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Exploring the many roles of mucus

Posted: 02 Apr 2018 08:59 PM PDT

In 2007, Katharina Ribbeck spent a year as a visiting scientist at Harvard Medical School. While there, she heard about a fellowship offered at Harvard that would provide the recipient with a lab, startup funding, and status as an independent investigator. The catch? Applicants had to propose starting a new field of study.

Up to that point in her career, Ribbeck had been studying the nuclear pore — a channel that regulates communication between a cell's nucleus and the rest of the cell. However, she was intrigued by the idea of studying mucus, which lines an enormous surface area of our bodies and plays a key role in maintaining health, yet at that time was not well-studied.

"So, I made a case for mucus," recalls Ribbeck, now an associate professor of biological engineering at MIT. "I said we should study mucus because it's a really amazing barrier. It allows us to integrate nutrients, it protects us from pathogens, and it allows us to communicate with the outside world. It's also a major obstacle to drug delivery. But we have no idea how it works."

Ribbeck got the fellowship, and ever since, she has been studying a substance that may have a high ick factor for some, but in reality is one of the most important defenses our body has against infection. Mucus also performs many other critical physiological functions, and by learning more about it, Ribbeck hopes to devise new ways to both diagnose and treat human disease.

"There is a lot of information about our health in mucus," she says. "Our goal for the next couple of years is to tap into this underutilized source of bioinformation and use it."

Looking at the big picture

Although Ribbeck's parents were originally from Germany and Austria, she spent much of her early childhood in Guyana and Brazil, where her father worked as an urban planner. The family returned to Heidelberg, Germany, when Ribbeck was in elementary school.

As a student, she was interested in science but also spent much of her time in the library perusing art books. One of her favorites was E.H. Gombrich's "The Story of Art," which she says has heavily influenced how she does science — a process she describes as similar to creating an artistic composition.

"A single experiment is a small part of a bigger picture, and in doing science, you create a bigger picture that is coherent, well-balanced, striking but not misleading, that communicates the essence of what you discovered," she says.

At the University of Heidelberg, Ribbeck studied biology and biochemistry, and she spent her senior year at the University of California at San Diego working on her diploma thesis in neurobiology. In graduate school, also at the University of Heidelberg, she began studying the biology of the nuclear pore.

Mucus, she says, "was never on my radar in grad school," but like mucus, nuclear pores also act as barriers. These pores are highly selective channels that allow some particles to pass through, while blocking others. Many nuclear pore proteins behave like hydrogels that form sticky network structures, almost like a spider web. This structure is similar to that of mucins, the molecules that make up mucus.

"If you take a few steps back, you see the nuclear pore is by no means the only filter that uses these gels. There is a whole class of materials that is based on very similar principles, where you have polymers that create meshes through which certain particles can pass through or not. Cartilage is another example; the extracellular matrix around tissues is another example," Ribbeck says.

After finishing her PhD, Ribbeck planned to start a research group in Germany, continuing her studies of the nuclear pore. However, her plans changed when a friend at Harvard Medical School suggested that she spend a year working in his lab. The decision was not easy for Ribbeck, but as she says, "it's the things you don't do that you regret. So I decided to go there, anticipating an interesting but not really life-changing year."

It was during that year, however, that Ribbeck applied for and received Harvard's Bauer Fellowship to begin studying mucus. After about a year and a half, she realized that the field would benefit from the expertise and new tools being developed in MIT's Department of Biological Engineering — in tissue science and engineering, microfluidics, and other areas. She got in touch with the department head, Doug Lauffenburger, and ended up joining the MIT faculty in 2010.

Detecting disease

Among the questions Ribbeck has pursued is why mucus is so successful at "taming" microbes that are normally pathogenic. Part of the answer is that mucus can suppress certain functions in microbes so that they can't form pathogenic aggregates called biofilms, which tend to be more harmful than the cells are individually.

Another major focus of her lab is analyzing how the stickiness and other biophysical properties of mucus change during illness, which could help researchers discover biomarkers that could be used to diagnose many different diseases. Last year, she published a study showing that changes in cervical mucus of pregnant women can reveal their risk of going into labor too early.

Other medical conditions that alter mucus include digestive diseases such as Crohn's disease and ulcerative colitis, as well as respiratory diseases. The "holy grail" of this effort, she says, is to link changes in saliva composition with diseases that affect mucosal surfaces elsewhere in the body.

"If you have aberrant mucus production in your mouth, there is a chance that this is true for other parts of the body," Ribbeck says. "So, we might be able to pick up, from saliva, disease conditions of remote mucosal surfaces. That will be very exciting because of course that is noninvasive yet informative."

Ribbeck says that her research is a natural topic of interest for children, which she takes advantage of to get them excited about science. She gives talks at the MIT Museum and Boston Museum of Science about her work, and she is also working on a children's book starring a shape-shifting character made of mucus, highlighting the many roles that mucus plays in our bodies.

"The intention here is to really introduce a field to the generations to come, so they grow up understanding that mucus is not a waste product. It's an integral part of our physiology and a really important piece of our health," Ribbeck says. "If we understand it, it can really give us a lot of information that will help us stay healthy and possibly treat diseases."

Monitor detects dangerously low white blood cell levels

Posted: 02 Apr 2018 10:30 AM PDT

One of the major side effects of chemotherapy is a sharp drop in white blood cells, which leaves patients vulnerable to dangerous infections. MIT researchers have now developed a portable device that could be used to monitor patients' white blood cell levels at home, without taking blood samples.

Such a device could prevent thousands of infections every year among chemotherapy patients, the researchers say. Their tabletop prototype records video of blood cells flowing through capillaries just below the surface of the skin at the base of the fingernail. A computer algorithm can analyze the images to determine if white blood cell levels are below the threshold that doctors consider dangerous.

"Our vision is that patients will have this portable device that they can take home, and they can monitor daily how they are reacting to the treatment. If they go below the threshold, then preventive treatment can be deployed," says Carlos Castro-Gonzalez, a postdoc in MIT's Research Laboratory of Electronics (RLE) and the leader of the research team.

In a paper appearing in Scientific Reports, the researchers showed that the device could accurately determine whether white blood cell levels were too low, in a study of 11 patients undergoing chemotherapy.

The paper's first author is Aurélien Bourquard, an RLE postdoc. Other team members who developed the new technology include RLE research engineer Ian Butterworth, former MIT postdoc Alvaro Sanchez-Ferro, and Technical University of Madrid graduate student Alberto Pablo Trinidad.

The researchers' prototype device, at right, can image through the skin at the base of the fingernail to generate video of white blood cells flowing through capillaries (left).

Aurélien Bourquard, a member of the research team, watches white blood cells flow through capillaries located at the base of the fingernail.

Preventing infection

The researchers began this project nearly four years ago as part of the Madrid-MIT M+Vision Consortium, which is now part of MIT linQ. The program draws postdocs from around the world to try to solve problems facing doctors and hospitals. In this case, the research team visited the oncology department of a Madrid hospital and found that low white cell levels in patients were making them susceptible to life-threatening infections.

Chemotherapy patients usually receive a dose every 21 days. After each dose, their white blood cell levels fall and then gradually climb again. However, doctors usually only test patients' blood just before a new dose, so they have no way of knowing if white blood cell levels drop to dangerous levels following a treatment.

"In the U.S., one in six chemotherapy patients ends up hospitalized with one of these infections while their white cells are particularly low," Castro-Gonzalez says. Those infections lead to long, expensive hospital stays and are fatal in about 7 percent of cases. The patients also have to miss their next chemotherapy dose, which sets back their cancer treatment.  

The MIT team estimated that if there were a way to detect when patients' white cell counts went below the threshold level, so they could be treated with prophylactic antibiotics and drugs that promote white blood cell growth, about half of the 110,000 infections that occur in chemotherapy patients in the United States every year could be prevented.

The technology the researchers used to tackle this problem consists of a wide-field microscope that emits blue light, which penetrates about 50 to 150 microns below the skin and is reflected back to a video camera. The researchers decided to image the skin at the base of the nail, known as the nailfold, because the capillaries there are located very close to the surface of the skin. These capillaries are so narrow that white blood cells must squeeze through one at a time, making them easier to see.

The technology does not provide a precise count of white blood cells, but reveals whether patients are above or below the threshold considered dangerous — defined as 500 neutrophils (the most common type of white blood cell) per microliter of blood.

Threshold detection

In the Scientific Reports study, the researchers tested the device in 11 patients at Massachusetts General Hospital and University Hospital La Paz in Madrid, at various points during their chemotherapy treatment. The approach proved 95 percent accurate for determining whether a patient's white cell levels were above or below the threshold.

To obtain enough data to make these classifications, the researchers recorded one minute of video per patient. Three blinded human assistants then watched the videos and noted whenever a white blood cell passed by. However, since submitting their paper, the researchers have been developing a computer algorithm to perform the same task automatically.

"Based on the feature-set that our human raters identified, we are now developing an AI and machine-vision algorithm, with preliminary results that indicate the same accuracy as the raters," Bourquard says.

The research team has applied for patents on the technology and has launched a company called Leuko, which is working on commercializing the technology with help from the MIT Innovation Initiative, the MIT Deshpande Center for Technological Innovation, the MIT Sandbox Innovation Fund, the Martin Trust Center for Entrepreneurship, the MIT Translational Fellows Program, and the MIT Venture Mentoring Service.

To help move the technology further toward commercialization, the researchers are building a new automated prototype. "Automating the measurement process is key to making a viable home-use device," Butterworth says. "The imaging needs to take place in the right spot on the patient's finger, and the operation of the device must be straightforward."

Using this new prototype, the researchers plan to test the device with additional cancer patients. They are also investigating whether they can get accurate results with shorter lengths of video.

They also plan to adapt the technology so that it can generate more precise white blood cell counts, which would make it useful for monitoring bone marrow transplant recipients or people with certain infectious diseases, Castro-Gonzalez says. This could also make it possible to determine whether chemotherapy patients can receive their next dose before 21 days have passed.

"There is a balancing act that oncologists must do," says Sanchez-Ferro. "Normally doctors want to make chemotherapy as intensive as possible but without getting people too immunosuppressed. Current 21-day cycles are based on statistics of what most patients can take, but if you are ready early, then they can potentially bring you back early and that can translate into better survival."

The research was funded by the NIH's Center for Future Technologies in Cancer Care, MIT's Deshpande Center, the Wallace H. Coulter Foundation at BU, the Madrid-MIT M+Vision Consortium, the EU FP7-PEOPLE-2011-COFUND Program, Fundación Ramón Areces, the MIT Undergraduate Research Opportunities Program (UROP), and the MIT Sandbox Innovation Fund.

Innovation fosters inclusive teaching at MIT

Posted: 02 Apr 2018 06:00 AM PDT

"What are we doing to enable every student at MIT to make the most of the opportunities that are here for them?" Vice Chancellor Ian A. Waitz posed this question at the start of the March 9 MacVicar Day symposium, which was titled "Inclusive Pedagogies: Building a Vibrant Community of Learners at MIT."

The MacVicar Faculty Fellows Program, which recognizes exceptional undergraduate teaching, was established in honor of Margaret MacVicar. MacVicar was, among many things, the first dean for undergraduate education, the founder of the Undergraduate Research Opportunities Program (UROP), and a crusader for diversity and inclusiveness at MIT.

This year's fellows are David Autor, the Ford Professor of Economics and associate head of the department; Christopher Capozzola, an associate professor of history; Shankar Raman, a professor of literature; and Merritt Roe Smith, the Leverett and William Cutten Professor of the History of Technology in the Department of History and the Program in Science, Technology, and Society (STS).

After introducing the 2018 fellows, Waitz noted several ways in which MIT has responded to calls for more inclusivity, including implicit bias training, increases to financial aid, and the creation of the special subjects MIT and Slavery and Designing the First Year at MIT. But, citing recent student survey responses, he acknowledged that there was still much to do. He hoped that the symposium would give the audience the opportunity to learn from instructors who have made considerable progress in these efforts.

The term "inclusive pedagogies" refers to classroom practices and teaching strategies that include, engage, and support all students. As the afternoon's presenters demonstrated, approaches to inclusive teaching can vary greatly, and the path to change is often unexpected and surprising.

The (stereotype) threat is real

The first speaker was Catherine Drennan, a professor of chemistry and biology and a professor and investigator with the Howard Hughes Medical Institute. She is also a 2015 MacVicar fellow.

Drennan recounted how several years ago she was asked to speak with underrepresented minority students majoring in chemistry, and was alarmed to find that there were only two. After meeting with one of the students, she learned that he was discouraged because he did not see anyone in the field who looked like him and did not feel that his teaching assistants believed in him.

Drennan recognized that the student was experiencing stereotype threat, the perceived danger of confirming a negative generalization about a racial, ethnic, gender, or cultural group. Worrying about being stereotyped can lead to feelings of being judged unfairly and can hurt students' performance, perpetuating the problem.

"I really like doing research in education," Drennan reflected. "I always learn something I'm not expecting when I ask questions."

Knowing that something had to change, she created a series of videos, which highlighted the diverse backgrounds of those in the field of chemistry, and a booklet, detailing stereotype threat and ways to counteract it. After implementing these materials in department-wide teaching assistant (TA) training, she began to host weekly "clicker competitions" in her 5.111 (Principles of Chemical Science) classes. Recitation groups, led by their TAs, faced off against each other to see who could answer the most questions correctly.

The competitions, which have been replicated at the University of California at Irvine, with similar results, allowed the TAs and students to bond. The TAs became more comfortable teaching and supporting their students, who in turn experienced a greater sense of belonging.

Active learning as inclusive learning

Katrina LaCurts, a lecturer in the electrical engineering and computer science department, presented the results of her attempt to make class participation more equitable and effective in 6.033 (Computer System Engineering).

6.033 is a communication-intensive within the major (CI-M) subject, and as such focuses heavily on writing and oral presentation. Each recitation is based on a different technical paper, which students are expected to read and be ready to discuss in class. In the past, discussions would often be dominated by just a few students, or students would arrive to class unprepared and disengaged.

Hoping that a more intimate environment would lead to more participation, LaCurts encouraged her recitation instructors to incorporate small group techniques into their classes. But she quickly discovered that there was a big difference between suggesting active learning and understanding what that entailed. She found, like Drennan had in 5.111, that change would come only when instructors were sufficiently trained.

After explaining the benefits of an active learning approach, LaCurts conducted training and worked with her instructors to apply it. When compared to prior offerings of the subject, from what LaCurts and her staff jokingly call "the dark times," students are more engaged and have a greater sense of camaraderie with their classmates. Furthermore, instructors have found that students exhibit less anxiety and a more thorough understanding of the material. Lessons are more effective and enjoyable for all involved.

Finding a home in education

Education subjects "recognize [students'] diverse set of interests and finds [a] home for them," said Eric Klopfer, a professor in and the director of the Scheller Teacher Education Program (STEP).

There is an overrepresentation of women and underrepresented minorities in the introductory education subjects. According to Klopfer, many students were motivated to take the class because of their personal experience as part of a group that "wasn't expected to succeed in math and science." Their success in STEM has compelled them to give back.

Students learn about inclusive pedagogies by implementing them at the K-12 level, designing games, teaching lessons, and making presentations. This practice of working in schools gives them firsthand experience of being both teacher and student. They observe not only the diverse backgrounds of the students themselves, but also the diversity of the ways in which students learn.

With this diversity in mind, Meredith Thompson, a research scientist at the Teaching Systems Lab (TSL) and STEP, presented Swipe Right for CS. The game, which is being developed as part of a UROP, allows teachers to practice connecting students' strengths and interests to computer science. Some rationales don't fit, Thompson explained, and feeling and understanding that students' motivations for learning vary is of enormous import to aspiring teachers.

Inquiry-based learning

Christine Ortiz, the former dean for graduate education and the current Morris Cohen Professor of Materials Science and Engineering, was the afternoon's final speaker.

In a new special subject, 3.S03 (Materials, Societal Impact and Social Innovation), Ortiz and her students explored what could happen if inclusion was incorporated into every step of the learning process. Ortiz cited the lack of inclusionary perspective in pedagogy as one of the causes for disparity in STEM fields.

In response to this inequality, the class examined two bodies of literature — course-based undergraduate research and scholarly work in equity. When considered together, these areas of study could inform one another and lead to new, innovative approaches in inquiry-based learning.

After students were equipped with a foundation of inclusive principles to internalize and use in their work, they completed a research project. Each step of the process was intentional, with careful consideration given to how to include ideas of equity. Ortiz provided continuous feedback to her students, making revision an iterative and edifying process. One of the completed projects looked at sustainability as a form of social justice, with students designing a process to recycle 3-D-printed materials. This class, Ortiz concluded, "was really a joy to teach."

In closing, Vice Chancellor Waitz expressed his appreciation for all of the presenters and their thoughtful efforts. "Thank you for trying new things. It's wonderful to see the impacts of this work."