’s hope for climate action, she says, comes from MIT students. “The greatest thing about our students is that they believe they can solve this problem,” she says. “We are not dispirited — we will keep working to find a solution.” (Comment on this)

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