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

April 19, 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

Eight members of the MIT community — Hari Balakrishnan, Sangeeta Bhatia, Emery N. Brown, Anantha Chandrakasan, Eric D. Evans, Karen K. Gleason, L. Rafael Reif, and Daniela Rus — are among the 67 new members and 12 foreign associates elected today to the National Academy of Engineering (NAE).

Election to the NAE is among the highest professional distinctions accorded to American engineers. Academy membership honors those who have made outstanding contributions to “engineering research, practice, or education, including, where appropriate, significant contributions to the engineering literature,” and to the “pioneering of new and developing fields of technology, making major advancements in traditional fields of engineering, or developing/implementing innovative approaches to engineering education.”  

Elected this year:

  • Hari Balakrishnan, the Fujitsu Professor in Electrical Engineering and Computer Science, was cited for his contributions to wired and wireless networks and distributed systems;
  • Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, was cited for her work in tissue engineering and tissue-regeneration technologies, stem-cell differentiation, and preclinical drug evaluation;
  • Emery N. Brown, the Edward Hood Taplin Professor of Medical Engineering and professor of computational neuroscience, was cited for his work on the development of neural signal-processing algorithms for understanding memory encoding and modeling of brain states of anesthesia;
  • Anantha Chandrakasan, the Joseph F. and Nancy P. Keithley Professor in Electrical Engineering and head of the Department of Electrical Engineering and Computer Science, was cited for his work on the development of low-power circuit and system design methods;
  • Eric D. Evans, director of MIT Lincoln Laboratory, was cited for the development of remote sensing systems, improvised explosive device (IED) detection, and ship antimissile defense;
  • Karen K. Gleason, associate provost and the Alexander and I. Michael Kasser Professor in the Department of Chemical Engineering, was cited for her invention, application development, scale-up, and commercialization of chemically vapor-deposited polymers;
  • L. Rafael Reif, president of MIT, was cited for his technical and educational contributions, and for university leadership; and
  • Daniela Rus, the Andrew and Erna Viterbi Professor in the Department of Electrical Engineering and Computer Science and director of the Computer Science and Artificial Intelligence Laboratory, was cited for contributions to distributed robotic systems.  

“MIT’s contribution to this year’s cohort is remarkable,” says Ian A. Waitz, dean of the School of Engineering and the Jerome C. Hunsaker Professor in the Department of Aeronautics and Astronautics. “I’m deeply gratified to see the accomplishments of so many members of our engineering community acknowledged. The range, depth, and scale of the accomplishments of these individuals is amazing.”

Including this year’s inductees, 131 current faculty and staff from MIT are members of the National Academy of Engineering. With this week’s announcement, NAE’s total U.S. membership stands at 2,263; the number of foreign associates is at 221.   

At least 14 MIT alumni were also named to the NAE this year, including Harry A. Atwater Jr. ’81, PhD ’87; Wesley G. Bush ’83, SM ’83; Jonathan P. Caulkins PhD ’90; Janet G. Hering PhD ’88; Thomas M. Jahns ’73, PhD ’78; John Klier ’84; Philip L-F Liu PhD ’74; Samir S. Mitragotri PhD ’96; Radia J. Perlman ’73, PhD ’88; Ghavam Shahidi ’81, PhD ’89; Doros N. Theodorou PhD ’85; Harry L. Van Trees Jr. ScD ’61; and Eric Franklin Wood ’73, ScD ’74.

By School of Engineering

After undergoing surgery to remove diseased sections of the colon, up to 30 percent of patients experience leakage from their sutures, which can cause life-threatening complications.

Many efforts are under way to create new tissue glues that can help seal surgical incisions and prevent such complications; now, a new study from MIT reveals that the effectiveness of such glues hinges on the state of the tissue in which they are being used.

The researchers found that a sealant they had previously developed worked much differently in cancerous colon tissue than in colon tissue inflamed with colitis. The finding suggests that for this sealant or any other kind of biomaterial designed to work inside the human body, scientists must take into account the environment in which the material will be used, instead of using a “one-size fits all” approach, according to the researchers.

“This paper shows why that mentality is risky,” says Natalie Artzi, a research scientist at MIT’s Institute for Medical Science and Engineering (IMES) and senior author of a paper describing the findings in the Jan. 28 online edition of Science Translational Medicine. “We present a new paradigm by which to design and examine materials. Detailed study of tissue and biomaterial interactions can open a new chapter in precision medicine, where biomaterials are chosen and rationally designed to match specific tissue types and disease states.”

After characterizing the adhesive material’s performance in different diseased tissues, the researchers created a model that allows them to predict how it will work in different environments, opening the door to a more personalized approach to treating individual patients.

Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology and a member of IMES, is also a senior author of the paper. The paper’s lead authors are graduate student Nuria Oliva and former graduate student Maria Carcole.

Exploring material properties

Artzi and Edelman originally developed this tissue glue several years ago by combining two polymers — dextran (a polysaccharide) and a highly branched chain called dendrimer. In a 2009 paper, the researchers demonstrated that such adhesives work better when tailored to specific organs. In their new paper, they explored what happens when an adhesive is used in the same organ but under different disease conditions.

They show that the adhesive actually performed better in cancerous colon tissue than in healthy tissue. However, it performed worse in tissue inflamed with colitis than in healthy tissue.

Further studies of the molecular interactions between the adhesive and tissue explained those differences in behavior. The tissue glue works through a system where molecules in the adhesive serve as “keys” that interact with “locks” — chemical structures called amines found in abundance in structural tissue known as collagen.

When enough of these locks and keys bind each other, the adhesive forms a tight seal. This system is disrupted in colitic tissue because the inflammation breaks down collagen. The more severe the inflammation, the less adhesion occurs. However, cancerous tissue tends to have excess collagen, so the adhesive ends up working better than in healthy tissue.

“Now we show that adhesive-material performance is not organ-dependent, but rather, disease type and state-dependent,” says Artzi, who is also an assistant professor at Harvard Medical School.

Predicting adhesion

Using this data, the researchers created a model to help them alter the composition of the material depending on the circumstances. By changing the materials’ molecular weight, the number of keys attached to each polymer, and the ratio of the two polymers, the researchers can tune it to perform best in different types and states of tissue.

An inherent property of the adhesive is that any unused keys are absorbed back into the polymer, preventing them from causing any undesired side effects. This would allow the researchers to create two or three different versions that could cover a wide range of tissues.

“We can take a biopsy from a patient for a quick readout of disease state that would serve as an input for our model, and the output is the precise material composition that should be used to attain adequate adhesion,” Artzi says. “This exercise can be done in a clinical setting.”

Joseph Bonventre, chief of the renal unit and director of the bioengineering division at Brigham and Women’s Hospital in Boston, agrees that the study represents an important step toward a more personalized approach.

“You want the best adhesive possible, and they really show how changes in the characteristics of the tissue will alter the adhesive character,” says Bonventre, who was not involved in the research. “They’re moving in the direction of doing a quick test in the operating room and selecting the biomaterial most likely to be effective, rather than developing biomaterials that try to work for all conditions.”

Doctors have begun using this kind of personalized approach when choosing drugs that match individual patients’ genetic profiles, but it has not yet spread to the selection of biomaterials such as tissue glue. The MIT team now hopes to move the sealant into clinical trials and has founded a company to help that process along.

“It’s something that we want to do as rapidly as possible,” Edelman says. “We’re excited. It’s not often that you have a technology that is this close to clinical introduction.”

The research was funded by the National Institutes of Health and the MIT Deshpande Center for Technological Innovation. 

By Anne Trafton | MIT News Office

The classroom and workplace are equally necessary components in the development of any student. The former teaches the fundamentals and theories of a specific field. The latter offers the chance to see how those theories play out with actual colleagues, bosses, and clients. Since markets can emerge from anywhere, that practical experience also needs to have a reach that extends beyond time zones and borders.

To address this, the MIT International Science and Technology Initiatives (MISTI) serves as a program to match students with companies, universities, and research organizations around the world in summer internships. It’s not merely a positive component for the students, it’s a necessary one. “This is a shrinking world and you either know how to work in multi-cultural teams or you are just not going to be successful,” says Rosabelli Coelho-Keyssar, program manager of MISTI-Brazil.

Growing for 20 years

MISTI started in 1994 in two countries. Now it’s in 19, established in places like China, Germany, France, India, and Israel, and growing in others like Brazil, Chile, Korea, Russia, and South Africa. The program has placed over 5,400 students — currently about 550 a year — in fully-funded internships with over 450 corporate partners and research laboratories. The industries span automotive, energy, health, electronics, management, and finance sectors, and the companies range from BMW, Canon, Covidien, Ferrari, Google, and Intel to Motorola, Pfizer, Samsung, Shell, and Siemens.

MIT undergraduate and graduate students start applying in the middle of the fall and can continue into the spring if positions are available, all while meeting certain requirements. They need to carry a minimum 4.0 out of 5.0 GPA. They’ll already have had work experience from previous internships. Because it’s international, students in most programs need to have the equivalent of two to four semesters in the local language, but since the program is known, students will start taking the necessary classes before they apply, says April Julich Perez, MISTI’s associate director. Adding to that, MISTI prepares the students on their destination’s current events, politics, and culture, and helps them handle various paperwork needs and the logistics of moving. The intent is for the student to relocate smoothly and be able to be productive from the first day on the job, Coelho-Keyssar says.

For companies, the advantage of working with MISTI is that they get access to MIT students and their networks — the people who will start future companies and be the next generation of faculty, says Chappell Lawson, associate professor of political science and MISTI faculty director. But while the program is a boost for a student’s prospects, MISTI is a partnership, not just a résumé builder. “The hosts have to believe in it, want to continue in it, and continue to cover the costs of an internship,” he says. “We expect the students will contribute, and we expect them to demonstrate their MIT work ethic, adding real value to their hosts.”

Creating a match with Covidien

MISTI is not a static program. Students can select from existing internships, but if one doesn’t exist, “We will just go out and try to find something that will fit that student’s interest,” Coelho-Keyssar says. One example was the teaming of healthcare company Covidien and Ricardo De Armas, a fourth-year mechanical engineering student who applied in late 2013 for a placement in the summer of 2014.

De Armas had an interest in medical devices. The Venezuelan native wanted to gain work experience in the field, and, while he was fluent in Spanish, he wanted to improve his Portuguese. An internship with those qualities didn’t exist, but MISTI staff connected with the MIT-Brazil program reached out to Covidien and created an opportunity, Coelho-Keyssar says. The Dublin-based global healthcare company was looking to expand its research and development presence in Brazil, says Cliff Emmons, vice president of research and development, tailored products, and emerging markets at Covidien.

The decision to partner with MIT wasn’t difficult. Emmons says the Institute is central to the medical device ecosystem; has established the “standard of an engineer”; and maintains an academic approach that isn’t purely academic. “It has an emphasis on creating businesses versus creating research papers. It’s critical to have that startup mentality,” he says.

But Covidien wasn’t just merely looking for competence or entrepreneurship. Any candidate also had to be able to quickly adapt to the local environment, both socially and in the workplace. The preparation that students receive was another part of what attracted Covidien to MISTI, Emmons says.

The company was setting up one of its Covidien Centers of Innovation, with a research and development lab in São Paulo, and De Armas was hired to assist the director as a project manager, helping to procure equipment, learning how it operates, and training others. The project came with challenges, Emmons says. The deadline was tight — the research and development lab had to be ready to open and enable health-care professionals to directly collaborate with research and development staff by the end of De Armas’ internship. Equipment from around the world had to be shipped, coordinated, and secured. And all of this was happening as Brazil hosted the World Cup.

Emmons says that entering into the program, the company was looking to invest in the development of global leaders. On that front, the partnership was successful. “There was a beautiful synergy between the goal of MISTI-Brazil and Covidien,” he says.

Covidien was also pleased with De Armas. The company knew from the outset that an MIT student would be technically smart, but the distinguishing factor that made De Armas exceed expectations was his overall fluency and his ability to immerse himself into the workplace. “I always knew that our Brazil commercial team viewed themselves as a family,” Emmons says, “and it’s fantastic to see this family grow.”

By Steve Calechman | MIT Industrial Liaison Program

Sophisticated medicine

April 19, 2015

“I’m mostly driven by how to fix things,” states Sangeeta Bhatia. “I’m always thinking about how to solve problems by repurposing tools.” Although not a mechanic, Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology (HST), Electrical Engineering and Computer Science (EECS), and Institute for Medical Engineering and Science (IMES), does run a repair shop of sorts. As director of the Laboratory for Multiscale Regenerative Technologies, she tackles some of medicine’s most intractable problems, developing sophisticated devices and methods for diagnosing and treating human disease.

Bhatia’s research defies traditional academic categories, drawing simultaneously on biological and medical sciences, and multiple engineering disciplines. She has generated dozens of patents, several business spinouts, and earned a host of major scientific honors, including the 2014 Lemelson-MIT Prize, a $500,000 award recognizing an outstanding American midcareer inventor, and the David and Lucile Packard Fellowship, given to the nation’s most promising young professors in science and engineering.

A member of the Koch Institute for Integrative Cancer Research, her unorthodox career got an early start, thanks in part to Bhatia’s self-described passion for “tinkering.” As a child, she could fix the family’s broken answering machine, and was handy with hot glue guns “in a Martha Stewart way.” Her father, recognizing her potential as an engineer, brought her to the lab of an MIT acquaintance who was using focused ultrasound to heat up tumors. Her encounter with technology used against deadly disease proved formative.

Bhatia was determined to become a biomedical engineer, earning an undergraduate degree in the field. She came to view the human body “as a fascinating machine” whose failures she might address by designing interventions. But it was while she was simultaneously pursuing her doctorate in medical engineering at MIT and her MD at Harvard Medical School that Bhatia’s core research concerns began to crystallize.

Investigating a potential artificial organ to process the blood of patients suffering liver failure, Bhatia improvised a novel approach. Borrowing microfabrication technology from the semiconductor industry, she arrayed liver cells on a synthetic surface, and to her delight, this hybrid tissue remained alive in the lab for weeks. Scientists had long sought a way to sustain liver cells ex vivo, and Bhatia had delivered a biomedical first.

With her innovative adaptation of engineering tools for medically useful applications, Bhatia conjured a unique research methodology. And she also found her primary research subject: “I had an ‘aha’ moment, and realized I loved studying the liver.”

Diseases of the liver, unlike those of other organs, don’t have ready treatments. Severe alcohol abuse, hepatitis, and a host of other liver diseases sicken and kill millions each year. In addition, many aspects of the liver remain a mystery, including its unique tissue architecture and ability to regenerate. “It seemed like an incredible opportunity; anything you provided might have an impact,” says Bhatia.

Motivated by this opportunity, Bhatia began generating a steady stream of liver-focused bioengineering tools. For instance, she transformed her hybrid microfabricated liver tissue into a platform for screening drugs outside the body. In a current study, Bhatia is using an artificial liver as a testing ground for a drug with the potential to destroy the malaria parasite at different stages of its life cycle.

She is also closing in on the “naively audacious” goal of building a replaceable liver for patients in need of a liver transplant. Her team has identified chemical compounds that send regeneration signals to liver cells, and she is now successfully growing human livers in mice.

Bhatia has more recently aimed her biotech arsenal at targets beyond the liver. Exploiting nanoparticles, she is devising an inexpensive urine test for cancer that could prove immensely useful in the developing world. She has also begun attacking two of the deadliest cancers, ovarian and pancreatic, designing nanomaterials that can penetrate tumors with a cargo of RNA to silence spreading cancer genes.

“As an engineer, I have a hammer, and look for the next nail,” Bhatia says. “But as a physician, I also want to pick problems with the most clinical impact.”

By Leda Zimmerman | MIT Spectrum