Study reveals why polymer stents failed

Many patients with heart disease have a metal stent implanted to keep their coronary artery open and prevent blood clotting that can lead to heart attacks. One drawback to these stents is that long-term use can eventually damage the artery.

Several years ago, in hopes of overcoming that issue, a new type of stent made from biodegradable polymers was introduced. Stent designers hoped that these devices would eventually be absorbed by the blood vessel walls, removing the risk of long-term implantation. At first, these stents appeared to be working well in patients, but after a few years these patients experienced more heart attacks than patients with metal stents, and the polymer stents were taken off the market.

MIT researchers in the Institute for Medical Engineering and Science and the Department of Materials Science and Engineering have now discovered why these stents failed. Their study also reveals why the problems were not uncovered during the development process: The evaluation procedures, which were based on those used for metal stents, were not well-suited to evaluating polymer stents.

“People have been evaluating polymer materials as if they were metals, but metals and polymers don’t behave the same way,” says Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT. “People were looking at the wrong metrics, they were looking at the wrong timescales, and they didn’t have the right tools.”

The researchers hope that their work will lead to a new approach to designing and evaluating polymer stents and other types of degradable medical devices.

“When we use polymers to make these devices, we need to start thinking about how the fabrication techniques will affect the microstructure, and how the microstructure will affect the device performance,” says lead author Pei-Jiang Wang, a Boston University graduate student who is doing hid PhD thesis with Edelman.

Edelman is the senior author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Feb. 26. Other authors include MIT research scientist Nicola Ferralis, MIT professor of materials science and engineering Jeffrey Grossman, and National University of Ireland Galway professor of engineering Claire Conway.

Microstructural flaws

The degradable stents are made from a polymer called poly-l-lactic acid (pLLA), which is also used in dissolvable sutures. Preclinical testing (studies done in the lab and with animal models) did not reveal any cause for concern. In human patients the stents appeared stable for the first year, but then problems began to arise. After three years, over 10 percent of patients had experienced a heart attack, including fatal heart attacks, or had to go through another medical intervention. That is double the rate seen in patients with metal stents.

After the stents were taken off the market, the team decided to try to figure out if there were any warning signs that could have been detected earlier. To do this, they used Raman spectroscopy to analyze the microstructure of the stents. This technique, which uses light to measure energy shifts in molecular vibrations, offers detailed information about the chemical composition of a material. Ferralis and Grossman modified and optimized the technique for studying stents.

The researchers found that at the microscopic level, polymer stents have a heterogeneous structure that eventually leads to structural collapse. While the outer layers of the stent have a smooth crystalline structure made of highly aligned polymers, the inner core tends to have a less ordered structure. When the stent is inflated, these regions are disrupted, potentially causing early loss of integrity in parts of the structure.

“Because the nonuniform degradation will cause certain locations to degrade faster, it will promote large deformations, potentially causing flow disruption,” Wang says.

When the stents become deformed, they can block blood flow, leading to clotting and potentially heart attacks. The researchers believe that the information they gained in this study could help stent designers come up with alternative approaches to fabricating stents, allowing them to possibly eliminate some of the structural irregularities.

A silent problem

Another reason that these problems weren’t detected earlier, according to the researchers, is that many preclinical tests were conducted for only about six months. During this time, the polymer devices were beginning to degrade at the microscopic level, but these flaws couldn’t be detected with the tools scientists were using to analyze them. Visible deformations did not appear until much later.

“In this period of time, they don’t visibly erode. The problem is silent,” Edelman says. “But by the end of three years, there’s a huge problem.”

The researchers believe that their new method for analyzing the device’s microstructure could help scientists better evaluate new stents as well as other types of degradable polymer devices.

“This method provides a tool that allows you to look at a metric that very early on tells you something about what will happen much later,” Edelman says. “If you know about potential issues in advance, you can have a better idea of where to look in animal models and clinical models for safety issues.”

The research was funded by Boston Scientific Corporation and the National Institutes of Health.

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Seeing the brain's electrical activity

Neurons in the brain communicate via rapid electrical impulses that allow the brain to coordinate behavior, sensation, thoughts, and emotion. Scientists who want to study this electrical activity usually measure these signals with electrodes inserted into the brain, a task that is notoriously difficult and time-consuming.

MIT researchers have now come up with a completely different approach to measuring electrical activity in the brain, which they believe will prove much easier and more informative. They have developed a light-sensitive protein that can be embedded into neuron membranes, where it emits a fluorescent signal that indicates how much voltage a particular cell is experiencing. This could allow scientists to study how neurons behave, millisecond by millisecond, as the brain performs a particular function.

“If you put an electrode in the brain, it’s like trying to understand a phone conversation by hearing only one person talk,” says Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT. “Now we can record the neural activity of many cells in a neural circuit and hear them as they talk to each other.”

Boyden, who is also a member of MIT’s Media Lab, McGovern Institute for Brain Research, and Koch Institute for Integrative Cancer Research, and an HHMI-Simons Faculty Scholar, is the senior author of the study, which appears in the Feb. 26 issue of Nature Chemical Biology. The paper’s lead authors are MIT postdocs Kiryl Piatkevich and Erica Jung.

Imaging voltage

For the past two decades, scientists have sought a way to monitor electrical activity in the brain through imaging instead of recording with electrodes. Finding fluorescent molecules that can be used for this kind of imaging has been difficult; not only do the proteins have to be very sensitive to changes in voltage, they must also respond quickly and be resistant to photobleaching (fading that can be caused by exposure to light).

Boyden and his colleagues came up with a new strategy for finding a molecule that would fulfill everything on this wish list: They built a robot that could screen millions of proteins, generated through a process called directed protein evolution, for the traits they wanted.

“You take a gene, then you make millions and millions of mutant genes, and finally you pick the ones that work the best,” Boyden says. “That’s the way that evolution works in nature, but now we’re doing it in the lab with robots so we can pick out the genes with the properties we want.”

The researchers made 1.5 million mutated versions of a light-sensitive protein called QuasAr2, which was previously engineered by Adam Cohen’s lab at Harvard University. (That work, in turn, was based on the molecule Arch, which the Boyden lab reported in 2010.) The researchers put each of those genes into mammalian cells (one mutant per cell), then grew the cells in lab dishes and used an automated microscope to take pictures of the cells. The robot was able to identify cells with proteins that met the criteria the researchers were looking for, the most important being the protein’s location within the cell and its brightness.

The research team then selected five of the best candidates and did another round of mutation, generating 8 million new candidates. The robot picked out the seven best of these, which the researchers then narrowed down to one top performer, which they called Archon1.

Mapping the brain

A key feature of Archon1 is that once the gene is delivered into a cell, the Archon1 protein embeds itself into the cell membrane, which is the best place to obtain an accurate measurement of a cell’s voltage.

Using this protein, the researchers were able to measure electrical activity in mouse brain tissue, as well as in brain cells of zebrafish larvae and the worm Caenorhabditis elegans. The latter two organisms are transparent, so it is easy to expose them to light and image the resulting fluorescence. When the cells are exposed to a certain wavelength of reddish-orange light, the protein sensor emits a longer wavelength of red light, and the brightness of the light corresponds to the voltage of that cell at a given moment in time.

The researchers also showed that Archon1 can be used in conjunction with light-sensitive proteins that are commonly used to silence or stimulate neuron activity — these are known as optogenetic proteins — as long as those proteins respond to colors other than red. In experiments with C. elegans, the researchers demonstrated that they could stimulate one neuron using blue light and then use Archon1 to measure the resulting effect in neurons that receive input from that cell.

Cohen, the Harvard professor who developed the predecessor to Archon1, says the new MIT protein brings scientists closer to the goal of imaging millisecond-timescale electrical activity in live brains.

“Traditionally, it has been excruciatingly labor-intensive to engineer fluorescent voltage indicators, because each mutant had to be cloned individually and then tested through a slow, manual patch-clamp electrophysiology measurement. The Boyden lab developed a very clever high-throughput screening approach to this problem,” says Cohen, who was not involved in this study. “Their new reporter looks really great in fish and worms and in brain slices. I’m eager to try it in my lab.”

The researchers are now working on using this technology to measure brain activity in mice as they perform various tasks, which Boyden believes should allow them to map neural circuits and discover how they produce specific behaviors.

“We will be able to watch a neural computation happen,” he says. “Over the next five years or so we’re going to try to solve some small brain circuits completely. Such results might take a step toward understanding what a thought or a feeling actually is.”

The research was funded by the HHMI-Simons Faculty Scholars Program, the IET Harvey Prize, the MIT Media Lab, the New York Stem Cell Foundation Robertson Award, the Open Philanthropy Project, John Doerr, the Human Frontier Science Program, the Department of Defense, the National Science Foundation, and the National Institutes of Health, including an NIH Director’s Pioneer Award.

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Event explores initial findings from “MIT and Slavery” class

In 1882, MIT students socialized in a drawing room that featured a replica of J.M.W. Turner’s painting, “The Slaveship,” which shows enslaved people drowning, thrown overboard during a storm as expendable cargo. The students’ commentary centered on the painting’s bold colors, but ignored the violent human narrative.

On Friday, Feb. 16, MIT senior Alaisha Alexander stood under a projection of that haunting image, and noted that absence in the campus dialogue of the time. Early MIT coursework also referred to scientific literature that validated slavery, she said, without encountering opposition from professors or students. “It’s not just about what is taught at a university. It’s also about what isn’t,” said Alexander, a mechanical engineering student. “Science and technology aren’t neutral.”

Alexander and other MIT students have begun exploring the university’s entanglement with the institution of slavery, in the process writing a more complete history, and helping to catalyze a national conversation about the legacies of slavery in science, engineering, and technical education. The source of this momentum is a new, ongoing undergraduate research course, “MIT and Slavery,” (21H.S01). Set in motion by MIT President L. Rafael Reif with School of Humanities, Arts, and Social Sciences (SHASS) Dean Melissa Nobles, the course was developed and taught by Craig Steven Wilder, the Barton L. Weller Professor of History and the nation’s leading expert on the links between universities and slavery, in collaboration with Nora Murphy, the MIT Archivist for Researcher Services.

How can history help us invent a better future?

The power of stories and seeking the facts were primary threads of discussion among the nine speakers during Friday’s event, the first of the “MIT and the Legacy of Slavery” dialogues that will engage the MIT community in considering responses to the course findings. A single MIT course rarely prompts community-wide conversations, but the research of the “MIT and Slavery” course speaks not only to more complete understanding of the Institute’s own history, but to the roots of ongoing culture-wide issues of justice, inclusion, and human rights.

“I believe the work of this class is important to the present — and to the future,” President Reif said in his welcoming remarks to around 200 faculty, students, alumni, and a livestream audience at the event. “Something I have always loved about the MIT community is that we seek, and we face, facts. What can history teach us now, as we work to invent the future? How can we make sure that the technologies we invent will indeed contribute to making a better world for all?”

The power of facts — and stories

Four MIT students from the first class presented well-researched information and narratives — previously obscured, forgotten, ignored — that shed new light on the history of science and technology in the U.S. One of many revelations unearthed in the course involves the story of MIT’s founder and first president William Barton Rogers. As Murphy discovered in the U.S. Census Slave Schedule of Virginia, before Rogers moved to Massachusetts in 1853, he owned six enslaved people, who, according to the census records, lived in his Virginia household.

This discovery hardly surprises scholars such as Wilder. In his words, “If we're surprised, our surprise is a measure of how successful we’ve been as a nation at erasing the history of slavery,” including its pervasive links with the economy and major institutions, in the Northeast as well as the South. Many U.S. engineering schools, for example, were originally funded by families whose wealth derived from textile, sugar, and mining operations, which depended, directly or indirectly, on the labor of enslaved people.

A new space for research and conversation

All the early findings from the new course, and those from future classes, will contribute to advancing a national dialogue, Wilder said: “We are not only participating in a larger exploration of the ties between American universities and slavery, we are leading a part of it.” Wilder said he hopes the MIT project inspires other science and technology institutions across the country to revisit their histories, and to form a collaborative research effort on the relationship between science, engineering, and the slave economies of the Atlantic World. Wilder is partnering with colleagues at New York University to convene several schools this spring to launch the initiative.

“The goal of our work is to collectively tell our story in the most honest, complicated, full, and transparent way that we can,” Wilder said during Friday’s event. Such a narrative will create space for much better conversations on campuses, in cities, in states, and across the country, he explained, adding that “what we mean by race, social justice, inclusion, and diversity” for the present and the future can only be understood when seen against an accurate historical backdrop.

Fundamental to the nation's history

In 1861, when MIT was founded, the political and social order in the U.S., along with its economy, was still fundamentally shaped by the institution of slavery, said Nobles, who provided an overview of the cultural and economic context in which MIT was founded, and will lead MIT’s process of community discussions to consider responses to the “MIT and Slavery” course findings.

The legacy of slavery is enmeshed in the histories of many of the country’s oldest and most prestigious institutions, said Nobles, who is also a professor of political science at MIT. “Slavery was so fundamental to our country’s history, economy, and politics that it would only be surprising if there were no connections at MIT.”

Indeed all scientific knowledge is embedded in a social context, said the course’s teaching assistant Clare Kim, a fifth-year PhD candidate. Her students visited the MIT archives and pored over old issues of the student newspaper The Tech and the MIT yearbook Technique. They also read faculty minutes, course catalogs, and a wealth of secondary source materials.

“These students interrogated not only our assumptions about MIT and slavery — but also race, science, and technology,” Kim said. She urged the audience to do more than passively receive the facts the class has found. “Go back to your labs and offices and look at your environment. Consider how the way you think about MIT — and science and technology — includes traces of the histories you are about to hear today.”

Insights from MIT students

Gasps were audible as Alexander, the mechanical engineering student, delved into early MIT silence around “The Slaveship” painting and other racialized art and literature. She ended her presentation by saying, “I encourage you to think about where different notions of science come from.”

Visual images were also the focus of first-year student Kelvin Green II’s research. Combing through early MIT student publications, Green II strove to understand early campus attitudes through the images that MIT students drew. He found racialized and mocking images of African-Americans; hooded figures evocative of the Klu Klux Klan; and an absence of images depicting African-Americans as students or engineers — an absence at odds with the actual occupations of black male Bostonians during the 1881-1911 time period.

When asked about the impact of these slavery-related findings on black students at MIT today, Green II reflected: “How do you quantify the experience of a black student confronted with the images I’ve put up?” Understanding racism, he continued, requires qualitative analysis, including listening to the stories of those most affected by it. “Engage in dialogue. If you don’t have a black friend, make a black friend!” he said to applause.

Sophomore Mahalaxmi Elango dug into MIT’s early curriculum for her project, and discovered not only an early focus on mining — an industry that had relied heavily on enslaved people — but also that slavery was a subject for academic discussion at MIT. A popular course in moral philosophy, for example, explored the relationship between technology and the economies of labor, including the labor of enslaved people. An 1873 political economy exam asked: “Define Labor, and prove that the service of slaves, or any involuntary work, is not labor in the economic sense.”

Charlotte Minsky, a sophomore majoring in earth, atmospheric, and planetary sciences, examined the careers of students who came to MIT in its first 15 years and found a large concentration of these students went into the railroad industry. She speculated that this focus emerged from the need to rebuild the South after the Civil War. “It’s essential to the narrative of early MIT that there’s a flow of money and ideas from the South to the North in the era of Reconstruction,” she said. Of MIT’s investigation into slavery, Minsky observed, “MIT is setting a precedent for similar institutions. We are showing that connections to slavery are very nuanced, and that science and technology are an aspect of this history that can longer be left in the wings.”

Raising questions

What skepticism there is about the “MIT and Slavery” research course takes the form of questions like the following, posed by a livestream viewer: “What gives anyone today the right to judge the actions of people in the distant past by modern popular moral standards?”

Wilder welcomed the opportunity to address that question. “Birth gives us the right,” he said, with a chuckle. “The idea that to judge the past by modern moral values is somehow ahistorical misunderstands what history is. History is the science of thinking about the past and how it influences the present.” The MIT community is capable of thinking about the past in constructive ways, he added. “One of the goals of the project is to create opportunities for us as a community — as communities — to wrestle with difficult issues in dialogue in a democratic and open way.”

Another community member asked one of the questions the project raises for education: “What would you say the implications of MIT’s findings are for teaching science and the history of science?” As an initial response, Kim noted that the “MIT and Slavery” course will itself be one example, continuing to research and share discoveries about the relationship between science, technology, and the social realities of which they are a part. She added, “We are asking people to think differently.”

Looking ahead

The value of this ongoing exploration is immeasurable, President Reif said. “If we have the courage to look at even the troubling parts of our history,” he said, “I believe we have a much better chance of approaching the present and the future with humility and self-awareness.”

The MIT and Legacy of Slavery dialogue will continue at MIT, led by Nobles who will announce plans for new opportunities to contribute ideas and reflections later this spring. The process Nobles envisions will be one of “looking at old things with new eyes.” In the meantime, and in parallel with the Institute-wide conversation, updates and information on the “MIT and Slavery” course findings will be posted to the course website.

Story prepared by SHASS Communications Editorial team: Meg Murphy and Emily Hiestand

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New digital archive showcases work from the Center for Advanced Visual Studies

In 1967, the newly established MIT Center for Advanced Visual Studies (CAVS), founded by professor György Kepes and conceived as a fellowship program for artists, welcomed its first three fellows. Pioneering work at the intersection of art, science, and technology quickly got underway, and in the following decades, more than 200 fellows arrived to participate in this globally influential program, along with researchers and graduate students.

Now, as part of a year-long celebration of the 50th anniversary of the founding of CAVS, a new interactive digital archive is offering public access to experimental work created by the fellows, including world-renowned artists such as Otto Piene, Aldo Tambellini, Yvonne Rainer, Nam June Paik, Muriel Cooper, and Stan VanDerBeek.

The digital archive was launched thanks to a grant from the National Endowment for the Arts to support the digitization and online presentation of the CAVS Special Collection, long held as slides and other original documentation at the Program for Art, Culture and Technology (ACT). ACT was formed in 2009 out of the merger of CAVS and MIT’s Visual Arts Program.  

“Fifty years ago, the founding of CAVS showed remarkable conviction and foresight,” says former ACT director and Associate Professor Gediminas Urbonas. “But what is even more remarkable is how the work and ideas that the CAVS fellows’ initiative produced are still relevant to our present world. We are living in the future that they imagined. And that work can help us address many of the crises that have and will emerge.”

The landing page of the site introduces users to an experimental, randomized three-dimensional environment of collection materials, which can be clicked through to view metadata (such as dates, locations, and descriptions) for each item. This feature allows users to experience a serendipitous visualization of the collection, encountering new materials at every turn. The design was inspired by the work of Muriel Cooper, a CAVS fellow, founding faculty member of the MIT Media Lab, and the first design director of the MIT Press.

Users can explore the collection by artist, subject (from environmental sound to sky art), or format (whether installations, drawings, booklets, photographs, videos, etc.). Topic tags show how materials are connected. The site provides more than 200 profiles of artist-fellows and alumni from CAVS; a timeline of the affiliations of fellows, visiting artists, and graduate students; and an interactive world map that illustrates the diverse global origins of the fellows.

Designed for both artists and academics, the site will grow to include research resources that document the process of creating art, such as proposals, administrative records, and correspondence. Posters, academic course booklets from the Master of Science in Visual Studies (SMVisS) degree program (now the Master of Science in Art, Culture, and Technology), and publications from exhibitions are now accessible. As the project continues, thousands of additional images, documents, and video files will be added.

Leadership for the project came from Urbonas, with project management by ACT archivist Jeremy Grubman. The MIT Libraries provided cataloging support, and the MIT Museum contributed materials from their CAVS-related holdings. The site was designed by NODE, a Berlin- and Oslo-based design studio, with development work by Bengler, an Oslo-based firm.

One component of the site makes it unique among visual art repositories: the ability for artists to annotate their works, sharing their inspirations and the process behind creating art. ACT has posted several sample annotations and will invite CAVS fellows more broadly to participate.

In one of the sample annotations, CAVS fellow Jon Goldman SMVisS '84 writes of his “nudibranch” sculptures: “I created nudibranch, a forty-foot cold-air inflatable sculpture ... to call attention to the most delicate of creatures as telltales for the health of their ecosystem. The bleaching of coral ecosystems worldwide was becoming a reality and I looked to these incredibly beautiful creatures as source models to become kinetic sculptures activated by the wind.”

Ellen Sebring SMVisS '86, another CAVS fellow, annotated a catalog of video art titled “Centervideo”: “The generation of video artists that I worked with at CAVS were across-the-board phenomenal. They had mountains of energy, openness, and the confidence, with the advent of portable cameras, to cast personal video as the interface between themselves and the world ... You can’t imagine the sudden freedom of the moving image being accessible.”

In addition to launching the digital archive, ACT is celebrating the CAVS50 anniversary by developing exhibitions, events, an international symposium, and a publication, all intended to explore ideas that emerged from CAVS — art and the environment, art at the civic scale, and art as it relates to the future — in a contemporary context.

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MIT students take back Putnam competition honors

A trio of MIT math undergrads has claimed the top team spot in the 78th annual William Lowell Putnam Mathematical Competition. MIT students dominated the competition, taking 17 of the top 25 spots from among 4,638 test-takers from 575 institutions last December. Of the five top scorers, who are named Putnam Fellows, four were from MIT. A total of 38 out of the 99 top scorers were MIT undergraduates.

With the announcement of the results, MIT can now claim the highest rank for four out of the past five years. Last year, the MIT team came in fourth.

"I am delighted that MIT undergraduates have again won first place in the 2017 Putnam Competition,” says Michael Sipser, the Donner Professor of Mathematics and Dean of Science at MIT. “This stunning performance reflects the extraordinary talent of our students and the superb coaching that they receive here. Kudos to all participants and to the Department of Mathematics.”

The Putman is one of the most prestigious mathematical competitions in the U.S. and Canada, requiring competitors to attempt to solve 12 brutally challenging problems in six hours. The highest exam score was 89 out of a possible 120 points. Only 20 percent of participants earned a score above 13.

The school with the first-place team receives an award of $25,000. Each first-place team member receives $1,000. Putnam Fellows receive an award of $2,500.

On the MIT team were Putnam veterans Allen Liu, who is in his third year, and seniors Sammy Luo and Yunkun Zhou. Zhou was MIT’s Putnam Fellow last year. This year’s Putnam Fellows are Omer Cerrahoglu, Jiyang Gao, Junyao Peng, and Ashwin Sah.

The Institute's Putnam exam preparation was run by Yufei Zhao SB '10, PhD '15, who was recently appointed as an assistant professor in the MIT Department of Mathematics. Zhao was named a Putnam Fellow in 2006, 2008, and 2009. He also ranked seventh in 2007.  

"I am incredibly proud of MIT students' amazing performance," says Zhao. "The success reminds us that the level of enthusiasm and strength of our math undergraduates is unmatched by anywhere else."

Students can prepare for the Putnam by taking 18.A34 (Mathematical Problem Solving Seminar), which last fall was taught by Zhao. As a freshman, Zhao had taken the class with professors Richard Stanley and Hartley Rogers. Each week in his seminar, Zhao presented a lecture on a specific topic for the students to solve in the next class.

“I get to see a lot of interesting and creative solutions presented by the students, and I think they had a fun time coming up and presenting their proof, often containing pretty cool and creative ideas,” Zhao says. “To be honest, there's very little that I can teach the group in a semester. The time is short, and they're all already so amazing. What I hope the seminar accomplished is to keep them interested in math problem solving, form a group so that they have friends to talk to, so that they don't end up getting rusty at solving math competition-type problems. Most of the top-performing students have had much more intensive competition training from their high school math contest days.”

Mathematics interim department head Michel Goemans offered his congratulations “to all participants and to Yufei Zhao.”

“It is a delight to have such a talented pool of students at MIT who are so passionate about mathematics,” Goemans says. “And let me also recognize the tremendous work of the admissions office, without whom this would have not been possible."

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MIT expands multidepartmental partnership with Imperial College London

Building on the success of existing partnerships, MIT’s Global Education and Career Development (GECD) is significantly expanding its academic exchange with Imperial College London, while continuing to grow the Imperial summer research exchange. Twelve MIT departments will now take part in one or both exchanges.

These augmented multidepartmental exchange programs will allow even more MIT undergraduates to participate in rigorous and enriching study abroad and research experiences at Imperial, a leading U.K. university that focuses exclusively on science, engineering, medicine, and business.

The academic exchange is transforming from a departmental exchange spanning two departments to a multidepartmental exchange involving nine departments. GECD will start sending students on the expanded academic exchange program this coming fall.

Meanwhile, the summer research exchange with Imperial has been growing steadily, from two departments in 2013 to 10 now.

“Such opportunities provide hugely valuable experiences in learning to learn and work in another culture and a different scientific environment,” says Professor Linn Hobbs of the MIT Department of Materials Science and Engineering. “Students find the experience challenging, exciting, and full of potential for both personal and intellectual growth.”

MIT’s partnership with Imperial began in 2013 with a summer research program for students from both schools’ departments of Materials Science and Physics. Hobbs spearheaded the exchange, working closely with Robin Grimes, professor of materials physics at Imperial and chief scientific advisor to the U.K.

Hobbs was also the impetus behind the academic exchange program that shortly followed, and has championed the development of both exchange programs. As part of the academic exchange, a corresponding number of Imperial students come to MIT to partake in courses and research.

Semester/year academic exchange

The academic exchange program offers the opportunity for two juniors each (four in the case of Electrical Engineering and Computer Science) from nine departments to spend either the spring semester of their junior year or their full junior year in the corresponding department at Imperial College London. Students apply through GECD and are selected jointly by faculty in their MIT department and GECD’s Global Education staff.

While on the exchange, students study on Imperial’s campus, which is located in central London’s posh Kensington and Chelsea neighborhoods steps away from such cultural attractions as the Science and Industry Museum, Royal Albert Hall, and numerous music and restaurant venues. Students take academic subjects that provide MIT transfer credit for core or restricted-elected subjects in their majors. In addition, Imperial offers UROP-like experiences whenever possible.

The 2019 academic year will initiate a two-year pilot for the expanded exchange that will enable student participation from seven new departments. These new departments, joining Materials Science and Engineering and Nuclear Science and Engineering, are: Mechanical Engineering; Chemistry; Electrical Engineering and Computer Science; Chemical Engineering; Earth, Atmospheric and Planetary Sciences; Aeronautics and Astronautics; and Mathematics.

Faculty as well as students are enthusiastic about the multidepartmental expansion. “We are excited to be initiating a student exchange with Imperial College London, one of the great research institutions of the world,” says Professor Haynes Miller in the Department of Mathematics. “Imperial has an excellent undergraduate program, one that will offer our students the same kind of perspective and growth that the Cambridge-MIT Exchange did. Thirty-seven of our majors spent a year as Cambridge students over the 16 years of the program. Each and every one gained from it in deep ways, and we anticipate the same results from the Imperial project. We look forward also to hosting an equal number of Imperial students here; their different perspectives will enrich the experience of our majors here in Cambridge, Massachusetts.”

Summer research exchange

Since its launch in 2013, the summer research exchange with Imperial has added new departments over the years and welcomed increasing numbers of participants. The research exchange is now open to undergraduates in Civil and Environmental Engineering, Materials Science and Engineering, Chemistry, Electrical Engineering and Computer Science, Physics, Chemical Engineering, Aeronautics and Astronautics, Mathematics, Biological Engineering, and Nuclear Science and Engineering. Each department nominates two students to participate each year. The faculty coordinators then work closely with their counterparts at Imperial to identify labs, faculty supervisors, and advisors for participating students.

The research exchange runs from late June through mid-August. During those weeks, MIT also welcomes Imperial students to its campus. Last summer, 18 MIT students and 18 Imperial students participated in the exchange, including rising MIT junior Yun Chang. Chang, an AeroAstro major who is also an Emerson fellow in piano, immersed himself in his lab’s research on quadrocopter 3-D SLAM implementation, savored the cosmopolitan world of London and Imperial, and attended numerous BBC classical music promenade concerts.

“Doing research at Imperial College London was an amazing experience, and was especially unique in that I got to meet people from all over the world,” says Chang. “I got to do interesting research, and I was able to broaden my horizons. I am already missing walking through Kensington Gardens on my way to Imperial every morning.”

MIT’s UROP office is an integral partner with GECD’s Global Education team for this program. As a co-sponsor, UROP provides student funding through hourly wages and an airfare stipend, while GECD funds MIT students’ accommodations in London.

Looking forward to future collaboration

“MIT is looking forward to a long-term partnership with Imperial College London,” says Julie Maddox, assistant dean for Global Education at GECD. “I’ve seen students profiting from their academic and research experiences at Imperial over the years and have been inspired by how they speak about their intellectual and personal growth. Likewise, Imperial students who come to our campus greatly contribute to our classes and labs and are enthusiastic about their experiences here.”

“I’m thrilled that we succeeded in growing both the academic and research exchanges with Imperial so more students from across MIT will be able to engage in these important opportunities,” adds Malgorzata Hedderick, associate dean for Global Education at GECD. “Imperial has been a very supportive partner over the years and we are excited to continue this mutually beneficial relationship. Huge thanks go to the MIT and Imperial faculty; none of this would have been possible without their leadership, dedication, and involvement.” 

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Human malaria parasites grown for the first time in dormant form

One of the biggest obstacles to eradicating malaria is a dormant form of the parasite that lurks in the livers of some patients. This dormant form is resistant to most antimalarial drugs and can reawaken months or years later, causing disease relapse.

Malaria researchers know little about the biology of these dormant parasites, so it has been difficult to develop drugs that target them. In an advance that could help scientist discover new drugs, MIT researchers have shown they can grow the dormant parasite in engineered human liver tissue for several weeks, allowing them to closely study how the parasite becomes dormant, what vulnerabilities it may have, and how it springs back to life.

After verifying that they had successfully cultivated the dormant form of the parasite, the researchers showed that they could also sequence its RNA and test its response to known and novel antimalarial drugs — both important steps toward finding ways to eradicate the disease.

“After 10 years of hard work, we were able to grow the organism, show it had all the functional hallmarks, perform a drug screen against it, and report the first transcriptome of this elusive form. I’m really excited because I believe it will open the door to both the basic biology of dormancy as well as the possibility of better medicines,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science. Bhatia is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and the senior author of the study.

MIT graduate student Nil Gural is the first author of the paper, which appears in the Feb. 22 issue of the journal Cell Host and Microbe.

MIT researchers captured video of malaria parasites budding off from infected cells. In this image, the parasites are getting ready to emerge from the cell. (Nil Gural)

After a few minutes, the parasites have emerged from the infected cell. (Nil Gural)

Persistent infections

Most human cases of malaria are caused by one of two parasite species, Plasmodium falciparum and Plasmodium vivax. Plasmodium vivax, while less deadly, produces dormant forms known as hypnozoites (so called because they are “hypnotized”), and can lead to recurring infections. 

In 1991, Aneityum, a small island in the Southwest Pacific, was chosen as a site to test possible measures to eradicate malaria. Researchers sprayed against mosquito larvae and supplied bed nets and malaria medicine across the entire island. These efforts led to the complete eradication of Plasmodium falciparum within a year. In contrast, it took five years to eliminate Plasmodium vivax.

“This dormant form has been seen as the critical barrier to eradication,” Bhatia says. “You can treat the symptoms of vivax malaria by killing all the parasites in the blood, but if hypnozoites linger in someone’s liver, these forms can reactivate and reinfect the blood of a patient. If a mosquito comes along and takes a blood meal, the cycle starts all over again. So, if we want to eradicate malaria, we have to eradicate the hypnozoite.”

The only existing drug that can kill hypnozoites is primaquine, but this drug cannot be used in large-scale eradication campaigns because it causes blood cells to rupture in people with a certain enzyme deficiency.

Bhatia’s team became aware of this problem in 2008, when the World Health Organization and the Bill and Melinda Gates Foundation called for a renewed effort to eradicate malaria, which infects more than 200 million people every year and killed an estimated 429,000 in 2015. Her lab is working with special micropatterned surfaces on which human liver cells can be grown, surrounded by supportive cells. This architecture creates a microenvironment in which human liver cells function much the same way as they do in humans, making it easier to establish, maintain, and study infections of the liver.

Bhatia, who initially used this technology to model hepatitis infections, realized it was also well-suited to studying the liver stage of malaria. She and her malaria team lead, Sandra March, began with Plasmodium falciparum, the strain that can be cultured in lab settings, and found that parasites grown in these liver tissue followed the same life cycle observed in natural infections. They also found that the system could be used to test responses to experimental malaria vaccines.

Following that success, Bhatia’s lab began working with Plasmodium vivax. Efforts to bring the parasite-infected mosquitoes into the United States were unsuccessful, so Gural, the paper’s lead author, traveled to collaborator Jetsumon Prachumsri’s lab in Thailand repeatedly to obtain samples from infected patients and perform the experiments there.

Using their new technology, the researchers showed that they could grow small forms of the parasite that had all of the known features of hypnozoites: persistence, sensitivity to primaquine, and the ability to “wake up” after a few weeks.

New drug targets

Once the researchers were confident that these forms were actually hypnozoites, they set out to do some further studies. First, they obtained six candidate antimalarials now in development and tested them for activity against their Plasmodium vivax samples. They found that none of them could kill established hypnozoites, which was what they had expected based on clinical trials. They now plan to test a larger set of new compounds, working with the nonprofit group Medicines for Malaria Venture, which has a collection of thousands of drug candidates.

Working with scientists at the Swanson Biotechnology Center at the Koch Institute and the Broad Institute of Harvard and MIT, the MIT team performed the first sequencing of the hypnozoite transcriptome. No one had been able to look this closely at hypnozoites before, and RNA sequencing revealed that the dormant forms were not transcriptionally silent, as had been expected, but instead express a different subset of genes than those found in their active counterparts.

“This is a very exciting study,” says Maria Mota, executive director of the Institute for Molecular Medicine at the University of Lisbon. “It provides not only the first transcriptional comparative characterization of replicating schizonts and hypnozoites of P. vivax, but most importantly demonstrates the feasibility of an in vitro platform to study hypnozoites without the need to use animals.”

In future studies, Bhatia, in collaboration with other MIT labs, plans to use single cell RNA-sequencing to identify gene signatures to uncover the signaling pathways that control hypnozoite dormancy and reactivation. The researchers will also study corresponding changes in gene expression of the infected liver cells. This approach could yield potential new drug candidates that would specifically target the dormant forms of the parasite, bringing the field closer to its goal of eradicating malaria. The researchers also hope to identify biomarkers that could be used to diagnose patients who have an otherwise undetectable dormant infection.

The research was funded by the Bill and Melinda Gates Foundation, the Broad Institute of Harvard and MIT, and the Koch Institute Support Grant from the National Cancer Institute.

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