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Monday, June 29th, 2015

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    12:00a
    Major step for implantable drug-delivery device

    An implantable, microchip-based device may soon replace the injections and pills now needed to treat chronic diseases: Earlier this month, MIT spinout Microchips Biotech partnered with a pharmaceutical giant to commercialize its wirelessly controlled, implantable, microchip-based devices that store and release drugs inside the body over many years.

    Invented by Microchips Biotech co-founders Michael Cima, the David H. Koch Professor of Engineering, and Robert Langer, the David H. Koch Institute Professor, the microchips consist of hundreds of pinhead-sized reservoirs, each capped with a metal membrane, that store tiny doses of therapeutics or chemicals. An electric current delivered by the device removes the membrane, releasing a single dose. The device can be programmed wirelessly to release individual doses for up to 16 years to treat, for example, diabetes, cancer, multiple sclerosis, and osteoporosis.

    Now Microchips Biotech will begin co-developing microchips with Teva Pharmaceutical, the world’s largest producer of generic drugs, to treat specific diseases, with licensing potential for other products. Teva paid $35 million up front, with additional milestone payments as the device goes through clinical trials before it hits the shelves.

    “Obviously, this is a huge validation of the technology,” Cima says. “A major pharmaceutical company sees how this technology can further their efforts to help patients.”

    Apart from providing convenience, Microchips Biotech says these microchips could also improve medication-prescription adherence — a surprisingly costly issue in the United States. A 2012 report published in the Annals of Internal Medicine estimated that Americans who don’t stick to prescriptions rack up $100 billion to $289 billion annually in unnecessary health care costs from additional hospital visits and other issues. Failure to follow prescriptions, the study also found, causes around 125,000 deaths annually and up to 10 percent of all hospitalizations.

    While its first partnership is for treating chronic diseases, Microchips Biotech will continue work on its flagship product, a birth-control microchip, backed by the Bill and Melinda Gates Foundation, that releases contraceptives and can be turned on and off wirelessly.

    Cima, who now serves on the Microchips Biotech board of directors with Langer, sees this hormone-releasing microchip as one of the first implantable “artificial organs” — because it acts as a gland. “A lot of the therapies are trying to chemically trick the endocrine systems,” Cima says. “We are doing that with this artificial organ we created.”

    Wild ideas

    Inspiration for the microchips came in the late 1990s, when Langer watched a documentary on mass-producing microchips. “I thought to myself, ‘Wouldn’t this be a great way to make a drug-delivery system?’” Langer says.

    He brought this idea to Cima, a chip-making expert who was taken aback by its novelty. “But being out-of-this-world is not something that needs to stop anybody at MIT,” Cima adds. “In fact, that should be the criterion.”

    So in 1999, Langer, Cima, and then-graduate student John Santini PhD ’99 co-founded MicroCHIPS, and invented a prototype for their microchip that was described in a paper published that year in Nature. (This entrepreneurial collaboration was the first of many for Cima and Langer over the next decade.)

    This dime-sized prototype contained only 34 reservoirs, each controlled by an individual wire connected to an external power source. At the time, they considered a broad range of practical, and somewhat fantastical, applications beyond drug delivery, including disease diagnostics and jewelry that could emit scents. “We were trying to find the killer application. We thought, ‘I have a hammer, what’s the right nail to hit?’” Cima says.

    For years, the technology underwent rigorous research and development at Microchips Biotech. But in 2011, Langer and Cima, and researchers from MicroCHIPS, conducted the microchips’ first human trials to treat osteoporosis — this time with wireless capabilities. In that study, published in a 2012 issue of Science Translational Medicine, microchips were implanted into seven elderly women, delivering teriparatide to strengthen bones. Results indicated that the chips delivered doses comparable to injections — and did so more consistently — with no adverse side effects.

    After that, the Gates Foundation took interest. “It wasn’t just a pie-in-the-sky idea anymore — we’re really treating patients,” Cima says. “That really captures people’s imaginations.”

    That study, combined with ongoing efforts in contraceptive-delivery microchips, led Cima to believe the microchips could someday, essentially, be considered the first artificial glands that could regulate potent hormones inside the body.

    This may sound like a wild idea — but Cima doesn’t think so. Consider the thousands of people living today with pacemakers, he says. “Pacemakers are delivering an electrical signal, fixing the pace of a heart, or detecting if the heart is not beating correctly, and trying to stimulate it,” Cima says. The chip “sends an endocrine or chemical signal, instead of an electrical signal.”

    MEMS innovations

    Microchips Biotech made several innovations in the microelectromechanical systems (MEMS) manufacturing process to ensure the microchips could be commercialized.

    A major innovation was enabling final assembly of the microchips at room temperature with hermetic seals. Any intense heat during final assembly, with hermetic sealing, could destroy the drugs already loaded into the reservoirs — which meant common methods of welding and soldering were off-limits.

    To do so, Microchips Biotech modified a cold-welding “tongue and groove” process. This meant depositing a soft, gold alloy in patterns on the top of the chip to create tongues, and grooves on the base. By pressing the top and base pieces together, the tongues fit into the grooves, and plastically deforms to weld the metal together.

    “Each one of these reservoirs, until you open it, [must be] completely sealed from any contaminant in the environment,” Cima says. “There was no precedent for that.”

    The company has also found ways to integrate electronics into the microchips to shrink down the device. Moving forward, Langer adds, the company could refine the microchips to be even smaller, yet carry the same volume of drugs. “This means making the drugs take up more volume [than] the electrical and other components,” he says. “That’s the next major challenge.”

    12:00a
    Automatic bug repair

    At the Association for Computing Machinery’s Programming Language Design and Implementation conference this month, MIT researchers presented a new system that repairs dangerous software bugs by automatically importing functionality from other, more secure applications.

    Remarkably, the system, dubbed CodePhage, doesn’t require access to the source code of the applications whose functionality it’s borrowing. Instead, it analyzes the applications’ execution and characterizes the types of security checks they perform. As a consequence, it can import checks from applications written in programming languages other than the one in which the program it’s repairing was written.

    Once it’s imported code into a vulnerable application, CodePhage can provide a further layer of analysis that guarantees that the bug has been repaired.

    “We have tons of source code available in open-source repositories, millions of projects, and a lot of these projects implement similar specifications,” says Stelios Sidiroglou-Douskos, a research scientist at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) who led the development of CodePhage. “Even though that might not be the core functionality of the program, they frequently have subcomponents that share functionality across a large number of projects.”

    With CodePhage, he says, “over time, what you’d be doing is building this hybrid system that takes the best components from all these implementations.”

    Sidiroglou-Douskos and his coauthors — MIT professor of computer science and engineering Martin Rinard, graduate student Fan Long, and Eric Lahtinen, a researcher in Rinard’s group — refer to the program CodePhage is repairing as the “recipient” and the program whose functionality it’s borrowing as the “donor.” To begin its analysis, CodePhage requires two sample inputs: one that causes the recipient to crash and one that doesn’t. A bug-locating program that the same group reported in March, dubbed DIODE, generates crash-inducing inputs automatically. But a user may simply have found that trying to open a particular file caused a crash.

    Carrying the past

    First, CodePhage feeds the “safe” input — the one that doesn’t induce crashes — to the donor. It then tracks the sequence of operations the donor executes and records them using a symbolic expression, a string of symbols that describes the logical constraints the operations impose.

    At some point, for instance, the donor may check to see whether the size of the input is below some threshold. If it is, CodePhage will add a term to its growing symbolic expression that represents the condition of being below that threshold. It doesn’t record the actual size of the file — just the constraint imposed by the check.

    Next, CodePhage feeds the donor the crash-inducing input. Again, it builds up a symbolic expression that represents the operations the donor performs. When the new symbolic expression diverges from the old one, however, CodePhage interrupts the process. The divergence represents a constraint that the safe input met and the crash-inducing input does not. As such, it could be a security check missing from the recipient.

    CodePhage then analyzes the recipient to find locations at which the input meets most, but not quite all, of the constraints described by the new symbolic expression. The recipient may perform different operations in a different order than the donor does, and it may store data in different forms. But the symbolic expression describes the state of the data after it’s been processed, not the processing itself.

    At each of the locations it identifies, CodePhage can dispense with most of the constraints described by the symbolic expression — the constraints that the recipient, too, imposes. Starting with the first location, it translates the few constraints that remain into the language of the recipient and inserts them into the source code. Then it runs the recipient again, using the crash-inducing input.

    If the program holds up, the new code has solved the problem. If it doesn’t, CodePhage moves on to the next candidate location in the recipient. If the program is still crashing, even after CodePhage has tried repairs at all the candidate locations, it returns to the donor program and continues building up its symbolic expression, until it arrives at another point of divergence.

    Automated future

    The researchers tested CodePhage on seven common open-source programs in which DIODE had found bugs, importing repairs from between two and four donors for each. In all instances, CodePhage was able to patch up the vulnerable code, and it generally took between two and 10 minutes per repair.

    As the researchers explain, in modern commercial software, security checks can take up 80 percent of the code — or even more. One of their hopes is that future versions of CodePhage could drastically reduce the time that software developers spend on grunt work, by automating those checks’ insertion.

    “The longer-term vision is that you never have to write a piece of code that somebody else has written before,” Rinard says. “The system finds that piece of code and automatically puts it together with whatever pieces of code you need to make your program work.”

    “The technique of borrowing code from another program that has similar functionality, and being able to take a program that essentially is broken and fix it in that manner, is a pretty cool result,” says Emery Berger, a professor of computer science at the University of Massachusetts at Amherst. “To be honest, I was surprised that it worked at all.”

    “The donor program was not written by the same people,” Berger explains. “They have different coding standards; they name variables differently; they use all kinds of different variables; the variables could be local; or they could be higher up in the stack. And CodePhage is able to identify these connections and say, ‘These variables correlate to these variables.’ Speaking in terms of organ donation, it transforms that code to make it a perfect graft, as if it had been written that way in the beginning. The fact that it works as well as it does is surprising — and cool.”

    10:55a
    Chisholm, Rivest, and Thompson appointed as new Institute Professors

    A marine biologist who studies tiny ocean organisms, a computer scientist who developed a global security standard, and an acclaimed violist who has performed with renowned orchestras have been awarded MIT’s highest faculty honor: the title of Institute Professor.

    Sallie “Penny” Chisholm, Ron Rivest, and Marcus Thompson join a small group of Institute Professors at MIT, now numbering 13, along with 10 Institute Professors emeriti. Their new appointments are effective July 1, making them the first faculty members to be named Institute Professors since 2008.

    MIT President L. Rafael Reif says, “Although our new Institute Professors were chosen as individuals, it is interesting to consider them together: Penny Chisholm, a pioneering field scientist whose discoveries revolutionized our understanding of the oceans; Ron Rivest, a brilliant theorist and problem-solver who ranks as one of the founding fathers of modern cryptography; and Marcus Thompson, among the most celebrated string performers in the United States today.

    “Their fields could not be more different,” Reif says. “Yet each is an explorer, creator, and teacher of the first order. Together they reflect the standard of faculty excellence that is a signature of MIT.”

    The appointments of Chisholm, Rivest, and Thompson as Institute Professors were announced today in an email to the faculty from Provost Martin Schmidt and Steven Hall, chair of the MIT faculty and a professor of aeronautics and astronautics.

    “This special position is a unique honor bestowed by the Faculty and Administration of MIT,” Schmidt and Hall wrote. “Such appointments recognize exceptional distinction by a combination of leadership, accomplishment, and service in the scholarly, educational, and general intellectual life of the Institute and wider community.”

    Sallie “Penny” Chisholm

    The world’s oceans are filled with a tiny bacterium, Prochlorococcus, that produces about 10 percent of the world’s oxygen — making this tiny creature fundamental to life on Earth.

    No one knows more about Prochlorococcus than MIT biologist Sallie “Penny” Chisholm, who has been the Lee and Geraldine Martin Professor in Environmental Studies at MIT since 2002. Indeed, she was a co-discoverer of Prochlorococcus in the 1980s, and has been heavily focused on it ever since, publishing a series of findings detailing how Prochlorococcus interacts with other creatures and influences the environment on a planetary scale — work that seems increasingly significant at a time when climate change may be altering the world’s oceans.

    Being named an Institute Professor “was really a total surprise and not something I had ever, ever considered,” Chisholm says. She is quick to emphasize the collaborative nature of her research, and credits colleagues and students for propelling her own research forward.

    Beyond that, Chisholm quips, “I have two things to thank: MIT and Prochlorococcus.”

    Chisholm grew up in Marquette, Michigan. After receiving her BA in biology from Skidmore College and her PhD in biology from the State University of New York at Albany, she arrived at MIT in 1976 as a marine ecologist studying microorganisms in MIT’s Department of Civil and Environmental Engineering. She soon found it to be a productive setting.

    “My career has been shaped by MIT,” Chisholm says. “The combination of science and engineering has been very powerful for my work. In my lab, we’ve always been able to mix the two together. There’s a continuum. Mix them together and watch people interact, and the combination is so much more powerful.”

    And while Chisholm’s research had produced significant advances by the 1990s, the advent of large-scale genomics created a new window into the evolution of Prochlorococcus, helping her lab to link the evolutionary, ecological, and molecular aspects of these microorganisms.

    “A major change happened about 15 years ago, when genomics entered marine biology,” Chisholm says. “And we were lucky enough to be on the forefront of that. … It’s completely changed the way I think about oceans and ecology and the field. It keeps getting more and more exciting.”

    Chisholm says that being named an Institute Professor “is not just about me, but my field, recognizing what I do and my students do as being something of value. That makes me as happy as the honor itself.”

    “Penny not only made a paradigm-shifting discovery in the study of oceans, but went on to pioneer a new field,” Hall says. “She’s applied her research to inform the debate about global warming in meaningful ways, and her successes have drawn many younger faculty to MIT.”

    Ron Rivest

    You are most likely reading this on a computer, so the odds are high that at some point — perhaps even within the last few minutes — you have benefitted from Ron Rivest’s landmark advances in computer security. In 1977, with colleagues Adi Shamir and Leonard Adleman, Rivest devised what quickly became known as the RSA public-key cryptosystem, which secures communications between computers using products of large prime numbers. The system has proven durable and remained unbroken.

    That is just one part of a distinguished career that has seen Rivest conduct research in cryptography, other aspects of computer and network security, algorithms, machine learning, and even voting technology. He has also taught well-received classes in all those fields, and co-authored a best-selling textbook, “Introduction to Algorithms,” that has been used by hundreds of thousands of students.

    “I was stunned to receive this recognition,” Rivest says. “I had no inkling that this was coming. It is a tremendous honor to be named an Institute Professor. Thank you, MIT!”

    Born and raised in Niskayuna, New York, Rivest received his undergraduate degree in mathematics from Yale University and a PhD in computer science at Stanford University before joining MIT — which is where he worked out the RSA idea, along with Shamir and Adleman. Rivest was named the Vannevar Bush Professor in the Department of Electrical Engineering and Computer Science in 2013.

    Among many global honors, Rivest received the Turing Award, the highest honor in computer science, in 2002. In 2010, Rivest was given MIT’s James R. Killian Jr. Faculty Achievement Award; his award citation called the RSA code a “wonderful example of elegant and abstract theory eventually having immense practical impact.”

    “I do hope this recognition, and the work I do, will help to inspire further advances in cryptography and computer security,” Rivest says. “MIT is a wonderful place to work, and has the rich array of talent needed to make such advances. I have been very pleased to see MIT increasing its efforts in these directions recently.”

    In addition to his research and teaching, Rivest has founded companies including RSA Security and VeriSign. He has also been an active participant in the Caltech/MIT Voting Technology Project, for which he has worked on systems aimed at confirming to voters that their votes have been correctly recorded and tallied, while still ensuring privacy for their ballot-box choices.

    “Both on campus and nationally, Ron is sought out for his wisdom on challenging problems,” Hall says. “He’s a tremendous scholar and innovator, and his continuing contributions to issues like secure voting reflect the best traditions of MIT.”

    Marcus Thompson

    A native of Bronx, New York, Marcus Thompson has been an influential presence at MIT for over four decades, as both an internationally recognized concert musician and a lauded instructor. He began playing the violin at age 6, switched to the viola at age 17, and had embarked on an active concert career by age 22. Thompson arrived at MIT as an assistant professor of music in 1973, and was named the Robert R. Taylor Professor of Music in 1995 — the same year he was named a Margaret MacVicar Faculty Fellow for exceptional teaching.

    Thompson’s violin studies began at a private neighborhood studio, and continued in the Juilliard Pre-College Division with the noted instructor Louise Behrend. Following nearly a decade of study with violist Walter Trampler, Thompson received Juilliard’s first doctoral degree in viola performance. He studied chamber music with members of the Juilliard, Amadeus, and Netherlands string quartets, and with Joseph Gingold and Felix Galimir.

    Thompson first earned public attention as a solo and chamber music player following an acclaimed recital debut at New York’s Carnegie Hall in the Young Concert Artists Series, along with other appearances in New York and Boston.  

    Since then, Thompson has performed as a soloist with many of the most prominent orchestras in the U.S. He has recorded with orchestras in Ljubljana, Slovenia, and in Prague, and performed premieres of works by MIT colleagues, including the West Coast premiere of “Viola Concerto,” by John Harbison, with the Los Angeles Chamber Orchestra; next season he will premiere a new work by MIT composer Elena Ruehr with the New Orchestra of Washington.

    A respected chamber musician, Thompson has appeared regularly at chamber music festivals and series on three continents, and frequently collaborated with groups including the Emerson, Jupiter, Borromeo, Muir, Calder, and Shanghai string quartets. He has served as artistic director of the Boston Chamber Music Society since 2009, where he has been hailed for innovative programming and artistic leadership.

    At MIT, Thompson has developed programs for the study and performance of solo repertoire and chamber music literature from five centuries. As a member of the viola faculty at the New England Conservatory of Music since 1983, Thompson has taught aspiring professionals who now hold positions in orchestras, chamber ensembles, and universities worldwide.

    “My initial reaction was that I was shocked, stunned, amazed,” Thompson says of learning of his appointment as an Institute Professor. “I’m also extremely grateful and humbled by the recognition not just of me, but the fact that there is music at MIT, and high-quality music. It’s a privilege to be at MIT, and to be recognized is just an honor.”

    For Thompson, teaching is a reward in itself. He says he feels proudest witnessing the musical activity of former students, and he feels a special pride in meeting the younger siblings or children of former students who themselves play in MIT’s many ensembles.

    “For so many students,” Thompson says, “the serious study of music is an integral part of Institute life, and often remains their most cherished memory of how we care for them. I see and hear music, fine music, great music-making, all over the Institute. Our students are very drawn to it, they’re very good at it, and it becomes part of their lifelong learning.”

    “Over his long career, Marcus has worked to give students access to a world-class music program that has changed MIT,” Hall says. “Many colleagues told us about his commitment to and generosity with students. Like Penny and Ron, Marcus is one of the great men and women of our faculty who inspire us every day.”

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