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A Summer of Protein Degradation and the Beauty of Basic Science

MSRP-Bio student Elizabeth Bond worked in the Baker Lab, investigating the macromolecular machines that roam the cell and gobble up unneeded proteins.

Raleigh McElvery
September 25, 2018

Elizabeth Bond’s greatest summer accomplishment is proudly displayed as the background image on her phone. To the casual observer, it looks like columns of black blobs, but to Bond this stained protein gel signifies that, after two long weeks, she successfully isolated her protein of interest. The snapshot also underscores that she’s found her “people” — the kind who, as she describes, “will freak out with you over a great looking gel.”

A rising senior at UMass Amherst, Bond joined 18 fellow MIT Summer Research Program in Biology (MSRP-Bio) students — collaborating in labs across the biology department and various MIT-affiliated institutes for 10 weeks. Together, they attended seminars, lectures, Q&A sessions, meals, and field trips while living in dorms and bonding over science and life in general.

“You’re with a group of other college students looking towards the future, and you’re all stressing out about what comes next,” she says. “That’s amazing because you’re able to talk about your different insecurities and anxieties. You have a built-in support system that you might not get by staying at your home institution over the summer.”

Bond grew up not too far from MIT in the quiet town of Boxford, Massachusetts. Before setting foot on campus, she expected MIT to be cutthroat and competitive. Instead, she found “a bunch of nerds who are willing to help other nerds learn, make mistakes, and be human beings.” The researchers she met were supportive and eager to share their insights, scientific or otherwise. “In addition to being really interesting, these conversations helped me feel that I fit in with a group of very intelligent scientists,” she says.

As a biochemistry major, Bond appreciates basic science because it allows her to probe biological phenomena with no immediate goal other than to understand the underlying mechanisms. “Maybe 10 years down the line my research will help someone’s translational work, but right now I can pursue knowledge for its own sake,” she says. “The beauty of basic science is that you’re able to study things because they’re cool, while also contributing to the body of work your lab family began before you.”

At UMass Amherst, she serves as an undergraduate research assistant, investigating AAA+ proteases — the same protein degradation machines she studied all summer in Tania Baker’s lab, mentored by graduate student Kristin Zuromski. Back home, Bond examines these proteases in bacteria, using a combination of microbiology and computational biology. As a member of the Baker lab, she studied these macromolecular machines leveraging biochemical approaches.

She likens AAA+ proteases to Pac-Men from the classic arcade game, roaming the cell and gobbling up misfolded, excess, or unneeded proteins. One of the AAA+ proteases studied in the Baker lab is ClpAP, which is comprised of the AAA+ unfoldase ClpA and its partner peptidase ClpP. Bond’s protein of interest this summer was ClpA, a hexameric protein depicted as a cylinder with a central channel. ClpA unfolds and threads protein substrates through its channel, which contains pore loop structures that protrude from the chamber and play important roles in the function of ClpA. From there, the proteins enter ClpP, where they are degraded into small peptide fragments.

There are two types of pore loops in ClpA, D1 and D2, but their respective roles in the recognition, unfolding, and movement of proteins for degradation are not fully characterized. Bond hoped to discern their roles relative to one another.

She introduced a mutation into the gene that encodes ClpA, switching one amino acid for another in the D2 pore loop, in a region thought to be critical for recognizing proteins targeted for degradation. This mutation would, in theory, lead to a variant of ClpA where the D1 pore loop retained normal activity, but the D2 pore loop was unable to function. She used chemical crosslinking to generate a ClpA dimer variant that was half wildtype and half mutant in the D2 pore loops, and monitored the ability of the assembled hexameric AAA+ protease to function.

By observing the degradation activity of this crosslinked ClpA variant containing three active and three inactive D2 pore loops in an alternating order, she hoped to get a better sense of the role the D2 pore loops play in ClpAP protease function.

Although there is still more to be done to answer this particular question, reflecting on the summer Bond feels her project went “surprisingly well,” despite being more challenging than she initially anticipated — primarily due to multi-week protein purification experiments and performing many procedures simultaneously. She arrived with the sole intention of bolstering her biochemistry knowledge, and left with a greater appreciation for the breadth of scientific fields she could pursue.

“MSRP-Bio gave me the chance to talk with students and faculty members working in multiple branches of science,” she says. “I study bacteria, but I can learn a lot from someone researching roundworms or cancer cells, or using computational approaches to biology. Those conversations prompted me to think more critically about my own research.”

Besides feeling integrated into the tightly-knit Baker lab, her favorite aspect of the summer was the bond she formed within her MSRP-Bio cohort. In addition to freaking out over protein gels, they started their own journal club, and they discussed personal struggles, family, where they came from, and where they want to go.

“A lot of students of color who come from underrepresented groups in science, like I do, have this anxiety about not being smart enough or not fitting in,” she says. “The program allows you to bond over these shared feelings and that is part of what makes it really amazing for students who are trying to do great things, but do not often feel fully represented.”

At the beginning of the summer, Bond hadn’t fully admitted to herself that she wanted to apply to grad school. “It was easier for me to be ambiguous about what I wanted to do, because it was scary to admit that grad school was something I might actually want,” she recalls. After a summer at MIT, she’s gained the confidence to apply and state her ambitions out loud.

“My project’s been amazing and great, but now I want to have my own body of work,” she says. “It’s something I have this great urge to do — and, because of MSRP-Bio, I’m ready for it.”

Photo credit: Raleigh McElvery
Chemists discover unexpected enzyme structure

Metal cluster in enzyme that breaks down carbon dioxide can switch between two different shapes.

Anne Trafton | MIT News Office
October 2, 2018

Many microbes have an enzyme that can convert carbon dioxide to carbon monoxide. This reaction is critical for building carbon compounds and generating energy, particularly for bacteria that live in oxygen-free environments.

This enzyme is also of great interest to researchers who want to find new ways to remove greenhouse gases from the atmosphere and turn them into useful carbon-containing compounds. Current industrial methods for transforming carbon dioxide are very energy-intensive.

“There are industrial processes that do these reactions at high temperatures and high pressures, and then there’s this enzyme that can do the same thing at room temperature,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute Investigator. “For a long time, people have been interested in understanding how nature performs this challenging chemistry with this assembly of metals.”

Drennan and her colleagues at MIT, Brandeis University, and Aix-Marseille University in France have now discovered a unique aspect of the structure of the “C-cluster” — the collection of metal and sulfur atoms that forms the heart of the enzyme carbon monoxide dehydrogenase (CODH). Instead of forming a rigid scaffold, as had been expected, the cluster can actually change its configuration.

“It was not what we expected to see,” says Elizabeth Wittenborn, a recent MIT PhD recipient and the lead author of the study, which appears in the Oct. 2 issue of the journal eLife.

A molecular cartwheel

Metal-containing clusters such as the C-cluster perform many other critical reactions in microbes, including splitting nitrogen gas, that are difficult to replicate industrially.

Drennan began studying the structure of carbon monoxide dehydrogenase and the C-cluster about 20 years ago, soon after she started her lab at MIT. She and another research group each came up with a structure for the enzyme using X-ray crystallography, but the structures weren’t quite the same. The differences were eventually resolved and the structure of CODH was thought to be well-established.

Wittenborn took up the project a few years ago, in hopes of nailing down why the enzyme is so sensitive to inactivation by oxygen and determining how the C-cluster gets put together.

To the researchers’ surprise, their analysis revealed two distinct structures for the C-cluster. The first was an arrangement they had expected to see — a cube consisting of four sulfur atoms, three iron atoms, and a nickel atom, with a fourth iron atom connected to the cube.

In the second structure, however, the nickel atom is removed from the cube-like structure and takes the place of the fourth iron atom. The displaced iron atom binds to a nearby amino acid, cysteine, which holds it in its new location. One of the sulfur atoms also moves out of the cube. All of these movements appear to occur in unison, in a movement the researchers describe as a “molecular cartwheel.”

“The sulfur, the iron, and the nickel all move to new locations,” Drennan says. “We were really shocked. We thought we understood this enzyme, but we found it is doing this unbelievably dramatic movement that we never anticipated. Then we came up with more evidence that this is actually something that’s relevant and important — it’s not just a fluke thing but part of the design of this cluster.”

The researchers believe that this movement, which occurs upon oxygen exposure, helps to protect the cluster from completely and irreversibly falling apart in response to oxygen.

“It seems like this is a safety net, allowing the metals to get moved to locations where they’re more secure on the protein,” Drennan says.

Douglas Rees, a professor of chemistry at Caltech, described the paper as “a beautiful study of a fascinating cluster conversion process.”

“These clusters have mineral-like features and it might be thought they would be ‘as stable as a rock,’” says Rees, who was not involved in the research. “Instead, the clusters can be dynamic, which confers upon them properties that are critical to their function in a biological setting.”

Not a rigid scaffold

This is the largest metal shift that has ever been seen in any enzyme cluster, but smaller-scale rearrangements have been seen in some others, including a metal cluster found in the enzyme nitrogenase, which converts nitrogen gas to ammonia.

“In the past, people thought of these clusters as really being these rigid scaffolds, but just within the last few years there’s more and more evidence coming up that they’re not really rigid,” Drennan says.

The researchers are now trying to figure out how cells assemble these clusters. Learning more about how these clusters work, how they are assembled, and how they are affected by oxygen could help scientists who are trying to copy their action for industrial use, Drennan says. There is a great deal of interest in coming up with ways to combat greenhouse gas accumulation by, for example, converting carbon dioxide to carbon monoxide and then to acetate, which can be used as a building block for many kinds of useful carbon-containing compounds.

“It’s more complicated than people thought. If we understand it, then we have a much better chance of really mimicking the biological system,” Drennan says.

The research was funded by the National Institutes of Health and the French National Research Agency.

A big new home for the ultrasmall

MIT.nano building, the largest of its kind, will usher in a new age of nanoscale advancements.

David L. Chandler | MIT News Office
September 24, 2018

Nanotechnology, the cutting-edge research field that explores ultrasmall materials, organisms, and devices, has now been graced with the largest, most sophisticated, and most accessible university research facility of its kind in the U.S.: It is the new $400 million MIT.nano building, which will have its official opening ceremonies next week.

The state-of-the-art facility includes two large floors of connected clean-room spaces that are open to view from the outside and available for use by an extraordinary number and variety of researchers across the Institute. It also features a whole floor of undergraduate chemistry teaching labs, and an ultrastable basement level dedicated to electron microscopes and other exquisitely sensitive imaging and measurement tools.

“In recent decades, we have gained the ability to see into the nanoscale with breathtaking precision. This insight has led to the development of tools and instruments that allow us to design and manipulate matter like nature does, atom by atom and molecule by molecule,” says Vladimir Bulović, the Fariborz Maseeh Professor in Emerging Technology and founding director of MIT.nano. “MIT.nano has arrived on campus at the dawn of the Nano Age. In the decades ahead, its open-access facilities for nanoscience and nanoengineering will equip our community with instruments and processes that can further harness the power of nanotechnology in service to humanity’s greatest challenges.”

“In terms of vibrations and electromagnetic noise, MIT.nano may be the quietest space on campus. But in a community where more than half of recently tenured faculty do work at the nanoscale, MIT.nano’s superb shared facilities guarantee that it will become a lively center of community and collaboration, says MIT President L. Rafael Reif. “I am grateful to the exceptional team — including Provost Martin Schmidt, Founding Director Vladimir Bulovic, and many others — that delivered this extraordinarily sophisticated building on an extraordinarily inaccessible construction site, making a better MIT so we can help to make a better world.”

Accessible and flexible

The 214,000-square-foot building, with its soaring glass facades, sophisticated design and instrumentation, and powerful air-exchange systems, lies at the heart of campus and just off the Infinite Corridor. It took shape during six years of design and construction, and was delivered exactly on schedule and on budget, a rare achievement for such a massive and technologically complex construction project.

“MIT.nano is a game-changer for the MIT research enterprise,” says Vice President for Research Maria Zuber. “It will provide measurement and imaging capabilities that will dramatically advance science and technology in disciplines across the Institute.”

At the heart of the building are two levels of clean rooms — research environments in which the air is continuously scrubbed and replaced to maintain a standard that allows no more than 100 particles of  0.5 microns or larger within a cubic foot of air. To achieve such cleanliness, work on the building has included strict filtration measures and access restrictions for more than a year, and at the moment, with the spaces not yet in full use, they far exceed that standard.

All of the lab and instrumentation spaces in the building will be used as shared facilities, accessible to any MIT researcher who needs the specialized tools that will be installed there over the coming months and years. The tools will be continually upgraded, as the building is designed to be flexible and ready for the latest advances in equipment for making, studying, measuring, and manipulating nanoscale objects — things measured in billionths of a meter, whether they be technological, biological, or chemical.

Many of the tools and instruments to be installed in MIT.nano are so costly and require so much support in services and operations that they would likely be out of reach for a single researcher or team. One of the instruments now installed and being calibrated in the basement imaging and metrology suites — sitting atop a 5-million-pound slab of concrete to provide the steadiest base possible — is a cryogenic transmission electron microscope. This multimillion dollar instrument is hosted in an equally costly room with fine-tuned control of temperature and humidity, specialized features to minimize the mechanical and electromagnetic interference, and a technical support team. The device, one of two currently being installed in MIT.nano, will enable detailed 3-D observations of cells or materials held at very low liquid-nitrogen temperatures, giving a glimpse into the exquisite nanoscale features of the soft-matter world.

Almost half of the MIT.nano’s footage is devoted to lab space — 100,000 square feet of it — which is about 100 times larger in size than the typical private lab space of a young experimental research group at MIT, Bulović says. Private labs typically take a few years to build out, and once in place often house valuable equipment that is idle for at least part of the time. It will similarly take a few years to fully build out MIT.nano’s shared labs, but Bulović expects that the growing collection of advanced instruments will rarely be idle. The instrument sets will be selected and designed to drastically improve a researcher’s ability to hit the ground running with access to the best tools from the start, he says.

Principal investigators often “find there’s a benefit to contributing tools to the community so they can be shared and perfected through their use,” Bulović says. “They recognize that as these tools are not needed for their own work 24/7, attracting additional instrument users can generate a revenue stream for the tool, which supports maintenance and future upgrades while also enhancing the research output of labs that would not have access to those tools otherwise.”

A facility sized to meet demand

Once MIT.nano is fully outfitted, over 2,000 MIT faculty and researchers are expected to use the new facilities every year, according to Bulović. Besides its clean-room floors, instrumentation floor, chemistry labs, and the top-floor prototyping labs, the new building also houses a unique facility at MIT: a two-story virtual-reality and visualization space called the Immersion Lab. It could be used by researchers studying subcellular-resolution images of biological tissues or complex computer simulations, or planetary scientists walking through a reproduced Martian surface looking for geologically interesting sites; it may even lend itself to artistic creations or performances, he says. “It’s a unique space. The beauty of it is it will connect to the huge datasets” coming from instruments such as the cryoelectron microscopes, or from simulations generated by artificial intelligence labs, or from other external datasets.

The chemistry labs on the building’s fifth floor, which can accommodate a dozen classes of a dozen students each, are already fully outfitted and in full use for this fall. The labs allow undergraduate chemistry students an exceptionally full and up-to-date experience of lab processes and tools.

“The Department of Chemistry is delighted to move into our new state-of-the-art Undergraduate Teaching Laboratories (UGTL) in MIT.nano,” says department head Timothy Jamison. “The synergy between our URIECA curriculum and this new space enables us to provide an even stronger educational foundation in experimental chemistry to our students. Vladimir Bulović and the MIT.nano team have been wonderful partners at all stages — throughout the design, construction, and move — and we look forward to other opportunities resulting from this collaboration and the presence of our UGTL in MIT.nano.”

The building itself was designed to be far more open and accessible than any comparable clean-room facility in the world. Those outside the labs can watch through MIT.nano’s many windows and see the use of these specialized devices and how such labs work. Meanwhile, researchers themselves can more easily interact with each other and see the sunshine and the gently waving bamboo plants outdoors as a reminder of the outside world that they are working to benefit.

A courtyard path on the south side of the building is named the Improbability Walk, in honor of the late MIT Institute Professor Emerita Mildred “Millie” Dresselhaus. The name is a nod to a statement by the beloved mentor, collaborator, teacher, and world-renowned pioneer in solid-state physics and nanoscale engineering, who once said, “My background is so improbable — that I’d be here from where I started.”

Those who walk through the building’s sunlight-soaked corridors and galleries will notice walls surfaced with panels of limestone from the Yangtze Platform of southwestern China. The limestone’s delicate patterns of fine horizontal lines are made up of tiny microparticles, such as bits of ancient microorganisms, laid down at the bottom of primeval waters before dinosaurs roamed the Earth. The very newest marvels to emerge in nanotechnology will thus be coming into existence right within view of some of their most ancient minuscule precursors.

School of Science welcomes 10 professors

New faculty join the departments of Biology, Brain and Cognitive Sciences, Chemistry, Physics, Mathematics, and Earth, Atmospheric and Planetary Sciences.

School of Science
September 21, 2018

The MIT School of Science recently welcomed 10 new professors in the departments of Biology Brain and Cognitive Sciences, Chemistry, Physics, Mathematics, and Earth, Atmospheric and Planetary Sciences.

Tristan Collins conducts research at the intersection of geometric analysis, partial differential equations, and algebraic geometry. In joint work with Valentino Tosatti, Collins described the singularity formation of the Ricci flow on Kahler manifolds in terms of algebraic data. In recent work with Gabor Szekelyhidi, he gave a necessary and sufficient algebraic condition for existence of Ricci-flat metrics, which play an important role in string theory and mathematical physics. This result lead to the discovery of infinitely many new Einstein metrics on the 5-dimensional sphere. With Shing-Tung Yau and Adam Jacob, Collins is currently studying the relationship between categorical stability conditions and existence of solutions to differential equations arising from mirror symmetry.

Collins earned his BS in mathematics at the University of British Columbia in 2009, after which he completed his PhD in mathematics at Columbia University in 2014 under the direction of Duong H. Phong. Following a four-year appointment as a Benjamin Peirce Assistant Professor at Harvard University, Collins joins MIT as an assistant professor in the Department of Mathematics.

Julien de Wit develops and applies new techniques to study exoplanets, their atmospheres, and their interactions with their stars. While a graduate student in the Sara Seager group at MIT, he developed innovative analysis techniques to map exoplanet atmospheres, studied the radiative and tidal planet-star interactions in eccentric planetary systems, and constrained the atmospheric properties and mass of exoplanets solely from transmission spectroscopy. He plays a critical role in the TRAPPIST/SPECULOOS project, headed by Université of Liège, leading the atmospheric characterization of the newly discovered TRAPPIST-1 planets, for which he has already obtained significant results with the Hubble Space Telescope. De Wit’s efforts are now also focused on expanding the SPECULOOS network of telescopes in the northern hemisphere to continue the search for new potentially habitable TRAPPIST-1-like systems.

De Wit earned a BEng in physics and mechanics from the Université de Liège in Belgium in 2008, an MS in aeronautic engineering and an MRes in astrophysics, planetology, and space sciences from the Institut Supérieur de l’Aéronautique et de l’Espace at the Université de Toulouse, France in 2010; he returned to the Université de Liège for an MS in aerospace engineering, completed in 2011. After finishing his PhD in planetary sciences in 2014 and a postdoc at MIT, both under the direction of Sara Seager, he joins the MIT faculty in the Department of Earth, Atmospheric and Planetary Sciences as an assistant professor.

Ila Fiete uses computational and theoretical tools to better understand the dynamical mechanisms and coding strategies that underlie computation in the brain, with a focus on elucidating how plasticity and development shape networks to perform computation and why information is encoded the way that it is. Her recent focus is on error control in neural codes, rules for synaptic plasticity that enable neural circuit organization, and questions at the nexus of information and dynamics in neural systems, such as understand how coding and statistics fundamentally constrain dynamics and vice-versa.

After earning a BS in mathematics and physics at the University of Michigan, Fiete obtained her PhD in 2004 at Harvard University in the Department of Physics. While holding an appointment at the Kavli Institute for Theoretical Physics at the University of California, Santa Barbara from 2004 to 2006, she was also a visiting member of the Center for Theoretical Biophysics at the University of California at San Diego. Fiete subsequently spent two years at Caltech as a Broad Fellow in brain circuitry, and in 2008 joined the faculty of the University of Texas at Austin. She joins the MIT faculty in the Department of Brain and Cognitive Sciences as an associate professor with tenure.

Ankur Jain explores the biology of RNA aggregation. Several genetic neuromuscular disorders, such as myotonic dystrophy and amyotrophic lateral sclerosis, are caused by expansions of nucleotide repeats in their cognate disease genes. Such repeats cause the transcribed RNA to form pathogenic clumps or aggregates. Jain uses a variety of biophysical approaches to understand how the RNA aggregates form, and how they can be disrupted to restore normal cell function. Jain will also study the role of RNA-DNA interactions in chromatin organization, investigating whether the RNA transcribed from telomeres (the protective repetitive sequences that cap the ends of chromosomes) undergoes the phase separation that characterizes repeat expansion diseases.

Jain completed a bachelor’s of technology degree in biotechnology and biochemical engineering at the Indian Institute of Technology Kharagpur, India in 2007, followed by a PhD in biophysics and computational biology at the University of Illinois at Urbana-Champaign under the direction of Taekjip Ha in 2013. After a postdoc at the University of California at San Francisco, he joins the MIT faculty in the Department of Biology as an assistant professor with an appointment as a member of the Whitehead Institute for Biomedical Research.

Kiyoshi Masui works to understand fundamental physics and the evolution of the universe through observations of the large-scale structure — the distribution of matter on scales much larger than galaxies. He works principally with radio-wavelength surveys to develop new observational methods such as hydrogen intensity mapping and fast radio bursts. Masui has shown that such observations will ultimately permit precise measurements of properties of the early and late universe and enable sensitive searches for primordial gravitational waves. To this end, he is working with a new generation of rapid-survey digital radio telescopes that have no moving parts and rely on signal processing software running on large computer clusters to focus and steer, including work on the Canadian Hydrogen Intensity Mapping Experiment (CHIME).

Masui obtained a BSCE in engineering physics at Queen’s University, Canada in 2008 and a PhD in physics at the University of Toronto in 2013 under the direction of Ue-Li Pen. After postdoctoral appointments at the University of British Columbia as the Canadian Institute for Advanced Research Global Scholar and the Canadian Institute for Theoretical Astrophysics National Fellow, Masui joins the MIT faculty in the Department of Physics as an assistant professor.

Phiala Shanahan studies theoretical nuclear and particle physics, in particular the structure and interactions of hadrons and nuclei from the fundamental (quark and gluon) degrees of freedom encoded in the Standard Model of particle physics. Shanahan’s recent work has focused on the role of gluons, the force carriers of the strong interactions described by quantum chromodynamics (QCD), in hadron and nuclear structure by using analytic tools and high-performance supercomputing. She recently achieved the first calculation of the gluon structure of light nuclei, making predictions that will be testable in new experiments proposed at Jefferson National Accelerator Facility and at the planned Electron-Ion Collider. She has also undertaken extensive studies of the role of strange quarks in the proton and light nuclei that sharpen theory predictions for dark matter cross-sections in direct detection experiments. To overcome computational limitations in QCD calculations for hadrons and in particular for nuclei, Shanahan is pursuing a program to integrate modern machine learning techniques in computational nuclear physics studies.

Shanahan obtained her BS in 2012 and her PhD in 2015, both in physics, from the University of Adelaide. She completed postdoctoral work at MIT in 2017, then held a joint position as an assistant professor at the College of William and Mary and senior staff scientist at the Thomas Jefferson National Accelerator Facility until 2018. She returns to MIT in the Department of Physics as an assistant professor.

Nike Sun works in probability theory at the interface of statistical physics and computation. Her research focuses in particular on phase transitions in average-case (randomized) formulations of classical computational problems. Her joint work with Jian Ding and Allan Sly establishes the satisfiability threshold of random k-SAT for large k, and relatedly the independence ratio of random regular graphs of large degree. Both are long-standing open problems where heuristic methods of statistical physics yield detailed conjectures, but few rigorous techniques exist. More recently she has been investigating phase transitions of dense graph models.

Sun completed BA mathematics and MA statistics degrees at Harvard in 2009, and an MASt in mathematics at Cambridge in 2010. She received her PhD in statistics from Stanford University in 2014 under the supervision of Amir Dembo. She held a Schramm fellowship at Microsoft New England and MIT Mathematics in 2014-2015 and a Simons postdoctoral fellowship at the University of California at Berkeley in 2016, and joined the Berkeley Department of Statistics as an assistant professor in 2016. She returns to the MIT Department of Mathematics as an associate professor with tenure.

Alison Wendlandt focuses on the development of selective, catalytic reactions using the tools of organic and organometallic synthesis and physical organic chemistry. Mechanistic study plays a central role in the development of these new transformations. Her projects involve the design of new catalysts and catalytic transformations, identification of important applications for selective catalytic processes, and elucidation of new mechanistic principles to expand powerful existing catalytic reaction manifolds.

Wendlandt received a BS in chemistry and biological chemistry from the University of Chicago in 2007, an MS in chemistry from Yale University in 2009, and a PhD in chemistry from the University of Wisconsin at Madison in 2015 under the direction of Shannon S. Stahl. Following an NIH Ruth L. Krichstein Postdoctoral Fellowship at Harvard University, Wendlandt joins the MIT faculty in the Department of Chemistry as an assistant professor.

Chengyang Xu specializes in higher-dimensional algebraic geometry, an area that involves classifying algebraic varieties, primarily through the minimal model program (MMP). MMP was introduced by Fields Medalist S. Mori in the early 1980s to make advances in higher dimensional birational geometry. The MMP was further developed by Hacon and McKernan in the mid-2000s, so that the MMP could be applied to other questions. Collaborating with Hacon, Xu expanded the MMP to varieties of certain conditions, such as those of characteristic p, and, with Hacon and McKernan, proved a fundamental conjecture on the MMP, generating a great deal of follow-up activity. In collaboration with Chi Li, Xu proved a conjecture of Gang Tian concerning higher-dimensional Fano varieties, a significant achievement. In a series of papers with different collaborators, he successfully applied MMP to singularities.

Xu received his BS in 2002 and MS in 2004 in mathematics from Peking University, and completed his PhD at Princeton University under János Kollár in 2008. He came to MIT as a CLE Moore Instructor in 2008-2011, and was subsequently appointed assistant professor at the University of Utah. He returned to Peking University as a research fellow at the Beijing International Center of Mathematical Research in 2012, and was promoted to professor in 2013. Xu joins the MIT faculty as a full professor in the Department of Mathematics.

Zhiwei Yun’s research is at the crossroads between algebraic geometry, number theory, and representation theory. He studies geometric structures aiming at solving problems in representation theory and number theory, especially those in the Langlands program. While he was a CLE Moore Instructor at MIT, he started to develop the theory of rigid automorphic forms, and used it to answer an open question of J-P Serre on motives, which also led to a major result on the inverse Galois problem in number theory. More recently, in his joint work with Wei Zhang, they give geometric interpretation of higher derivatives of automorphic L- functions in terms of intersection numbers, which sheds new light on the geometric analogue of the Birch and Swinnerton-Dyer conjecture.

Yun earned his BS at Peking University in 2004, after which he completed his PhD at Princeton University in 2009 under the direction of Robert MacPherson. After appointments at the Institute for Advanced Study and as a CLE Moore Instructor at MIT, he held faculty appointments at Stanford and Yale. He returned to the MIT Department of Mathematics as a full professor in the spring of 2018.

Parasite’s riff on essential enzyme highlights unique biology
Nicole Giese Rura | Whitehead Institute
September 18, 2018

Cambridge, Mass. — The primary currency of energy in cells—adenosine triphosphate (ATP)—is essential for their survival and without it, cellular processes would seize. In the apicomplexan Toxoplasma gondii (T. gondii), a parasite that Whitehead Member Sebastian Lourido studies, key components of the ATP synthase—the enzyme responsible for ATP production—have remained elusive. While investigating indispensable proteins with unknown functions, Lourido and Diego Huet, a postdoctoral researcher in Lourido’s lab, identified a critical component of the enzyme. While highly conserved from yeast to humans, it proved to be considerably different in T. gondii. The findings, published online September 11 in the journal eLife, underscore the unique biology of these parasites and highlight differences between them and their human hosts.

More closely related to plants than to animals, the single-celled apicomplexans are among the most common and deadly human pathogens. According to the World Health Organization, every year these diseases sicken hundreds of millions, kill hundreds of thousands—primarily children—and cost billions of dollars to treat. Species of apicomplexans cause malaria (Plasmodium spp.), cryptosporidiosis (Cryptosporidium spp.), and toxoplasmosis (T. gondii).

Using a CRISPR-based genetic screen that they had adapted to T. gondii, Lourido and Huet had previously identified about 200 genes in T. gondii that are fitness-conferring and specific to apicomplexans. Of that cadre, a few were localized to the mitochondria, where cells manufacture ATP, the cellular currency of energy. Because those genes have not been annotated previously, and the proteins encoded by them have no known function, Huet ran their protein sequences through a database that compared them to protein sequences with known structures.

One of the proteins came back with an interesting hit: it shares structural similarity, but not sequence similarity, with an integral part of the ATP synthase. Most of the protein subunits that compose the apicomplexan ATP synthase have been identified, but key components of the stator—a portion of the enzyme essential for its function—was not yet known.

When Huet experimentally removed the function of the stator subunit in T. gondii, the parasites’ growth stalled, their mitochondria were misshapen and shrunken, and energy production halted—all traits typical of interrupted ATP synthase function.

Because the apicomplexan ATP synthase varies so much from its hosts’ version, those differences, like the unusual stator, could serve as future drug targets. But for Lourido, who is also an assistant professor of biology at Massachusetts Institute of Technology (MIT), the unique stator protein emphasizes how unique and extraordinary apicomplexan organisms are compared to us and their other hosts.

This work was supported by the National Institutes of Health (NIH grants 1DP5OD017892, R21AI123746, and K99AI137218).

* * *

Sebastian Lourido’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

* * *

Full Citation:

“Identification of cryptic subunits from an apicomplexan ATP synthase”

eLife, online September 11, 2018.  DOI: 10.7554/eLife.38097

Diego Huet (1) , Esther Rajendran (2) , Giel G van Dooren (2) , Sebastian Lourido (1,3*).

1. Whitehead Institute for Biomedical Research, Cambridge, United States

2. Research School of Biology, Australian National University, Canberra, Australia

3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

New perspectives at the bench

Three MIT postdocs earn competitive Howard Hughes Medical Institute fellowships that support diversity in the sciences.

David Orenstein | Erika Reinfeld | Lisa Girard | Picower Institute for Learning and Memory
September 12, 2018

In recognition of their exceptional potential to be leaders in the life sciences, three MIT postdocs at the Koch, Picower, and Whitehead institutes at MIT are among 15 young researchers to earn Hanna Gray Fellowships from the Howard Hughes Medical Institute (HHMI), the Chevy Chase, Maryland-based organization has announced.

The early-career awards are given to individuals around the U.S. who are from racial, gender, ethnic, and other groups underrepresented in the life sciences. The fellowships will support their work with up to $1.4 million in funding over eight years, enough to last well into a tenure track position after they complete their postdoctoral studies.

“This program will help us retain the most diverse talent in science,” HHMI President Erin O’Shea said in the announcement. “We feel it’s critically important in academia to have exceptional people from all walks of life, all cultures, and all backgrounds — people who can inspire the next generation of scientists.”

MIT’s three Hanna Gray Fellows are Matheus Victor, who works in the lab of Li-Huei Tsai in the Picower Institute for Learning and Memory; Quinton Smith, who works in Sangeeta Bhatia’s lab at the Koch Institute for Integrative Cancer Research; and Jarrett Smith, who works in the David Bartel Lab at the Whitehead Institute for Biomedical Research.

Jarrett Smith

Jarrett Smith was always interested in science, but no one in his family had ever received a PhD, making biology research feel like an unlikely career path for him. Nevertheless, he followed his passion, which led him to his PhD program at the Johns Hopkins University School of Medicine. Despite his strong academic performance, Smith began graduate school with doubts about his ability to become a scientist. His mentors were incredible teachers, he says, but their self-assuredness could be intimidating.

“They were absolutely my role models, but I didn’t think of them as having gone through what I was going through. In the first few years, I felt like I had a lot of catching up to do,” Smith says.

Now, as a postdoc in David Bartel’s lab at the Whitehead Institute, he studies how cells respond to stress. When a cell is exposed to environmental stressors such as heat, UV radiation, or viral infection, proteins and RNAs in the cell may clump together into dense aggregates called stress granules. The exact function of stress granules and their potential role in disease are unknown, so Smith is investigating changes in the cell linked to their formation. His findings could shed light on a potential role for stress granules in cancer, infection, and neurodegenerative disease.

“I’m grateful for the support that the fellowship will provide during the formative years of my career,” Smith says. “This kind of opportunity gives you the confidence to set ambitious research goals and find out what you can accomplish.”

Quinton Smith

Quinton Smith fell in love with regenerative medicine the summer after his sophomore year of college. Working on an epidemiological study at the University of New Mexico Cancer Research Facility in his hometown of Albuquerque, Smith found himself extracting DNA from hundreds of mouthwash samples in order to answer overarching questions about the biological and behavioral factors that contribute to cancer.

The experience left him with a strong appreciation for the complexities of human disease, and an even stronger desire to translate his knowledge into better interventions for patients. To this end, he completed his PhD at Johns Hopkins University, exploring a variety of engineering techniques to control and probe the differentiation of pluripotent stem cells. In 2017 he joined the laboratory of Sangeeta Bhatia, the John J. and Dorothy Wilson Professor at MIT’s Institute for Medical Engineering and Science and Electrical Engineering and Computer Science and director of the Marble Center for Cancer Nanomedicine.

By then, the lab had already demonstrated success developing implantable “mini-livers” able to engraft and respond to regenerative stimuli in mice with damaged livers. However, the design is incomplete and Smith wants to incorporate a biliary tree to guide hepato-secreted bile acids that aid in the breakdown of fats but pose as a potential toxin to these therapeutic grafts. He is working to build such a tree with an unexpected tool — microfluidic vessels, forged by biomaterial-encapsulated acupuncture needles that, once removed, can be used to create a network of biliary-lined tunnels through which bile can flow.

The ability to bolster cutting-edge research is but one benefit of Smith’s HHMI award. He and Bhatia praise the seeds the program plants within the academic environment, providing much-needed visibility that achievements in STEM are, and will continue to be, driven by scientists from all walks of life.

“I think this program is directing a shift in what a researcher looks like, offering a motivating exposure to the next generation of students who have the potential to impact science regardless of their background,” Smith says. “This is an incredible and humbling opportunity to explore my passion for the promise of regenerative medicine, and to have the resources to tinker and extend my creativity around translational research.”

Matheus Victor

As a graduate student at Washington University in St. Louis, Matheus Victor, a native of Recife, Brazil, who came to Florida at the age of 15, learned that in the U.S., Latino immigrants are rare among scientific researchers. But there he was, pursuing his dreams to become a neuroscientist. The realization inspired him to lead a Latin American student group at WashU and to conduct outreach activities including creating bilingual curricula for local students.

“I was so privileged to be in a top tier graduate program pursuing my interest,” he said. “How many people get to pursue an interest? We live in a world where you have to earn money and you have to feed your family.”

Now he’s a new postdoc at MIT’s Picower Institute for Learning and Memory in the lab of Institute director and Picower Professor Li-Huei Tsai, with a prestigious fellowship that will support him as he embarks on two investigations of the role of specific cell types in brain aging and cognitive decline.

In one, he plans to turn human induced pluripotent stem cells into microglia, an immune cell of the nervous system increasingly implicated in Alzheimer’s disease, and implant them in the brains of mice where the original microglia have been removed. With this chimera model Victor can test how microglia with different genetic variations act in a mammalian brain to see how those variations might contribute to disease pathology.

In the other, he is interested in studying how inhibitory interneurons change in the aging brain. The neurons are of particular interest because they are the source of a crucial brain rhythm that is notably reduced in Alzheimer’s disease. Understanding more about how they function and falter could help explain that important change.

Jarrett Smith receives Hanna Gray Fellowship from HHMI
Greta Friar | Whitehead Institute
September 12, 2018

Cambridge, Mass — Jarrett Smith, postdoctoral researcher in David Bartel’s lab at the Whitehead Institute, has been announced as a recipient of the Howard Hughes Medical Institute (HHMI)’s 2018 Hanna Gray fellowship. The fellowship supports outstanding early career scientists from groups underrepresented in the life sciences. Each of this year’s fifteen awardees will be given up to $1.4 million dollars in funding over the course of their postdoctoral program and beginning of a tenure-track faculty position.

“This program will help us retain the most diverse talent in science,” said HHMI President Erin O’Shea. “We feel it’s critically important in academia to have exceptional people from all walks of life, all cultures, and all backgrounds – people who can inspire the next generation of scientists.”

For Smith, who began his postdoctoral training in the Bartel lab in January, finding out he got the fellowship was a defining moment.

“I’m grateful for the support that the fellowship will provide during the formative years of my career,” Smith says. “This kind of opportunity gives you the confidence to set ambitious research goals and find out what you can accomplish.”

In the Bartel lab, Smith studies how cells respond to stress. When a cell is exposed to environmental stressors such as heat, UV radiation, or viral infection, proteins and RNAs in the cell may clump together into dense aggregates called stress granules. Several diseases are associated with altered stress granule formation, but the exact function of stress granules and their potential role in disease are unknown. Smith is investigating changes in the cell linked to their formation. His findings could shed light on a potential role for stress granules in cancer, viral infection, and neurodegenerative disease.

Growing up, Smith was always interested in science but no one in his family had ever received a PhD, making biology research feel like an unlikely career path for him. Nevertheless, he followed his passion, which led him to a PhD program at the Johns Hopkins University School of Medicine. Despite his strong academic performance, Smith began graduate school with doubts about his ability to become a scientist. His mentors were incredible teachers but their self-assuredness could be intimidating.

“They were absolutely my role models, but I didn’t think of them as having gone through what I was going through. In the first few years, I felt like I had a lot of catching up to do,” Smith said.

Smith says he was frequently inspired and guided by his graduate school mentor, Geraldine Seydoux. Under her tutorship he became more confident in his abilities.

“I try to pick mentors who are the kind of scientist I aspire to be,” Smith said.

With that tenet in mind, he set his sights on David Bartel’s lab for his postdoctoral research. He had heard that Bartel was a great mentor and knew the Bartel lab had expertise in all of the research techniques he wanted to learn. Since arriving at Whitehead Institute, Smith says he has experienced support not only from Bartel, but from the entire lab as well.

“Jarrett’s graduate experience with P granules in nematodes brings much appreciated expertise to our lab, and we are all excited about what he will discover here on stress-granule function,” Bartel says. “Receiving this fellowship is a well-deserved honor, and I am very happy for him.”

Smith noted that he is deeply grateful for the community he’s found at Whitehead Institute. However, he also noted that throughout his scientific career he has typically been the only black person in the room. One of the joys of applying for the fellowship was meeting the rest of the candidates, a diverse and impressive group of scientists, he says. He looks forward to seeing the other fellows again at meetings hosted by the HHMI.

“I’ve never really had a scientific role model that shared those experiences or that I could identify with in that way,” Smith says, but he hopes that future aspiring scientists won’t have to go through the same experience. His brother-in-law recently began an undergraduate major in biology. Smith enjoys being there to answer his questions about school work or life as a researcher.

“I’d never ask him if he thinks of me as a role model,” Smith says, laughing. “But I’m glad that I have the chance to help people who—like I did—might question whether they could be successful in the sciences.” With the support of the fellowship and his lab, and an exciting research question he is eager to tackle, Smith has never been more certain that he belongs right where he is.

A Summer of Science

Victor Rivera-Santana, a chemistry major at the University of Puerto Rico at Mayagüez, visited MIT Biology for 10 weeks to investigate protein form and function.

August 30, 2018

Victor Rivera-Santana grew up on the western edge of Puerto Rico, in what he refers to as an “atmosphere of science.” His mother is a professor of animal science at the University of Puerto Rico at Mayagüez, and in elementary school he would attend her lectures about the effects of environment and hormones on animal behavior. Three years ago, Rivera-Santana enrolled there as an undergraduate, and has been studying chemistry ever since — with the exception of this past summer, when he became a full-fledged member of the MIT Biology Department for 10 weeks during MIT’s Summer Research Program in Biology (MSRP­-Bio).

Rivera-Santana remembers being drawn to basic research because of its simple, pure, and noble nature, stemming from the creativity of the researcher. “Science almost always has an application, so the fact that researchers in basic science are not looking for an application per se doesn’t mean their work won’t have one in the future,” he says. “The researcher fulfills his or her own curiosity, and afterwards someone else can find a way to put that into practice in society.”

A rising senior, Rivera-Santana chose chemistry because he enjoyed analyzing the minute building blocks of life, but wasn’t sure which field he would ultimately pursue. With chemistry, he could engineer the major to encompass biology and physics as well, which would give him “a taste of everything.”

At first he didn’t know what post-graduation life might hold. However, two weeks into the MSRP-Bio program he’d made up his mind: a PhD. “I like the people, I like the passion, and most importantly I like the research — everything is so interesting it’s hard to pick,” he says.

Rivera-Santana applied to MSRP-Bio early last January because he had it on good authority from three independent sources that this was the program for him. First a good friend and former MSRP-Bio student suggested it, then his professor, and finally his father.

He had two main expectations coming in. First, that everyone would be intimidating and aloof. “Boy was I wrong,” he says. “The MIT faculty are really accessible and engage you as a potential researcher. You can stop them as they’re walking down the hall, or ask them questions during the scheduled Q&A sessions.”

Second, he expected everyone would be hardworking, irrespective of their area of focus. “I was very pleased to find that’s the case,” he says. “I have not met one person at MIT who would not go the extra mile to do their job correctly.”

Rivera-Santana worked in Thomas Schwartz’s lab, investigating an aggregate of proteins known as the nuclear pore complex (NPC), which is embedded in the nuclear envelope and controls the passage of proteins, RNAs, and even ribosomal subunits between the cytoplasm and the nucleus. Although the NPC is vital to cellular survival, its structure is not yet fully understood.

The Schwartz lab goes bit by bit, studying each of its components and their interactions with one another. Rivera-Santana concentrated on one NPC protein in particular, Nup93, parsing its role and design. He hopes this work will eventually help scientists understand the complex as a whole, “because as the name says, it’s complex.”

Rivera-Santana studied four different variants of Nup93, working to express each variant by itself in bacteria. Most of his days in lab went by “either very slowly or very quickly.” He would spend the beginning of the week growing the bacteria to express his proteins — a relatively low-key process since the bacteria “essentially take care of themselves.” The latter half of the week, though, when he began the purification process, was more fast-paced. It involved extracting and purifying the proteins from the bacterial cytosol, while at the same time taking steps to prevent the proteins from becoming damaged, such as keeping them at low temperatures by performing the purification steps in the cold room.

“Purifying is the really challenging part, but it’s also the most fun,” Rivera-Santana says. “I had to work at four degrees Celsius, and I’m from Puerto Rico so you can just imagine how I bear the temperature,” he adds.

Looking back, his most exciting summer experience was purifying his first protein. “I just felt this bundle of joy well up inside me,” he says. “When I ran it through the gel to check its identity and I saw that beautiful blob of ‘ink’ that told me I had my protein, I just felt so happy.”

While Rivera-Santana thoroughly enjoyed his experiences in lab, he was also thrilled to meet other budding researchers and explore Boston’s museums and brick buildings. His proudest moment was cooking his first meal for his new MSRP-Bio friends (a classic Puerto Rican dish: rice, beans, chicken, and plantains). He enjoys putting smiles on people’s faces, “especially when those grins are full of food.” After all, MSRP-Bio isn’t just about being at MIT; it’s also about meeting people and being part of the community.

He also learned he could live by himself, thousands of miles from his family. And he’s prepared to do it again next summer, perhaps in the same lab. “I’m definitely considering doing MSRP-Bio again,” he says. “And I’m certainly also thinking about MIT for graduate school.”

Until then, the three things he’ll miss the most — in no particularly order — are his MSRP-Bio cohort, his lab mentor, and the tasty East Coast cherries.

Photo credit: Raleigh McElvery
Exploring cancer metabolism

Matthew Vander Heiden seeks new cancer treatments that exploit tumor cells’ abnormal metabolism.

Anne Trafton | MIT News Office
August 28, 2018

Nearly 100 years ago, the German chemist Otto Warburg discovered that cancer cells metabolize nutrients differently than most normal cells. His discovery launched the field of cancer metabolism research, but interest in this area waned; by the 1970s most cancer scientists had shifted their focus to the genetic mutations that drive cancer development.

In the past decade or so, interest in cancer metabolism has resurged, and the first drugs that target cancer cells’ abnormal metabolism were approved to treat leukemia in 2017.

“Cancer metabolism is a very sophisticated field at this point,” says Matthew Vander Heiden, an associate professor of biology at MIT. “We have a lot better understanding of what nutrients cancer cells use and what determines how those nutrients are used. This has led to different ways to think about drugs.”

Vander Heiden, who is also a member of MIT’s Koch Institute for Integrative Cancer Research, is one of the people responsible for the recent surge in cancer metabolism research. As a graduate student and postdoc, he published some of the first studies of how cancer cells alter their metabolism, and now his lab at MIT is devoted to the topic.

“All of the time that I was in grad school and working as a postdoc, I was never working in a lab that was dedicated to studying metabolism. So my vision, if someone gave me a job, was to set up a lab that could really be built in a way that would allow us to ask questions about metabolism,” he says.

Metabolism and cancer

Vander Heiden grew up in a small town in Wisconsin, and unlike most of his high school classmates, he headed out of state for college, to the University of Chicago. He was interested in science, so decided on a pre-med track. A work-study job in a plant biology lab led him to discover that he also enjoyed doing research.

“At that point I already had this idea I was going to go to medical school, but then the idea of MD/PhD came up, and I ended up going down that path,” Vander Heiden says.

While in the MD/PhD program at the University of Chicago Medical School, he worked in the lab of Craig Thompson, now president of Memorial Sloan Kettering Cancer Center. At that time, Thompson was studying the biochemical regulation of apoptosis, the programmed cell death pathway. For his PhD thesis, Vander Heiden investigated the function of a protein called Bcl-x, which is a regulator of apoptosis found in the membranes of mitochondria — cell organelles responsible for generating energy.

“That project really got me thinking about how the mitochondria work and how metabolism works,” Vander Heiden recalls. “At the time, I came to the realization that we don’t understand cell metabolism anywhere near as well as we thought we did, and someone should really study this.”

After finishing his degrees, he spent five years doing clinical training, then decided to pursue research in cancer metabolism.

“Altered metabolism has been known about in cancer for 100 years, but few people were studying it,” Vander Heiden says. “The challenge was finding a lab that would allow me to study metabolism and cancer, which in 2004-2005 was not such an obvious thing to do.”

He ended up going to Harvard Medical School to work with Lewis Cantley, who studies signaling pathways in cells and was receptive to the idea of exploring cancer metabolism. There, Vander Heiden began studying an enzyme called pyruvate kinase M2 (PKM2), which is involved in regulation of glycolysis, a biochemical process that cells use to break down sugar for energy.

In 2008, Vander Heiden, Cantley, and others at Harvard Medical School reported that when cells shift between normal and Warburg (cancer-associated) metabolism, they start using PKM2 instead of PKM1, the enzyme that adult cells normally use for glycolysis. Cantley and Craig Thompson have since founded a company, Agios Pharmaceuticals, that is developing potential drugs that target PKM2, as well as other molecules involved in cancer metabolism.

While at Harvard, Vander Heiden also worked on a paper that contributed to the eventual development of drugs that target cancer cells with a mutation in the IDH gene. These drugs, the first modern FDA-approved cancer drugs that target metabolism, shut off an alternative pathway used by cancer cells with the IDH mutation.

New drug targets

In 2010, Vander Heiden became one of the first new faculty members hired after the creation of MIT’s Koch Institute, where he set up a lab focused on metabolism, particularly cancer metabolism.

His research has yielded many insights into the abnormal metabolism of cancer cells. In one study, together with other MIT researchers, he found that tumor cells turn on an alternative pathway that allows them to build lipids from the amino acid glutamine instead of the glucose that healthy cells normally use. He also found that altering the behavior of PKM2 to make it act more like PKM1 could stop tumor cell growth.

Studies such as these can offer insights that may help researchers to develop drugs that starve tumor cells of the nutrients they need, offering a new way to fight cancer, Vander Heiden says.

“If one wants to develop drugs that target metabolism, one really needs to focus on the context in which it’s happening, which is the environment of the cell plus the genetics of the cell,” he says. “That is what defines the sensitivity to drugs.”

Tissue architecture affects chromosome segregation

Biologists discover that the environment surrounding a cell plays an integral role in its ability to accurately segregate its chromosomes.

Ashley Junger | Koch Institute
August 24, 2018

All growth and reproduction relies on a cell’s ability to replicate its chromosomes and produce accurate copies of itself. Every step of this process takes place within that cell.

Based on this observation, scientists have studied the replication and segregation of chromosomes as a phenomenon exclusively internal to the cell. They traditionally rely on warm nutritional cultures that promote growth but bear little resemblance to the cell’s external surroundings while in its natural environment.

New research by a group of MIT biologists reveals that this long-held assumption is incorrect. In a paper published this week, they describe how some types of cells rely on signals from surrounding tissue in order to maintain chromosome stability and segregate accurately.

Kristin Knouse, a fellow at the Whitehead Institute, is the lead author of the paper, which was published online in the journal Cell on Aug. 23. Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research, is the senior author.

“The main takeaway from this paper is that we must study cells in their native tissues to really understand their biology,” Amon says. “Results obtained from cell lines that have evolved to divide on plastic dishes do not paint the whole picture.”

When cells replicate, the newly duplicated chromosomes line up within the cell and cellular structures pull one copy to each side. The cell then divides down the middle, separating one copy of each chromosome into each new daughter cell.

At least, that’s how it’s supposed to work. In reality, there are sometimes errors in the process of separating chromosomes into daughter cells, known as chromosome mis-segregation. Some errors simply result in damage to the DNA. Other errors can result in the chromosomes being unevenly divided between daughter cells, a condition called aneuploidy.

These errors are almost always harmful to cell development and can be fatal. In developing embryos, aneuploidy can cause miscarriages or developmental disorders such as Down syndrome. In adults, chromosome instability is seen in a large number of cancers.

To study these errors, scientists have historically removed cells from their surrounding tissue and placed them into easily controlled plastic cultures.

“Chromosome segregation has been studied in a dish for decades,” Knouse says. “I think the assumption was … a cell would segregate chromosomes the same way in a dish as it would in a tissue because everything was happening inside the cell.”

However, in previous work, Knouse had found that reported rates for aneuploidy in cells grown in cultures was much higher than the rates she found in cells that had grown within their native tissue. This prompted her and her colleagues to investigate whether the surroundings of a cell influence the accuracy with which that cell divided.

To answer this question, they compared mis-segregation rates between five different cell types in native and non-native environments.

But not all cells’ native environments are the same. Some cells, like those that form skin, grow in a very structured context, where they always have neighbors and defined directions for growth. Other cells, however, like cells in the blood, have greater independence, with little interaction with the surrounding tissue.

In the new study, the researchers observed that cells that grew in structured environments in their native tissues divided accurately within those tissues. But once they were placed into a dish, the frequency of chromosome mis-segregation drastically increased. The cells that were less tied to structures in their tissue were not affected by the lack of architecture in culture dishes.

The researchers found that maintaining the architectural conditions of the cell’s native environment is essential for chromosome stability. Cells removed from the context of their tissue don’t always faithfully represent natural processes.

The researchers determined that architecture didn’t have an obvious effect on the expression of known genes involved in segregation. The disruption in tissue architecture likely causes mechanical changes that disrupt segregation, in a manner that is independent of mutations or gene expression changes.

“It was surprising to us that for something so intrinsic to the cell — something that’s happening entirely within the cell and so fundamental to the cell’s existence — where that cell is sitting actually matters quite a bit,” Knouse says.

Through the Cancer Genome Project, scientists learned that despite high rates of chromosome mis-segregation, many cancers lack any mutations to the cellular machinery that controls chromosome partitioning. This left scientists searching for the cause of the increase of these division errors. This study suggests that tissue architecture could be the culprit.

Cancer development often involves disruption of tissue architecture, whether during tumor growth or metastasis. This disruption of the extracellular environment could trigger chromosome segregation errors in the cells within the tumor.

“I think [this paper] really could be the explanation for why certain kinds of cancers become chromosomally unstable,” says Iain Cheeseman, a professor of biology at MIT and a member of the Whitehead Institute, who was not involved in the study.

The results point not only to a new understanding of the cellular mechanical triggers and effects of cancers, but also to a new understanding of how cell biology must be studied.

“Clearly a two-dimensional culture system does not faithfully recapitulate even the most fundamental processes, like chromosome segregation,” Knouse says. “As cell biologists we really must start recognizing that context matters.”

This work was supported by the National Institutes of Health, the Kathy and Curt Marble Cancer Research Fund, and the Koch Institute Support (core) Grant from the National Cancer Institute.