The MIT Media Lab this week launched a wellness initiative designed to spark innovation in the area of health and wellbeing, and to promote healthier workplace and lifestyle behaviors.  

With support from the Robert Wood Johnson Foundation (RWJF), which is providing a $1 million grant, the new initiative will address the role of technology in shaping our health, and explore new approaches and solutions to wellbeing. The program is built around education and student mentoring; prototyping tools and technologies that support physical, mental, social, and emotional wellbeing; and community initiatives that will originate at the Media Lab, but be designed to scale.

The program begins with the fall course “Tools for Well Being,” followed by “Health Change Lab” in the spring. In addition to concept and technology development, these courses will feature seminars by noted experts who will address a wide range of topics related to wellness. These talks will be open to the public, and made available online. Speakers will include Walter Willett, a physician and noted nutrition researcher; Chuck Czeisler, a physician and sleep expert; Ben Sawyer, a game developer for health applications; Matthew Nock, an expert in suicide prevention; Dinesh John, a researcher on health sciences and workplace activity; Lisa Mosconi, a neuroscientist studying the prevention of Alzheimer’s disease; and Martin Seligman, a founder of the field of positive psychology. More information about the courses, speakers, and presentation topics and dates can be found at: http://wellbeing.media.mit.edu.

The RWJF grant will also support five graduate-level research fellows from the Program in Media Arts and Sciences who will be part of a year-long training program. The funding will enable each fellow to design, build, and deploy novel tools to promote wellbeing and health behavior change at the Media Lab, and then at scale.

One of the significant ways that this program will impact Media Lab culture is in the review of all thesis proposals submitted by students in media arts and sciences. Media Lab faculty recently added a new requirement that all proposals consider the impact of the work on human wellbeing.

Other Media Lab-wide aspects of the initiative include:

  • A monthly health challenge that would engage the entire lab, with review and analysis of each month’s deployment to help inform the next month’s initiative.
  • Pairing students with one another — to build awareness of wellbeing as a social function, not just a perosonal goal, and to draw on people’s inclination to solve the problems of others differently than their own.

“Wellbeing is a very hard problem that has yet to be solved by psychologists, psychiatrists, neuroscientists, biologists or other experts in the scientific community,” says Rosalind Picard, a professor of media arts and sciences and one of the three principal investigators on the initiative. “It’s time to bring MIT ingenuity to the challenge.”

“RWJF is working to build a culture of health in the U.S. where all people have opportunities to make healthy choices and lead healthy lifestyles. Technology has long shaped the patterns of everyday life, and it is these patterns­ — of how we work, eat, sleep, socialize, recreate and get from place to place — that largely determine our health,” says Stephen Downs, chief technology and information officer at RWJF. “We’re excited to see the Media Lab turn its creative talents and its significant influence to the challenge of developing technologies that will make these patterns of everyday life more healthy.”

Along with Picard, the other two principal investigators on the Advancing Wellness initiative are Pattie Maes, the Alex W. Dreyfoos Professor of Media Arts and Sciences, and Kevin Slavin, an assistant professor of media arts and sciences.

PhD student Karthik Dinakar, a Reid Hoffman Fellow at the Media Lab, will co-teach the two courses with the three principal investigators. Susan Silbey, the Leon and Anne Goldberg Professor of Humanities, Sociology and Anthropology, will also create independent assessments through the year on the impact of this project.

By Alexandra Kahn | MIT Media Lab

A new technique for studying the lifecycle of the hepatitis B virus could help researchers develop a cure for the disease.

In a paper published today in the journal Proceedings of the National Academy of Sciences, Sangeeta Bhatia of MIT and Charles Rice of Rockefeller University describe using microfabricated cell cultures to sustain hepatitis B virus in human liver cells, allowing them to study immune responses and drug treatments.

Around 400 million people worldwide are infected with the hepatitis B virus (HBV); of those, one-third will go on to develop life-threatening complications, such as cirrhosis and liver cancer.

Although there is an effective HBV vaccine, only around 50 percent of people in some countries where the disease is endemic are vaccinated. A complete cure for the disease is very rare, once someone has been chronically infected.

“Once a liver cell is infected, the viral genome persists inside the nucleus, and that can reactivate later,” says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science. “So although we have a vaccine, it’s important to find a way to study this persistent form of the virus to try to identify treatments that could efficiently clear it.”

“Finicky” hepatocytes

To develop a treatment for HBV, researchers need to be able to study infected liver cells, known as hepatocytes, so they can understand how the virus interacts with them.

But while researchers have previously been able to infect cultures of human hepatocytes with HBV, the cells’ limited lifespan has made it difficult to study the virus, says Bhatia, who is also a Howard Hughes Medical Institute investigator and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

“That’s because the hepatocyte — the main cell in the liver — is unstable,” she says. “It’s a very finicky cell, and when you isolate it from the liver and try to culture it under conventional conditions, it rapidly loses its repertoire of liver functions.”

So the team set out to develop a technique to keep the liver cells stable and functioning long enough to monitor their response to the virus and antiviral drugs.

They based their approach on a system they had previously developed for studying the hepatitis C virus, in which they were able to successfully infect human hepatocytes with the virus and use it to compare antiviral regimens.

The hepatocytes are first patterned onto surfaces dotted with tiny spots of collagen, and then surrounded by supportive tissue made up of stromal cells, which act as connective tissue and support the hepatocytes in carrying out their liver functions.

Two complementary systems

To apply the technique to infection with HBV, the researchers developed two complementary systems. One uses primary hepatocytes obtained from livers donated for transplant; the second uses stem cells derived from human skin samples and guided into hepatocyte-like cells, Bhatia says.

When they compared the relative merits of the two systems, they found that the primary liver cells had a stronger immune response when infected with the virus than the stem cell progeny. However, unlike the primary hepatocytes, the hepatocyte-like cells offer an unlimited supply of test cells, since the researchers can simply grow more as required, Bhatia says.

“But that being said, both systems were able to grow this persistent nuclear form [of HBV], so we think they offer complementary tools,” she says.

The paper’s lead authors are Amir Shlomai of Rockefeller University, and graduate student Vyas Ramanan and former postdoc Robert E. Schwartz, both of MIT.

To investigate whether the cell cultures could be used to test new treatments for the disease, the researchers monitored their response to two existing drugs. They found that the infected cultures responded to the drugs in the same way that liver cells inside the body are known to do. This means the systems could be used to help predict how effective new treatments will be in eradicating the virus from liver cells, Bhatia says.

Having developed the technique, the researchers now plan to begin using it to investigate new treatments for HBV. They also plan to use the model to study liver cells’ natural antiviral response in more detail, and in particular to try to understand why cells from different donors have different immune responses to the disease.

Raymond Chung, vice chief of the gastrointestinal unit at Massachusetts General Hospital, who was not involved in the research, says that despite the availability of effective vaccines, researchers have made few inroads into eliminating HBV. “While we have excellent suppressive therapies, there are no truly curative treatments, in large measure because we have been handicapped by the lack of robust cell-culture models that support HBV infection,” he says.

“The new approach described here provides one avenue by which we may more effectively study the HBV lifecycle, and in so doing identify new agents that block additional steps in that lifecycle,” he adds. “Using such an approach could bring us one step closer to a cure for HBV.”

By Helen Knight | MIT News correspondent

Seven MIT faculty members are among 204 leaders from academia, business, public affairs, the humanities and the arts elected to the American Academy of Arts and Sciences, the academy announced today.

One of the nation’s most prestigious honorary societies, the academy is also a leading center for independent policy research. Members contribute to academy publications, as well as studies of science and technology policy, energy and global security, social policy and American institutions, the humanities and culture, and education.

Those elected from MIT this year are:

  • Elazer Reuven Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology
  • Michael Greenstone, the 3M Professor of Environmental Economics
  • Keith Adam Nelson, a professor of chemistry
  • Paul A. Seidel, a professor of mathematics
  • Gigliola Staffilani, the Abby Rockefeller Mauzé Professor of Mathematics
  • Sherry Roxanne Turkle, the Abby Rockefeller Mauzé Professor of the Social Studies of Science and Technology
  • Robert Dirk van der Hilst, the Schlumberger Professor of Earth Sciences and head of the Department of Earth, Atmospheric and Planetary Sciences

“It is a privilege to honor these men and women for their extraordinary individual accomplishments,” Don Randel, chair of the academy’s Board of Directors, said in a statement. “The knowledge and expertise of our members give the Academy a unique capacity — and responsibility — to provide practical policy solutions to the pressing challenges of the day. We look forward to engaging our new members in this work.”

The new class will be inducted at a ceremony held on Oct. 11 at the academy’s headquarters in Cambridge.

Since its founding in 1780, the academy has elected leading “thinkers and doers” from each generation, including George Washington and Benjamin Franklin in the 18th century, Daniel Webster and Ralph Waldo Emerson in the 19th century, and Albert Einstein and Winston Churchill in the 20th century. The current membership includes more than 250 Nobel laureates and more than 60 Pulitzer Prize winners.

By News Office

The following notice was sent Thursday afternoon to individuals at MIT and Harvard Medical School by representatives of the joint Harvard-MIT Health Sciences and Technology (HST) program. Eliana Hechter was a student in HST who had been working toward an M.D. degree from Harvard.

To the Harvard Medical School, MIT, and HST Communities:

It is with great sadness that we report the untimely death of Dr. Eliana Hechter, a first-year MD student in HST. Her family notified the medical school this morning, and have not yet made definitive plans regarding services or a memorial. As information becomes available, we will share it with you. We encourage students, administration, and faculty to come together as a community to remember Eliana as a student with tremendous promise, and one who has been lost far too soon.

Losing a member of our community is always difficult and we want to remind you that there are resources here to help you with grief or stress (please see below).

David Cohen, Emery Brown, Matthew Frosch, Patty Cunningham, and Rick Mitchell

— on behalf of HST

MIT Medical’s Mental Health and Counseling Service

E23 — 3rd Floor

On weekdays: call 617-253-2916 to schedule an appointment

For more urgent issues, visit them during walk-in hours on weekday afternoons from 2–4 p.m.

For very urgent issues, call one of the numbers below; a mental health clinician is on call and available 24 hours a day, seven days a week:

Weekdays (M-Th 8 a.m.–7 p.m., F 8 a.m.–5 p.m.): 617-253-2916

Nights/weekends: 617-253-4481

Chaplains at MIT

Contact information for individual Chaplains is available online here:

http://studentlife.mit.edu/rl/mit-chaplains

MIT’s Office of the Dean for Graduate Education (ODGE)

3-132

The office provides two pamphlets, “How to help someone in distress” and the MIT Medical brochure “Caring for our community.”

See also: http://web.mit.edu/student/personal_support.html

By News Office

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

A paper diagnostic for cancer

September 19, 2014

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

Solving chromosomes’ structure

September 19, 2014

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