MIT spinoff WiCare, founded by mechanical engineering alumna Danielle Zurovcik SM ’07, PhD ’12, has been named one of six finalists in this year’s Hult Prize competition.

The Hult Prize Foundation is a nonprofit organization focused on supporting social entrepreneurs. This year’s challenge is to solve non-communicable disease in urban slums, and winners receive $1M in seed funding.

Zurovcik, who developed a revolutionary negative pressure wound therapy pump (NPWT) as a PhD student in MechE, started WiCare (Worldwide Innovative Healthcare Inc.) with the goal of bringing high-quality medical devices to low-income countries. She is currently a fellow in the D-Lab Scale-Ups fellowship program.

Her Wound-Pump differs from other NPWT pumps on the market because of its unique materials, application method, and size. Standard pumps cost approximately $100 per day to overcome their inefficient energy usage, preventing low- and middle-income patients from utilizing the therapy. But because the Wound-Pump eliminates such energy waste, it costs less than $2 to manufacture and doesn’t require electricity at all.

Hult Prize finalists will give their presentations this summer, and the winner will be announced in September.

By Alissa Mallinson | Department of Mechanical Engineering

Cancer rates in developing nations have climbed sharply in recent years, and now account for 70 percent of cancer mortality worldwide. Early detection has been proven to improve outcomes, but screening approaches such as mammograms and colonoscopy, used in the developed world, are too costly to be implemented in settings with little medical infrastructure.  

To address this gap, MIT engineers have developed a simple, cheap, paper test that could improve diagnosis rates and help people get treated earlier. The diagnostic, which works much like a pregnancy test, could reveal within minutes, based on a urine sample, whether a person has cancer. This approach has helped detect infectious diseases, and the new technology allows noncommunicable diseases to be detected using the same strategy.

The technology, developed by MIT professor and Howard Hughes Medical Institute investigator Sangeeta Bhatia, relies on nanoparticles that interact with tumor proteins called proteases, each of which can trigger release of hundreds of biomarkers that are then easily detectable in a patient’s urine.

“When we invented this new class of synthetic biomarker, we used a highly specialized instrument to do the analysis,” says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science. “For the developing world, we thought it would be exciting to adapt it instead to a paper test that could be performed on unprocessed samples in a rural setting, without the need for any specialized equipment. The simple readout could even be transmitted to a remote caregiver by a picture on a mobile phone.”

Bhatia, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, is the senior author of a paper describing the particles in the Proceedings of the National Academy of Sciences the week of Feb. 24. The paper’s lead authors are graduate student Andrew Warren, postdoc Gabriel Kwong, and former postdoc David Wood.

Amplifying cancer signals

In 2012, Bhatia and colleagues introduced the concept of a synthetic biomarker technology to amplify signals from tumor proteins that would be hard to detect on their own. These proteins, known as matrix metalloproteinases (MMPs), help cancer cells escape their original locations by cutting through proteins of the extracellular matrix, which normally holds cells in place.

The MIT nanoparticles are coated with peptides (short protein fragments) targeted by different MMPs. These particles congregate at tumor sites, where MMPs cleave hundreds of peptides, which accumulate in the kidneys and are excreted in the urine.

In the original version of the technology, these peptides were detected using an instrument called a mass spectrometer, which analyzes the molecular makeup of a sample. However, these instruments are not readily available in the developing world, so the researchers adapted the particles so they could be analyzed on paper, using an approach known as a lateral flow assay — the same technology used in pregnancy tests.

To create the test strips, the researchers first coated nitrocellulose paper with antibodies that can capture the peptides. Once the peptides are captured, they flow along the strip and are exposed to several invisible test lines made of other antibodies specific to different tags attached to the peptides. If one of these lines becomes visible, it means the target peptide is present in the sample. The technology can also easily be modified to detect multiple types of peptides released by different types or stages of disease.

“This is a clever and inspired technology to develop new exogenous compounds that can detect clinical conditions with aberrantly high protease concentrations,” says Samuel Sia, an associate professor of biological engineering at Columbia University who was not involved in the research. “Extending this technology to detection by strip tests is a big leap forward in bringing its use to outpatient clinics and decentralized health settings.”

In tests in mice, the researchers were able to accurately identify colon tumors, as well as blood clots. Bhatia says these tests represent the first step toward a diagnostic device that could someday be useful in human patients.

“This is a new idea — to create an excreted biomarker instead of relying on what the body gives you,” she says. “To prove this approach is really going to be a useful diagnostic, the next step is to test it in patient populations.”

Developing diagnostics

To help make that happen, the research team recently won a grant from MIT’s Deshpande Center for Technological Innovation to develop a business plan for a startup that could work on commercializing the technology and performing clinical trials.

Bhatia says the technology would likely first be applied to high-risk populations, such as people who have had cancer previously, or had a family member with the disease. Eventually, she would like to see it used for early detection throughout developing nations.

Such technology might also prove useful in the United States, and other countries where more advanced diagnostics are available, as a simple and inexpensive alternative to imaging. “I think it would be great to bring it back to this setting, where point-of-care, image-free cancer detection, whether it’s in your home or in a pharmacy clinic, could really be transformative,” Bhatia says.

With the current version of the technology, patients would first receive an injection of the nanoparticles, then urinate onto the paper test strip. To make the process more convenient, the researchers are now working on a nanoparticle formulation that could be implanted under the skin for longer-term monitoring.

The team is also working to identify signatures of MMPs that could be exploited as biomarkers for other types of cancer, as well as for tumors that have metastasized.

The research was funded by a National Science Foundation Graduate Research Fellowship, a Mazumdar-Shaw International Oncology Fellowship, the Ruth L. Kirschstein National Research Service Award from the National Institutes of Health, the Burroughs Wellcome Fund, the National Cancer Institute, and the Howard Hughes Medical Institute.

By Anne Trafton, MIT News Office

To evaluate school quality, states require students to take standardized tests; in many cases, passing those tests is necessary to receive a high-school diploma. These high-stakes tests have also been shown to predict students’ future educational attainment and adult employment and income.

Such tests are designed to measure the knowledge and skills that students have acquired in school — what psychologists call “crystallized intelligence.” However, schools whose students have the highest gains on test scores do not produce similar gains in “fluid intelligence” — the ability to analyze abstract problems and think logically — according to a new study from MIT neuroscientists working with education researchers at Harvard University and Brown University.

In a study of nearly 1,400 eighth-graders in the Boston public school system, the researchers found that some schools have successfully raised their students’ scores on the Massachusetts Comprehensive Assessment System (MCAS). However, those schools had almost no effect on students’ performance on tests of fluid intelligence skills, such as working memory capacity, speed of information processing, and ability to solve abstract problems.

“Our original question was this: If you have a school that’s effectively helping kids from lower socioeconomic environments by moving up their scores and improving their chances to go to college, then are those changes accompanied by gains in additional cognitive skills?” says John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences, and senior author of a forthcoming Psychological Science paper describing the findings.

Instead, the researchers found that educational practices designed to raise knowledge and boost test scores do not improve fluid intelligence. “It doesn’t seem like you get these skills for free in the way that you might hope, just by doing a lot of studying and being a good student,” says Gabrieli, who is also a member of MIT’s McGovern Institute for Brain Research.

Measuring cognition

This study grew out of a larger effort to find measures beyond standardized tests that can predict long-term success for students. “As we started that study, it struck us that there’s been surprisingly little evaluation of different kinds of cognitive abilities and how they relate to educational outcomes,” Gabrieli says.

The data for the Psychological Science study came from students attending traditional, charter, and exam schools in Boston. Some of those schools have had great success improving their students’ MCAS scores — a boost that studies have found also translates to better performance on the SAT and Advanced Placement tests.

The researchers calculated how much of the variation in MCAS scores was due to the school that students attended. For MCAS scores in English, schools accounted for 24 percent of the variation, and they accounted for 34 percent of the math MCAS variation. However, the schools accounted for very little of the variation in fluid cognitive skills — less than 3 percent for all three skills combined.

In one example of a test of fluid reasoning, students were asked to choose which of six pictures completed the missing pieces of a puzzle — a task requiring integration of information such as shape, pattern, and orientation.

“It’s not always clear what dimensions you have to pay attention to get the problem correct. That’s why we call it fluid, because it’s the application of reasoning skills in novel contexts,” says Amy Finn, an MIT postdoc and lead author of the paper.

Even stronger evidence came from a comparison of about 200 students who had entered a lottery for admittance to a handful of Boston’s oversubscribed charter schools, many of which achieve strong improvement in MCAS scores. The researchers found that students who were randomly selected to attend high-performing charter schools did significantly better on the math MCAS than those who were not chosen, but there was no corresponding increase in fluid intelligence scores.

However, the researchers say their study is not about comparing charter schools and district schools. Rather, the study showed that while schools of both types varied in their impact on test scores, they did not vary in their impact on fluid cognitive skills. 

“What’s nice about this study is it seems to narrow down the possibilities of what educational interventions are achieving,” says Daniel Willingham, a professor of psychology at the University of Virginia who was not part of the research team. “We’re usually primarily concerned with outcomes in schools, but the underlying mechanisms are also important.”

The researchers plan to continue tracking these students, who are now in 10th grade, to see how their academic performance and other life outcomes evolve. They have also begun to participate in a new study of high school seniors to track how their standardized test scores and cognitive abilities influence their rates of college attendance and graduation.

Implications for education

Gabrieli notes that the study should not be interpreted as critical of schools that are improving their students’ MCAS scores. “It’s valuable to push up the crystallized abilities, because if you can do more math, if you can read a paragraph and answer comprehension questions, all those things are positive,” he says.

He hopes that the findings will encourage educational policymakers to consider adding practices that enhance cognitive skills. Although many studies have shown that students’ fluid cognitive skills predict their academic performance, such skills are seldom explicitly taught.

“Schools can improve crystallized abilities, and now it might be a priority to see if there are some methods for enhancing the fluid ones as well,” Gabrieli says.

Some studies have found that educational programs that focus on improving memory, attention, executive function, and inductive reasoning can boost fluid intelligence, but there is still much disagreement over what programs are consistently effective.

The research was a collaboration with the Center for Education Policy Research at Harvard University, Transforming Education, and Brown University, and 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 Brigham and Women’s Hospital have shown that they can grow unlimited quantities of intestinal stem cells, then stimulate them to develop into nearly pure populations of different types of mature intestinal cells. Using these cells, scientists could develop and test new drugs to treat diseases such as ulcerative colitis.

The small intestine, like most other body tissues, has a small store of immature adult stem cells that can differentiate into more mature, specialized cell types. Until now, there has been no good way to grow large numbers of these stem cells, because they only remain immature while in contact with a type of supportive cells called Paneth cells.

In a new study appearing in the Dec. 1 online edition of Nature Methods, the researchers found a way to replace Paneth cells with two small molecules that maintain stem cells and promote their proliferation. Stem cells grown in a lab dish containing these molecules can stay immature indefinitely; by adding other molecules, including inhibitors and activators, the researchers can control what types of cells they eventually become.

“This opens the door to doing all kinds of things, ranging from someday engineering a new gut for patients with intestinal diseases to doing drug screening for safety and efficacy. It’s really the first time this has been done,” says Robert Langer, the David H. Koch Institute Professor, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the paper’s senior authors.

Jeffrey Karp, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, is also a senior author of the paper. The paper’s lead author is Xiaolei Yin, a postdoc at the Koch Institute and Brigham and Women’s Hospital.

From one cell, many

The inner layer of the intestines has several critical functions. Some cells are specialized to absorb nutrients from digested food, while others form a barrier that secretes mucus and prevents viruses and bacteria from entering cells. Still others alert the immune system when a foreign pathogen is present.

This layer, known as the intestinal epithelium, is coated with many small indentations known as crypts. At the bottom of each crypt is a small pool of epithelial stem cells, which constantly replenish the specialized cells of the intestinal epithelium, which only live for about five days. These stem cells can become any type of intestinal epithelial cell, but don’t have the pluripotency of embryonic stem cells, which can become any cell type in the body.

If scientists could obtain large quantities of intestinal epithelial stem cells, they could be used to help treat gastrointestinal disorders that damage the epithelial layer. Recent studies in animals have shown that intestinal stem cells delivered to the gut can attach to ulcers and help regenerate healthy tissue, offering a potential new way to treat ulcerative colitis.

Using those stem cells to produce large populations of specialized cells would also be useful for drug development and testing, the researchers say. With large quantities of goblet cells, which help control the immune response to proteins found in food, scientists could study food allergies; with enteroendocrine cells, which release hunger hormones, they could test new treatments for obesity.

“If we had ways of performing high-throughput screens on large numbers of these very specific cell types, we could potentially identify new targets and develop completely new drugs for diseases ranging from inflammatory bowel disease to diabetes,” Karp says.

Controlling cell fate

In 2007, Hans Clevers, a professor at the Hubrecht Institute in the Netherlands, identified a marker for intestinal epithelial stem cells — a protein called Lgr5. Clevers, who is an author of the new Nature Methods paper, also identified growth factors that enable these stem cells to reproduce in small quantities in a lab dish and spontaneously differentiate into mature cells, forming small structures called organoids that mimic the natural architecture of the intestinal lining.

In the new study, the researchers wanted to figure out how to keep stem cells proliferating but stop them from differentiating, creating a nearly pure population of stem cells. This has been difficult to do because stem cells start to differentiate as soon as they lose contact with a Paneth cell.

Paneth cells control two signaling pathways, known as Notch and Wnt, which coordinate cell proliferation, especially during embryonic development. The researchers identified two small molecules, valproic acid and CHIR-99021, that work together to induce stem cells to proliferate and prevent them from differentiating into mature cells.

When the researchers grew mouse intestinal stem cells in a dish containing these two small molecules, they obtained large clusters made of 70 to 90 percent stem cells.

Once the researchers had nearly pure populations of stem cells, they showed that they could drive them to develop into particular types of intestinal cells by adding other factors that influence the Wnt and Notch pathways. “We used different combinations of inhibitors and activators to drive stem cells to differentiate into specific populations of mature cells,” Yin says.

This approach also works in mouse stomach and colon cells, the researchers found. They also showed that the small molecules improved the proliferation of human intestinal stem cells. They are now working on engineering intestinal tissues for patient transplant and developing new ways to rapidly test the effects of drugs on intestinal cells.

Another potential use for these cells is studying the biology that underlies stem cells’ special ability to self-renew and to develop into other cell types, says Ramesh Shivdasani, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute.

“There are a lot of things we don’t know about stem cells,” says Shivdasani, who was not part of the research team. “Without access to large quantities of these cells, it’s very difficult to do any experiments. This opens the door to a systematic, incisive, reliable way of interrogating intestinal stem cell biology.”

The research was funded by the National Institutes of Health, a Harvard Institute of Translational Immunology/Helmsley Trust Pilot Grant in Crohn’s Disease, and the European Molecular Biology Organization.
By Anne Trafton, MIT News Office

Scientists first discovered chromosomes in the late 1800s, after the light microscope was invented. Using these microscopes, biologist Walter Flemming observed many tightly wound, elongated structures in cell nuclei. Later, it was found that chromosomes are made from DNA, the cell’s genetic material.

Since then, scientists have proposed many possible ways that DNA molecules might fold into 3-D condensed chromosomes. Now, researchers at MIT and the University of Massachusetts Medical School have obtained novel data on the 3-D organization of condensed human chromosomes and built the first comprehensive model of such chromosomes.

In this model, DNA forms loops that emanate from a flexible scaffold; the loops are tightly compressed along the scaffold. “This is a very efficient way of packing DNA material,” says Leonid Mirny, an associate professor of health sciences and technology and physics at MIT and a senior author of a paper describing the findings in the Nov. 7 online edition of Science.

This condensed state, seen only when cells are dividing, allows cells to neatly separate and distribute their chromosomes so that each daughter cell receives the full complement of genetic material. At all other times, the chromosomes are more loosely organized inside the cell nucleus.

Job Dekker, a professor of biochemistry and molecular pharmacology at UMass, is also a senior author of the paper. Lead authors are MIT graduate student Maxim Imakaev, Harvard University graduate student Geoffrey Fudenberg, and UMass postdoc Natalia Naumova. Other authors are UMass researcher Ye Zhan and UMass bioinformatician Bryan Lajoie.

Layers of structure

Chromosomes are complex molecules with several levels of organization, allowing cells to cram 2 meters of DNA into a nucleus that is only one hundredth of a millimeter in diameter. Long strands of DNA wind around proteins called histones, giving rise to a “beads on a string” structure. Several models have been proposed to explain how those strands of millions of beads are arranged inside tightly packed chromosomes.

“There is no shortage of models of how DNA is folded inside a chromosome,” says Mirny, who is a member of MIT’s Institute for Medical Engineering and Sciences. “Every high-school biology textbook has a drawing of chromosomes folding. If you look at these drawings you might get the impression that the problem has been solved, but if you look carefully you see that all these drawings all very different.”

To help determine which model is correct, the researchers used a technology developed in Dekker’s lab called Hi-C, which performs genomewide analysis of the proximity of genomic regions. This reveals the frequency of interaction for every pair of regions in the entire genome.

The challenge, however, lies in generating an overall chromosome structure based on Hi-C data. “Given a three-dimensional structure, it is straightforward to find all contacts; however, reconstructing three-dimensional structures from contact frequencies is much more difficult,” Imakaev says.

In 2009, researchers including Imakaev, Mirny, and Dekker used Hi-C to demonstrate that during most of a cell’s life, when it is not dividing, DNA is organized as a fractal globule, in which DNA is not tangled or knotted.

Hi-C also showed that regions with more active genes tend to cluster together in easily accessible compartments, and unused regions form more densely packed clusters. The organization of each chromosome varies among cell types, because every type of cell uses different sets of genes to carry out its function. This means that each chromosome acquires a specific 3-D organization depending on which genes a cell is using.

Chromosomes during cell division

In the new paper, the researchers found that as cells begin to divide, chromosomes are completely reorganized. First, all chromosome-specific and cell type-specific patterns of organization, which are necessary for gene regulation, disappear. Instead, all chromosomes are folded in a similar way as cells begin to undergo cell division, or mitosis. However, the chromosomes do not form the exact same structure every time they condense.

“Unlike proteins, which fold into very defined structures, the chromosomes form a completely different condensed object every time,” Fudenberg says. “It appears similar macroscopically but the individual regions of the genome can be folded in very different ways in different cells.”

The Hi-C technique “provides a modern day molecular microscope, with the power to see inside of these bodies and elucidate their principles of organization,” wrote Nancy Kleckner, a professor of molecular and cellular biology at Harvard University, in a perspective article accompanying the Science paper. The researchers “combine chromosome conformation capture with polymer physics simulations to provide a new, yet satisfyingly familiar, view,” she wrote.

The researchers believe that two stages are required to achieve the loop-on-a-scaffold structure: First, the chromatin forms loops — each of which contains about 80,000 to 120,000 DNA base pairs — radiating out from a scaffold made of DNA and some proteins. Then, the chromosome compresses itself along its central axis, where the scaffold is located.

While molecular details of the second stage remain mysterious, scientists have a good guess for what might be responsible for the first stage of chromosome folding: A team at Northwestern University recently proposed that proteins called condensins drive chromosome condensation by latching on to the DNA and extruding loops. To test this hypothesis in greater detail, the MIT team is now collaborating with these researchers.

Beyond characterizing condensed chromosomes, this study also opens the door for future work to understand mechanisms of chromosome condensation, cell memory, and epigenetic cell reprogramming.

The research was funded by the National Cancer Institute, the National Human Genome Research Institute, the Human Frontier Science Program, and the W.M. Keck Foundation.

By Anne Trafton, MIT News Office

After suffering a traumatic brain injury, patients are often placed in a coma to give the brain time to heal and allow dangerous swelling to dissipate. These comas, which are induced with anesthesia drugs, can last for days. During that time, nurses must closely monitor patients to make sure their brains are at the right level of sedation — a process that MIT’s Emery Brown describes as “totally inefficient.”

“Someone has to be constantly coming back and checking on the patient, so that you can hold the brain in a fixed state. Why not build a controller to do that?” says Brown, the Edward Hood Taplin Professor of Medical Engineering in MIT’s Institute for Medical Engineering and Science, who is also an anesthesiologist at Massachusetts General Hospital (MGH) and a professor of health sciences and technology at MIT.

Brown and colleagues at MGH have now developed a computerized system that can track patients’ brain activity and automatically adjust drug dosages to maintain the correct state. They have tested the system  — which could also help patients who suffer from severe epileptic seizures — in rats and are now planning to begin human trials.

Maryam Shanechi, a former MIT grad student who is now an assistant professor at Cornell University, is the lead author of the paper describing the computerized system in the Oct. 31 online edition of the journal PLoS Computational Biology.

Tracking the brain

Brown and his colleagues have previously analyzed the electrical waves produced by the brain in different states of activity. Each state — awake, asleep, sedated, anesthetized and so on — has a distinctive electroencephalogram (EEG) pattern.

When patients are in a medically induced coma, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. This pattern, known as burst suppression, allows the brain to conserve vital energy during times of trauma.

As a patient enters an induced coma, the doctor or nurse controlling the infusion of anesthesia drugs tries to aim for a particular number of “bursts per screen” as the EEG pattern streams across the monitor. This pattern has to be maintained for hours or days at a time.

“If ever there were a time to try to build an autopilot, this is the perfect time,” says Brown, who is a professor in MIT’s Department of Brain and Cognitive Sciences. “Imagine that you’re going to fly for two days and I’m going to give you a very specific course to maintain over long periods of time, but I still want you to keep your hand on the stick to fly the plane. It just wouldn’t make sense.”

To achieve automated control, Brown and colleagues built a brain-machine interface — a direct communication pathway between the brain and an external device that typically assists human cognitive, sensory or motor functions. In this case, the device — an EEG system, a drug-infusion pump, a computer and a control algorithm — uses the anesthesia drug propofol to maintain the brain at a target level of burst suppression.

The system is a feedback loop that adjusts the drug dosage in real time based on EEG burst-suppression patterns. The control algorithm interprets the rat’s EEG, calculates how much drug is in the brain, and adjusts the amount of propofol infused into the animal second-by-second.

The controller can increase the depth of a coma almost instantaneously, which would be impossible for a human to do accurately by hand. The system could also be programmed to bring a patient out of an induced coma periodically so doctors could perform neurological tests, Brown says.

This type of system could take much of the guesswork out of patient care, says Sydney Cash, an associate professor of neurology at Harvard Medical School.

“Much of what we do in medicine is making educated guesses as to what’s best for the patient at any given time,” says Cash, who was not part of the research team. “This approach introduces a methodology where doctors and nurses don’t need to guess, but can rely on a computer to figure out — in much more detail and in a time-efficient fashion — how much drug to give.”

Monitoring anesthesia

Brown believes that this approach could easily be extended to control other brain states, including general anesthesia, because each level of brain activity has its own distinctive EEG signature.

“If you can quantitatively analyze each state’s signature in real time and you have some notion of how the drug moves through the brain to generate those states, then you can build a controller,” he says.

There are currently no devices approved by the U.S. Food and Drug Administration (FDA) to control general anesthesia or induced coma. However, the FDA has recently approved a device that controls sedation not using EEG readings.

The MIT and MGH researchers are now preparing applications to the FDA to test the controller in humans.

The research was funded by the National Institutes of Health through a Pioneer Award and a Transformative Research Award.
By Anne Trafton, MIT News Office

Life-threatening blood clots can form in anyone who sits on a plane for a long time, is confined to bed while recovering from surgery, or takes certain medications.

There is no fast and easy way to diagnose these clots, which often remain undetected until they break free and cause a stroke or heart attack. However, new technology from MIT may soon change that: A team of engineers has developed a way to detect blood clots using a simple urine test.

The noninvasive diagnostic, described in a recent issue of the journal ACS Nano, relies on nanoparticles that detect the presence of thrombin, a key blood-clotting factor.

Such a system could be used to monitor patients who are at high risk for blood clots, says Sangeeta Bhatia, senior author of the paper and the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science.

“Some patients are at more risk for clotting, but existing blood tests are not consistently able to detect the formation of new clots,” says Bhatia, who is also a senior associate member of the Broad Institute and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

Lead authors of the paper are Kevin Lin, a graduate student in chemical engineering, and Gabriel Kwong, a postdoc in IMES. Other authors are Andrew Warren, a graduate student in Health Sciences and Technology (HST), and former HST postdoc David Wood.

Sensing thrombin

Blood clotting is produced by a complex cascade of protein interactions, culminating in the formation of fibrin, a fibrous protein that seals wounds. The last step of this process — the conversion of fibrinogen to fibrin — is controlled by an enzyme called thrombin.

Current tests for blood clotting are very indirect, Bhatia says. One, known as the D-dimer test, looks for the presence of fibrin byproducts, which indicates that a clot is being broken down, but will not detect its initial formation.

Bhatia and her colleagues developed their new test based on a technology they first reported last year for early detection of colorectal cancer. “We realized the same exact technology would work for blood clots,” she says. “So we took the test we had developed before, which is an injectable nanoparticle, and made it a thrombin sensor.”

The system consists of iron oxide nanoparticles, which the Food and Drug Administration has approved for human use, coated with peptides (short proteins) that are specialized to interact with thrombin. After being injected into mice, the nanoparticles travel throughout the body. When the particles encounter thrombin, the thrombin cleaves the peptides at a specific location, releasing fragments that are then excreted in the animals’ urine.

Once the urine is collected, the protein fragments can be identified by treating the sample with antibodies specific to peptide tags included in the fragments. The researchers showed that the amount of these tags found in the urine is directly proportional to the level of blood clotting in the mice’s lungs.

In the previous version of the system, reported last December in Nature Biotechnology, the researchers used mass spectrometry to distinguish the fragments by their mass. However, testing samples with antibodies is much simpler and cheaper, the researchers say.

Rapid screening

Bhatia says she envisions two possible applications for this kind of test. One is to screen patients who come to the emergency room complaining of symptoms that might indicate a blood clot, allowing doctors to rapidly triage such patients and determine if more tests are needed.

“Right now they just don’t know how to efficiently define who to do the more extensive workup on. It’s one of those things that you can’t afford to miss, so patients can get an unnecessarily expensive workup,” Bhatia says.

Another application is monitoring patients who are at high risk for a clot — for example, people who have to spend a lot of time in bed recovering from surgery. Bhatia is working on a urine dipstick test, similar to a pregnancy test, that doctors could give patients when they go home after surgery.

“If a patient is at risk for thrombosis, you could send them home with a 10-pack of these sticks and say, ‘Pee on this every other day and call me if it turns blue,’” she says.

The technology could also be useful for predicting recurrence of clots, says Henri Spronk, an assistant professor of biochemistry at Maastricht University in the Netherlands.

“High levels of activation markers have been related to recurrent thrombosis, but they don’t have good sensitivity or specificity. Through application of the nanoparticles, if proven well-tolerated and nontoxic, alterations in the normal low levels of physiological thrombin generation might be easily detected,” says Spronk, who was not part of the research team.

Bhatia plans to launch a company to commercialize the technology, with funding from MIT’s Deshpande Center for Technological Innovation. Other applications for the nanoparticle system could include monitoring and diagnosing cancer. It could also be adapted to track liver, pulmonary, and kidney fibrosis, Bhatia says.

The research was funded by the Koch Institute Frontier Research Fund, the Kathy and Curt Marble Cancer Research Fund, the Mazumdar-Shaw International Oncology Fellows Program, the Burroughs Wellcome Fund, and the Deshpande Center.
By Anne Trafton, MIT News Office

MIT’s new Institute for Medical Engineering and Science (IMES) is tackling some of the world’s biggest health challenges through an interdisciplinary approach that will seek new ways to diagnose and treat infectious, neurological and cardiovascular diseases.

Solving those challenges will require bringing together many types of expertise, said MIT President L. Rafael Reif, who urged researchers to “be bold, think big, and save the world” at an inaugural symposium, held Sept. 25, to celebrate IMES’s launch.

The new institute aims to become a hub for medical research, IMES director Arup Chakraborty said, allowing MIT scientists and engineers to work more closely with hospitals, medical-device manufacturers, and pharmaceutical companies in the Boston and Cambridge area.

“We aim to serve as a strong integrative force across the MIT campus and bring together our work in discovery, innovation and entrepreneurship and partner with hospitals, Harvard Medical School and industry to create the future of medicine and health care. There is no better location in the world than here to try and do this,” said Chakraborty, the Robert T. Haslam Professor of Chemical Engineering, Chemistry, Physics and Biological Engineering at MIT.

IMES, which is now home to the Harvard-MIT Division of Health Sciences and Technology (HST), will also train the next generation of innovators at both the graduate and undergraduate levels. IMES will add a new program with the MIT Sloan School of Management and a new curriculum in health-care informatics, said Emery Brown, associate director of IMES. “We’re going to expand on what is already a 40-year success with the HST program with Harvard Medical School,” said Brown, the Edward Hood Taplin Professor of Medical Engineering at MIT.

IMES also includes MIT’s Medical Electronic Device Realization Center, which is devoted to developing new medical devices for diagnosis and disease monitoring, in collaboration with industrial partners.

Grand challenges

Speakers at the symposium outlined some of the health challenges now facing the world and offered thoughts on how to tackle them.

Gregory Petsko, a professor of neurology and neuroscience at Weill Cornell Medical College, said that as life spans continue to increase around the world, more and more people will suffer from neurological disorders such as Alzheimer’s disease. “The older you get, the greater your risk for one of the major neurodegenerative diseases,” he said.

There are now 5 million people with Alzheimer’s in the United States, a figure that is expected to grow to nearly 14 million by 2050. At the same time, the worldwide total is projected to reach 100 million.

Petsko, who described potential drugs he is developing to interfere with the formation of Alzheimer’s plaques, said he and other scientists need help from engineers to find optimal ways to deliver their drugs to the brain. Engineers can also lend their expertise in designing devices that can test for disease biomarkers that scientists may discover in the future, he said.

“This is a problem that largely is going to have to have engineering solutions. We have to find biomarkers, but there have to be ways to identify those markers in living people inexpensively and, in some cases, rapidly,” Petsko said.

Trevor Mundel, president of the global health program at the Bill and Melinda Gates Foundation, said he hopes the foundation and IMES will have opportunities to work together.

“I see a lot of synergies and intersections between IMES and the Gates Foundation,” Mundel said. “At the high level, we both want to have real impact and do things in the real world, not just be theoretical and have some abstract discussions.”

Mundel said that when creating new technology for developing countries, it is critical to be aware of the local environment and the needs of the people living there. For example, a recently deployed diagnostic device for tuberculosis turned out to be ill-suited to remote clinics because it took too long to produce a result.

“We had in mind a profile of what was really needed, and what we got out was not quite there. What I have found out is that ‘not quite there,’ in these infrastructure-poor areas, is not there at all,” Mundel said. “The global-health community all too often produces products which were almost there, but they’re not good enough for the countries and the infrastructure where they actually need to be deployed.”

Building bridges across disciplines

While IMES is breaking new ground, it is also building on a long history of medical research at MIT. In 2011, Reif, then MIT’s provost, asked a faculty committee to examine the future of HST, established in 1969 to train physician-scientists.

The committee found that while many scientists and engineers at MIT were working on projects together, these efforts were not centrally organized. Furthermore, MIT was not taking full advantage of its close proximity to nearby world-class hospitals. IMES was established in July 2012 to formalize and strengthen those connections.

“We needed a structure that would allow MIT and its clinical colleagues to make the most of each other’s strengths, working together on the most important problems and seizing opportunities to drive systemic change,” Reif said at yesterday’s symposium.

In establishing IMES, Chakraborty and others drew inspiration from the Koch Institute for Integrative Cancer Research at MIT and the Ragon Institute of Harvard, MIT and Massachusetts General Hospital.

Bruce Walker, director of the Ragon Institute, said he launched that institute, whose mission is to develop HIV vaccines, because he had become frustrated with the isolated nature of most HIV research. It was difficult to bring in scientists or engineers from outside the field and even harder to obtain funding for innovative interdisciplinary projects, he told symposium attendees.

“Our feeling was the full toolbox had never really been applied to the HIV problem, and my sense from interactions with the Broad Institute and others that I had begun to get engaged with here was that we could really accelerate progress if we could get more engineers and physicists and computational biologists to come to the table,” Walker said.

Likewise, Koch Institute director Tyler Jacks wanted to bring new perspectives and expertise to MIT’s research on cancer. In 2010, cancer biologists and engineers moved into a new Koch Institute building, which is designed to foster chance interactions and new collaborations, Jacks said.

Making sure that scientists and engineers have ample opportunities to talk about their research and learn the language of other fields is key to successful collaborations, Jacks said.

“I sometimes describe this place like Ellis Island,” he said. “You’ve got people bumping into each other who don’t speak the same language. Chemical engineers have to talk to molecular biologists. Mechanical engineers have to talk to cell biologists. This takes some effort, and we’ve worked quite hard to try to enable better communication and education among the people who are experiencing the Koch Institute.”

After the symposium, IMES hosted a preview of its new lab space, which comprises 15,000 square feet on the third floor of Building E25. Funding to renovate the space was provided by Susan and Phillip (Terry) Ragon.
By Anne Trafton, MIT News Office

About 10 percent of the U.S. population suffers from dyslexia, a condition that makes learning to read difficult. Dyslexia is usually diagnosed around second grade, but the results of a new study from MIT could help identify those children before they even begin reading, so they can be given extra help earlier.

The study, done with researchers at Boston Children’s Hospital, found a correlation between poor pre-reading skills in kindergartners and the size of a brain structure that connects two language-processing areas.

Previous studies have shown that in adults with poor reading skills, this structure, known as the arcuate fasciculus, is smaller and less organized than in adults who read normally. However, it was unknown if these differences cause reading difficulties or result from lack of reading experience.

“We were very interested in looking at children prior to reading instruction and whether you would see these kinds of differences,” says John Gabrieli, the Grover M. Hermann Professor of Health Sciences and Technology, professor of brain and cognitive sciences and a member of MIT’s McGovern Institute for Brain Research.

Gabrieli and Nadine Gaab, an assistant professor of pediatrics at Boston Children’s Hospital, are the senior authors of a paper describing the results in the Aug. 14 issue of the Journal of Neuroscience. Lead authors of the paper are MIT postdocs Zeynep Saygin and Elizabeth Norton.

The path to reading

The new study is part of a larger effort involving approximately 1,000 children at schools throughout Massachusetts and Rhode Island. At the beginning of kindergarten, children whose parents give permission to participate are assessed for pre-reading skills, such as being able to put words together from sounds.

“From that, we’re able to provide — at the beginning of kindergarten — a snapshot of how that child’s pre-reading abilities look relative to others in their classroom or other peers, which is a real benefit to the child’s parents and teachers,” Norton says.

The researchers then invite a subset of the children to come to MIT for brain imaging. The Journal of Neuroscience study included 40 children who had their brains scanned using a technique known as diffusion-weighted imaging, which is based on magnetic resonance imaging (MRI).

This type of imaging reveals the size and organization of the brain’s white matter — bundles of nerves that carry information between brain regions. The researchers focused on three white-matter tracts associated with reading skill, all located on the left side of the brain: the arcuate fasciculus, the inferior longitudinal fasciculus (ILF) and the superior longitudinal fasciculus (SLF).

When comparing the brain scans and the results of several different types of pre-reading tests, the researchers found a correlation between the size and organization of the arcuate fasciculus and performance on tests of phonological awareness — the ability to identify and manipulate the sounds of language.

Phonological awareness can be measured by testing how well children can segment sounds, identify them in isolation, and rearrange them to make new words. Strong phonological skills have previously been linked with ease of learning to read. “The first step in reading is to match the printed letters with the sounds of letters that you know exist in the world,” Norton says.

The researchers also tested the children on two other skills that have been shown to predict reading ability — rapid naming, which is the ability to name a series of familiar objects as quickly as you can, and the ability to name letters. They did not find any correlation between these skills and the size or organization of the white-matter structures scanned in this study.

Brian Wandell, director of Stanford University’s Center for Cognitive and Neurobiological Imaging, says the study is a valuable contribution to efforts to find biological markers that a child is likely to need extra help to learn to read.

“The work identifies a clear marker that predicts reading, and the marker is present at a very young age. Their results raise questions about the biological basis of the marker and provides scientists with excellent new targets for study,” says Wandell, who was not part of the research team.

Early intervention

The left arcuate fasciculus connects Broca’s area, which is involved in speech production, and Wernicke’s area, which is involved in understanding written and spoken language. A larger and more organized arcuate fasciculus could aid in communication between those two regions, the researchers say.

Gabrieli points out that the structural differences found in the study don’t necessarily reflect genetic differences; environmental influences could also be involved. “At the moment when the children arrive at kindergarten, which is approximately when we scan them, we don’t know what factors lead to these brain differences,” he says.

The researchers plan to follow three waves of children as they progress to second grade and evaluate whether the brain measures they have identified predict poor reading skills.

“We don’t know yet how it plays out over time, and that’s the big question: Can we, through a combination of behavioral and brain measures, get a lot more accurate at seeing who will become a dyslexic child, with the hope that that would motivate aggressive interventions that would help these children right from the start, instead of waiting for them to fail?” Gabrieli says.

For at least some dyslexic children, offering extra training in phonological skills can help them improve their reading skills later on, studies have shown.

The research was funded by the National Institutes of Health, the Poitras Center for Affective Disorders Research, the Ellison Medical Foundation and the Halis Family Foundation.
By Anne Trafton, MIT News Office

Although malaria has been eradicated in many countries, including the United States, it still infects more than 200 million people worldwide, killing nearly a million every year. In regions where malaria is endemic, people rely on preventive measures such as mosquito netting and insecticides. Existing drugs can help, but the malaria parasite is becoming resistant to many of them. 

Scientists working to develop new drugs and vaccines hope to target the parasite in the earliest stages of an infection, when it quietly reproduces itself in the human liver.

In a major step toward that goal, a team led by MIT researchers has now developed a way to grow liver tissue that can support the liver stage of the life cycle of the two most common species of malaria, Plasmodium falciparum and Plasmodium vivax. This system could be used to test drugs and vaccines against both species, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT.

Bhatia is the senior author of a paper describing the liver-tissue system in the July 17 issue of the journal Cell Host & Microbe. The paper’s lead author is Sandra March, a research scientist in Bhatia’s lab, and scientists from the Broad Institute, Sanaria Inc. and the University of Lisbon also contributed to the research.

Reproducing infection

The malaria life cycle has several stages. Once the parasite infects a human victim, through a mosquito bite, it takes up residence in the liver. The parasite spends about a week in the liver, producing tens of thousands of copies that eventually burst free to infect blood cells. After this initial infection, P. vivax can lurk for weeks, months or even years, reactivating to cause another malaria bout.

So far, researchers have been able to grow P. falciparum in human blood and, to a certain extent, in its liver stages, but they have not been able to reliably grow P. vivax in either stage. P. falciparum has the highest malaria mortality rate, but P. vivax can cause debilitating, long-term infections. To eradicate malaria, drugs and vaccines that target both species will probably be needed, Bhatia says.

Bhatia — who is also a senior associate member of the Broad Institute and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science — has previously created micropatterned surfaces on which liver tissue can be grown, surrounded by supportive cells. These engineered cells survive for up to six weeks and mimic most of the functions of liver cells in the body, including drug metabolism and production of liver proteins. 

Using unique, frozen samples of P. falciparum obtained in collaboration with Stephen L. Hoffman and his team at Sanaria, the researchers infected healthy liver cells and observed the development of liver-stage parasites using an automated imaging system designed in collaboration with Anne Carpenter’s group at the Broad Institute. This system allows them to quickly evaluate not only how much infection has occurred, but also the effects of potential drugs. They can also measure how weakened forms of the parasites, which could be used as vaccines, perform in the liver.

To test the system’s usefulness, the researchers studied a P. falciparum vaccine that is now in clinical trials. For a weakened, or attenuated, parasite to succeed as a vaccine, it must infect the liver and progress enough to raise an immune response, but then arrest and not reach the blood stage. The researchers showed that the vaccine now in trials does follow that trajectory.

The new system could also be used for larger-scale drug studies than previously possible, Bhatia says. Researchers now use liver cancer cells grown in the lab to study P. falciparum infection, but those cells have deficient drug metabolism and keep growing instead of providing a quiet home for the parasite to persist.

Seeking P. vivax

Obtaining enough P. vivax samples to test the system took several years, but the team eventually acquired samples, flown in from Thailand, India and South America. Using these samples, they were able to grow P. vivax in liver tissue and show that it produces small persistent parasites that appear to be dormant forms called hypnozoites.

“We don’t want to call them hypnozoites yet, because nobody has a gold-standard marker for them, but we have persistent small forms that live for three weeks. So we are optimistic and doing more to wake them up again. Reactivation would be the ultimate confirmation,” Bhatia says.

Technologies that permit high-throughput screening of drugs against hypnozoites would be “a tremendous advance of global-health importance,” says Kevin Baird, vice director of the Eijkman Oxford Clinical Research Unit in Indonesia. “This paper shows the formation of what are very likely hypnozoites, but demonstration of their maturation (and therefore likely utility in screening chemotherapeutics) remains to be achieved in this system or anywhere else.”

The researchers are now working on confirming that the P. vivax they grew in the liver tissue really did create hypnozoites. Once this is confirmed, they plan to start testing some candidate drugs, now in development, against P. vivax.

The research was funded by the Bill and Melinda Gates Foundation, Medicines for Malaria Venture, the National Institute of Allergy and Infectious Disease, the National Institutes of Health and the Howard Hughes Medical Institute.
By Anne Trafton, MIT News Office