Author: mantulin

Biologists discover how pancreatic tumors lead to weight loss

Shortfall of digestive enzymes can lead to tissue breakdown in early stages of pancreatic cancer.

Anne Trafton | MIT News Office
June 20, 2018

Patients with pancreatic cancer usually experience significant weight loss, which can begin very early in the disease. A new study from MIT and Dana-Farber Cancer Institute offers insight into how this happens, and suggests that the weight loss may not necessarily affect patients’ survival.

In a study of mice, the researchers found that weight loss occurs due to a reduction in key pancreatic enzymes that normally help digest food. When the researchers treated these mice with replacement enzymes, they were surprised to find that while the mice did regain weight, they did not survive any longer than untreated mice.

Pancreatic cancer patients are sometimes given replacement enzymes to help them gain weight, but the new findings suggest that more study is needed to determine whether that actually benefits patients, says Matt Vander Heiden, an associate professor of biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

“We have to be very careful not to draw medical advice from a mouse study and apply it to humans,” Vander Heiden says. “The study does raise the question of whether enzyme replacement is good or bad for patients, which needs to be studied in a clinical trial.”

Vander Heiden and Brian Wolpin, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, are the senior authors of the study, which appears in the June 20 issue of Nature. The paper’s lead authors are Laura Danai, a former MIT postdoc, and Ana Babic, an instructor in medicine at Dana-Farber.

Starvation mode

In a 2014 study, Vander Heiden and his colleagues found that muscle starts breaking down very early in pancreatic cancer patients, usually long before any other signs of the disease appear.

Still unknown was how this tissue wasting process occurs. One hypothesis was that pancreatic tumors overproduce some kind of signaling factor, such as a hormone, that circulates in the bloodstream and promotes breakdown of muscle and fat.

However, in their new study, the MIT and Dana-Farber researchers found that this was not the case. Instead, they discovered that even very tiny, early-stage pancreatic tumors can impair the production of key digestive enzymes. Mice with these early-stage tumors lost weight even though they ate the same amount of food as normal mice. These mice were unable to digest all of their food, so they went into a starvation mode where the body begins to break down other tissues, especially fat.

The researchers found that when they implanted pancreatic tumor cells elsewhere in the body, this weight loss did not occur. That suggests the tumor cells are not secreting a weight-loss factor that circulates in the bloodstream; instead, they only stimulate tissue wasting when they are in the pancreas.

The researchers then explored whether reversing this weight loss would improve survival. Treating the mice with pancreatic enzymes did reverse the weight loss. However, these mice actually survived for a shorter period of time than mice that had pancreatic tumors but did not receive the enzymes. That finding, while surprising, is consistent with studies in mice that have shown that calorie restriction can have a protective effect against cancer and other diseases.

“It turns out that this mechanism of tissue wasting is actually protective, at least for the mice, in the same way that limiting calories can be protective for mice,” Vander Heiden says.

Human connection

The intriguing findings from the mouse study prompted the research team to see if they could find any connection between weight loss and survival in human patients. In an analysis of medical records and blood samples from 782 patients, they found no link between degree of tissue wasting at the time of diagnosis and length of survival. That finding is important because it could reassure patients that weight loss does not necessarily mean that the patient will do worse, Vander Heiden says.

“Sometimes you can’t do anything about this weight loss, and this finding may mean that just because the patient is eating less and is losing weight, that doesn’t necessarily mean that they’re shortening their life,” he says.

The researchers say that more study is needed to determine if the same mechanism they discovered in mice is also occurring in human cancer patients. Because the mechanism they found is very specific to pancreatic tumors, it may differ from the underlying causes behind tissue wasting seen in other types of cancer and diseases such as HIV.

“From a mechanistic standpoint, this study reveals a very different way to think about what could be causing at least some weight loss in pancreatic cancer, suggesting that not all weight loss is the same across different cancers,” Vander Heiden says. “And it raises questions that we really need to study more, because some mechanisms may be protective and some mechanisms may be bad for you.”

Clary Clish, director of the Metabolomics Platform at the Broad Institute, and members of his research group also contributed to this work. The research was funded, in part, by the Lustgarten Foundation, a National Institutes of Health Ruth Kirschstein Fellowship, Stand Up 2 Cancer, the Ludwig Center for Molecular Oncology at MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the MIT Center for Precision Cancer Medicine, and the National Institutes of Health.

Ankur Jain joins Whitehead Institute and the Department of Biology

Biophysicist will investigate the biology of RNA aggregation.

Merrill Meadow | Whitehead Institute
June 11, 2018

Biophysicist Ankur Jain will join the Whitehead Institute as its newest member this coming September. Jain will also be appointed an assistant professor in the MIT Department of Biology. In his research, he will use a combination of innovative approaches to investigate the biology of RNA aggregation.

While it is understood that protein aggregation is a key factor in certain neurological diseases, relatively little is known about RNA aggregation, its underlying biology, and the role it plays in disease. A class of neurological disorders called repeat expansion diseases, which includes amyotrophic lateral sclerosis (ALS) and fragile X syndrome, are marked by stretches of DNA nucleotide repeats in their cognate disease gene. The presence of repeats is associated with clumps of RNA aggregates and RNA binding proteins that undergo phase transition to form an “RNA gel” in the nucleus. At the Whitehead Institute, Jain will continue his investigation into the properties of these RNA aggregates in order to learn how they form, what properties they possess, and how they could be disrupted to restore normal cellular processes. Jain will use nuclear speckles — areas in the nucleus associated with pre-mRNA splicing — as a model for physiological RNA-protein granules.

His lab will also investigate the role of RNA-DNA interactions in chromatin organization — the complex, dynamic structure of DNA and proteins in the nucleus. There are instances of nucleotide repeats in our genome that occur even in the absence of repeat expansion disease genes. Repetitive DNA sequences at the end of our chromosomes interact with proteins to form our telomeres, structures critical for chromosome maintenance. Jain will study the RNA transcribed from the telomeric sequences in order to understand their structure and if they undergo phase separation similar to the one seen in repeat expansion diseases. In addition, Jain will build on his specialized expertise in quantitative light microscopy to drive development of new imaging-based technologies.

“Ankur brings an approach grounded in a combination of soft-matter physics and cell biology to help pioneer an important — potentially ground-breaking — way of investigating and understanding RNA aggregation and RNA-DNA interaction,” says David C. Page, Whitehead Institute director and member. “His insights are exciting, and the intellectual and scientific creativity he brings to his research is energizing.”

Jain is currently completing a postdoc with Ronald Vale at University of California at San Francisco. He earned a PhD in biophysics and computational biology from the University of Illinois at Urbana-Champaign in 2013, and a bachelor’s degree (with honors) in biotechnology and biochemical engineering from Indian Institute of Technology Kharagpur in 2007. He holds a National Institutes of Health Pathway to Independence Award (also known as a K99 Award), and has been a lead author on peer-reviewed studies in the journals Nature and Proceedings of the National Academy of Sciences.

“Understanding the biology of RNA aggregation and phase separation has the potential to crack open long-time mysteries in cell biology,” Jain explains. “I am grateful for the chance to pursue my investigations in the intellectually rich and scientifically fruitful environment that Whitehead Institute and MIT have to offer.”

Network of diverse noncoding RNAs acts in the brain

Scientists identify the first known network consisting of three types of regulatory RNAs.

Nicole Giese Rura | Whitehead Institute
June 7, 2018

Scientists at MIT’s Whitehead Institute have identified a highly conserved network of noncoding RNAs acting in the mammalian brain. While gene regulatory networks are well described, this is the first documented regulatory network comprised of three types of noncoding RNA: microRNA, long noncoding RNA, and circular RNA. The finding, which is described online this week in the journal Cell, expands our understanding of how several noncoding RNAs can interact to regulate each other.

This sophisticated network, which is conserved in placental mammals, intrigued Whitehead Member David Bartel, whose lab identified it.

“It has been quite an adventure to unravel the different elements of this network,” says Bartel, who is also a professor of biology at MIT and investigator with the Howard Hughes Medical Institute. “When we removed the long noncoding RNA, we saw huge increases in the microRNA, which, with the help of a second microRNA turned out to reduce the levels of the circular RNA.”

RNA may be best known for acting as a template during protein production, but most RNA molecules in the cell do not actually code for proteins. Many play fundamental roles in the splicing and translation of protein-coding RNAs, whereas others play regulatory roles. MicroRNAs, as the name would suggest, are small, about 22 nucleotides (nucleotides are the building blocks of RNA); long noncoding RNAs (lncRNAs) are longer than 200 nucleotides; and circular RNAs (circRNAs) are looped RNAs formed by atypical splicing of either lncRNAs or protein-coding RNAs. These three types of noncoding RNAs have been shown previously to be vital for controlling protein-coding gene expression, and in some instances their dysregulation is linked to cancer or other diseases.

Previous work by Bartel and Whitehead member and MIT Professor Hazel Sive identified hundreds of lncRNAs conserved in vertebrate animals, including Cyrano, which contains an unusual binding site for the microRNA miR-7.

In the current research, Ben Kleaveland, a postdoc in Bartel’s lab and first author of the Cell paper, delves into Cyrano’s function in mice. His results are surprising: a regulatory network centered on four noncoding RNAs — a lncRNA, a circRNA, and two microRNAs — acting in mammalian neurons. The network employs multiple interactions between these noncoding RNAs to ultimately ensure that the levels of one microRNA, miR-7, are kept extremely low and the levels of one circRNA, Cdr1as, are kept high.

Several aspects of this highly tuned network are unique. The lncRNA Cyrano targets miR-7 for degradation. Cyrano is exceptionally efficient, and in some cells, reduces miR-7 by an astounding 98 percent — a stronger effect than scientists have ever documented for this phenomenon, called target RNA-directed microRNA degradation. In the described network, unchecked miR-7 indirectly leads to degradation of the circRNA Cdr1as. CircRNAs such as this one are usually highly stable because the RNA degradation machinery needs to latch onto the end of an RNA molecule before the machinery can operate. In the case of Cdr1as, the circRNA contains a prodigious number of sites that can interact with miR-7: 130 in mice and 73 in humans. As these sites are bound by miR-7, another microRNA, miR-671, springs into action and directs slicing of the Cdr1as. This renders Cdr1as vulnerable to degradation.

The network’s precise function still eludes researchers, but evidence suggests that it may be important in brain function. All four components of the network are enriched in the brain, particularly in neurons, and recently, Cdr1as has been reported to influence neuronal activity in mice.

“We’re in the early stages of understanding this network, and there’s so much left to discover,” Kleaveland says. “Our current hypothesis is that Cdr1as is not only regulated by miR-7 but also facilitates miR-7 function by delivering this microRNA to neuronal synapses.”

This work was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

Meet the School of Science’s tenured professors for 2018

Six faculty members are granted tenure in four departments.

Bendta Schroeder | School of Science
June 4, 2018

The School of Science has announced that six members of its faculty have been granted tenure by MIT.

This year’s newly tenured associate professors are:

Daniel Cziczo studies the interrelationship of atmospheric aerosol particles and cloud formation and its impact on the Earth’s climate system. Airborne particles can impact climate directly by absorbing or scattering solar and terrestrial radiation and indirectly by acting as the seeds on which cloud droplets and ice crystals form. Cziczo’s experiments include using small cloud chambers in the laboratory to mimic atmospheric conditions that lead to cloud formation and observing clouds in situ from remote mountaintop sites or through the use of research aircraft.

Cziczo earned a BS in aerospace engineering from the University of Illinois at Urbana-Champaign in 1992, and afterwards spent two years at the NASA Jet Propulsion Laboratory performing spacecraft navigation. Cziczo earned a PhD in geophysical sciences in 1999 from the University of Chicago under the direction of John Abbatt. Following research appointments at the Swiss Federal Institute of Technology and then the Pacific Northwest National Laboratory, where he directed the Atmospheric Measurement Laboratory, Cziczo joined the MIT faculty in the Department of Earth, Atmospheric and Planetary Sciences in 2011.

Matthew Evans focuses on gravitational wave detector instrument science, aiming to improve the sensitivity of existing detectors and designing future detectors. In addition to his work on the Advanced the Laser Interferometer Gravitational-Wave Observatory (LIGO) detectors, Evans explores the physical processes that set fundamental limits on the sensitivity of future gravitational wave detectors. Of particular interest are the quantum and thermal limitations which have the strongest impact on ground-based detectors like LIGO and also play a role in the related fields of ultra-stable frequency references and macroscopic quantum measurement.

Evans received a BS in physics from Harvey Mudd College in 1996 and a PhD from Caltech in 2002. After postdoctoral work on LIGO at Caltech, Evans moved to the European Gravitational Observatory to work on the Virgo project. In 2007, he took a research scientist position at MIT working on the Advanced LIGO project, where he helped design and build its interferometer. He joined the MIT faculty in the Department of Physics in 2013.

Anna Frebel studies the chemical and physical conditions of the early universe, and how the oldest, still-surviving stars can be used to obtain constraints on the nature of the very first stars and early supernova explosions, and associated stellar element nucleosynthesis. She is best known for her discoveries and subsequent spectroscopic analyses of 13 billion-year-old stars in the Milky Way and ancient faint stars in the least luminous dwarf galaxies, to uncover unique information about the physical and chemical conditions of the early Universe. With this work, she has been able to obtain a more comprehensive view of the formation of our Milky Way Galaxy with its extended stellar halo because the formation history of each galaxy is imprinted in the chemical signatures of its stars. To extract this information, Frebel is also involved in a large supercomputing project that simulates the formation and evolution of large galaxies like the Milky Way.

Frebel received her PhD from the Australian National University in 2007. After a W. J. McDonald Postdoctoral Fellowship at the University of Texas at Austin, she completed a Clay Postdoctoral Fellowship at the Harvard-Smithsonian Center for Astrophysics in 2009. Frebel joined the MIT faculty in the Department of Physics in 2012.

Aram Harrow works to understand the capabilities of the quantum computers and quantum communication devices and in the process creates connections to other areas of theoretical physics, mathematics, and computer science. As a graduate student, Harrow developed the idea of “coherent classical communication,” which along with his work on the resource inequality method, has greatly simplified the understanding of quantum information theory. Harrow has also produced foundational work on the role of representation theory in quantum algorithms and quantum information theory. In 2008, Harrow, Hassidim, and Lloyd developed a quantum algorithm for solving linear systems of equations that provides a rare example of an exponential quantum speedup for a practical problem. Recently Harrow has been investigating properties of entanglement, such as approximate “superselection” and “monogamy” principles with the goal of better understanding not only entanglement and its uses, but also the related areas of quantum communication, many-body physics, and convex optimization.

Harrow received his undergraduate degree in 2001 and his PhD in 2005 from MIT. After his PhD, he spent five years as a lecturer at the University of Bristol and then two years as a research assistant professor at the University of Washington. Harrow returned to MIT to join the faculty in the Department of Physics in 2013.

Adam Martin studies how cells and tissues change shape during embryonic development, giving rise to organs with distinct shapes and structure. He has developed a system to visualize and quantify the movement of molecules, cells, and tissues during tissue folding in the fruit fly early embryo, where cells and motor proteins within these cells can be readily imaged by confocal microscopy on the time scale of seconds. Tissue folding in the fruit fly involves conserved genes that also function to form the mammalian neural tube, which gives rise to the mammalian brain and spinal cord. Martin combines live imaging with genetic, cell biological, computational, and biophysical approaches to dissect the molecular and cellular mechanisms that sculpt tissues. In addition, the lab examines how tissues grow and are remodeled during development, investigating processes such as cell division and the epithelial-mesenchymal transition.

After Martin received a BS in biology from Cornell University in 2000, he completed his PhD in molecular and cell biology under the direction of David Drubin and Matthew Welch at the University of California at Berkeley in 2006. After a postdoctoral fellowship at Princeton University in the laboratory of Eric Weischaus, Martin joined the MIT faculty in the Department of Biology in 2011.

Kay Tye dissects the synaptic and cellular mechanisms in emotion and reward processing with the goal of understanding how they underpin addiction-related behaviors and frequently co-morbid disease states such as attention-deficit disorder, anxiety, and depression. Using an integrative approach including optogenetics, pharmacology, and both in vivo and ex vivo electrophysiology, she explores such problems as how neural circuits differently encode positive and negative cues from the environment; if and how perturbations in neural circuits mediating reward processing, fear, motivation, memory, and inhibitory control underlie the co-morbidity of substance abuse, attention-deficit disorder, anxiety, and depression; and how emotional states such as increased anxiety might increase the propensity for substance abuse by facilitating long-term changes associated with reward-related learning.

Tye received her BS in brain and cognitive sciences from MIT in 2003 and earned her PhD in 2008 at the University of California at San Francisco under the direction of Patricia Janak. After she completed her postdoctoral training with Karl Deisseroth at Stanford University in 2011, she returned to the MIT Department of Brain and Cognitive Sciences as a faculty member in 2012.

Gerald Fink wins faculty’s Killian Award

Biologist honored for his work developing yeast as a model organism for genetic studies.

Anne Trafton | MIT News Office
May 16, 2018

Gerald Fink, an MIT biologist and former director of the Whitehead Institute, has been named the recipient of the 2018-2019 James R. Killian Jr. Faculty Achievement Award.

Fink, the Margaret and Herman Sokol Professor in Biomedical Research and American Cancer Society Professor of Genetics, was honored for his work in the development of baker’s yeast, Saccharomyces cerevisiae. Fink’s work transformed yeast into the leading model for studying the genetics of eukaryotes, organisms whose cells contain nuclei.

“Professor Fink is among the very few scientists who can be singularly credited with fundamentally changing the way we approach biological problems. He has made numerous seminal contributions to understanding the fundamentals of all nucleated life on the planet, significantly advancing our knowledge of many cellular processes critical to life systems and human diseases,” according to the award citation, which was read at the May 16 faculty meeting by Michael Strano, the chair of the Killian Award selection committee and the Carbon P. Dubbs Professor of Chemical Engineering at MIT.

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. “From understanding how cells are formed and function, to understanding cancer and developing insights into aging, his research has proved critical to modern day science,” the award committee wrote of Fink.

Fink, who was inspired to go into science partly by the Soviet Union’s launch of the Sputnik satellite in 1957, began studying yeast while working toward his PhD at Yale University in the 1960s.

“I studied yeast as a graduate student, when it was an extremely unpopular organism,” Fink recalls. “In fact, I was cautioned by my thesis advisor not to tackle it because it was an intractable system.”

Despite that warning, Fink dove into studies of yeast metabolism — in particular, the mechanism that yeast uses to regulate amino acid biosynthesis. At the time, yeast engineering was impeded because there was no way to insert a gene into yeast cells. Then, in 1976, Fink developed a way to insert any DNA into yeast cells, thus allowing researchers to study gene functions in eukaryotic cells in a way that was previously impossible.

“That technology dramatically changed everything, because it made it possible to insert a gene from any organism into yeast,” Fink says.

Fink’s advance allowed scientists to manipulate the yeast genome at will, turning the organism into a cell factory. This technology enabled the current large-scale production of vaccines, drugs (including insulin), and biofuels in yeast.

Fink, who joined the MIT faculty in 1982, currently studies the fungus Candida albicans — which can cause thrush, yeast infections, and severe blood infections — in hopes of developing new antifungal drugs. His lab recently discovered how this human pathogen switches back and forth from its usual yeast form to an invasive filamentous form.

Fink taught genetics to MIT undergraduates and graduate students for many years, and as director of the Whitehead Institute from 1990 to 2001 oversaw the Whitehead’s contribution to the Human Genome Project.

“The Human Genome Project would not have happened here at MIT if it had not been for the unique structure of the Whitehead Institute, which was able to move quickly,” Fink says. “We committed resources and space from the Whitehead to propel the project forward.”

In 2003, the Whitehead/MIT Center for Genome Research became the cornerstone of the newly launched Broad Institute. “MIT’s premier place in the world of biological research is due in no small part to Professor Fink’s selfless, tireless, and generally unheralded work in creating and nurturing these institutions,” reads the award citation.

In 2003, Fink chaired the National Academy of Sciences Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology, which provided the nation with guidance on how to deal with the threat of bioterrorism without jeopardizing scientific progress.

Fink has received many other honors, including the National Academy of Sciences Award in Molecular Biology, the George W. Beadle Award from the Genetics Society of America, and the Gruber International Prize in Genetics. He has served as president of both the American Association for the Advancement of Science and the Genetics Society of America, and he is an elected member or fellow of the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine, and the American Philosophical Society.

3Q: Hazel Sive on MIT-Africa

Faculty director discusses the future of the initiative and Africa’s position as a global priority for the Institute.

Sarah McDonnell | MIT News Office
May 8, 2018

In 2017, MIT released a report entitled “A Global Strategy for MIT,” which offered a framework for the Institute’s ever-growing international activities in education, research, and innovation. The report, written by Richard Lester, associate provost for MIT overseeing international activities, offered recommendations organized around three broad themes: bringing MIT to the world, bringing the world to MIT, and strengthening governance and operations. 

Specifically, Lester identified China, Latin America, and Africa as global priorities and regions where the Institute should expand engagement.  

Reflecting that increased focus, the MIT-Africa initiative, led by Faculty Director Hazel Sive, a professor in the Department of Biology and member of the Whitehead Institute for Biomedical Research, has launched a new website, africa.mit.edu, to further formalize MIT’s commitment to expanding its already robust presence in Africa. Sive spoke with MIT News about the initiative’s future and Africa’s position as a global priority for MIT.

Q: Can you start by explaining what the MIT-Africa initiative is?

A: MIT-Africa began in 2014 as a mechanism to promote and communicate connections between MIT students, faculty, and staff, and African counterparts in the spheres of research, education, and innovation.

Together with the enthusiastic participation of many faculty, senior staff, and students, I originated the MIT-Africa initiative because a number of us who are either from Africa (I am from South Africa) or interested in the continent were doing important work together with African colleagues. We thought that the strong connections MIT was making in Africa should be understood more broadly, and that tremendous synergies would develop from sharing our work and promoting joint projects.

The initiative provided the first public face of MIT engagement with Africa, comprising a portal to disseminate information, and a means to invite potential collaborators to connect with MIT. We developed community through the MIT-Africa Interest Group; through supporting student groups such as the African Students Association and through a growing network of MIT students who have interned or worked in Africa.

MIT-Africa both consolidates Africa-relevant opportunities and directly promotes new programs. Multiple MIT initiatives and units include an Africa focus: the MIT International Science and Technology Initiatives (MISTI), D-Lab, the Abdul Latif Jameel Poverty Action Lab (J-PAL), the Abdul Latif Jameel World Water and Food Security Lab (J-WAFS), the Abdul Latif Jameel World Education Lab (J-WEL), the Environmental Solutions Initiative (ESI), MITx, the Legatum Center, and others.

The tagline for MIT-Africa is “Collaborating for impact,” and through the pillars of research, education, and innovation, our goal is to develop even more substantial collaborations between the MIT community and in Africa.

Q: What are your thoughts on Africa’s inclusion as a priority in MIT’s recent global strategy report?

A: We are very pleased that MIT has recognized the importance of Africa in the world and as a focus for the Institute.

At the outset of the MIT-Africa initiative, we brought together an Africa Advisory Committee for strategic discussions. Last year, at the request of Richard Lester, we put together a strategic plan for MIT engagement in Africa, and the findings in this document interfaced with his decision to define Africa as a global priority for MIT.

In our plan, we made it clear that MIT priorities overlap with issues of vital importance to Africa — in tackling critical challenges relating to the environment, climate change, energy, population growth, food, health, education, industry, and urbanization. We are confident that this emphasis will facilitate expanded connections between MIT and our African collaborators and supporters.

A useful outcome of formalizing MIT’s priority of Africa engagement is recognition of our already extensive engagement with Africa. MIT has projects in half the countries of Africa! There are hundreds of examples in progress, from water utilization in Mozambique to entrepreneurship in South Africa and education in Nigeria. We are well-represented, and this engagement is growing rapidly.

The new website is both a way to acknowledge the outstanding scholarship and work already progressing on the continent, as well as a call to expand collaborations in a high impact way.

Q: What’s next for MIT-Africa?  

A:  Our strategic discussions identified key priorities over the next five years. These include: higher visibility of MIT in Africa through “MIT-Africa” branding, coordination in purpose and scope of MIT engagement in Africa, increased student internship and travel opportunities, increased research funding, new collaborations in education, expanded innovation presence, revised Africa-relevant education at MIT, and increased numbers of African trainees at MIT.

We are well on our way to meeting these goals, aided by a team with broad experience. For example, in 2014, we sent two students to Africa through MISTI, and last year we sent 92, so this has been a hugely fast-growing program. The MISTI Global Seed Fund Program newly includes Africa, and units such as J-WAFS, J-WEL, and ESI offer research funding that can be focused on Africa. A key aspect encompasses our alumni who envision a significant and influential African and African diaspora alumni group.

The distinguished MIT-Africa Working Group advises on policy, strategy, and implementation. Many members are leaders of other MIT initiatives, facilitating development of intersecting and productive joint programs with MIT-Africa.

All of this takes effort and collaborators, and we look forward to an expanded set of connections. We extend an invitation to potential collaborators: Come and speak with us. The expertise at MIT is enormous, and our focus on Africa-relevant engagement will have outcomes that advance intellectual, societal, and economic trajectories.

Biologists discover function of gene linked to familial ALS

Study in worms reveals gene loss can lead to accumulation of waste products in cells.

Anne Trafton | MIT News Office
May 4, 2018

MIT biologists have discovered a function of a gene that is believed to account for up to 40 percent of all familial cases of amyotrophic lateral sclerosis (ALS). Studies of ALS patients have shown that an abnormally expanded region of DNA in a specific region of this gene can cause the disease.

In a study of the microscopic worm Caenorhabditis elegans, the researchers found that the gene has a key role in helping cells to remove waste products via structures known as lysosomes. When the gene is mutated, these unwanted substances build up inside cells. The researchers believe that if this also happens in neurons of human ALS patients, it could account for some of those patients’ symptoms.

“Our studies indicate what happens when the activities of such a gene are inhibited — defects in lysosomal function. Certain features of ALS are consistent with their being caused by defects in lysosomal function, such as inflammation,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, and the senior author of the study.

Mutations in this gene, known as C9orf72, have also been linked to another neurodegenerative brain disorder known as frontotemporal dementia (FTD), which is estimated to affect about 60,000 people in the United States.

“ALS and FTD are now thought to be aspects of the same disease, with different presentations. There are genes that when mutated cause only ALS, and others that cause only FTD, but there are a number of other genes in which mutations can cause either ALS or FTD or a mixture of the two,” says Anna Corrionero, an MIT postdoc and the lead author of the paper, which appears in the May 3 issue of the journal Current Biology.

Genetic link

Scientists have identified dozens of genes linked to familial ALS, which occurs when two or more family members suffer from the disease. Doctors believe that genetics may also be a factor in nonfamilial cases of the disease, which are much more common, accounting for 90 percent of cases.

Of all ALS-linked mutations identified so far, the C9orf72 mutation is the most prevalent, and it is also found in about 25 percent of frontotemporal dementia patients. The MIT team set out to study the gene’s function in C. elegans, which has an equivalent gene known as alfa-1.

In studies of worms that lack alfa-1, the researchers discovered that defects became apparent early in embryonic development. C. elegans embryos have a yolk that helps to sustain them before they hatch, and in embryos missing alfa-1, the researchers found “blobs” of yolk floating in the fluid surrounding the embryos.

This led the researchers to discover that the gene mutation was affecting the lysosomal degradation of yolk once it is absorbed into the cells. Lysosomes, which also remove cellular waste products, are cell structures which carry enzymes that can break down many kinds of molecules.

When lysosomes degrade their contents — such as yolk — they are reformed into tubular structures that split, after which they are able to degrade other materials. The MIT team found that in cells with the alfa-1 mutation and impaired lysosomal degradation, lysosomes were unable to reform and could not be used again, disrupting the cell’s waste removal process.

“It seems that lysosomes do not reform as they should, and material accumulates in the cells,” Corrionero says.

For C. elegans embryos, that meant that they could not properly absorb the nutrients found in yolk, which made it harder for them to survive under starvation conditions. The embryos that did survive appeared to be normal, the researchers say.

Neuronal effects

The researchers were able to partially reverse the effects of alfa-1 loss in the C. elegans embryos by expressing the human protein encoded by the c9orf72 gene. “This suggests that the worm and human proteins are performing the same molecular function,” Corrionero says.

If loss of C9orf72 affects lysosome function in human neurons, it could lead to a slow, gradual buildup of waste products in those cells. ALS usually affects cells of the motor cortex, which controls movement, and motor neurons in the spinal cord, while frontotemporal dementia affects the frontal areas of the brain’s cortex.

“If you cannot degrade things properly in cells that live for very long periods of time, like neurons, that might well affect the survival of the cells and lead to disease,” Corrionero says.

Many pharmaceutical companies are now researching drugs that would block the expression of the mutant C9orf72. The new study suggests certain possible side effects to watch for in studies of such drugs.

“If you generate drugs that decrease c9orf72 expression, you might cause problems in lysosomal homeostasis,” Corrionero says. “In developing any drug, you have to be careful to watch for possible side effects. Our observations suggest some things to look for in studying drugs that inhibit C9orf72 in ALS/FTD patients.”

The research was funded by an EMBO postdoctoral fellowship, an ALS Therapy Alliance grant, a gift from Rose and Douglas Barnard ’79 to the McGovern Institute, and a gift from the Halis Family Foundation to the MIT Aging Brain Initiative.

Fasting boosts stem cells’ regenerative capacity

A drug treatment that mimics fasting can also provide the same benefit, study finds.

Anne Trafton | MIT News Office
May 1, 2018

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.

This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study from MIT biologists. The researchers found that fasting dramatically improves stem cells’ ability to regenerate, in both aged and young mice.

In fasting mice, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative. The researchers found that they could also boost regeneration with a molecule that activates the same metabolic switch. Such an intervention could potentially help older people recovering from GI infections or cancer patients undergoing chemotherapy, the researchers say.

“Fasting has many effects in the intestine, which include boosting regeneration as well as potential uses in any type of ailment that impinges on the intestine, such as infections or cancers,” says Omer Yilmaz, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. “Understanding how fasting improves overall health, including the role of adult stem cells in intestinal regeneration, in repair, and in aging, is a fundamental interest of my laboratory.”

David Sabatini, an MIT professor of biology and member of the Whitehead Institute for Biomedical Research and the Koch Institute, is also a senior author of the paper, which appears in the May 3 issue of Cell Stem Cell.

“This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat,” Sabatini says. “Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies.”

The paper’s lead authors are Whitehead Institute postdoc Maria Mihaylova and Koch Institute postdoc Chia-Wei Cheng.

Boosting regeneration

For many decades, scientists have known that low caloric intake is linked with enhanced longevity in humans and other organisms. Yilmaz and his colleagues were interested in exploring how fasting exerts its effects at the molecular level, specifically in the intestine.

Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover.

“Intestinal stem cells are the workhorses of the intestine that give rise to more stem cells and to all of the various differentiated cell types of the intestine. Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage,” Yilmaz says. “In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells.”

After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to “mini-intestines” known as organoids.

The researchers found that stem cells from the fasting mice doubled their regenerative capacity.

“It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven,” Mihaylova says. “This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this.”

Metabolic switch

Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids.

The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.

They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs. “That was also very surprising,” Cheng says. “Just activating one metabolic pathway is sufficient to reverse certain age phenotypes.”

Jared Rutter, a professor of biochemistry at the University of Utah School of Medicine, described the findings as “interesting and important.”

“This paper shows that fasting causes a metabolic change in the stem cells that reside in this organ and thereby changes their behavior to promote more cell division. In a beautiful set of experiments, the authors subvert the system by causing those metabolic changes without fasting and see similar effects,” says Rutter, who was not involved in the research. “This work fits into a rapidly growing field that is demonstrating that nutrition and metabolism has profound effects on the behavior of cells and this can predispose for human disease.”

The findings suggest that drug treatment could stimulate regeneration without requiring patients to fast, which is difficult for most people. One group that could benefit from such treatment is cancer patients who are receiving chemotherapy, which often harms intestinal cells. It could also benefit older people who experience intestinal infections or other gastrointestinal disorders that can damage the lining of the intestine.

The researchers plan to explore the potential effectiveness of such treatments, and they also hope to study whether fasting affects regenerative abilities in stem cells in other types of tissue.

The research was funded by the National Institutes of Health, the V Foundation, a Sidney Kimmel Scholar Award, a Pew-Stewart Trust Scholar Award, the Kathy and Curt Marble Cancer Research Fund, the MIT Stem Cell Initiative through Fondation MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the American Federation of Aging Research, the Damon Runyon Cancer Research Foundation, the Robert Black Charitable Foundation, a Koch Institute Ludwig Postdoctoral Fellowship, a Glenn/AFAR Breakthroughs in Gerontology Award, and the Howard Hughes Medical Institute.

Single-cell database to propel biological studies

Whitehead team analyzes transcriptomes for roughly 70,000 cells in planarians, creates publicly available database to drive further research.

Nicole Davis | Whitehead Institute
April 20, 2018

A team at Whitehead Institute and MIT has harnessed single-cell technologies to analyze over 65,000 cells from the regenerative planarian flatworm, Schmidtea mediterranea, revealing the complete suite of actives genes (or “transcriptome”) for practically every type of cell in a complete organism. This transcriptome atlas represents a treasure trove of biological information on planarians, which is the subject of intense study in part because of its unique ability to regrow lost or damaged body parts. As described in the April 19 advance online issue of the journal Science, this new, publicly available resource has already fueled important discoveries, including the identification of novel planarian cell types, the characterization of key transition states as cells mature from one type to another, and the identity of new genes that could impart positional cues from muscles cells — a critical component of tissue regeneration.

“We’re really at the beginning of an amazing era,” says senior author Peter Reddien, a member of Whitehead Institute, professor of biology at MIT, and investigator with the Howard Hughes Medical Institute. “Just as genome sequences became indispensable resources for studying the biology of countless organisms, analyzing the transcriptomes of every cell type will become another fundamental tool — not just for planarians, but for many different organisms.”

The ability to systematically reveal which genes in the genome are active within an individual cell flows from a critical technology known as single-cell RNA sequencing. Recent advances in the technique have dramatically reduced the per-cell cost, making it feasible for a single laboratory to analyze a suitably large number of cells to capture the cell type diversity present in complex, multi-cellular organisms.

Reddien has maintained a careful eye on the technology from its earliest days because he believed it offered an ideal way to unravel planarian biology. “Planarians are relatively simple, so it would be theoretically possible for us to capture every cell type. Yet they still have a sufficiently large number of cells — including types we know little or even nothing about,” he explains. “And because of the unusual aspects of planarian biology — essentially, adults maintain developmental information and progenitor cells that in other organisms might be present transiently only in embryos — we could capture information about mature cells, progenitor cells, and information guiding cell decisions by sampling just one stage, the adult.”

Two and a half years ago, Reddien and his colleagues — led by first author Christopher Fincher, a graduate student in Reddien’s laboratory — set out to apply single-cell RNA sequencing systematically to planarians. The group isolated individual cells from five regions of the animal and gathered data from a total of 66,783 cells. The results include transcriptomes for rare cell types, such as those that comprise on the order of 10 cells out of an adult animal that consists of roughly 500,000 to 1 million cells.

In addition, the researchers uncovered some cell types that have yet to be described in planarians, as well cell types common to many organisms, making the atlas a valuable tool across the scientific community. “We identified many cells that were present widely throughout the animal, but had not been previously identified. This surprising finding highlights the great value of this approach in identifying new cells, a method that could be applied widely to many understudied organisms,” Fincher says.

“One main important aspect of our transcriptome atlas is its utility for the scientific community,” Reddien says. “Because many of the cell types present in planarians emerged long ago in evolution, similar cells still exist today in various organisms across the planet. That means these cell types and the genes active within them can be studied using this resource.”

The Whitehead team also conducted some preliminary analyses of their atlas, which they’ve dubbed “Planarian Digiworm.” For example, they were able to discern in the transcriptome data a variety of transition states that reflect the progression of stem cells into more specialized, differentiated cell types. Some of these cellular transition states have been previously analyzed in painstaking detail, thereby providing an important validation of the team’s approach.

In addition, Reddien and his colleagues knew from their own prior, extensive research that there is positional information encoded in adult planarian muscle — information that is required not only for the general maintenance of adult tissues but also for the regeneration of lost or damaged tissue. Based on the activity pattern of known genes, they could determine roughly which positions the cells had occupied in the intact animal, and then sort through those cells’ transcriptomes to identify new genes that are candidates for transmitting positional information.

“There are an unlimited number of directions that can now be taken with these data,” Reddien says. “We plan to extend our initial work, using further single-cell analyses, and also to mine the transcriptome atlas for addressing important questions in regenerative biology. We hope many other investigators find this to be a very valuable resource, too.”

This work was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Eleanor Schwartz Charitable Foundation.

Countering mitochondrial stress

Scientists discover a pathway that monitors a protein import into mitochondria and elicits a cellular response when the process goes awry.

Raleigh McElvery | Department of Biology
April 13, 2018

If there’s one fact that most people retain from elementary biology, it’s that mitochondria are the powerhouses of the cell. As such, they break down molecules and manufacture new ones to generate the fuel necessary for life. But mitochondria rely on a stream of proteins to sustain this energy production. Nearly all their proteins are manufactured in the surrounding gel-like cytoplasm, and must be imported into the mitochondria to keep the powerhouse running.

A duo of MIT biologists has revealed what happens when a traffic jam of proteins at the surface of the mitochondria prevents proper import. They describe how the mitochondria communicate with the rest of the cell to signal a problem, and how the cell responds to protect the mitochondria. This newly-discovered molecular pathway, called mitoCPR, detects import mishaps and preserves mitochondrial function in the midst of such stress.

“This is the first mechanism identified that surveils mitochondrial protein import, and helps mitochondria when they can’t get the proteins they need,” says Angelika Amon, the Kathleen and Curtis Marble Professor of Cancer Research in the MIT Department of Biology, who is also a member of the Koch Institute for Integrative Cancer Research at MIT, a Howard Hughes Medical Institute Investigator, and senior author of the study. “Responses to mitochondrial stress have been established before, but this one specifically targets the surface of the mitochondria, clearing out the misfolded proteins that are stuck in the pores.”

Hilla Weidberg, a postdoc in Amon’s lab, is the lead author of the study, which appears in Science on April 13.

Fueling the powerhouse

Mitochondria likely began as independent entities long ago, before being engulfed by host cells. They eventually gave up control and moved most of their important genes to a different organelle, the nucleus, where the rest of the cell’s genetic blueprint is stored. The protein products from these genes are ultimately made in the cytoplasm outside the nucleus, and then guided to the mitochondria. These “precursor” proteins contain a special molecular zip code that guides them through the channels at the surface of the mitochondria to their respective homes.

The proteins must be unfolded and delicately threaded through the narrow channels in order to enter the mitochondria. This creates a precarious situation; if the demand is too high, or the proteins are folded when they shouldn’t be, a bottleneck forms that none shall pass. This can simply occur when the mitochondria expand to make more of themselves, or in diseases like deafness-dystonia syndrome and Huntington’s.

“The machinery that we’ve identified seems to evict proteins that are sitting on the surface of the mitochondria and sends them for degradation,” Amon says. “Another possibility is that this mitoCPR pathway might actually unfold these proteins, and in doing so give them a second chance to be pushed through the membrane.”

Two other pathways were recently identified in yeast that also respond to accumulated mitochondrial proteins. However, both simply clear protein refuse from the cytoplasm around the mitochondria, rather than removing the proteins collecting on the mitochondria themselves.

“We knew about various responses to mitochondrial stress, but no one had described a response to protein import defects that specifically protected the mitochondria, and that’s exactly what mitoCPR does,” Weidberg says. “We wanted to know how the cell reacts to these problems, so we set out to overload the import machinery, causing many proteins to rush into the mitochondrion at the same time and clog the pores, triggering a cellular response.”

“What makes our cells absolutely dependent on mitochondria is one of those million-dollar questions in cell biology,” says Vlad Denic, professor of molecular and cellular biology at Harvard University. “This study reveals an interesting flip-side to that question: When you make mitochondrial life artificially tough, are they programmed to say ‘help us’ so the host cell comes to their rescue? The possible ramifications of such work in terms of human development and disease could be very impressive.”

A pathway to understanding

Roughly two decades ago, researchers began to notice that the genes required to defend cells against drugs and other foreign substances — together, called the multidrug resistance (MDR) response — were also expressed in yeast mitochondrial mutants for some unknown reason. This suggested that the protein in charge of binding to the DNA and initiating the MDR response must have a dual purpose, sometimes triggering a second, separate pathway as well. But precisely how this second pathway related to mitochondria remained a mystery.

“Twenty years ago, scientists recognized mitoCPR as some kind of mechanism against mitochondrial dysfunction,” Weidberg says. “Today we’ve finally characterized it, given it a name, and identified its precise function: to help mitochondrial protein import.”

As the import process slows, Amon and Weidberg determined that the protein that initiates mitoCPR — the transcription factor Pdr3 — binds to DNA within the nucleus, inducing the expression of a gene known as CIS1. The resultant Cis1 protein binds to the channel at the surface of the mitochondrion, and recruits yet another protein, the AAA+ adenosine triphosphatase Msp1, to help clear unimported proteins from the mitochondrial surface and mediate their degradation. Although the MDR response pathway differs from that of mitoCPR, both rely on Pdr3 activation. In fact, mitoCPR requires it.

“Whether the two pathways interact with one another is a very interesting question,” Amon says. “The mitochondria make a lot of biosynthetic molecules, and blocking that function by messing with protein import could lead to the accumulation of intermediate metabolites. These can be toxic to the cell, so you could imagine that activating the MDR response might pump out harmful intermediates.”

The question of what activates Pdr3 to initiate mitoCPR is still unclear, but Weidberg has some ideas related to signals stemming from the build-up of toxic metabolite intermediates. It’s also yet to be determined whether an analogous pathway exists in more complex organisms, although there is some evidence that the mitochondria do communicate with the nucleus in other eukaryotes besides yeast.

“This was just such a classic study,” Amon says. “There were no sophisticated high-throughput methodologies, just traditional, simple molecular biology and cell biology assays with a few microscopes. It’s almost like something you’d see out of the 1980s. But that just goes to show — to this day — that’s how many discoveries are made.”

The research was funded by the National Institutes of Health and by the Koch Institute Support (core) Grant from the National Cancer Institute. Amon is also an investigator of the Howard Hughes Medical Institute and the Glenn Foundation for Biomedical Research. Weidberg was supported by the Jane Coffin Childs Memorial Fund, the European Molecular Biology Organization Long-Term Fellowship, and the Israel National Postdoctoral Program for Advancing Women in Science.