Medical devices designed to reside in the stomach have a variety of applications, including prolonged drug delivery, electronic monitoring, and weight-loss intervention. However, these devices, often created with nondegradable elastic polymers, bear an inherent risk of intestinal obstruction as a result of accidental fracture or migration. As such, they are usually designed to remain in the stomach for a limited time.

Now, researchers at MIT’s Koch Institute for Integrative Cancer Research and Massachusetts General Hospital (MGH) have created a polymer gel that overcomes this safety concern and could allow for the development of long-acting devices that reside in the stomach, including orally delivered capsules that can release drugs over a number of days, weeks, or potentially months following a single administration.

This polymer is pH-responsive: It is stable in the acidic stomach environment but dissolves in the small intestine’s near-neutral pH, allowing for safe passage through the remainder of the gastrointestinal (GI) tract. The material is also elastic, allowing for the compression and folding of devices into easily ingestible capsules — meaning this polymer can be used to create safe devices designed for extremely prolonged residence in the stomach.

“One of the issues with any device in the GI tract is that there’s the potential for an obstruction, which is a medical emergency potentially requiring surgical intervention,” says Koch Institute research affiliate Giovanni Traverso, also a gastroenterologist at MGH and an instructor at Harvard Medical School. “A material like this represents a real advance because it is both safe and stable in the stomach environment.”

Traverso and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, are the senior authors of a paper in the July 27 issue of Nature Materials that describes the application of this new polymer gel for creating gastric devices. Shiyi Zhang, a postdoc at the Koch Institute, is the paper’s lead author.

Safely stretching

Designing devices for the stomach is a complicated matter of sizes and shapes. The stomach naturally empties its contents in a matter of hours, so for devices to be retained, they must be wider than the pylorus — the valve at the end of the stomach, about 1.5 to 2 centimeters in diameter, that allows gastric contents to pass into the small intestine. However, because the most convenient path to deliver these devices is through the esophagus, which is only marginally wider than the pylorus, the researchers were interested in developing a polymer with elastic properties.

“An elastic device can be folded into something small, such as a capsule, and be easily ingested through the esophagus before expanding in the stomach, restoring its original shape,” Zhang says. “When you have a device that’s larger than the pylorus, there’s a much higher probability that it will be retained longer in the stomach.”

But the size and shape of existing devices with elastic polymers have been limited by safety concerns, as there is a greater risk for fracture if a device is too large or too complex. Because of this, the researchers wanted their polymer to also be enteric — or have a mechanism that would enable it to pass through the stomach unaltered before disintegrating in the intestines.

“To lower any possible risk of obstruction, we wanted a material that could dissolve in the intestines, thereby dissociating the device, and safely pass out of the body,” Zhang says.

To create this new material, the researchers synthesized an elastic polymer and combined it in solution with a clinically utilized enteric polymer. Adding hydrochloric acid and centrifuging the solution resulted in a flexible, yet resilient, polymer gel that exhibits both elastic and enteric properties.

The researchers used the gel polycaprolactone (PCL), a nontoxic, degradable polyester, to construct several device prototypes. They first created ring-shaped devices by using the gel to link arcs of PCL in a circular mold. These elastic devices had a diameter of 3 centimeters — wider than the pylorus — before they were folded into orally ingestible capsules.

In testing the capsules in pigs, the researchers found that the rings expanded into their original shape within 15 minutes of ingestion and remained in the stomach for up to seven days. After the device passed out of the stomach, the polymer gel dissolved, allowing for the safe passage of the small PCL pieces without obstruction. The researchers also created larger devices in various shapes that could be folded and delivered through the esophagus with the assistance of an endoscope. These devices remained in the stomach for up to five days, after which the gel similarly dissolved, allowing for the remnants of the device to safely pass.

Improving adherence

The combined enteric and elastic properties of this polymer gel could significantly improve the design and adoption of gastric-resident devices. Devices that could incorporate this material include bariatric devices for the treatment of obesity, which control how hungry or full a person feels; ingestible electronics, which can diagnose and monitor a variety of conditions in the GI tract; or extended-release drug-delivery systems that could last for weeks or months after a single administration.

“This delivery system provides a flexible and smooth external covering that slowly disintegrates, which could release drugs or small devices for monitoring and imaging the GI tract,” says Edith Mathiowitz, a professor of medical science and engineering at Brown University who was not involved with this study. “This is a very smart approach.”

In particular, the authors say they are excited for the drug-delivery applications of this technology. With further work in adjusting the polymer composition or the design of the system, they say that they could tailor devices to release drugs over a specific timeframe of up to weeks or months at a time. MIT is negotiating an exclusive license agreement with Lyndra, an early-stage biotechnology company developing novel oral drug-delivery systems, for this and other related technologies.

“I’m delighted to see these new oral systems provide an opportunity that I’ve not seen previously — enabling patients to swallow a single pill that can then act for whatever length of time is desired,” Langer says.

Such single-administration events could improve medication adherence, which remains a major clinical barrier. According to the World Health Organization, patients’ adherence to long-term therapies for chronic illnesses is only 50 percent in developed countries, with lower rates of adherence in developing nations. Medication nonadherence costs the U.S. an estimated $100 billion every year, the bulk of which comes in the form of unnecessary hospitalizations. The researchers also say that single-administration delivery systems for the radical treatment of malaria and other infections could significantly benefit from these technologies.

In a March 2015 commentary piece in Nature, Traverso and Langer wrote that the GI tract is an area rife with opportunity for prolonged drug delivery in tackling this global health problem. With this new material, which can be used to create extended-release systems via swallowable “pills,” they envision an emerging field of orally delivered devices that can maximize adherence and therapeutic efficacy.

The paper’s other authors include Andrew Bellinger, Dean Glettig, Ross Barman, Young-Ah Lee, Cody Cleveland, Veronica Montgomery, and Li Gu from MIT; Jiahua Zhu from Oak Ridge National Laboratory; and Landon Nash and Duncan Maitland from Texas A&M University.

This research was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health, and the Alexander von Humboldt Foundation.

By Kevin Leonardi | MIT News Office

Astronauts on the International Space Station (ISS) have a number of exercise options, including a mechanical bicycle bolted to the floor, a weightlifting machine strapped to the wall, and a strap-down treadmill. They spend a significant portion of each day working out to ward off the long-term effects of weightlessness, but many still suffer bone loss, muscle atrophy, and issues with balance and their cardiovascular systems. 

To counteract such debilitating effects, research groups around the world are investigating artificial gravity — the notion that astronauts, exposed to strong centrifugal forces, may experience the effects of gravity, even in space. Engineers have been building and testing human centrifuges — spinning platforms that, at high speeds, generate G-forces strong enough to mimic gravity. An astronaut, riding in a centrifuge, would presumably feel gravity’s reinforcing effects.

Now engineers at MIT have built a compact human centrifuge with an exercise component: a cycle ergometer that a person can pedal as the centrifuge spins. The centrifuge was sized to just fit inside a module of the ISS. After testing the setup on healthy participants, the team found the combination of exercise and artificial gravity could significantly lessen the effects of extended weightlessness in space — more so than exercise alone.

Laurence Young, the Apollo Program Professor in MIT’s Department of Aeronautics and Astronautics, says artificial gravity would be a huge benefit for astronauts, particularly those embarking on long-duration space missions, such as a journey to Mars. The risks, he says, are uncertain, but potentially significant.

“With exploration-class missions, like Mars, where you’re gone for three years, you could run the risk of having astronauts not sufficiently conditioned to perform effectively, and also to not be in good health when they finally get to the surface of Mars,” says Young, a former NASA payload specialist. “You really don’t want to send a jellyfish to represent us on another planet.”

Young says a human centrifuge aboard a Mars-bound spacecraft would help keep an astronaut in shape over the many months it would take to get to the Red Planet. He and his colleagues, former graduate students Ana Diaz and Chris Trigg, have published results from their experiments in the journal Acta Astronautica.

Spinning up artificial gravity

The team’s compact centrifuge resembles a rotating metal cage with three main elements: a chair; a cycle ergometer, or the mechanical portion of a stationary bicycle; and a suite of sensors to measure cardiovascular variables such as blood pressure, heart rate, respiration rate, muscle activity, and foot forces.

The researchers conducted experiments to test human responses and exercise performance at varying levels of artificial gravity. The experiments involved 12 healthy subjects, who participated in three sessions, each consisting of a bicycling workout under one of three artificial gravity levels: zero G, in which the centrifuge did not rotate; 1 G, measured at the feet, in which the centrifuge spun at 28 revolutions per minute (rpm); and 1.4 G, also measured at the feet, at 32 rpm.

“When it spins around, we create centrifugal force, which depends on the angular velocity, or how fast we are rotating — the higher the angular velocity, the greater the artificial gravity,” Diaz says.

During each session, participants were asked to pedal for 15 minutes at three workout intensities, or levels of resistance, set by the cycle ergometer. The remaining 10 minutes involved spinning up and slowing down the centrifuge.

Beyond a “universal solution”

After each session, participants filled out a survey to gauge symptoms such as motion sickness and light-headedness. Overall, Diaz found that participants tolerated the experiments well, suffering little motion sickness even while spinning at relatively high velocities. Participants only reported feelings of discomfort while initially speeding up and slowing down.

“During the spinning process, participants were pushed against the chair due to the centrifugal force, making them sit comfortably, and facilitating their leg biomechanics for biking,” Diaz says.

As the researchers increased the centrifuge’s spin, raising its artificial gravity, participants used correspondingly more force to pedal — an unsurprising but encouraging result.

“That tells us that if we use artificial gravity, we’re able to get higher foot forces, and we know higher foot forces are good for bones, and help you generate more bone,” Diaz says. “Even if we expected this, we were able to quantify it and find a relationship between foot forces and artificial gravity.”

Similarly, as artificial gravity intensified, so did participants’ overall cardiovascular activity, a response that Diaz says may be beneficial over the long term.

Young says the study may begin to bridge two seemingly opposing camps: those who believe exercise alone will prevent bone loss, muscle atrophy, and other effects of extended weightlessness, and those who believe in artificial gravity as the solution.

“I think the principal finding here is supporting the conclusion that exercise alone is not a sufficient countermeasure,” Young says. “For the first time, we’re showing there’s a symbiosis when one combines the best aspects of exercise, and the best aspects of artificial gravity. So I feel this is an important demonstration.”

This research was funded in part by the National Space Biomedical Research Institute and a Skoltech/MIT seed grant.

By Jennifer Chu | MIT News Office

Named for the pioneering medical researcher, the Hugh Hampton Young Fellowship is one of the Office of the Dean for Graduate Education’s (ODGE) most prestigious awards. A famed urologist, Young was not only an innovator in medical science, his curiosity and intellectual drive also stirred him in other endeavors such as civic enhancement, the arts, and the burgeoning field of aviation.  Accordingly, the goal of the Hugh Hampton Young Fellowship is to not only recognize academic achievement, but also exceptional personal and character strengths, with heavy emphasis on the perceived overall potential of the candidate to have a positive impact on humanity.

Established in 1965 through an anonymous donor, roughly 150 students have benefited from this award over the last 50 years. “The Hugh Hampton Young Fellowship has always been handled slightly differently than our other opportunities,” says ODGE Manager of Graduate Fellowships Scott Tirrell. “As a stipulation of the award, recipients are chosen by an external selection committee largely comprised of former Hugh Hampton Young Fellowship recipients. Through careful evaluation of candidate application material and personal interviews, the committee seeks individuals exhibiting a blend of broad focus, leadership, and initiative.”

The committee has selected seven new recipients as the 2015-16 fellowship cohort. They will join a legacy of exceptional individuals, and will hopefully go on to make positive impacts on society in the tradition of Young himself. (Accomplishments of former Hugh Hampton Young Fellowship recipients can be seen on the ODGE website.)

John Arroyo is a PhD student in the Department of Urban Studies and Planning. He received his master’s in city planning and a certificate in urban design from MIT and a BA in public relations, with a concentration in planning and development, from the University of Southern California. His professional career includes community development, housing, and arts and cultural programming experience with various nonprofits, foundations, and government agencies. Prior to MIT he was an Executive Fellow at the Coro Foundation’s Southern California Center for Civic Leadership. Arroyo is interested in the interrelationship between the built environment, migration, and policy. In particular, his comparative research investigates how the public-built environment influences and reshapes sociocultural behavior among transnational Latino migrants, and how local urban planning and design policies react to this adjustment phenomenon in both U.S. receiving communities and native Latin American sending communities (Mexico and Central America). In 2012 he co-created Project 51’s “Play the L.A. River,” a public humanities project dedicated to increasing awareness of and access to the Los Angeles River as a civic space.

Or Gadish is a PhD candidate in Health Sciences and Technology at MIT’s Institute for Medical Engineering and Science. His thesis work seeks to combine the advances of vascular biology, biomaterials and tissue engineering, and cancer biology to better understand the relationship between cancer cells and tumor-resident endothelial cells (EC), the cells that line all blood vessels. While healthy ECs are anti-tumorigenic, tumors transform ECs into a pro-tumorigenic state. As such, Gadish is also looking closely at the relationship between tumor-transformed ECs and their healthy brethren, which can be grown in vitro, embedded on biomaterial scaffolds, and implanted next to tumors to both inhibit cancer cell processes and rescue transformed ECs.

Steven Keating is a PhD candidate in the Department of Mechanical Engineering focused on novel platforms for additive manufacturing, synthetic biology, and designed growth. Based out of the Mediated Matter group at the MIT Media Lab, his research covers a diverse range including building-scale 3-D printing, microfluidic digital fabrication, and open patient data access. From gears to genomes, he is interested in exploring new design possibilities. Keating has lectured and helped instruct for several MIT design courses — including 2.00b (Toy Product Design), 2.009 (Product Engineering Processes), MAS.500 (Hands on Foundations in Media Technology), and MAS.S64 (Special Subject in Media Technology) — and is a patient advocate for open health data. Calgary is his hometown and he is invigorated by curiosity, creativity, and maple syrup.

Georgia Lagoudas is a PhD candidate in the Department of Biological Engineering. She completed her undergraduate degree at Rice University in bioengineering. She is interested in investigating the microbes inside of our bodies — in particular our lungs — and how these microbes are associated with health. We have only recently discovered that bacteria exist in the healthy lungs, but we do not have a clear understanding of their role. Lagoudas is focused on using mice as a model system to study the dynamics of the lung microbial population and investigate how changes in the immune system or health status might alter these microbes.

William Li is a PhD candidate in the Department of Electrical Engineering and Computer Science focused on data science on open government datasets. He develops and applies methods to analyze and visualize large collections of text documents to answer research questions in computational social science and promote public understanding of law, politics, and public policy. Li’s recent work includes predicting the authors of unsigned Supreme Court opinions, quantifying repeated text in Congress, and measuring the complexity of our laws using language and software engineering metrics. Along with these research interests, Li helps run the MIT Assistive Technology Club and co-taught 6.811 (Principles and Practice of Assistive Technology) in 2014, a full-semester course that focuses on accessibility and assistive technologies for people with disabilities. 

Mitali Thakor, a continuing Hugh Hampton Young Fellow, is a PhD candidate in the MIT Program in History, Anthropology, and Science, Technology, and Society. Her dissertation uses feminist anthropological methods to explore the global carceral politics of anti-trafficking, pornography, and child exploitation in the context of emerging digital technologies. She has conducted fieldwork in the U.S., Netherlands, and Thailand, and hopes that her research will inform critical and comprehensive practices to reduce exploitation and victimization. Outside of research, Mitali is a campus peer educator and organizer on issues of sexual violence and healthy relationships, and is also active with local anti-racist and queer feminist political organizations. Prior to MIT, Mitali worked on community sexual health research in the Philippines, and also holds BA degrees in feminist studies and anthropology from Stanford University.

Iris Zielske is an MS and MBA candidate in the Leaders for Global Operations program. She holds a BS in industrial and systems engineering and a BA in linguists from the University of Florida. As a part of her studies at MIT she has worked with LV Prasad Eye Institute on a designing a prototype for a wearable, electronic device for students with low vision in India and worked with Gradian Health Systems on evaluating their after-sales service strategy for anesthesia machines in East Africa. Her thesis research focuses on digital identification systems for biotechnology supply chains.

By Office of the Dean for Graduate Education

Engineers at MIT and the University of California at San Diego (UCSD) have devised a new way to detect cancer that has spread to the liver, by enlisting help from probiotics — beneficial bacteria similar to those found in yogurt.

Many types of cancer, including colon and pancreatic, tend to metastasize to the liver. The earlier doctors can find these tumors, the more likely that they can successfully treat them.

“There are interventions, like local surgery or local ablation, that physicians can perform if the spread of disease in the liver is confined, and because the liver can regenerate, these interventions are tolerated. New data are showing that those patients may have a higher survival rate, so there’s a particular need for detecting early metastasis in the liver,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Electrical Engineering and Computer Science at MIT.

Using a harmless strain of E. coli that colonizes the liver, the researchers programmed the bacteria to produce a luminescent signal that can be detected with a simple urine test. Bhatia and Jeff Hasty, a professor of biology at UCSD, are the senior authors of a paper describing the new approach this week in the journal Science Translational Medicine. Lead authors are MIT postdoc Tal Danino and UCSD postdoc Arthur Prindle.

Microbial help

Previous studies had shown that bacteria can penetrate and grow in the tumor microenvironment, where there are lots of nutrients and the body’s immune system is compromised. Because of this, scientists have been trying for many years to develop bacteria as a possible vehicle for cancer treatment.

The MIT and UCSD researchers began exploring this idea a few years ago, but soon expanded their efforts to include the concept of creating a bacterial diagnostic.

To turn bacteria into diagnostic devices, the researchers engineered the cells to express the gene for a naturally occurring enzyme called lacZ that cleaves lactose into glucose and galactose. In this case, lacZ acts on a molecule injected into the mice, consisting of galactose linked to luciferin, a luminescent protein naturally produced by fireflies. Luciferin is cleaved from galactose and excreted in the urine, where it can easily be detected using a common laboratory test.

At first, the researchers were interested in developing these bacteria for injection into patients, but then decided to investigate the possibility of delivering the bacteria orally, just like the probiotic bacteria found in yogurt. To achieve that, they integrated their diagnostic circuits into a harmless strain of E. coli called Nissle 1917, which is marketed as a promoter of gastrointestinal health.

In tests with mice, the researchers found that orally delivered bacteria do not accumulate in tumors all over the body, but they do predictably zero in on liver tumors because the hepatic portal vein carries them from the digestive tract to the liver.

“We realized that if we gave a probiotic, we weren’t going to be able to get bacteria concentrations high enough to colonize the tumors all over the body, but we hypothesized that if we had tumors in the liver they would get the highest dose from an oral delivery,” says Bhatia, who is a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

This allowed the team to develop a diagnostic specialized for liver tumors. In tests in mice with colon cancer that has spread to the liver, the probiotic bacteria colonized nearly 90 percent of the metastatic tumors.

In the mouse experiments, animals that were given the engineered bacteria did not exhibit any harmful side effects.

More sensitive detection

The researchers focused on the liver not only because it is a natural target for these bacteria, but also because the liver is hard to image with conventional imaging techniques like CT scanning or magnetic resonance imaging (MRI), making it difficult to diagnose metastatic tumors there.

With the new system, the researchers can detect liver tumors larger than about one cubic millimeter, offering more sensitivity than existing imaging methods. This kind of diagnostic could be most useful for monitoring patients after they have had a colon tumor removed because they are at risk for recurrence in the liver, Bhatia says.

Andrea Califano, a professor of biological sciences at Columbia University, says the study is “seminal and thought-provoking in terms of clearing a new path for investigating what can be done for early detection of cancer,” adding that the therapeutic possibilities are also intriguing.

“These bacteria could be engineered to cause genetic disruption of cancer cell function, deliver drugs, or reactivate the immune system,” says Califano, who was not involved in the research.

The MIT team is now pursuing the idea of using probiotic bacteria to treat cancer, as well as for diagnosing it.

The research was funded by the Ludwig Center for Molecular Oncology at MIT, a Prof. Amar G. Bose Research Grant, the National Institutes of Health through the San Diego Center for Systems Biology, and the Koch Institute Support Grant from the National Cancer Institute.

By Anne Trafton | MIT News Office

Sangeeta Bhatia has been named the recipient of the 2015 Heinz Award for Technology, the Economy, and Employment.

The Heinz Family Foundation, which administers the award, cites Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, for her seminal work in tissue engineering and disease detection. She is also recognized for her passion in promoting the advancement of women in science, technology, engineering, and mathematics (STEM) fields. The award includes an unrestricted prize of $250,000.

The Heinz Awards pay tribute to the memory of the late U.S. Senator H. John Heinz III by celebrating his belief that individuals have both the power and responsibility to change the world for the better. In his honor, the Heinz Family Foundation annually recognizes individuals for their extraordinary contributions to arts and humanities; environment; human condition; public policy; and technology, the economy, and employment.

“John Heinz believed that individuals have the power and responsibility to improve the human condition. I believe this wholeheartedly and feel enormously privileged to have received training in engineering, biology, and medicine that enables my team to do interdisciplinary work that impacts human health,” says Bhatia, who also is a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. “This type of recognition helps to bring science into the public eye so that everyone can appreciate the dedication and innovation that is happening in laboratories all over the country.”

Bhatia’s team pioneered the fabrication of artificial human microlivers, which are being used by many biopharmaceutical companies to test the toxicity of drug candidates. Bhatia is also using microlivers in the lab to model malaria infection and test drugs that can eradicate malaria parasites completely — even the parasite reservoirs that remain in the liver after a patient’s symptoms subside. Bhatia hopes to eventually develop implantable liver tissue as a complement or substitute for whole-organ transplant.

In her study of cancer and the tumor microenvironment, Bhatia and her laboratory have developed synthetic biomarkers that are paving the way for simple, low-cost cancer diagnostics. Their engineered nanoparticles interact with tumor proteins in the body and release hundreds of these biomarkers, which can be detected in urine. One application relies on a paper-strip urine test that can reveal the presence of cancer within minutes in mouse models. This point-of-care, low-budget technology holds great promise for earlier cancer detection in the developing world and other settings with limited medical infrastructure.

Aside from her work in developing new solutions for liver disease and cancer, Bhatia is an advocate for bringing more women into STEM fields — especially at a young age. While a graduate student at MIT, Bhatia helped start Keys to Empowering Youth (KEYs), a program that engages middle school girls with science and engineering through hands-on activities and mentorship from MIT students. Bhatia continues to advise KEYs and MIT’s Society of Women Engineers chapter, which manages the program.

“I’m hopeful that the visibility associated with this award can inspire young girls by showing them what a rewarding profession — and life — STEM can yield,” she says.

Bhatia will receive her award on May 13 at a ceremony in Pittsburgh. There, she will be honored along with the Heinz Award recipients in the four other categories: Roz Chast, a best-selling illustrator and cartoonist (arts and humanities); Frederica Perera, an environmental health researcher at Columbia University (environment); William McNulty and Jacob Wood, founders of Team Rubicon (human condition); and Aaron Wolf, a geoscientist and professor at Oregon State University (public policy).

By Kevin Leonardi | Karen Shaner

Correctly diagnosing a person with cancer — and identifying the specific type of cancer — makes all the difference in successfully treating a patient.

Today your doctor might draw from a dozen or so similar cases and a big book of guidelines. But what if he or she could instead plug your test results and medical history into a computer program that has crunched millions of pieces of similar data?

That sort of future is looking increasingly possible thanks to researchers at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL). Working with a team from Massachusetts General Hospital (MGH), PhD student Yuan Luo and MIT Professor Peter Szolovits have developed a computational model that aims to automatically suggest cancer diagnoses by learning from thousands of data points from past pathology reports. The work has been published this month in the Journal of the American Medical Informatics Association.

Better lymphoma diagnoses

The researchers focused on the three most prevalent subtypes of lymphoma, a common cancer with more than 50 distinct subtypes that are often difficult to distinguish. According to Ephraim Hochberg, director of the Center for Lymphoma at MGH and one of the paper’s co-authors, upwards of 5 to 15 percent of lymphoma cases are initially misdiagnosed or misclassified, which can be a significant problem since different lymphomas require dramatically different treatment plans.

For example, Hochberg recently saw a patient who had been mistakenly told that her lymphoma was incurable. If he hadn’t accurately diagnosed her and put her on an aggressive plan, it might have been too late to counteract the cancer.

Lymphoma classification has long been a source of debate for pathologists and clinicians. There were at least five different sets of guidelines until 2001, when the World Health Organization (WHO) published a consensus classification. In 2008 the WHO revised its guidelines in a labor-intensive process that involved an eight-member steering committee and over 130 pathologists and hematologists around the world. In addition, only around 1,400 cases from Europe and North America were reviewed to cover 50 subtypes, meaning that on average a subtype’s diagnosis criteria was based on what happened to only a limited number of people.

Meanwhile, large medical institutions like MGH often archive decades of pathology reports. This got the MIT researchers thinking about whether they could tap into these resources to develop automated tools that could improve doctors’ understanding of how to diagnose lymphomas.

“It is important to ensure that classification guidelines are up-to-date and accurately summarized from a large number of patient cases,” says Luo, who is first author on the paper. “Our work combs through detailed medical cases to help doctors more comprehensively capture the subtle distinctions between lymphomas.”

Doctor-friendly models

Luo emphasizes that such machine-learning models need to be not only accurate but also interpretable to clinicians. The WHO guidelines’ criteria are outlined via a panel of test results that are themselves relations among medical concepts such as tumor cells and surface antigens. In order to capture the relations, the researchers converted sentences from pathology reports into a graph representation where graph nodes are medical concepts and graph edges are syntactic/semantic dependencies. As described in their previous paper, they then collected frequently occurring subgraphs that correspond to relations that specify test results.

“Clinicians’ diagnostic reasoning is based on multiple test results simultaneously,” Luo says. “Thus it is necessary for us to automatically group subgraphs in a way that corresponds to the panel of test results. This makes the model interpretable to clinicians instead of being a black-box, as they often complain about many other machine learning models.”

The core contribution of this work is to use a technique called Subgraph Augmented Non-negative Tensor Factorization (SANTF). In SANTF, data from the 800 or so medical cases are organized as a three-dimensional table where the dimensions correspond to the set of patients, the set of frequent subgraphs, and the collection of words appearing in and near each data element mentioned in the reports. This scheme clusters each of these dimensions simultaneously, using the relationships in each dimension to constrain those in the others. By examining the resulting clusters, the researchers can link test result panels to lymphoma subtypes.

“The promise of Luo’s work, if applied to very large data sets, is that the criteria that would then help to identify these clusters can inform doctors about how to understand the range of lymphomas and their clinical relationships to each other,” Peter Szolovits says.

“Most natural-language processing in clinical reporting has focused on identifying important phrases or attributes, and not the more difficult task of recognizing relationships and concepts,” explains Professor Wendy Chapman, chair of the department of biomedical informatics at the University of Utah. “Medical experts with years of experience are able to understand not just the words, but the deeper implications. This research gets us a step closer to developing robust computer models that can achieve that level of comprehension.”

On top of that, the SANTF model does not require labeled training data, which makes it possible to automate the process of knowledge discovery. Szolovits is confident that that the team’s model can help doctors make more accurate lymphoma diagnoses based on more comprehensive evidence — and could even be incorporated into future WHO guidelines.

“Our ultimate goal is to be able to focus these techniques on extremely large amounts of lymphoma data, on the order of millions of cases,” says Szolovits. “If we can do that, and identify the features that are specific to different subtypes, then we’d go a long way towards making doctors’ jobs easier — and, maybe, patients’ lives longer.”

By Adam Conner-Simons | CSAIL

Four MIT graduate students and an alumnus are among 30 new recipients nationwide of the Paul and Daisy Soros Fellowships for New Americans.

The four current or incoming MIT graduate students who have won Soros Fellowships are Stephanie Speirs, whose mother emigrated from Korea, and who will pursue an MBA at the MIT Sloan School of Management; Yakir Reshef, from Israel, and Andre Shomorony, from Brazil, both of whom are currently enrolled in the Harvard-MIT Health Sciences and Technology (HST) program; and Krzysztof Franaszek, from Poland, who will enroll in HST this spring.

In addition, alumnus Allen Lin ’11, MEng ’11, whose parents are Taiwanese immigrants, will use his Soros Fellowship to pursue a PhD in systems biology at Harvard University.

The Soros Fellowships, established in 1997, award $90,000 for immigrants and children of immigrants to complete graduate studies in the United States. Applicants may propose graduate work in any discipline, and are selected for their potential to make significant contributions to American society, culture, or their academic field.

This year’s 30 winners were selected from a pool of 1,200 applicants. Including this year’s winners, 18 MIT students and alumni have won Soros Fellowships since 2010.

Krzysztof Franaszek

Photo: Christopher Smith

Krzysztof Franaszek emigrated from Poland with his parents; his father, a theoretical physicist, and his mother, a neuropharmacologist, both now work at federal research institutions in Maryland. With an interest in biological science and technology, Franaszek completed his undergraduate degree in cell biology and economics at the University of Maryland; as an undergraduate, he was named as a Howard Hughes Medical Institute Undergraduate Research Fellow.

Franaszek, who aspires to establish a biotechnology and medical research company to develop treatments for age-dependent diseases, is pursuing training as a physician-scientist. With a Gates-Cambridge Scholarship, he is currently completing a PhD in pathology at Cambridge University, focusing on how molecular genetics techniques can combat viral diseases; Franaszek’s Soros Fellowship will allow him to pursue an MD through the HST.

Allen Lin

Photo: Christopher Smith

Alumnus Allen Lin, whose parents emigrated from Taiwan, grew up in New Jersey. He came to MIT with an interest in complex systems; as an undergraduate, he immersed himself in the study of synthetic biology, computer science, technology policy, and public health.

In 2011, Lin was named a Marshall Scholar; as an MIT undergraduate, he also received a Barry M. Goldwater Scholarship and a Department of Homeland Security Scholarship for his research.

Lin holds three degrees from MIT, all awarded in 2011: a bachelor’s in electrical engineering and computer science (EECS), and in biological-chemical engineering, and a master’s in EECS. Following his graduation, Lin’s Marshall Scholarship allowed him to complete an MPhil in technology policy at Cambridge University, followed by an MS in public health at the London School of Hygiene and Tropical Medicine.

The Soros Fellowship will support Lin’s PhD studies in systems biology at Harvard. His research focuses on developing cost-effective vaccines and treatments for infections, particularly HIV, that disproportionally affect marginalized populations. 

Yakir Reshef

Photo: Christopher Smith

HST graduate student Yakir Reshef, whose father is Romanian and mother is Iraqi, was born in Israel and spent his early childhood in a suburb of Jerusalem. He then moved to Kenya with his parents, who work in the medical and public health fields, before the family settled in Maryland.

Passionate about math and computer science, Reshef majored in mathematics as an undergraduate at Harvard, where he developed a method to detect associations between pairs of variables in large data sets. This research resulted in a publication in the journal Science. After completing his undergraduate work, Reshef returned to Israel as a Fulbright Scholar, conducting research in mathematics and computer science at the Weizmann Institute of Science.

Reshef, who aims to use his computational knowledge to analyze medical data and improve outcomes for patients, is now training as a physician-scientist. The Soros Fellowship will support his studies in HST, through which he plans to obtain an MD and a PhD in computer science.

Andre Shomorony

Photo: Christopher Smith

Andre Shomorony grew up in Rio de Janeiro, in a family with Jewish and European roots. When Shomorony was 15, his parents, who were engineers in Brazil, decided to move with their three sons to Florida. The transition was difficult: Shomorony had to learn English, and adapt to a new culture, while his parents struggled to find stable employment.

Despite these difficulties, Shomorony won a full scholarship to Yale University through QuestBridge, an organization that supports low-income, high-achieving students. When his father developed pancreatic cancer, Shomorony turned his interests toward biomedical research. At Yale, he studied the development of techniques to generate tissues for use in transplantation, stem-cell therapy, and reconstructive surgery — work that resulted in a paper in the journal Chemistry Letters on which he was first author. He has since worked at Boston Children’s Hospital, developing a technique for noninvasive, extracorporeal blood filtration to treat sepsis.

Driven by his interests in research, clinical work, and serving underrepresented patient populations, Shomorony enrolled in HST, pursuing an MD while conducting biomedical engineering research. Ultimately, he wants to use his background in biomedical engineering to improve surgical procedures. As an aspiring physician, he intends to work at the intersection of reconstructive plastic surgery, otolaryngology, and surgical oncology.

Stephanie Speirs

Photo: Christopher Smith

Born in Hawaii, Stephanie Speirs was raised by a single mother who emigrated from Korea. Growing up with two siblings, Speirs gained an appreciation for hard work at an early age, earning money to help her mother with expenses. Through these early experiences, she became committed to domestic and international social change.

Speirs received her bachelor’s degree from Yale, and then earned a master’s degree from Princeton University in public affairs and international development. Her interest in government led Speirs to work as a field organizer for Barack Obama’s 2008 presidential campaign; she then went on to work at the National Security Council (NSC), developing policy for the Middle East. In her work at the NSC, Speirs traveled to Yemen and Pakistan, where she focused on economic development.

Speirs’ passion for international development led her to become a fellow at Acumen, a nonprofit venture capital fund that works to reduce poverty in the developing world. In addition, Speirs co-founded Solstice Initiative, a nonprofit whose mission is to give low-income households access to solar energy.

The Soros Fellowship will allow Speirs to complete her MBA at MIT Sloan, giving her the business knowledge to continue developing Solstice Initiative, and furthering her work as an agent of social change.

By Nora Delaney | GECD: Global Education

Many years of research have shown that for students from lower-income families, standardized test scores and other measures of academic success tend to lag behind those of wealthier students.

A new study led by researchers at MIT and Harvard University offers another dimension to this so-called “achievement gap”: After imaging the brains of high- and low-income students, they found that the higher-income students had thicker brain cortex in areas associated with visual perception and knowledge accumulation. Furthermore, these differences also correlated with one measure of academic achievement — performance on standardized tests.

“Just as you would expect, there’s a real cost to not living in a supportive environment. We can see it not only in test scores, in educational attainment, but within the brains of these children,” says MIT’s John Gabrieli, the Grover M. Hermann Professor in Health Sciences and Technology, professor of brain and cognitive sciences, and one of the study’s authors. “To me, it’s a call to action. You want to boost the opportunities for those for whom it doesn’t come easily in their environment.”

This study did not explore possible reasons for these differences in brain anatomy. However, previous studies have shown that lower-income students are more likely to suffer from stress in early childhood, have more limited access to educational resources, and receive less exposure to spoken language early in life. These factors have all been linked to lower academic achievement.

In recent years, the achievement gap in the United States between high- and low-income students has widened, even as gaps along lines of race and ethnicity have narrowed, says Martin West, an associate professor of education at the Harvard Graduate School of Education and an author of the new study.

“The gap in student achievement, as measured by test scores between low-income and high-income students, is a pervasive and longstanding phenomenon in American education, and indeed in education systems around the world,” he says. “There’s a lot of interest among educators and policymakers in trying to understand the sources of those achievement gaps, but even more interest in possible strategies to address them.”

Allyson Mackey, a postdoc at MIT’s McGovern Institute for Brain Research, is the lead author of the paper, which appears the journal Psychological Science. Other authors are postdoc Amy Finn; graduate student Julia Leonard; Drew Jacoby-Senghor, a postdoc at Columbia Business School; and Christopher Gabrieli, chair of the nonprofit Transforming Education.

Explaining the gap

The study included 58 students — 23 from lower-income families and 35 from higher-income families, all aged 12 or 13. Low-income students were defined as those who qualify for a free or reduced-price school lunch.

The researchers compared students’ scores on the Massachusetts Comprehensive Assessment System (MCAS) with brain scans of a region known as the cortex, which is key to functions such as thought, language, sensory perception, and motor command.

Using magnetic resonance imaging (MRI), they discovered differences in the thickness of parts of the cortex in the temporal and occipital lobes, whose primary roles are in vision and storing knowledge. Those differences correlated to differences in both test scores and family income. In fact, differences in cortical thickness in these brain regions could explain as much as 44 percent of the income achievement gap found in this study.

Previous studies have also shown brain anatomy differences associated with income, but did not link those differences to academic achievement.

“A number of labs have reported differences in children’s brain structures as a function of family income, but this is the first to relate that to variation in academic achievement,” says Kimberly Noble, an assistant professor of pediatrics at Columbia University who was not part of the research team.

In most other measures of brain anatomy, the researchers found no significant differences. The amount of white matter — the bundles of axons that connect different parts of the brain — did not differ, nor did the overall surface area of the brain cortex.

The researchers point out that the structural differences they did find are not necessarily permanent. “There’s so much strong evidence that brains are highly plastic,” says Gabrieli, who is also a member of the McGovern Institute. “Our findings don’t mean that further educational support, home support, all those things, couldn’t make big differences.”

In a follow-up study, the researchers hope to learn more about what types of educational programs might help to close the achievement gap, and if possible, investigate whether these interventions also influence brain anatomy.

“Over the past decade we’ve been able to identify a growing number of educational interventions that have managed to have notable impacts on students’ academic achievement as measured by standardized tests,” West says. “What we don’t know anything about is the extent to which those interventions — whether it be attending a very high-performing charter school, or being assigned to a particularly effective teacher, or being exposed to a high-quality curricular program — improves test scores by altering some of the differences in brain structure that we’ve documented, or whether they had those effects by other means.”

The research was funded by the Bill and Melinda Gates Foundation and the National Institutes of Health.

By Anne Trafton | MIT News Office

Researchers at MIT and Northwestern University have developed a new peer-to-peer networking tool that enables sufferers of anxiety and depression to build online support communities and practice therapeutic techniques.

In a study involving 166 subjects who had exhibited symptoms of depression, the researchers compared their tool with an established technique known as expressive writing. The new tool yielded better outcomes across the board, but it had particular advantages in two areas: One was in training subjects to use a therapeutic technique called cognitive reappraisal, and the other was in improving the mood of subjects with more severe symptoms.

“We really wanted to see two things,” says Rob Morris, who led the work as a PhD student in media arts and sciences at MIT. After graduating in February, Morris is now commercializing the technology through a New York-based company he co-founded, called Koko. “Could people get clinical benefits from it? That’s hypothesis one,” he says.

“Hypothesis two is, ‘Will people be engaged and use this regularly?’” Morris adds. “There’s a lot of great work in building web apps and mobile apps to provide psychotherapy without a therapist in the loop — it’s these self-guided programs. There’s almost a decade of research showing that these things can produce really profound improvements for people. The problem is that, once you release them out into the wild, people just don’t use them. The way we designed our platform was to really mimic some of the interaction paradigms that underlie very engaging social programs.”

On that score, too, the results of the study were encouraging. The average subject in the control group used the expressive-writing tool 10 times over the three weeks of the study, with each session lasting about three minutes. The average subject using the new tool logged in 21 times, with each session lasting about nine minutes.

Buggy thinking

Morris; his thesis advisor, Rosalind Picard, an MIT professor of media arts and sciences; and Stephen Schueller, a clinical psychologist at Northwestern, describe the study in a paper appearing this week in the Journal of Medical Internet Research.

Morris, who had majored in psychology as an undergrad at Princeton University, initially enrolled in a PhD program in psychology in California. But he concluded that a traditional psychology program wouldn’t grant him enough latitude in researching the therapeutic potential of information technology, a topic that quickly captured his interest. So he applied instead to do graduate work in Picard’s Affective Computing Group, which specifically investigates the intersection of computing technologies and human emotions.

“I was at MIT without an engineering degree and really trying to race to learn computer programming,” Morris recalls. He found himself spending a lot of time on a programmers’ question-and-answer site called Stack Overflow. “Whenever I had a bug or was stuck on something, I would go on there, and almost miraculously, this crowd of programmers would come and help me,” he says. “It was just this intuition that, just as we can get people on Stack Overflow to help us identify and fix bugs in code, perhaps we can harness a crowd to help us fix bugs in our thinking.”

People suffering from depression frequently exhibit what Morris describes as “maladaptive thought patterns”: You lose your job, and you conclude that you’ll never find another one; your roommate comes home and shuts herself up in her room, and you assume it’s because of something you’ve done.

Psychologists have sorted these thought patterns into categories. Predicting your future unemployability is an instance of “fortune-telling”; assuming you know your roommate’s motivations is “mind-reading.” Others include “overgeneralization,” “catastrophizing,” and “all-or-nothing thinking.”

Cognitive reappraisal involves, first, identifying maladaptive thought patterns and, second, trying to recast the events that precipitated them in a different light: The job you lost offered no room for promotion and wasn’t aligned with your interests, anyway; your roommate has been having trouble at work and may have just had a fight with a colleague.

Strength in numbers

A user of the new tool — which Morris calls Panoply — logs on and, in separate fields, records both a triggering event and his or her response to it. This much of the application was duplicated exactly for the expressive-writing tool used by the control group in the study.

With Panoply, however, members of the network then vote on the type of thought pattern represented by the poster’s reaction to the triggering event and suggest ways of reinterpreting it. As users demonstrate more and more familiarity with techniques of cognitive reappraisal, they graduate from describing their own experiences, to offering diagnoses of other people’s thought patterns, to suggesting reinterpretations.

“We really wanted to see that people are utilizing this skill over and over again, not only in response to their own stressors but also as teachers to other people,” Morris says. “We can surmise that it’s a little easier to practice some of these psychotherapeutic skills for other people before turning them toward themselves. But we don’t have data supporting that.”

For their study, Morris, Picard, and Schueller recruited subjects who described themselves as under stress, something that correlates highly with depression. Volunteers were asked to complete three questionnaires. One is a depression measure that’s standard in the field. Another assesses perseverative thinking, and the third assesses skill at cognitive reappraisal. After three weeks using either Panoply or the expressive-writing tool, the subjects again completed the same three questionnaires.

Network effects

To simulate a large network of users — and ensure that Panoply users would receive replies even if they were posting in the middle of the night — Morris hired online workers through Amazon’s Mechanical Turk crowdsourcing application to supplement the comments made by study subjects. Each Mechanical Turk worker received a brief training in cognitive reappraisal, and about 1,000 contributed to the study.

“It took a lot of time to figure out how to teach people these skills and give them examples of what to do in a way that is easily understood in a handful of minutes,” Morris says. “Some of them wanted to sign up afterwards. They were like, ‘Wow, I never knew I had these bugs in my thinking, too.’”

“What I like about the crowdsourcing idea is that it’s sort of tackling two things in a nice way,” says James Gross, a professor of psychology at Stanford University, who has studied cognitive reappraisal. “One is that reappraisal, although powerful, can break down when you most need it. And so this is saying, ‘Hey, instead of relying on intrinsic regulation, let’s try extrinsic regulation, where we’re going to get some help from other people.’

“But the second thing is that when you’re depressed, you can withdraw from other people. So now you’ve got this double whammy, where you’ve got a high level of negative emotion, making it more difficult to reappraise, and you’re isolating yourself from other people, which means that you’re not going to be as likely to get extrinsic regulation. What they’ve done is nicely address both of these issues by saying, ‘Hey, we can help with reappraisal, even if you’re feeling a bit depressed, by helping you leverage outside input that you wouldn’t otherwise get. I think this is a promising approach.”

By Larry Hardesty | MIT News Office

Chemotherapy often shrinks tumors at first, but as cancer cells become resistant to drug treatment, tumors can grow back. A new nanodevice developed by MIT researchers can help overcome that by first blocking the gene that confers drug resistance, then launching a new chemotherapy attack against the disarmed tumors.

The device, which consists of gold nanoparticles embedded in a hydrogel that can be injected or implanted at a tumor site, could also be used more broadly to disrupt any gene involved in cancer.

“You can target any genetic marker and deliver a drug, including those that don’t necessarily involve drug-resistance pathways. It’s a universal platform for dual therapy,” says Natalie Artzi, a research scientist at MIT’s Institute for Medical Engineering and Science (IMES), an assistant professor at Harvard Medical School, and senior author of a paper describing the device in the Proceedings of the National Academy of Sciences the week of March 2.

To demonstrate the effectiveness of the new approach, Artzi and colleagues tested it in mice implanted with a type of human breast tumor known as a triple negative tumor. Such tumors, which lack any of the three most common breast cancer markers — estrogen receptor, progesterone receptor, and Her2 — are usually very difficult to treat. Using the new device to block the gene for multidrug resistant protein 1 (MRP1) and then deliver the chemotherapy drug 5-fluorouracil, the researchers were able to shrink tumors by 90 percent in two weeks.

Overcoming resistance

MRP1 is one of many genes that can help tumor cells become resistant to chemotherapy. MRP1 codes for a protein that acts as a pump, eliminating cancer drugs from tumor cells and rendering them ineffective. This pump acts on several drugs other than 5-fluorouracil, including the commonly used cancer drug doxorubicin.

“Drug resistance is a huge hurdle in cancer therapy and the reason why chemotherapy, in many cases, is not very effective”, says João Conde, an IMES postdoc and lead author of the PNAS paper.

To overcome this, the researchers created gold nanoparticles coated with strands of DNA complementary to the sequence of MRP1 messenger RNA — the snippet of genetic material that carries DNA’s instructions to the rest of the cell.

These strands of DNA, which the researchers call “nanobeacons,” fold back on themselves to form a closed hairpin structure. However, when the DNA encounters the correct mRNA sequence inside a cancer cell, it unfolds and binds to the mRNA, preventing it from generating more molecules of the MRP1 protein. As the DNA unfolds, it also releases molecules of 5-fluorouracil that were embedded in the strand. This drug then attacks the tumor cell’s DNA, since MRP1 is no longer around to pump it out of the cell.

“When we silence the gene, the cell is no longer resistant to that drug, so we can deliver the drug that now regains its efficacy,” Conde says.

When each of these events occurs — sensing the MRP1 protein and releasing 5-fluorouracil — the device emits fluorescence of different wavelengths, allowing the researchers to visualize what is happening inside the cells. Because of this, the particles could also be used for diagnosis — specifically, determining if a certain cancer-related gene is activated in tumor cells.

Controlled drug release

The DNA-coated gold nanoparticles are embedded in an adhesive gel that stays in place and coats the tumor after being implanted. This local administration of the particles protects them from degradation that might occur if they were administered throughout the body, and also enables sustained drug release, Artzi says.

In their mouse studies, the researchers found that the particles could silence MRP1 for up to two weeks, with continuous drug release over that time, effectively shrinking tumors.

This approach could be adapted to deliver any kind of drug or gene therapy targeted to a specific gene involved in cancer, the researchers say. They are now working on using it to silence a gene that stimulates gastric tumors to metastasize to the lungs.

“This is an impressive study that harnesses expertise at the interface of materials science, nanotechnology, biology, and medicine to enhance the efficacy of traditional chemotherapeutics,” says Jeffrey Karp, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who was not involved in the research. “Hopefully this approach will perform in studies beyond 14 days and be translatable to patients, who are desperate for new and more effective treatment regimens.”

Graduate student Nuria Oliva is also an author of the paper. The research was funded by the National Cancer Institute and a Marie Curie International Outgoing Fellowship.

By Anne Trafton | MIT News Office