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

March 6, 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

March 6, 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

Once a patient infected with the Ebola hemorrhagic virus starts showing symptoms, it can take several hours under the best conditions, and up to several days in remote areas, to get diagnostic results using conventional tests, such as identification of viral RNA. Further complicating the process, Ebola symptoms are very similar to those of other fevers, such as typhoid and malaria. Because time is of the essence in tracking Ebola and preventing its spread, researchers at MIT’s Institute for Medical Engineering and Science (IMES) are working on a new device that uses nanoparticles to capture the virus in patient blood samples and would offer much faster results. Lee Gehrke, the Hermann von Helmholtz Professor in IMES and a professor of microbiology and immunology at Harvard Medical School, described the project to MIT News.

Q. How does your experimental device detect Ebola and other diseases in patient blood samples?

A. One can detect Ebola, like any other hemorrhagic virus, in two ways: with lots of instruments or without lots of instruments. The media contains reports of a new Ebola test every week these days, and most of those are “black boxes” that have of lots moving parts and specialized chemical kits. Lots of these devices end up breaking down in the developing world. 

We prefer a simple device, so we made paper with inkjet-printed molecules and specially tuned nanoparticles that bind to the virus. Then we use lasers to create fluidic pathways that control specific binding reactions of our Ebola-specific molecules. Our lab has traditionally been an RNA virus lab, so we are very interested in translating molecular-scale information into a macro-scale diagnostic that would improve health care.  

Q. How could such a device help to monitor and contain disease outbreaks such as the current Ebola outbreak?

A. Surveillance and acute triage. Once health care professionals use our paper fluidic device to detect the virus, they can isolate that patient and initiate a treatment plan in minutes. Waiting an hour for lab results could mean infecting the rest of the waiting room. A fast diagnostic is more than convenient; it really affects the system of care. 

Given large-scale usage, we can aggregate the diagnostic results into a crowd-sourced, real-time surveillance platform. The goal is to anticipate the spread of the epidemic in a distributed manner. We’re not going to stop Ebola by counting what happened yesterday; rather, we have to be able to detect what’s happening now so we can make predictions about the future. Our goal is for every first aid kit, every clinic, and every home in a village to have a cheap, rapid test where they can self-report results within 30 minutes. It’s giving all these great platforms for mobile health a verifiable ground-truth mechanism, just like a meteorologist relies on small weather stations across Massachusetts to make forecasts about tomorrow’s chance of snow.

Sierra Leone, Liberia, and Guinea are not going to develop their own Centers for Disease Control and Prevention overnight. This is one way to advance their epidemiological preparedness. The data can be analyzed in real time to provide early warning of virus infections, and to monitor the locations of virus infections. 

Q. What stage of development is the device in now? What future steps are needed before it can be deployed?

A. The device detects Ebola and other viruses in the laboratory. We are in the middle of exciting engineering field studies and animal studies to evaluate device efficacy for deployment. We have a great team of collaborations around the world and around the country and everyone is moving as fast as possible to implement the technology with our clinical partners in West Africa. The next major step after validating the detection is selecting the right diffusion strategy — do we mass-manufacture a specific detection device? Or do we create local production protocols that would be adaptable in producing a variety of different types of devices dependent on need? Do we stamp out molds for the housing, or 3-D print locally? We have to be able to simulate field temperatures and humidity in the lab to make sure the devices are field-rugged. These are the types of questions we are discussing in the lab and in the field every week so that the technology helps people as soon as possible.

By Anne Trafton | MIT News Office

Koch Institute faculty member Sangeeta Bhatia has been selected as one of Foreign Policy magazine’s 100 Leading Global Thinkers of 2014 for her work in developing inexpensive and noninvasive diagnostics for the early detection of colon cancer.

The annual list identifies top minds with translational ideas in politics, business, technology, the arts, and the sciences that have the potential to impact millions around the world. This year’s list, published today, has a particular focus on disruptive ideas and technologies. The honorees were recognized today at an event in Washington, D.C., where U.S. Secretary of State John Kerry was the keynote speaker.

Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, was specifically recognized for her work in developing accessible diagnostics for colon cancer that would enable earlier detection.

If colon cancer is detected early, while cancer cells are confined to the colon or rectum, the five-year survival rate for patients is 90 percent. However, such early detection represents only 40 percent of diagnoses, hindered in large part by expensive and invasive tests, such as colonoscopies.

Bhatia and her lab recognized this critical gap and developed nanoparticles and a simple, inexpensive, paper-strip urine test that can reveal the presence of cancer within minutes. With this diagnostic, the researchers envision that patients would be injected with nanoparticles that amplify signals from tumor proteins, naturally occurring biomarkers that are not otherwise detectable due to their location and small numbers. When tumor proteins interact with the nanoparticles, hundreds of synthetic biomarkers are released and then excreted in the urine. Similar to a home pregnancy test, Bhatia’s paper-strip system can, in mouse models, reveal the presence of cancer in minutes.

This sort of point-of-care test could represent a significant advance in bringing cancer detection to developing nations and remote locations that lack extensive medical infrastructure. In countries where more advanced diagnostics are available, synthetic biomarkers could be beneficial as an inexpensive and noninvasive alternative to traditional diagnostics.

While Bhatia’s paper-strip diagnostic has thus far only been tested in mice, she is working to commercialize this technology to accelerate its delivery to patients. She and her team are also adapting the diagnostic for other medical applications, such as fibrosis, thrombosis, and prostate cancer.

Bhatia received the 2014 Lemelson-MIT Prize in recognition for her work in cancer detection and in liver-tissue engineering. She is also a Howard Hughes Medical Institute Investigator, a member of MIT’s Institute for Medical Engineering and Science, and a member of the Broad Institute of MIT and Harvard.

By Kevin Leonardi | Koch Institute