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Lucy Jakub
April 13, 2020
Consider the fruit fly, Drosophila melanogaster. Though it’s only a couple of millimeters long, its body is intricately complex. But it began, as most animals do, as an amorphous blastula—a hollow ball of dividing cells. During embryonic development, the structures of the body emerge as cells multiply and change shape, sculpting tissues into the mature forms dictated by the genetic code. One of the first structural changes is gastrulation, during which the blastula becomes multilayered with an ectoderm, mesoderm, and endoderm. In the developing fly, this occurs through a tissue folding mechanism. The first fold is the invagination of the mesoderm, when cells fated to become muscles contract and curl inward, leaving the cells fated to become skin on the exterior.
Biologists have traditionally focused on how cells generate force to understand cell and tissue shape change. But researchers at MIT have found that there’s another important, though often overlooked, player in tissue folding: cell division, or mitosis. By combining live-imaging with genetic mutations of developing Drosophila embryos, they observed that cell constriction and division can act together to promote folding, and that mitosis interferes with the accumulation of motor proteins that allows cells to generate force.
“What the results tell us is that the cell cycle and cell division might need to be tightly regulated relative to other shape changes that are happening in the tissue,” says Adam Martin, the senior author of the study published on March 13 in Molecular Biology of the Cell. “They present a new paradigm for thinking about how tissue shape might be regulated during development, and provide insight into what might cause birth defects in humans.” Clint Ko PhD ’20, a former graduate student in the Martin lab, was lead author of the study.
In 2000, three different labs identified a genetic mutation that caused premature cell division in developing Drosophila embryos. They found that the gene tribbles, named for the fuzzy, rapidly-reproducing animals in Star Trek, regulates cell division in the mesoderm of the fly, ensuring that cells only divide at the appropriate time. When that gene is deleted, cell division occurs before the mesoderm can properly internalize. What was notable about this mutant was that the blastula never folded, and remained a ball of cells instead of an envelope of tissue with an inside and an outside. This observation led researchers to believe that cell cycle regulation somehow regulates tissue folding. But, at the time, there was no live-imaging technology to visualize how cells changed in the developing embryo.
By using a fluorescent protein to visualize chromosome condensation, which marks the start of mitosis and the cell’s preparation for division, the researchers were able to use live-cell imaging to see how premature division might be interfering with cell constriction. When a cell prepares to divide, it expands and becomes rounded, before elongating—shape changes that exert force on neighboring cells. But something else was going on, too.Specifically, researchers in the Martin lab wanted to see what was happening to networks of the motor protein myosin, which allows cells to contract, in the tribbles mutant. Myosin is the same protein that allows our muscle tissue to contract when we flex. To facilitate tissue folding in the developing fly, myosin is concentrated at the top of the cells in the mesoderm, where they form the surface of the blastula. As this myosin constricts, the outer surface of the tissue shrinks and contracts inward.
“We noticed that when the cells are dividing, the apical myosin networks that are present disappear,” says Ko. Cells that had already begun to contract relaxed when they entered mitosis, indicating that it’s a loss of contractility in the tribbles mutant that prevents folding. The researchers suspect netbet sports bettingthat this reversal occurs because mitosis disrupts signaling from the gene RhoA, which regulates contractility and cell shape changes during development. An undergraduate researcher in the lab, Prateek Kalakuntla, showed that regulation of RhoA changes at the start of mitosis.
“Initially we were just curious about the tribbles mutant,” says Ko. “But then we started exploring other ways of looking at how cell divisions affect myosin accumulation in cells.” They utilized a mutation in which the gene fog, which is located upstream of myosin activation on the genome, was overexpressed. (Fog is short for “folded gastrulation.”) Cells in the Drosophila ectoderm don’t normally contract, but with ectopic fog overexpression, those cells activated myosin, too. With live-cell imaging, the researchers observed furrows develop across the ectoderm.
“It was a bit unexpected to see these tissues folding when they shouldn’t be folding,” says Ko. Specifically, the folds occurred along the boundaries of mitotic domains, regions of spatiotemporally patterned cell divisions that occur in coordinated pulses. “That led to this sort of novel idea that cell divisions—particularly when they’re in this pattern where they’re interspersed between contractile cells—can actually promote tissue folding.”
Understanding the genetic basis for tissue folding, and how our genes control the development of specific bodily features, can help determine how birth defects arise during development. “If cell cycle control is misregulated during development, it could actually alter the shape of that tissue,” says Martin. The study paves the way for further research into how exactly the location of myosin in the cell is regulated, and how it is affected at the molecular level by cell division.
“We observed that when these cells enter mitosis, the localization of myosin activators changes. But we don’t really know how it changes,” says Ko. “That would be a pretty interesting research problem, especially considering that it’s such an integral part of force generation in cells.” Kalakuntla has begun investigating what controls these regulators, which will be an avenue of future research for the lab.
Top image: Myosin networks, in green, contract cell membranes in the mesoderm of a developing Drosophila embryo. Credit: Martin lab.
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“Apical Constriction Reversal upon Mitotic Entry Underlies Different Morphogenetic Outcomes of Cell Division”
Molecular Biology of the Cell, online March 4, 2020, DOI: 10.1091/mbc.E19-12-0673
Clint S. Ko, Prateek Kalakuntla, and Adam C. Martin
Three MIT undergraduates who use computer science to explore human biology and health honored for their academic achievements.
Fernanda Ferreira | School of Science
April 10, 2020
MIT students Katie Collins, Vaishnavi Phadnis, and Vaibhavi Shah have been selected to receive a Barry Goldwater Scholarship for the 2020-21 academic year. Over 5,000 college students from across the United States were nominated for the scholarships, from which only 396 recipients were selected based on academic merit.
The Goldwater scholarships have been conferred since 1989 by the Barry Goldwater Scholarship and Excellence in Education Foundation. These scholarships have supported undergraduates who go on to become leading scientists, engineers, and mathematicians in their respective fields. All of the 2020-21 Goldwater Scholars intend to obtain a doctorate in their area of research, including the three MIT recipients.
Katie Collins, a third-year majoring in brain and cognitive sciences with minors in computer science and biomedical engineering, got involved with research in high school, when she worked on computational models of metabolic networks and synthetic gene networks in the lab of Department of Electrical Engineering and Computer Science Professor Timothy Lu at MIT. It was this project that led her to realize how challenging it is to model and analyze complex biological networks. She also learned that machine learning can provide a path for exploring these networks and understanding human diseases. This realization has coursed a scientific path for Collins that is equally steeped in computer science and human biology.
Over the past few years, Collins has become increasingly interested in the human brain, particularly what machine learning can learn from human common-sense reasoning and the way brains process sparse, noisy data. “I aim to develop novel computational algorithms to analyze complex, high-dimensional data in biomedicine, as well as advance modelling paradigms to improve our understanding of human cognition,” explains Collins. In his letter of recommendation, Professor Tomaso Poggio, the Eugene McDermott Professor in the Department of Brain and Cognitive Sciences and one of Collins’ mentors, wrote, “It is very difficult to imagine a better candidate for the Goldwater fellowship.” Collins plans to pursue a PhD studying machine learning or computational neuroscience and to one day run her own lab. “I hope to become a professor, leading a research program at the interface of computer science and cognitive neuroscience.”
Vaishnavi Phadnis, a second-year majoring in computer science and molecular biology, sees molecular and cellular biology as the bridge between chemistry and life, and she’s been enthralled with understanding that bridge since 7th grade, when she learned about the chemical basis of the cell. Phadnis spent two years working in a cancer research lab while still in high school, an experience which convinced her that research was not just her passion but also her future. “In my first week at MIT, I approached Professor Robert Weinberg, and I’ve been grateful to do research in his lab ever since,” she says.
“Vaishnavi’s exuberance makes her a joy to have in the lab,” wrote Weinberg, who is the Daniel Ludwig Professor in the Department of Biology. Phadnis is investigating ferroptosis, NetBet live casinoa recently discovered, iron-dependent form of cell death that may be relevant in neurodegeneration and also a potential strategy for targeting highly aggressive cancer cells. “She is a phenomenon who has vastly exceeded our expectations of the powers of someone her age,” Weinberg says. Phadnis is thankful to Weinberg and all the scientific mentors, both past and present, that have inspired her along her research path. Deciphering the mechanisms behind fundamental cellular processes and exploring their application in human diseases is something Phadnis plans to continue doing in her future as a physician-scientist after pursuing an MD/PhD. “I hope to devote most of my time to leading my own research group, while also practicing medicine,” she says.
Vaibhavi Shah, a third-year studying biological engineering with a minor in science, technology and society, spent a lot of time in high school theorizing ways to tackle major shortcomings in medicine and science with the help of technology. “When I came to college, I was able to bring some of these ideas to fruition,” she says, working with both the Big Data in Radiology Group at the University of California at San Francisco and the lab of Professor Mriganka Sur, the Newton Professor of Neuroscience in the Department of Brain and Cognitive Sciences.
Shah is particularly interested in integrating innovative research findings with traditional clinical practices. According to her, technology, like computer vision algorithms, can be adopted to diagnose diseases such as Alzheimer’s, allowing patients to start appropriate treatments earlier. “This is often harder to do at smaller, rural institutions that may not always have a specialist present,” says Shah, and algorithms can help fill that gap. One of aims of Shah’s research is to improve the efficiency and equitability of physician decision-making. “My ultimate goal is to improve patient outcomes, and I aim to do this by tackling emerging scientific questions in machine learning and artificial intelligence at the forefront of neurology,” she says. The clinic is a place Shah expects to be in the future after obtaining her physician-scientist training, saying, “I hope to a practicing neurosurgeon and clinical investigator.”
The Barry Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Senator Barry Goldwater, a soldier and statesman who served the country for 56 years. Awardees receive scholarships of up to $7,500 a year to cover costs related to tuition, room and board, fees, and books.
An internship with MIT Biology can get you on your way.
Raleigh McElvery
April 7, 2020
For the past several years, MIT Biology has been training undergraduates, graduate students, and research associates in the craft of science communication. In an effort to foster professional development and share the exciting research that transpires on campus, our communications team offers science writing and multimedia internships. We develop these positions to align with the interests of our interns, who often help out on a volunteer basis. Assignments range from assisting with videos and podcasts to writing news stories and profiles, aiding with social media, and chronicling the history of the department. After honing their own skills, many of our interns have successfully competed for prestigious communications fellowships, graduate programs in science writing, and communications jobs. Take a look at what they’ve done, and contact us if you’re a member of the department interested in joining our team.
Justin Chen PhD ’18 (Spring 2017 – Spring 2018)
Justin Chen earned his PhD in Hazel Sive’s lab, using frog embryos to model human craniofacial development. As a science writing intern, he composed student profiles for the department website and articles on research papers for MIT News. After graduating from MIT, he earned an AAAS Mass Media and Science and Engineering Fellowship, which he spent at STAT News publishing breaking news and profiles of scientists. He is currently an external affairs associate at OpenBiome, where he drafts press releases, annual reports, academic publications, and patient education materials, while helping to manage the website and social media. In addition to his work at Openbiome, he authors personal essays as a writer-in-residence at Porter Square Books.
Nafisa Syed SB ’19 (Spring 2019)
Nafisa Syed earned her bachelor’s degree in Biology (Course 7), with minors in Science Writing (Course 21W) and Brain and Cognitive Sciences (Course 9). She was an editor at The Tech, MIT Undergraduate Research Journal (MURJ), and Rune Literary Magazine, while completing a UROP in Evelina Fedorenko’s lab studying the brain’s language regions. As an intern at MIT Biology, Nafisa generated content for the internal newsletter, spearheaded social media campaigns, and analyzed data displaying the distribution of life science funding across the Institute. She is currently earning her master’s degree at MIT’s Graduate Program in Science Writing.
Saima Sidik (Spring 2019 – Spring 2020)
Saima Sidik is a research associate in Sebastian Lourido’s lab, where she studies how the parasite Toxoplasma gondii causes disease. In addition to authoring articles on scientific research for her blog, 10X Objective, Saima composes student profiles for the department website and MIT News, news briefs, and archival pieces about the history of biology at MIT. Starting this fall, she will begin her master’s degree at MIT’s Graduate Program in Science Writing.
Lucy Jakub (Fall 2019- Spring 2020)
Lucy Jakub served as the editorial assistant at The New York Review of Books for two years before entering MIT’s Graduate Program in Science Writing in the fall of 2019. As an intern for MIT Biology, she writes news briefs for the department website, student profiles for MIT News, and articles on recent events, in addition to generating the internal newsletter and social media campaigns. Her work has also appeared in Harper’s Magazine and National Geographic.
Sebastian Swanson (Fall 2018 – present)
Sebastian Swanson is a fourth-year graduate student in Amy Keating’s lab, studying the principles of protein-protein interactions in order to develop algorithms for peptide design. As an undergraduate at the University of Minnesota, he served as an officer and co-chair of MinneCinema Studios, which produces a variety of multimedia projects ranging from mock TV episodes to short films. He is currently the department’s primary cinematographer, filming faculty profiles and short videos on research projects.
Are you a member of the MIT Biology community interested in honing your scientific communication skills? Contact biowebmaster@mit.edu to discuss potential internship opportunities.
Neurons that store abstract representations of past experiences are activated when a new, similar event takes place.
Anne Trafton | MIT News Office
April 6, 2020
Imagine you are meeting a friend for dinner at a new restaurant. You may try dishes you haven’t had before, and your surroundings will be completely new to you. However, your brain knows that you have had similar experiences — perusing a menu, ordering appetizers, and splurging on dessert are all things that you have probably done when dining out.
MIT neuroscientists have now identified populations of cells that encode each of these distinctive segments of an overall experience. These chunks of memory, stored in the hippocampus, are activated whenever a similar type of experience takes place, and are distinct from the neural code that stores detailed memories of a specific location.
The researchers believe that this kind of “event code,” which they discovered in a study of mice, may help the brain interpret novel situations and learn new information by using the same cells to represent similar experiences.
“When you encounter something new, there are some really new and notable stimuli, but you already know quite a bit about that particular experience, because it’s a similar kind of experience to what you have already had before,” says Susumu Tonegawa, a professor of biology and neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory.
Tonegawa is the senior author of the study, which appears today in Nature Neuroscience. Chen Sun, an MIT graduate student, is the lead author of the paper. New York University graduate student Wannan Yang and Picower Institute technical associate Jared Martin are also authors of the paper.
Encoding abstraction
It is well-established that certain cells in the brain’s hippocampus are specialized to store memories of specific locations. Research in mice has shown that within the hippocampus, neurons called place cells fire when the animals are in a specific location, or even if they are dreaming about that location.
In the new study, the MIT team wanted to investigate whether the hippocampus also stores representations of more abstract elements of a memory. That is, instead of firing whenever you enter a particular restaurant, such cells might encode “dessert,” no matter where you’re eating it.
To test this hypothesis, the researchers measured activity in neurons of the CA1 region of the mouse hippocampus as the mice repeatedly ran a four-lap maze. At the end of every fourth lap, the mice were given a reward. As expected, the researchers found place cells that lit up when the mice reached certain points along the track. However, the researchers also found sets of cells that were active during one of the four laps, but not the others. About 30 percent of the neurons in CA1 appeared to be involved in creating this “event code.”
“This gave us the initial inkling that besides a code for space, cells in the hippocampus also care about this discrete chunk of experience called lap 1, or this discrete chunk of experience called lap 2, or lap 3, or lap 4,” Sun says.
To further explore this idea, the researchers trained mice to run a square maze on day 1 and then a circular maze on day 2, in which they also received a reward after every fourth lap. They found that the place cells changed their activity, reflecting the new environment. However, the same sets of lap-specific cells were activated during each of the four laps, regardless of the shape of the track. The lap-encoding cells’ activity also remained consistent when laps were randomly shortened or lengthened.
“Even in the new spatial locations, cells still maintain their coding for the lap number, suggesting that cells that were coding for a square lap 1 have now been transferred to code for a circular lap 1,” Sun says.
The researchers also showed that if they used optogenetics to inhibit sensory input from a part of the brain called the medial entorhinal cortex (MEC), lap-encoding did not occur. They are now investigating what kind of input the MEC region provides to help the hippocampus create memories consisting of chunks of an experience.
Two distinct codes
These findings suggest that, indeed, every time you eat dinner, similar memory cells are activated, no matter where or what you’re eating. The researchers theorize that the hippocampus contains “two mutually and independently manipulatable codes,” Sun says. One encodes continuous changes in location, time, and sensory input, while the other organizes an overall experience into smaller chunks that fit into known categories such as appetizer and dessert.
“We believe that both types of hippocampal codes are useful, and both are important,” Tonegawa says. “If we want to remember all the details of what happened in a specific experience, moment-to-moment changes that occurred, then the continuous monitoring is effective. But on the other hand, when we have a longer experience, if you put it into chunks, and remember the abstract order of the abstract chunks, that’s more effective than monitoring this long process of continuous changes.”
NetBet live casinoThe new MIT results “significantly advance our knowledge about the function of the hippocampus,” says Gyorgy Buzsaki, a professor of neuroscience at New York University School of Medicine, who was not part of the research team.
“These findings are significant because they are telling us that the hippocampus does a lot more than just ‘representing’ space or integrating paths into a continuous long journey,” Buzsaki says. “From these remarkable results Tonegawa and colleagues conclude that they discovered an ‘event code,’ dedicated to organizing experience by events, and that this code is independent of spatial and time representations, that is, jobs also attributed to the hippocampus.”
Tonegawa and Sun believe that networks of cells that encode chunks of experiences may also be useful for a type of learning called transfer learning, which allows you to apply knowledge you already have to help you interpret new experiences or learn new things. Tonegawa’s lab is now working on trying to find cell populations that might encode these specific pieces of knowledge.
The research was funded by the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, and the JPB Foundation.
April 1, 2020
April 2, 2020
March 30, 2020
Junior Emily O’Rourke traveled to South Africa to investigate epidemics and returned with a broader outlook on her fundamental disease research.
Raleigh McElvery
March 31, 2020
Growing up in El Paso, Texas near the border of the U.S. and Mexico, Emily O’Rourke could venture across cultures in less time than it takes most people to commute to work. In fact, her dad would make this short trip each day for his job as a mechanical engineer. Watching him cross over so frequently reminded O’Rourke that “ideas and skills don’t stop at the border.” O’Rourke herself would visit Mexico to see relatives, and these experiences seeded aspirations to spearhead international scientific collaborations. Now a junior in Course 7 (Biology), O’Rourke is continuing to add stamps to her passport while exploring the global implications of disease research.
O’Rourke chose MIT because it offered a particularly wide array of study abroad programs, in addition to having top-tier research opportunities. One such study abroad program, MIT International Science and Technology Initiatives (MISTI), operates 25 regional programs, matching undergraduate and graduate students with fully-funded internship, research, and teaching opportunities in over 40 countries. The summer after her first year, O’Rourke participated in MISTI’s MIT-Italy Program in order to gain some research experience in the realm of urban planning. For six weeks, she investigated the urban effects of sea level rise while living in Venice.
When she returned to campus for her sophomore year, O’Rourke was intending to double major in physics and biology. But she ultimately opted to drop physics and pursue the life sciences once she started working in Becky Lamason’s lab in the Department of Biology.
“I started to see how biology worked on a practical level,” she says. “I get to experience a hands-on connection by running DNA on a gel and doing other experiments. During our weekly lab meetings, I witness scientific stories as they unfold.”
More recently, the duo has begun to examine how Sca4 may coopt another protein in the host cell, known as clathrin, for its own malicious means. “Sca4 is a really big protein and we still don’t know its entire structure,” O’Rourke says, “and we’re hoping to uncover some new functions.”The Lamason lab investigates how parasites hijack host cells processes in order to spread infection. O’Rourke is working with graduate student Cassandra Vondrak to probe the proteins that allow the tick-borne Rickettsia parkeri to migrate from one cell to the next. Their protein of interest, surface cell antigen 4 (Sca4), is secreted by the bacterium and binds to the host’s cell membrane, reducing the tension across the membrane and allowing Rickettsia to punch through to the neighboring cell. O’Rourke and Vondrak aim to determine how Rickettsia releases Sca4, in the hopes of piecing together a general mechanism by which pathogens propagate.
While O’Rourke was studying infectious disease on a cellular level, she heard about an opportunity to explore epidemics on a global scale. Each January, the Harvard-MIT Program in Health Sciences and Technology sponsors a two-week class in South Africa called Evolution of an Epidemic. The class, taught by Professor of the Practice Bruce Walker, covers the medical, scientific, and political responses to new diseases, focusing on the HIV/AIDS epidemic. Walker, who is also the director of the Ragon Institute of MGH, MIT and Harvard, is a world leader in the study of immune control and evasion in HIV infection. Since then, he’s developed strong connections and research partnerships in South Africa where the disease is most prevalent.
O’Rourke enrolled in Evolution of an Epidemic, and MISTI helped her to plan her trip. On January 16, she landed in Johannesburg, the first of three destinations. The cohort of students from MIT, Harvard, and the African Leadership Academy attended lectures, spoke with patients, and met medical professionals.
After Johannesburg, the class traveled to Durban where they visited traditional healers who were learning to administer HIV/AIDS tests as part of the iTeach program.
“We had the chance to ask these healers how they felt about interacting with Western medicine, and whether it clashed with their traditional values,” O’Rourke says. “They said HIV was so new that they couldn’t draw upon ancient wisdom from their ancestors to treat it. They were directing patients towards Western treatments because they’d seen the devastation the disease could cause.”
At their third and final netbet sports bettingdestination, the province of KwaZulu-Natal, O’Rourke toured the FRESH Program. Twice a week, as part of a clinical trial, healthy African women around O’Rourke’s age attend classes that address topics like self-esteem, gender-based violence, HIV prevention, career development, and computer training. Before each session, the women are tested for HIV/AIDS, so if they contract it the researchers can treat it early and learn more about the disease’s initial stages.
“I really liked going there because it helped me see a direct connection between science and social good,” O’Rourke says. “It showed the value of talking to patients and asking about their experiences, rather than just looking at study outcomes.”
After two weeks, O’Rourke returned to MIT Biology and the Lamason lab with a broader outlook on her parasite research. “I’m able to see how my works fits into a larger context,” she says, “and how it may eventually have far-reaching impacts on disease evolution and spread.”
O’Rourke still plans to pursue fundamental biological research, but intends to seek out international collaborations focused on global health as well. It’s hard to leave the MIT bubble, she says, but it’s worth it. “Traveling can really broaden your perspective as a scientist, and inform your research in unexpected ways.”
Photos courtesy of Emily O’Rourke
Posted 4.1.20
Repurposing a drug used for blood clots may help Covid-19 patients in danger of respiratory failure, researchers suggest.
Anne Trafton | MIT News Office
March 26, 2020
Researchers at MIT and the University of Colorado at Denver have proposed a stopgap measure that they believe could help Covid-19 patients who are in acute respiratory distress. By repurposing a drug that is now used to treat blood clots, they believe they could help people in cases where a ventilator is not helping, or if a ventilator is not available.
Three hospitals in Massachusetts and Colorado are developing plans to test this approach in severely ill Covid-19 patients. The drug, a protein called tissue plasminogen activator (tPA), is commonly given to heart attack and stroke victims. The approach is based on emerging data from China and Italy that Covid-19 patients have a profound disorder of blood clotting that is contributing to their respiratory failure.
“If this were to work, which I hope it will, it could potentially be scaled up very quickly, because every hospital already has it in their pharmacy,” says Michael Yaffe, a David H. Koch Professor of Science at MIT. “We don’t have to make a new drug, and we don’t have to do the same kind of testing that you would have to do with a new agent. This is a drug that we already use. We’re just trying to repurpose it.”
Yaffe, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and an intensive care physician at Boston’s Beth Israel Deaconess Medical Center/Harvard Medical School, is the senior author of a paper describing the new approach.
The paper, which appears in the Journal of Trauma and Acute Care Surgery, was co-authored by Christopher Barrett, a surgeon at Beth Israel Deaconess and a visiting scientist at MIT; Hunter Moore, Ernest Moore, Peter Moore, and Robert McIntyre of the University of Colorado at Denver; Daniel Talmor of Beth Israel Deaconess; and Frederick Moore of the University of Florida.
Breaking up clots
In one large-scale study of the Covid-19 outbreak in Wuhan, China, it was found that 5 percent of patients required intensive care and 2.3 percent required a ventilator. Many doctors and public health officials in the United States worry that there may not be enough ventilators for all Covid-19 patients who will need them. In China and Italy, a significant number of the patients who required a ventilator went on to die of respiratory failure, despite maximal support, indicating that there is a need for additional treatment approaches.
The treatment that the MIT and University of Colorado team now proposes is based on many years of research into what happens in the lungs during respiratory failure. In such patients, blood clots often form in the lungs. Very small clots called microthrombi can also form in the blood vessels of the lungs. These tiny clots prevent blood from reaching the airspaces of the lungs, where blood normally becomes oxygenated.
The researchers believe that tPA, which helps to dissolve blood clots, may help patients in acute respiratory distress. A natural protein found in our bodies, tPA converts plasminogen to an enzyme called plasmin, which breaks down clots. Larger amounts are often given to heart attack patients or stroke victims to dissolve the clot causing the heart attack or stroke.
Animal experiments, and one human trial, have shown potential benefits of this approach in treating respiratory distress. In the human trial, performed in 2001, 20 patients who were in respiratory failure following trauma or sepsis were given drugs that activate plasminogen (urokinase or streptokinase, but not tPA). All of the patients in the trial had respiratory distress so severe that they were not expected to survive, but 30 percent of them survived following treatment.
That is the only study using plasminogen activators to treat respiratory failure in humans to date, largely because improved ventilator strategies have been working well. This appears not to be the case for many patients with Covid-19, Yaffe says.
The idea to try this treatment in Covid-19 patients arose, in part, because the Colorado and MIT research team has spent the last several years studying the inflammation and abnormal bleeding that can occur in the lungs following traumatic injuries. It turns out that Covid-19 patients also suffer from inflammation-linked tissue damage, which has been seen in autopsy results from those patients and may contribute to clot formation.
“What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with Covid-19 are hypercoagulable, meaning that they are clotting off their IVs, and having kidney and heart failure netbet online sports bettingfrom blood clots, in addition to lung failure. There’s plenty of basic science to support the idea that this concept should be beneficial,” Yaffe says. “The tricky part, of course, is figuring out the right dose and route of administration. But the target we are going after is well-validated.”
Potential benefits
The researchers will test tPA in patients under the FDA’s “compassionate use” program, which allows experimental drugs to be used in cases where there are no other treatment options. If the drug appears to help in an initial set of patients, its use could be expanded further, Yaffe says.
“We learned that the clinical trial will be funded by BARDA [the Biomedical Advanced Research and Development Authority], and that Francis Collins, the NIH director, was briefed on the approach yesterday afternoon,” he says. “Genentech, the manufacturer of tPA, has already donated the drug for the initial trial, and indicated that they will rapidly expand access if the initial patient response is encouraging.”
Based on the latest data from their colleagues in Colorado, these groups plan to deliver the drug both intravenously and/or instill it directly into the airways. The intravenous route is currently used for stroke and heart attack patients. Their idea is to give one dose rapidly, over a two-hour period, followed by an equivalent dose given more slowly over 22 hours. Applied BioMath, a company spun out by former MIT researchers, is now working on computational models that may help to refine the dosing schedule.
“If it were to work, and we don’t yet know if it will, it has a lot of potential for rapid expansion,” Yaffe says. “The public health benefits are obvious. We might get people off ventilators quicker, and we could potentially prevent people from needing to go on a ventilator.”
The hospitals planning to test this approach are Beth Israel Deaconess, the University of Colorado Anschultz Medical Campus, and Denver Health. The research that led to this proposal was funded by the National Institutes of Health and the Department of Defense Peer Reviewed Medical Research Program.