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

Quick test for Ebola

May 27, 2015

When diagnosing a case of Ebola, time is of the essence. However, existing diagnostic tests take at least a day or two to yield results, preventing health care workers from quickly determining whether a patient needs immediate treatment and isolation.

A new test from MIT researchers could change that: The device, a simple paper strip similar to a pregnancy test, can rapidly diagnose Ebola, as well as other viral hemorrhagic fevers such as yellow fever and dengue fever.

“As we saw with the recent Ebola outbreak, sometimes people present with symptoms and it’s not clear what they have,” says Kimberly Hamad-Schifferli, a visiting scientist in MIT’s Department of Mechanical Engineering and a member of the technical staff at MIT’s Lincoln Laboratory. “We wanted to come up with a rapid diagnostic that could differentiate between different diseases.”

Hamad-Schifferli and Lee Gehrke, the Hermann L.F. von Helmholtz Professor in MIT’s Institute for Medical Engineering and Science (IMES), are the senior authors of a paper describing the new device in the journal Lab on a Chip. The paper’s lead author is IMES postdoc Chun-Wan Yen, and other authors are graduate student Helena de Puig, IMES postdoc Justina Tam, IMES instructor Jose Gomez-Marquez, and visiting scientist Irene Bosch.

Color-coded test

Currently, the only way to diagnose Ebola is to send patient blood samples to a lab that can perform advanced techniques such as polymerase chain reaction (PCR), which can detect genetic material from the Ebola virus. This is very accurate but time-consuming, and some areas of Africa where Ebola and other fevers are endemic have limited access to this kind of technology.

The new device relies on lateral flow technology, which is used in pregnancy tests and has recently been exploited for diagnosing strep throat and other bacterial infections. Until now, however, no one has applied a multiplexing approach, using multicolored nanoparticles, to simultaneously screen for multiple pathogens. 

“For many hemorrhagic fever viruses, like West Nile and dengue and Ebola, and a lot of other ones in developing countries, like Argentine hemorrhagic fever and the Hantavirus diseases, there are just no rapid diagnostics at all,” says Gehrke, who began working with Hamad-Schifferli four years ago to develop the new device.

Unlike most existing paper diagnostics, which test for only one disease, the new MIT strips are color-coded so they can be used to distinguish among several diseases. To achieve that, the researchers used triangular nanoparticles, made of silver, that can take on different colors depending on their size.

The researchers created red, orange, and green nanoparticles and linked them to antibodies that recognize Ebola, dengue fever, and yellow fever. As a patient’s blood serum flows along the strip, any viral proteins that match the antibodies painted on the stripes will get caught, and those nanoparticles will become visible. This can be seen by the naked eye; for those who are colorblind, a cellphone camera could be used to distinguish the colors.

“When we run a patient sample through the strip, if you see an orange band you know they have yellow fever, if it shows up as a red band you know they have Ebola, and if it shows up green then we know that they have dengue,” Hamad-Schifferli says.

This process takes about 10 minutes, allowing health care workers to rapidly perform triage and determine if patients should be isolated, helping to prevent the disease from spreading further.

Warren Chan, an associate professor at the University of Toronto Institute of Biomaterials and Biomedical Engineering, says he is impressed with the device because it not only offers faster diagnosis, but also requires smaller patient blood samples, as just one test strip can detect multiple diseases. “It’s a step up from what everyone else is doing,” says Chan, who was not involved in the research. “They’re targeting diseases that are really relevant to what’s going on in the world at this point, and have shown that they can detect them simultaneously.”

Faster triage

The researchers envision their new device as a complement to existing diagnostic technologies, such as PCR.

“If you’re in a situation in the field with no power and no special technologies, if you want to know if a patient has Ebola, this test can tell you very quickly that you might not want to put that patient in a waiting room with other people who might not be infected,” says Gehrke, who is also a professor of microbiology and immunology at Harvard Medical School. “That initial triage can be very important from a public health standpoint, and there could be a follow-up test later with PCR or something to confirm.”

The researchers hope to obtain Food and Drug Administration approval to begin using the device in areas where the Ebola outbreak is still ongoing. In order to do that, they are now testing the device in the lab with engineered viral proteins, as well as serum samples from infected animals.

This type of device could also be customized to detect other viral hemorrhagic fevers or other infectious diseases, by linking the silver nanoparticles to different antibodies.

“Thankfully the Ebola outbreak is dying off, which is a good thing,” Gehrke says. “But what we’re thinking about is what’s coming next. There will undoubtedly be other viral outbreaks. It might be Sudan virus, it might be another hemorrhagic fever. What we’re trying to do is develop the antibodies needed to be ready for the next outbreak that’s going to happen.”

The research was funded by the National Institute of Allergy and Infectious Disease.

By Anne Trafton | MIT News Office

For patients with diabetes, insulin is critical to maintaining good health and normal blood-sugar levels. However, it’s not an ideal solution because it can be difficult for patients to determine exactly how much insulin they need to prevent their blood sugar from swinging too high or too low.

MIT engineers hope to improve treatment for diabetes patients with a new type of engineered insulin. In tests in mice, the researchers showed that their modified insulin can circulate in the bloodstream for at least 10 hours, and that it responds rapidly to changes in blood-sugar levels. This could eliminate the need for patients to repeatedly monitor their blood sugar levels and inject insulin throughout the day.

“The real challenge is getting the right amount of insulin available when you need it, because if you have too little insulin your blood sugar goes up, and if you have too much, it can go dangerously low,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor in MIT’s Department of Chemical Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. “Currently available insulins act independent of the sugar levels in the patient.”

Anderson and Robert Langer, the David H. Koch Institute Professor at MIT, are the senior authors of a paper describing the engineered insulin in this week’s Proceedings of the National Academy of Sciences. The paper’s lead authors are Hung-Chieh (Danny) Chou, former postdoc Matthew Webber, and postdoc Benjamin Tang. Other authors are technical assistants Amy Lin and Lavanya Thapa, David Deng, Jonathan Truong, and Abel Cortinas.

Glucose-responsive insulin

Patients with Type I diabetes lack insulin, which is normally produced by the pancreas and regulates metabolism by stimulating muscle and fat tissue to absorb glucose from the bloodstream. Insulin injections, which form the backbone of treatment for diabetes patients, can be deployed in different ways. Some people take a modified form called long-acting insulin, which stays in the bloodstream for up to 24 hours, to ensure there is always some present when needed. Other patients calculate how much they should inject based on how many carbohydrates they consume or how much sugar is present in their blood.

The MIT team set out to create a new form of insulin that would not only circulate for a long time, but would be activated only when needed — that is, when blood-sugar levels are too high. This would prevent patients’ blood-sugar levels from becoming dangerously low, a condition known as hypoglycemia that can lead to shock and even death.

To create this glucose-responsive insulin, the researchers first added a hydrophobic molecule called an aliphatic domain, which is a long chain of fatty molecules dangling from the insulin molecule. This helps the insulin circulate in the bloodstream longer, although the researchers do not yet know exactly why that is. One theory is that the fatty tail may bind to albumin, a protein found in the bloodstream, sequestering the insulin and preventing it from latching onto sugar molecules.

The researchers also attached a chemical group called PBA, which can reversibly bind to glucose. When blood-glucose levels are high, the sugar binds to insulin and activates it, allowing the insulin to stimulate cells to absorb the excess sugar.

The research team created four variants of the engineered molecule, each of which contained a PBA molecule with a different chemical modification, such as an atom of fluorine and nitrogen. They then tested these variants, along with regular insulin and long-acting insulin, in mice engineered to have an insulin deficiency.

To compare each type of insulin, the researchers measured how the mice’s blood-sugar levels responded to surges of glucose every few hours for 10 hours. They found that the engineered insulin containing PBA with fluorine worked the best: Mice that received that form of insulin showed the fastest response to blood-glucose spikes.

“The modified insulin was able to give more appropriate control of blood sugar than the unmodified insulin or the long-acting insulin,” Anderson says.

The new molecule represents a significant conceptual advance that could help scientists realize the decades-old goal of better controlling diabetes with a glucose-responsive insulin, says Michael Weiss, a professor of biochemistry and medicine at Case Western Reserve University.

“It would be a breathtaking advance in diabetes treatment if the Anderson/Langer technology could accomplish the translation of this idea into a routine treatment of diabetes,” says Weiss, who was not part of the research team.

New alternative

Giving this type of insulin once a day instead of long-acting insulin could offer patients a better alternative that reduces their blood-sugar swings, which can cause health problems when they continue for years and decades, Anderson says. The researchers now plan to test this type of insulin in other animal models and are also working on tweaking the chemical composition of the insulin to make it even more responsive to blood-glucose levels.

“We’re continuing to think about how we might further tune this to give improved performance so it’s even safer and more efficacious,” Anderson says.

The research was funded by the Leona M. and Harry B. Helmsley Charitable Trust, the Tayebati Family Foundation, the National Institutes of Health, and the Juvenile Diabetes Research Foundation.

By Anne Trafton | MIT News Office

In 2008, the World Health Organization announced a global effort to eradicate malaria, which kills about 800,000 people every year. As part of that goal, scientists are trying to develop new drugs that target the malaria parasite during the stage when it infects the human liver, which is crucial because some strains of malaria can lie dormant in the liver for several years before flaring up.

A new advance by MIT engineers could aid in those efforts: The researchers have discovered a way to grow liver-like cells from induced pluripotent stem cells. These cells can be infected with several strains of the malaria parasite and respond to existing drugs the same way that mature liver cells taken from human donors do.

Such cells offer a plentiful source for testing potential malaria drugs because they can be made from skin cells. New drugs are badly needed, since some forms of the malaria parasite have become resistant to existing treatments, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology (HST) and Electrical Engineering and Computer Science at MIT.

“Drug resistance is emerging that we are continually chasing. The thinking behind the call to eradication is that we can’t be chasing resistance and distributing bed nets to protect from mosquitoes forever. Ideally, we would rid ourselves of the pathogen entirely,” says Bhatia, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

These cells, described in the Feb. 5 online issue of Stem Cell Reports, could also allow scientists to test drugs on cells from people with different genetic backgrounds, who may respond differently to malaria infection and treatment.

The paper’s lead author is Shengyong Ng, a graduate student in MIT’s Department of Biological Engineering and IMES. Other authors of the paper are former IMES postdoc Robert Schwartz; MIT research scientist Sandra March; IMES research technician Ani Galstian; HST graduate students Nil Gural and Jing Shan; former IMES research technician Mythili Prabhu; and Maria Mota, a researcher at the Instituto de Medicina Molecular in Portugal.

Modeling infection

Until now, malaria researchers have not had many reliable ways to test new drugs in liver tissue. “What’s historically been done is people have tried to make do with the systems that were available,” Bhatia says.

Those systems include testing drugs in cancerous liver cells or in mice infected with a rodent-specific version of the malaria parasite. However, cancerous cells divide much more frequently than normal adult liver cells, and are missing some of the genes required for drug metabolism. The mouse model is not ideal because the rodent version of malaria is different from the human one, so drugs that are successful in mice don’t always work in humans.

In 2013, Bhatia and colleagues showed that they could mode malaria infection in adult liver cells, known as hepatocytes, taken from human donors. However, this generates only a limited supply from each donor, and not all of the cells work well for drug studies.

The researchers then turned to induced pluripotent stem cells. These immature cells can be generated from human skin cells by adding several genes known as reprogramming factors. Once the cells are reprogrammed, they can be directed to form differentiated adult cells by adding specific growth factors.

To create liver cells, the researchers added a series of growth factors, including hepatocyte growth factor. Working with Charles Rice of Rockefeller University and Stephen Duncan of the Medical College of Wisconsin, Bhatia’s lab generated these cells in 2012 and used them to model infection of hepatitis C. However, these cells, known as hepatocyte-like cells, did not seem to be as mature as real adult liver cells.

In the new study, the MIT team found that these cells could be infected with several strains of malaria, but did not have the same drug responses as adult liver cells. In particular, they were not sensitive to primaquine, which works only if cells have a certain set of drug-metabolism enzymes found in mature liver cells. This is important because primaquine is one of only two drugs approved to treat liver-stage malaria, and many of the drugs now in development are based on primaquine.

To induce the cells to become more mature and turn on these metabolic enzymes, the researchers added a molecule they had identified in a previous study. This compound, which the researchers call a “maturin,” stimulated the cells to turn on those enzymes, which made them sensitive to primaquine treatment.

“This study is a major breakthrough,” says Dyann Wirth, chair of the Department of Immunology and Infectious Diseases at the Harvard School of Public Health, who was not part of the research team. “This technique may prove not only a useful tool for finding drugs that will target the liver stage of the parasite, but it could also contribute to our fundamental understanding of the parasite.”

Toward better drugs

The MIT team is now working with the nonprofit foundation Medical Malaria Ventures to test about 10 potential malaria drugs that are in the pipeline, first using adult donor liver cells and then the hepatocyte-like cells generated in this study.

These cells could also prove useful to help identify new drug targets. In this study, the researchers found that the liver-like cells can be infected with malaria when they are still in the equivalent of fetal stages of development, when they become cells known as hepatoblasts, which are precursors to hepatocytes.

In future studies, the researchers plan to investigate which genes get turned on at the point when the cells become susceptible to infection, which may suggest new targets for malaria drugs. They also hope to compare the genes needed for malaria infection with those needed for hepatitis infection, in hopes of identifying common pathways to target for both diseases.

The research was funded by the Bill and Melinda Gates Foundation; the Singapore Agency for Science, Technology and Research; and the Howard Hughes Medical Institute.

By Anne Trafton | MIT News Office