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News Article | February 15, 2017
Site: news.mit.edu

Forbes‘ sixth annual 30 Under 30 list calls itself “the most definitive gathering of today’s leading young change-makers and innovators” who are not yet 30 years old. As in past years, the MIT community is well-represented throughout. At least 30 MITers are spread among the 600 names and 20 diverse categories in this year’s list. (According to Forbes, the 600 honorees were narrowed from an applicant list of more than 15,000.) The MIT faculty, staff, students, and alumni named to the 2017 Forbes’ 30 Under 30 are listed below with the category for which they were recognized in parentheses. Noam Angrist ’13 (social entrepreneur), cofounder of Young 1ove. “Based in Botswana, where 22 percent of the population has HIV, Young 1ove has developed a curriculum that has reached over 35,000 students in more than 360 schools.” Ricky Ashenfelter MBA ’15 (social entrepreneur), cofounder of Spoiler Alert. “Spoiler Alert’s mission is to ensure that no food surplus goes to waste … making it easy to sustainably deal with excess food.” Alessandro Babini SM ‘15 (sports), cofounder of Humon. “Alessandro’s company is building a wearable device that measures oxygen levels in muscles to determine how hard athletes should push themselves.” Adam Behrens (health care), MIT postdoc at the Koch Institute for Integrative Cancer Research. “Working in the lab of serial biotech entrepreneur Robert Langer, Behrens is taking on germs in the developing world.” Archit Bhise ’13 and Vinayak Ramesh ’12 (health care), cofounders of Wellframe. “Wellframe sells insurance companies a mobile app that helps patients manage complex sets of conditions (think of the problem of having both diabetes and cancer). The insurance company also gets a dashboard that helps them stay in close touch with patients.” Raja Bobbili ’08 (finance), analyst at Abrams Capital. “Bobbili works with four other investment staff to manage one of Wall Street’s most concentrated and successful portfolios.” Christina Bognet ’10 (consumer tech), CEO of Platejoy. “Bognet leads PlateJoy, a nutrition startup that curates specialized recipes for users based on diet and weight-loss needs.” Brad Cordova SM ’13 (enterprise technology), cofounder of TrueMotion. “[TrueMotion] set out to make driving safer through the use of data and analytics, as well as help insurance companies identify risky and cautious drivers.” Mackey Craven ’10, SM ’10 (venture capital), partner of OpenView Partners. “Craven sits on the board at Scalr and is a board observer at Datadog, UserTesting, Socrata, SwiftStack, and Skytap.” Prarthna Desai ’11 (health care), operations at Zipline. “[Desai] is leading efforts to integrate the medicine-delivery-by-drone service with the health care system in Rwanda.” Melissa Gymrek ’11, PhD ’16 (science), assistant professor at the University of California at San Diego. “Gymrek studies genetic variation in humans, particularly at what’s known as short tandem repeats.” Jiang He (health care), MIT postdoc at the Institute for Medical Engineering and Science. “[He] used a new technology called single-virus tracking, super-resolution imaging to understand more about how influenza infects cells.” Sean Hunt SM ’13, PhD ’16 (manufacturing and industry), cofounder of Solugen, Inc. “Solugen has developed a scaled, sustainable process to create hydrogen peroxide from plants.” Christina Karapataki SM ’12 (energy), principal at Schlumberger. “Karapataki makes venture capital investments on behalf of Schlumberger, the world’s biggest oilfield services company.” James Karraker ’12, MEng ’13 (consumer tech), co-founder of Scriptdash. “Karraker is one of two cofounders behind ScriptDash, which bills itself as a ‘modern pharmacy’ and sends drugs directly to customers.” Kai Kloepfer (consumer tech), MIT freshman and founder of Biofire Technologies. “For the last three years, [Kloepfer] has been developing a gun that can only be fired when it reads its owner’s fingerprint.” Hasier Larrea SM ’15 (manufacturing and industry), foudner of Ori. “[Ori] allows for a number of configurations, from bedroom to office to living room, and back again, all controlled from one control panel.” John Lewandowski (social entrepreneurs), MIT grad student in mechanical engineering and founder of the Disease Diagnostic Group. “Disease Diagnostic Group screens patients for malaria in just five seconds with a reusable handheld device.” Curtis Liu ’10 and Spensser Skates ’10 (enterprise technology), cofounders of Amplitude Analytics. “Skates and Liu…cofounded their second company on the floor of Liu’s bedroom in 2012: Amplitude. The San Francisco, Calif.-based startup aims to help companies build better products through advanced analytics and has raised $26 million in funding to date.” Jessica McKellar ’09, MEng ’10 (enterprise tech), director of engineering at Dropbox. “McKellar joined Dropbox three years ago when the company acquired Zulip, the real-time collaboration startup McKellar cofounded in 2012.” Stefanie Mueller (science), MIT assistant professor of electrical engineering and computer science. “Mueller’s work focuses on the computer science of ‘physical data,’ such as that involved in 3-D printing.” Jacob Rubens PhD ’16 (science), associate at Flagship Pioneering. “[Rubens] works to develop science, strategy and intellectual property for promising science-based startups.” Phiala Shanahan (science), MIT postdoc in the Department of Physics. “Shanahan researches the physics of atomic nuclei, and her work has implications for understanding dark matter and physics beyond the Standard Model.” Mark Smith PhD ’14 (science), cofounder of OpenBiome. “Like a blood bank for human stool, the nonprofit’s work has helped over 18,000 patients.” Justin Solomon (science), MIT assistant professor in electrical engineering and computer science. “Solomon researches geometric problems in computer graphics, computer vision, and machine learning.” John Urschel (science), MIT grad student in mathematics and Baltimore Ravens guard. “Urschel has published six peer-reviewed mathematics papers to date and has three more ready for review. All this while playing guard for the Baltimore Ravens.” Tim Wang (health care), MIT grad student in biology and cofounder of KSQ Therapeutics. “Wang cofounded KSQ Therapeutics, a drug company that uses his work using the gene-editing technology CRISPR, to look for new drugs.” Kwami Williams ’12 (social entrepreneurs), cofounder of MoringaConnect. “MoringaConnect takes the moringa tree, a plant common in arid climates like Africa, and turns it into beauty products and pre-packaged snacks.”


News Article | February 15, 2017
Site: news.mit.edu

Many scientists are pursuing ways to treat disease by delivering DNA or RNA that can turn a gene on or off. However, a major obstacle to progress in this field has been finding ways to safely deliver that genetic material to the correct cells. Encapsulating strands of RNA or DNA in tiny particles is one promising approach. To help speed up the development of such drug-delivery vehicles, a team of researchers from MIT, Georgia Tech, and the University of Florida has now devised a way to rapidly test different nanoparticles to see where they go in the body. “Drug delivery is a really substantial hurdle that needs to be overcome,” says James Dahlman, a former MIT graduate student who is now an assistant professor at Georgia Tech and the study’s lead author. “Regardless of their biological mechanisms of action, all genetic therapies need safe and specific drug delivery to the tissue you want to target.” This approach, described in the Proceedings of the National Academy of Sciences the week of Feb. 6, could help scientists target genetic therapies to precise locations in the body. “It could be used to identify a nanoparticle that goes to a certain place, and with that information we could then develop the nanoparticle with a specific payload in mind,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES). The paper’s senior authors are Anderson; Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute; and Eric Wang, a professor at the University of Florida. Other authors are graduate student Kevin Kauffman, recent MIT graduates Yiping Xing and Chloe Dlott, MIT undergraduate Taylor Shaw, and Koch Institute technical assistant Faryal Mir. Finding a reliable way to deliver DNA to target cells could help scientists realize the potential of gene therapy — a method of treating diseases such as cystic fibrosis or hemophilia by delivering new genes that replace missing or defective versions. Another promising approach for new therapies is RNA interference, which can be used to turn off overactive genes by blocking them with short strands of RNA known as siRNA. Delivering these types of genetic material into body cells has proven difficult, however, because the body has evolved many defense mechanisms against foreign genetic material such as viruses. To help evade these defenses, Anderson’s lab has developed nanoparticles, including many made from fatty molecules called lipids, that protect genetic material and carry it to a particular destination. Many of these particles tend to accumulate in the liver, in part because the liver is responsible for filtering blood, but it has been more difficult to find particles that target other organs. “We’ve gotten good at delivering nanoparticles into certain tissues but not all of them,” Anderson says. “We also haven’t really figured out how the particles’ chemistries influence targeting to different destinations.” To identify promising candidates, Anderson’s lab generates libraries of thousands of particles, by varying traits such as their size and chemical composition. Researchers then test the particles by placing them on a particular cell type, grown in a lab dish, to see if the particles can get into the cells. The best candidates are then tested in animals. However, this is a slow process and limits the number of particles that can be tried. “The problem we have is we can make a lot more nanoparticles than we can test,” Anderson says. To overcome that hurdle, the researchers decided to add “barcodes,” consisting of a DNA sequence of about 60 nucleotides, to each type of particle. After injecting the particles into an animal, the researchers can retrieve the DNA barcodes from different tissues and then sequence the barcodes to see which particles ended up where. “What it allows us to do is test many different nanoparticles at once inside a single animal,” Dahlman says. The researchers first tested particles that had been previously shown to target the lungs and the liver, and confirmed that they did go where expected. Then, the researchers screened 30 different lipid nanoparticles that varied in one key trait — the structure of a component known as polyethylene glycol (PEG), a polymer often added to drugs to increase their longevity in the bloodstream. Lipid nanoparticles can also vary in their size and other aspects of their chemical composition. Each of the particles was also tagged with one of 30 DNA barcodes. By sequencing barcodes that ended up in different parts of the body, the researchers were able to identify particles that targeted the heart, brain, uterus, muscle, kidney, and pancreas, in addition to liver and lung. In future studies, they plan to investigate what makes different particles zero in on different tissues. The researchers also performed further tests on one of the particles, which targets the liver, and found that it could successfully deliver siRNA that turns off the gene for a blood clotting factor. Victor Koteliansky, director of the Skoltech Center for Functional Genomics, described the technique as an “innovative” way to speed up the process of identifying promising nanoparticles to deliver RNA and DNA. “Finding a good particle is a very rare event, so you need to screen a lot of particles. This approach is faster and can give you a deeper understanding of where particles will go in the body,” says Kotelianksy, who was not involved in the research. This type of screen could also be used to test other kinds of nanoparticles such as those made from polymers. “We’re really hoping that other labs across the country and across the world will try our system to see if it works for them,” Dahlman says. The research was funded by an MIT Presidential Fellowship, a National Defense Science and Engineering Graduate Fellowship, a National Science Foundation Graduate Research Fellowship, the MIT Undergraduate Research Opportunities Program, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, and the National Institutes of Health.


News Article | February 10, 2017
Site: www.biosciencetechnology.com

Many scientists are pursuing ways to treat disease by delivering DNA or RNA that can turn a gene on or off. However, a major obstacle to progress in this field has been finding ways to safely deliver that genetic material to the correct cells. Encapsulating strands of RNA or DNA in tiny particles is one promising approach. To help speed up the development of such drug-delivery vehicles, a team of researchers from MIT, Georgia Tech, and the University of Florida has now devised a way to rapidly test different nanoparticles to see where they go in the body. “Drug delivery is a really substantial hurdle that needs to be overcome,” said James Dahlman, a former MIT graduate student who is now an assistant professor at Georgia Tech and the study’s lead author. “Regardless of their biological mechanisms of action, all genetic therapies need safe and specific drug delivery to the tissue you want to target.” This approach, described in the Proceedings of the National Academy of Sciences the week of Feb. 6, could help scientists target genetic therapies to precise locations in the body. “It could be used to identify a nanoparticle that goes to a certain place, and with that information we could then develop the nanoparticle with a specific payload in mind,” said Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES). The paper’s senior authors are Anderson; Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute; and Eric Wang, a professor at the University of Florida. Other authors are graduate student Kevin Kauffman, recent MIT graduates Yiping Xing and Chloe Dlott, MIT undergraduate Taylor Shaw, and Koch Institute technical assistant Faryal Mir. Finding a reliable way to deliver DNA to target cells could help scientists realize the potential of gene therapy — a method of treating diseases such as cystic fibrosis or hemophilia by delivering new genes that replace missing or defective versions. Another promising approach for new therapies is RNA interference, which can be used to turn off overactive genes by blocking them with short strands of RNA known as siRNA. Delivering these types of genetic material into body cells has proven difficult, however, because the body has evolved many defense mechanisms against foreign genetic material such as viruses. To help evade these defenses, Anderson’s lab has developed nanoparticles, including many made from fatty molecules called lipids, that protect genetic material and carry it to a particular destination. Many of these particles tend to accumulate in the liver, in part because the liver is responsible for filtering blood, but it has been more difficult to find particles that target other organs. “We’ve gotten good at delivering nanoparticles into certain tissues but not all of them,” Anderson said. “We also haven’t really figured out how the particles’ chemistries influence targeting to different destinations.” To identify promising candidates, Anderson’s lab generates libraries of thousands of particles, by varying traits such as their size and chemical composition. Researchers then test the particles by placing them on a particular cell type, grown in a lab dish, to see if the particles can get into the cells. The best candidates are then tested in animals. However, this is a slow process and limits the number of particles that can be tried. “The problem we have is we can make a lot more nanoparticles than we can test,” Anderson said. To overcome that hurdle, the researchers decided to add “barcodes,” consisting of a DNA sequence of about 60 nucleotides, to each type of particle. After injecting the particles into an animal, the researchers can retrieve the DNA barcodes from different tissues and then sequence the barcodes to see which particles ended up where. “What it allows us to do is test many different nanoparticles at once inside a single animal,” Dahlman said. The researchers first tested particles that had been previously shown to target the lungs and the liver, and confirmed that they did go where expected. Then, the researchers screened 30 different lipid nanoparticles that varied in one key trait — the structure of a component known as polyethylene glycol (PEG), a polymer often added to drugs to increase their longevity in the bloodstream. Lipid nanoparticles can also vary in their size and other aspects of their chemical composition. Each of the particles was also tagged with one of 30 DNA barcodes. By sequencing barcodes that ended up in different parts of the body, the researchers were able to identify particles that targeted the heart, brain, uterus, muscle, kidney, and pancreas, in addition to liver and lung. In future studies, they plan to investigate what makes different particles zero in on different tissues. The researchers also performed further tests on one of the particles, which targets the liver, and found that it could successfully deliver siRNA that turns off the gene for a blood clotting factor. Victor Koteliansky, director of the Skoltech Center for Functional Genomics, described the technique as an “innovative” way to speed up the process of identifying promising nanoparticles to deliver RNA and DNA. “Finding a good particle is a very rare event, so you need to screen a lot of particles. This approach is faster and can give you a deeper understanding of where particles will go in the body,” said Kotelianksy, who was not involved in the research. This type of screen could also be used to test other kinds of nanoparticles such as those made from polymers. “We’re really hoping that other labs across the country and across the world will try our system to see if it works for them,” Dahlman said. The research was funded by an MIT Presidential Fellowship, a National Defense Science and Engineering Graduate Fellowship, a National Science Foundation Graduate Research Fellowship, the MIT Undergraduate Research Opportunities Program, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, and the National Institutes of Health.


News Article | January 26, 2016
Site: www.biosciencetechnology.com

In patients suffering from Type 1 diabetes, the immune system attacks the pancreas, eventually leaving patients without the ability to naturally control blood sugar. These patients must carefully monitor the amount of sugar in their blood, measuring it several times a day and then injecting themselves with insulin to keep their blood sugar levels within a healthy range. However, precise control of blood sugar is difficult to achieve, and patients face a range of long-term medical problems as a result. A better diabetes treatment, many researchers believe, would be to replace patients’ destroyed pancreatic islet cells with healthy cells that could take over glucose monitoring and insulin release. This approach has been used in hundreds of patients, but it has one major drawback — the patients’ immune systems attack the transplanted cells, requiring patients to take immunosuppressant drugs for the rest of their lives. Now, a new advance from MIT, Boston Children’s Hospital, and several other institutions may offer a way to fulfill the promise of islet cell transplantation. The researchers have designed a material that can be used to encapsulate human islet cells before transplanting them. In tests on mice, they showed that these encapsulated human cells could cure diabetes for up to six months, without provoking an immune response. Although more studies are needed, this approach “has the potential to provide diabetics with a new pancreas that is protected from the immune system, which would allow them to control their blood sugar without taking drugs. That’s the dream,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and a research fellow in the Department of Anesthesiology at Boston Children’s Hospital. Anderson is the senior author of two studies describing this method in the Jan. 25 issues of Nature Medicine and Nature Biotechnology. Researchers from Harvard University, the University of Illinois at Chicago, the Joslin Diabetes Center, and the University of Massachusetts Medical School also contributed to the research. Since the 1980s, a standard treatment for diabetic patients has been injections of insulin produced by genetically engineered bacteria. While effective, this type of treatment requires great effort by the patient and can generate large swings in blood sugar levels. At the urging of JDRF director Julia Greenstein, Anderson, Langer, and colleagues set out several years ago to come up with a way to make encapsulated islet cell transplantation a viable therapeutic approach. They began by exploring chemical derivatives of alginate, a material originally isolated from brown algae. Alginate gels can be made to encapsulate cells without harming them, and also allow molecules such as sugar and proteins to move through, making it possible for cells inside to sense and respond to biological signals. However, previous research has shown that when alginate capsules are implanted in primates and humans, scar tissue eventually builds up around the capsules, making the devices ineffective. The MIT/Children’s Hospital team decided to try to modify alginate to make it less likely to provoke this kind of immune response. “We decided to take an approach where you cast a very wide net and see what you can catch,” said Arturo Vegas, a former MIT and Boston Children’s Hospital postdoc who is now an assistant professor at Boston University. Vegas is the first author of the Nature Biotechnology paper and co-first author of the Nature Medicine paper. “We made all these derivatives of alginate by attaching different small molecules to the polymer chain, in hopes that these small molecule modifications would somehow give it the ability to prevent recognition by the immune system.” After creating a library of nearly 800 alginate derivatives, the researchers performed several rounds of tests in mice and nonhuman primates. One of the best of those, known as triazole-thiomorpholine dioxide (TMTD), they decided to study further in tests of diabetic mice. They chose a strain of mice with a strong immune system and implanted human islet cells encapsulated in TMTD into a region of the abdominal cavity known as the intraperitoneal space. The pancreatic islet cells used in this study were generated from human stem cells using a technique recently developed by Douglas Melton, a professor at Harvard University who is an author of the Nature Medicine paper. Following implantation, the cells immediately began producing insulin in response to blood sugar levels and were able to keep blood sugar under control for the length of the study, 174 days. “The really exciting part of this was being able to show, in an immune-competent mouse, that when encapsulated these cells do survive for a long period of time, at least six months,” said Omid Veiseh, a senior postdoc at the Koch Institute and Boston Children’s hospital, co-first author of the Nature Medicine paper, and an author of the Nature Biotechnology paper. “The cells can sense glucose and secrete insulin in a controlled manner, alleviating the mice’s need for injected insulin.” The researchers also found that 1.5-millimeter diameter capsules made from their best materials (but not carrying islet cells) could be implanted into the intraperitoneal space of nonhuman primates for at least six months without scar tissue building up. “The combined results from these two papers suggests that these capsules have real potential to protect transplanted cells in human patients,” said Robert Langer, the David H. Koch Institute Professor at MIT, a senior research associate at Boston’s Children Hospital, and co-author on both papers.  “We are so pleased to see this research in cell transplantation reach these important milestones.” Cherie Stabler, an associate professor of biomedical engineering at the University of Florida, said this approach is impressive because it tackles all aspects of the problem of islet cell delivery, including finding a source of cells, preventing an immune response, and developing a suitable delivery material. “It’s such a complex, multipronged problem that it’s important to get people from different disciplines to address it,” said Stabler, who was not involved in the research. “This is a great first step towards a clinically relevant, cell-based therapy for Type I diabetes.” The researchers now plan to further test their new materials in nonhuman primates, with the goal of eventually performing clinical trials in diabetic patients. If successful, this approach could provide long-term blood sugar control for such patients. “Our goal is to continue to work hard to translate these promising results into a therapy that can help people,” Anderson said. “Being insulin-independent is the goal,” Vegas said. “This would be a state-of-the-art way of doing that, better than any other technology could. Cells are able to detect glucose and release insulin far better than any piece of technology we’ve been able to develop.” The researchers are also investigating why their new material works so well. They found that the best-performing materials were all modified with molecules containing a triazole group — a ring containing two carbon atoms and three nitrogen atoms. They suspect this class of molecules may interfere with the immune system’s ability to recognize the material as foreign. The work was supported, in part, by the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, and the Tayebati Family Foundation. Other authors of the papers include MIT postdoc Joshua Doloff; former MIT postdocs Minglin Ma and Kaitlin Bratlie; MIT graduate students Hok Hei Tam and Andrew Bader; Jeffrey Millman, an associate professor at Washington University School of Medicine; Mads Gürtler, a former Harvard graduate student; Matt Bochenek, a graduate student at the University of Illinois at Chicago; Dale Greiner, a professor of medicine at the University of Massachusetts Medical School; Jose Oberholzer, an associate professor at the University of Illinois at Chicago; and Gordon Weir, a professor of medicine at the Joslin Diabetes Center.


News Article | August 22, 2016
Site: news.mit.edu

Researchers at MIT and the University of California at San Diego (UCSD) have recruited some new soldiers in the fight against cancer — bacteria. In a study appearing in the July 20 of Nature, the scientists programmed harmless strains of bacteria to deliver toxic payloads. When deployed together with a traditional cancer drug, the bacteria shrank aggressive liver tumors in mice much more effectively than either treatment alone. The new approach exploits bacteria’s natural tendency to accumulate at disease sites. Certain strains of bacteria thrive in low-oxygen environments such as tumors, and suppression of the host’s immune system also creates favorable conditions for bacteria to flourish. “Tumors can be friendly environments for bacteria to grow, and we’re taking advantage of that,” says Sangeeta Bhatia, who is the John and Dorothy Wilson Professor of Health Sciences and Electrical Engineering and Computer Science at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and its Institute for Medical Engineering and Science. Bhatia and Jeff Hasty, a professor of bioengineering at UCSD, are the senior authors of the paper. Lead authors are UCSD graduate student Omar Din and former MIT postdoc Tal Danino, who is now an assistant professor of biomedical engineering at Columbia University. The research team began looking into the possibility of harnessing bacteria to fight cancer several years ago. In a study published last year focusing on cancer diagnosis, the researchers engineered a strain of probiotic bacteria (similar to those found in yogurt) to express a genetic circuit that produces a luminescent signal, detectable with a simple urine test, if liver cancer is present. These harmless strains of E. coli, which can be either injected or consumed orally, tend to accumulate in the liver because one of the liver’s jobs is to filter bacteria out of the bloodstream. In their new study, the researchers delivered artificial genetic circuits into the bacteria, that allow the microbes to kill cancer cells in three different ways. One circuit produces a molecule called hemolysin, which destroys tumor cells by damaging their cell membranes. Another produces a drug that induces the cell to undergo programmed suicide, and the third circuit releases a protein that stimulates the body’s immune system to attack the tumor. To prevent potential side effects from these drugs, the researchers added another genetic circuit that allows the cells to detect how many other bacteria are in their environment, through a process known as quorum sensing. When the population reaches a predetermined target level, the bacterial cells self-destruct, releasing their toxic contents all at once. A few of the cells survive to begin the cycle again, which takes about 18 hours, allowing for repeated release of the drugs. “That allows us to maintain the burden of the bacteria in the whole organism at a low level and to keep pumping the drugs only into the tumor,” Bhatia says. The researchers tested the bacteria in mice with a very aggressive form of colon cancer that spreads to the liver. The bacteria accumulated in the liver and began their cycle of growth and drug release. On their own, they reduced tumor growth slightly, but when combined with the chemotherapy drug 5-fluorouracil, often used to treat liver cancer, they achieved a dramatic reduction in tumor size — much more extensive than if the drug was used on its own. This approach is well suited to liver tumors because bacteria taken orally have high exposure there, Bhatia says. “If you want to treat tumors outside the gut or liver with this strategy, then you would need to give a higher dose, inject them directly into the tumor, or add additional homing strategies,” she says. In previous studies, the researchers found that engineered bacteria that escape from the liver are effectively cleared by the immune system, and that they tend to thrive only in tumor environments, which should help to minimize any potential side effects. Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich, calls the new approach “unconventional” and “highly promising.” “This is a fascinating, refreshing, and beautiful concept,” says Fussenegger, who was not involved in the study. “In a world of mainstream cancer therapy concepts with often limited success, new therapy strategies are badly needed.” The researchers are now working on programming the bacteria to deliver other types of lethal cargo. They also plan to investigate which combinations of bacterial strains and tumor-targeting circuits would be the most effective against different types of tumors. The study was funded by the San Diego Center for Systems Biology, the National Institute of General Medical Sciences, the Ludwig Center for Molecular Oncology at MIT, an Amar G. Bose Research Grant, the Howard Hughes Medical Institute, a Koch Institute Support Grant from the National Cancer Institute, and a Core Center Grant from the National Institute of Environmental Health Sciences.


News Article | February 15, 2017
Site: www.eurekalert.org

CAMBRIDGE, MA - Sequencing messenger RNA molecules from individual cells offers a glimpse into the lives of those cells, revealing what they're doing at a particular time. However, the equipment required to do this kind of analysis is cumbersome and not widely available. MIT researchers have now developed a portable technology that can rapidly prepare the RNA of many cells for sequencing simultaneously, which they believe will enable more widespread use of this approach. The new technology, known as Seq-Well, could allow scientists to more easily identify different cell types found in tissue samples, helping them to study how immune cells fight infection and how cancer cells respond to treatment, among other applications. "Rather than trying to pick one marker that defines a cell type, using single-cell RNA sequencing we can go in and look at everything a cell is expressing at a given moment. By finding common patterns across cells, we can figure out who those cells are," says Alex K. Shalek, the Hermann L.F. von Helmholtz Career Development Assistant Professor of Health Sciences and Technology, an assistant professor of chemistry, and a member of MIT's Institute for Medical Engineering and Science. Shalek and his colleagues have spent the past several years developing single-cell RNA sequencing strategies. In the new study, he teamed up with J. Christopher Love, an associate professor of chemical engineering at MIT's Koch Institute for Integrative Cancer Research, to create a new version of the technology that can rapidly analyze large numbers of cells, with very simple equipment. "We've combined his technologies with some of ours in a way that makes it really accessible for researchers who want to do this type of sequencing on a range of different clinical samples and settings," Love says. "It overcomes some of the barriers that are facing the adoption of these techniques more broadly." Love and Shalek are the senior authors of a paper describing the new technique in the Feb. 13 issue of Nature Methods. The paper's lead authors are Research Associate Todd Gierahn and graduate students Marc H. Wadsworth II and Travis K. Hughes. Most cells in the human body express only a fraction of the genes found in their genome. Those genes are copied into molecules of messenger RNA, also known as RNA transcripts, which direct the cells to build specific proteins. Each cell's gene expression profile varies depending on its function. Sequencing the RNA from many individual cells of a blood or tissue sample offers a way to distinguish the cells based on patterns of gene expression. This gives scientists the opportunity to determine cell functions, including their roles in disease or response to treatment. Key to sequencing large populations of cells is keeping track of which RNA transcripts came from which cell. The earliest techniques for this required sorting the cells into individual tubes or compartments of multiwell plates, and then separately transforming each into a sequencing library. That process works well but can't handle large samples containing thousands of cells, such as blood samples or tissue biopsies, and costs between $25 and $35 per cell. Shalek and others have recently developed microfluidic techniques to help automate and parallelize the process considerably, but the amount of equipment required makes it impossible to be easily transported. Shalek and Love, who have worked on other projects together, realized that technology Love had previously developed to analyze protein secretions from single cells could be adapted to do single-cell RNA sequencing rapidly and inexpensively using a portable device. Over the past several years, Love's lab has developed a microscale system that can isolate individual cells and measure the antibodies and other proteins that each cell secretes. The device resembles a tiny ice cube tray, with individual compartments for each cell. Love also developed a process known as microengraving that uses these trays, which can hold tens of thousands of cells, to measure each cell's protein secretions. To use this approach for sequencing RNA, the researchers created arrays of nanowells that each capture a single cell plus a barcoded bead to capture the RNA fragments. The nanowells are sealed with a semipermeable membrane that allows the passage of chemicals needed to break the cells apart, while the RNA stays contained. After the RNA binds to the beads, it is removed and sequenced. Using this process, the cost per cell is less than $1. Similar to previous single-cell RNA sequencing techniques, the Seq-Well process captures and analyzes about 10 to 15 percent of the total number of RNA transcripts per cell. "That is still a very rich set of information that maps to several thousand genes," Love says. "If you look at sets of these genes, you can start to understand the identity of those cells based on the sets of genes that are expressed in common." In this paper, the researchers used Seq-Well to analyze immune cells called macrophages, which were infected with tuberculosis, allowing them to identify different pre-existing populations and responses to infection. Shalek and members of his lab also brought the technology to South Africa and analyzed tissue samples from TB- and HIV-infected patients there. "Having a simple system that can go everywhere I think is going to be incredibly empowering," Shalek says. Love's lab is now using this approach to analyze immune cells from people with food allergies, which could help researchers determine why some people are more likely to respond well to therapies designed to treat their allergies. "There are still a lot of unknowns in chronic diseases, and these types of tools help you uncover new insights," Love says. The research team has also joined forces with clinical investigators at Dana-Farber/Harvard Cancer Center to apply this technology toward the discovery of new combination immunotherapies to treat cancer as part of the Bridge Project partnership. The research was funded by the Searle Scholars Program, the Beckman Young Investigator Program, an NIH New Innovator Award, the Bill and Melinda Gates Foundation, the Ragon Institute, the Burroughs Wellcome Foundation, the W.M. Keck Foundation, the U.S. Army Research Office through MIT's Institute for Soldier Nanotechnologies, and the Koch Institute Support Grant from the National Cancer Institute.


News Article | February 15, 2017
Site: phys.org

Encapsulating strands of RNA or DNA in tiny particles is one promising approach. To help speed up the development of such drug-delivery vehicles, a team of researchers from MIT, Georgia Tech, and the University of Florida has now devised a way to rapidly test different nanoparticles to see where they go in the body. "Drug delivery is a really substantial hurdle that needs to be overcome," says James Dahlman, a former MIT graduate student who is now an assistant professor at Georgia Tech and the study's lead author. "Regardless of their biological mechanisms of action, all genetic therapies need safe and specific drug delivery to the tissue you want to target." This approach, described in the Proceedings of the National Academy of Sciences the week of Feb. 6, could help scientists target genetic therapies to precise locations in the body. "It could be used to identify a nanoparticle that goes to a certain place, and with that information we could then develop the nanoparticle with a specific payload in mind," says Daniel Anderson, an associate professor in MIT's Department of Chemical Engineering and a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES). The paper's senior authors are Anderson; Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute; and Eric Wang, a professor at the University of Florida. Other authors are graduate student Kevin Kauffman, recent MIT graduates Yiping Xing and Chloe Dlott, MIT undergraduate Taylor Shaw, and Koch Institute technical assistant Faryal Mir. Finding a reliable way to deliver DNA to target cells could help scientists realize the potential of gene therapy—a method of treating diseases such as cystic fibrosis or hemophilia by delivering new genes that replace missing or defective versions. Another promising approach for new therapies is RNA interference, which can be used to turn off overactive genes by blocking them with short strands of RNA known as siRNA. Delivering these types of genetic material into body cells has proven difficult, however, because the body has evolved many defense mechanisms against foreign genetic material such as viruses. To help evade these defenses, Anderson's lab has developed nanoparticles, including many made from fatty molecules called lipids, that protect genetic material and carry it to a particular destination. Many of these particles tend to accumulate in the liver, in part because the liver is responsible for filtering blood, but it has been more difficult to find particles that target other organs. "We've gotten good at delivering nanoparticles into certain tissues but not all of them," Anderson says. "We also haven't really figured out how the particles' chemistries influence targeting to different destinations." To identify promising candidates, Anderson's lab generates libraries of thousands of particles, by varying traits such as their size and chemical composition. Researchers then test the particles by placing them on a particular cell type, grown in a lab dish, to see if the particles can get into the cells. The best candidates are then tested in animals. However, this is a slow process and limits the number of particles that can be tried. "The problem we have is we can make a lot more nanoparticles than we can test," Anderson says. To overcome that hurdle, the researchers decided to add "barcodes," consisting of a DNA sequence of about 60 nucleotides, to each type of particle. After injecting the particles into an animal, the researchers can retrieve the DNA barcodes from different tissues and then sequence the barcodes to see which particles ended up where. "What it allows us to do is test many different nanoparticles at once inside a single animal," Dahlman says. The researchers first tested particles that had been previously shown to target the lungs and the liver, and confirmed that they did go where expected. Then, the researchers screened 30 different lipid nanoparticles that varied in one key trait—the structure of a component known as polyethylene glycol (PEG), a polymer often added to drugs to increase their longevity in the bloodstream. Lipid nanoparticles can also vary in their size and other aspects of their chemical composition. Each of the particles was also tagged with one of 30 DNA barcodes. By sequencing barcodes that ended up in different parts of the body, the researchers were able to identify particles that targeted the heart, brain, uterus, muscle, kidney, and pancreas, in addition to liver and lung. In future studies, they plan to investigate what makes different particles zero in on different tissues. The researchers also performed further tests on one of the particles, which targets the liver, and found that it could successfully deliver siRNA that turns off the gene for a blood clotting factor. Victor Koteliansky, director of the Skoltech Center for Functional Genomics, described the technique as an "innovative" way to speed up the process of identifying promising nanoparticles to deliver RNA and DNA. "Finding a good particle is a very rare event, so you need to screen a lot of particles. This approach is faster and can give you a deeper understanding of where particles will go in the body," says Kotelianksy, who was not involved in the research. This type of screen could also be used to test other kinds of nanoparticles such as those made from polymers. "We're really hoping that other labs across the country and across the world will try our system to see if it works for them," Dahlman says. Explore further: DNA 'barcoding' allows rapid testing of nanoparticles for therapeutic delivery More information: Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1620874114


Approximately one in 20 people will develop colorectal cancer in their lifetime, making it the third-most prevalent form of the disease in the U.S. In Europe, it is the second-most common form of cancer. The most widely used first line of treatment is surgery, but this can result in incomplete removal of the tumor. Cancer cells can be left behind, potentially leading to recurrence and increased risk of metastasis. Indeed, while many patients remain cancer-free for months or even years after surgery, tumors are known to recur in up to 50 percent of cases. Conventional therapies used to prevent tumors recurring after surgery do not sufficiently differentiate between healthy and cancerous cells, leading to serious side effects. In a paper published today in the journal Nature Materials, researchers at MIT describe an adhesive patch that can stick to the tumor site, either before or after surgery, to deliver a triple-combination of drug, gene, and photo (light-based) therapy. Releasing this triple combination therapy locally, at the tumor site, may increase the efficacy of the treatment, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research. The general approach to cancer treatment today is the use of systemic, or whole-body, therapies such as chemotherapy drugs. But the lack of specificity of anticancer drugs means they produce undesired side effects when systemically administered. What’s more, only a small portion of the drug reaches the tumor site itself, meaning the primary tumor is not treated as effectively as it should be. Indeed, recent research in mice has found that only 0.7 percent of nanoparticles administered systemically actually found their way to the target tumor. “This means that we are treating both the source of the cancer — the tumor — and the metastases resulting from that source, in a suboptimal manner,” Artzi says. “That is what prompted us to think a little bit differently, to look at how we can leverage advancements in materials science, and in particular nanotechnology, to treat the primary tumor in a local and sustained manner.” The researchers have developed a triple-therapy hydrogel patch, which can be used to treat tumors locally. This is particularly effective as it can treat not only the tumor itself but any cells left at the site after surgery, preventing the cancer from recurring or metastasizing in the future. Firstly, the patch contains gold nanorods, which heat up when near-infrared radiation is applied to the local area. This is used to thermally ablate, or destroy, the tumor. These nanorods are also equipped with a chemotherapy drug, which is released when they are heated, to target the tumor and its surrounding cells. Finally, gold nanospheres that do not heat up in response to the near-infrared radiation are used to deliver RNA, or gene therapy to the site, in order to silence an important oncogene in colorectal cancer. Oncogenes are genes that can cause healthy cells to transform into tumor cells. The researchers envision that a clinician could remove the tumor, and then apply the patch to the inner surface of the colon, to ensure that no cells that are likely to cause cancer recurrence remain at the site. As the patch degrades, it will gradually release the various therapies. The patch can also serve as a neoadjuvant, a therapy designed to shrink tumors prior to their resection, Artzi says. When the researchers tested the treatment in mice, they found that in 40 percent of cases where the patch was not applied after tumor removal, the cancer returned. But when the patch was applied after surgery, the treatment resulted in complete remission. Indeed, even when the tumor was not removed, the triple-combination therapy alone was enough to destroy it. The technology is an extraordinary and unprecedented synergy of three concurrent modalities of treatment, according to Mauro Ferrari, president and CEO of the Houston Methodist Research Institute, who was not involved in the research. “What is particularly intriguing is that by delivering the treatment locally, multimodal therapy may be better than systemic therapy, at least in certain clinical situations,” Ferrari says. Unlike existing colorectal cancer surgery, this treatment can also be applied in a minimally invasive manner. In the next phase of their work, the researchers hope to move to experiments in larger models, in order to use colonoscopy equipment not only for cancer diagnosis but also to inject the patch to the site of a tumor, when detected. “This administration modality would enable, at least in early-stage cancer patients, the avoidance of open field surgery and colon resection,” Artzi says. “Local application of the triple therapy could thus improve patients’ quality of life and therapeutic outcome.” Artzi is joined on the paper by João Conde, Nuria Oliva, and Yi Zhang, of IMES. Conde is also at Queen Mary University in London.


News Article | September 19, 2016
Site: news.mit.edu

The spread of malignant cells around the body, known as metastasis, is the leading cause of mortality in women with breast cancer. Now, a new gene therapy technique being developed by researchers at MIT is showing promise as a way to prevent breast cancer tumors from metastasizing. The treatment, described in a paper published today in the journal Nature Communications, uses microRNAs — small noncoding RNA molecules that regulate gene expression — to control metastasis. The therapy could be used alongside chemotherapy to treat early-stage breast cancer tumors before they spread, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research in collaboration with Noam Shomron, an assistant professor on the faculty of medicine at Tel-Aviv University in Israel. “The idea is that if the cancer is diagnosed early enough, then in addition to treating the primary tumor [with chemotherapy], one could also treat with specific microRNAs, in order to prevent the spread of cancer cells that cause metastasis,” Artzi says. The regulation of gene expression by microRNAs is known to be important in preventing the spread of cancer cells. Recent studies by the Shomron team in Tel-Aviv have shown that disruption of this regulation, for example by genetic variants known as single nucleotide polymorphisms (SNPs), can have a significant impact on gene expression levels and lead to an increase in the risk of cancer. To identify the specific microRNAs that play a role in breast cancer progression and could therefore potentially be used to suppress metastasis, the research teams first carried out an extensive bioinformatics analysis. They compared three datasets: one for known SNPs; a second for sites at which microRNAs bind to the genome; and a third for breast cancer-related genes known to be associated with the movement of cells. This analysis revealed a variant, or SNP, known as rs1071738, which influences metastasis. They found that this SNP disrupts binding of two microRNAs, miR-96 and miR-182. This disruption in turn prevents the two microRNAs from controlling the expression of a protein called Palladin. Previous research has shown that Palladin plays a key role in the migration of breast cancer cells, and their subsequent invasion of otherwise healthy organs. When the researchers carried out in vitro experiments in cells, they found that applying miR-96 and miR-182 decreased the expression of Palladin levels, in turn reducing the ability of breast cancer cells to migrate and invade other tissue. “Previous research had discussed the role of Palladin in controlling migration and invasion (of cancer cells), but no one had tried to use microRNAs to silence those specific targets and prevent metastasis,” Artzi says. “In this way we were able to pinpoint the critical role of these microRNAs in stopping the spread of breast cancer.” The researchers then developed a method to deliver engineered microRNAs to breast cancer tumors. They embedded nanoparticles containing the microRNAs into a hydrogel scaffold, which they then implanted into mice. They found that this allowed efficient and precise delivery of the microRNAs to a target breast cancer tumor site. The treatment resulted in a dramatic reduction in breast cancer metastasis, says Artzi. “We can locally change the cells in order to prevent metastasis from occurring,” she says. To increase the effectiveness of the treatment even further, the researchers then added the chemotherapy drug cisplatin to the nanoparticles. This led to a significant reduction in both the growth of the primary tumor, and its metastasis. “We believe local delivery is much more effective (than systemic treatment), because it gives us a much higher effective dose of the cargo, in this case the two microRNAs and the cisplatin,” she says. “The research offers the potential for combined experimental therapeutics with traditional chemotherapy in cancer metastasis,” says Julie Teruya-Feldstein, a professor of pathology at Mount Sinai Hospital in New York, who was not involved in the study. The research team, which also includes MIT post doc Joao Conde and graduate student Nuria Oliva, both from IMES; graduate student Avital Gilam and postdoc Daphna Weissglas-Volkov, from Tel-Aviv University; and Eitan Friedman, an oncogeneticist from Chaim Sheba Medical Center in Israel, now hopes to move on to larger animal studies of the treatment. “We are very excited about the results so far, and the efficacy seems to be really good. So the next step will be to move on to larger models and then to clinical trials, although there is still a long way to go,” Artzi says.


News Article | October 26, 2016
Site: www.eurekalert.org

CAMBRIDGE, MA -- The use of general anesthesia for surgery has not changed fundamentally since it was first introduced 170 years ago. Patients are still left to come around in their own time following withdrawal of the drug. However, some patients can take a considerable amount of time to wake up, holding up the use of expensive operating rooms and occupying medical staff who must keep them under close observation. Now researchers at MIT and Massachusetts General Hospital have moved a step closer to a treatment to rapidly awaken patients after administration of a general anesthetic, following a study of the mechanism that allows people to regain consciousness. In a paper published today in the journal PNAS, the researchers demonstrate that activating dopamine neurons in the ventral tegmental area (VTA) of the brain causes active emergence from general anesthesia. This is important because the mechanism by which we regain consciousness following general anesthetic has so far been poorly understood, according to Ken Solt, a research affiliate in the Department of Brain and Cognitive Sciences at MIT and an anesthesiologist at Massachusetts General Hospital. He led the research alongside Emery Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and an anesthesiologist at Massachusetts General Hospital. "The process of how the neural circuits come back online following anesthesia has not really been studied in depth, and this is something that interested us from a clinical standpoint, because we are investigating ways to rapidly reverse anesthesia," Solt says. The researchers have previously demonstrated that Ritalin, the drug commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD), can bring anesthetized rats out of anesthesia almost immediately. Ritalin is a stimulant that increases levels of the neurotransmitter dopamine, which is known to promote wakefulness. But the specific dopamine circuits in the brain that regulate arousal from an anesthetic remained unclear. To determine the precise mechanism involved, the researchers used optogenetics to selectively activate dopamine neurons in the VTA of anesthetized mice. The researchers first engineered dopamine neurons in the mice's VTA to express light-sensitive proteins. They were then able to activate these specific neurons by shining blue laser light at them. The engineered mice were placed under a steady dose of anesthetic until they were unconscious and on their backs. Lying on their back in this way is a sure sign that a rodent is unconscious, as even while asleep their righting reflex would normally cause them to flip onto their front sides to make them less vulnerable to predators. The researchers then activated the neurons with light, causing them to release dopamine. This prompted the animals to immediately wake up and flip over, and in many cases to begin walking around. "Dopamine neurons in the VTA are traditionally thought of as playing a key role in reward, motivation, and drug addiction but had not really been well characterized in the context of arousal," Solt says. "But we discovered that by activating dopamine neurons in this very specific part of the brain, we were able to reverse the state of general anesthesia and wake up the animals." As well as freeing up valuable operating room time, developing a treatment to rapidly bring people out of anesthesia may also lessen the side effects, according to Brown. For example, many people feel groggy after anesthesia and find that their brains do not work very well. "We want to get the patient's cognitive processes back to exactly where they were before they had anesthesia," Brown says. "It's a given that a high fraction of older patient's brains in particular will not work as well after anesthesia." The researchers have also found that Ritalin can improve respiratory function, which can also be adversely affected by anesthesia. The researchers are now conducting further experiments in mice to determine whether cognitive function is fully restored following anesthesia when using Ritalin. They are also carrying out trials of Ritalin in humans, to confirm that it does accelerate recovery from general anesthetic. "We have all seen that perfect wake-up following general anesthesia, where the patient is talking and perfectly comfortable and out of the recovery room in a very short period of time," says Brown, who is also the associate director of MIT's Institute for Medical Engineering and Science. "Every anesthetic should end in this way, but it will never happen if anesthesiologists stay wedded to their old processes," he says. "We are trying to create a new phase for anesthesia practice in which you actively turn someone's brain back on after having general anesthesia."

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