Research Area: Biochemistry, Biophysics, and Structural Biology

Phillip A. Sharp

Education

  • PhD, 1969, University of Illinois, Urbana-Champaign
  • BA, 1966, Chemistry and Math, Union College

Research Summary

We investigate small, non-coding RNAs called microRNAs (miRNAs), which regulate over half of the genes in mammalian cells at the stages of translation and mRNA stability. We are also interested in the processes underlying transcription from the anti-sense strand (so-called “divergent” transcription), as well as the relationship between elongation of transcription, RNA splicing, and chromatin modifications.

Awards

  • AACR Award for Lifetime Achievement in Cancer Research, 2020
  • AACR Distinguished Award for Extraordinary Scientific Innovation and Exceptional Leadership in Cancer Research and Biomedical Science, 2018
  • Royal Society of London, Foreign Fellow, 2011
  • National Science Foundation, National Medal of Science, 2004
  • The Nobel Foundation, Nobel Prize in Physiology or Medicine, 1993
  • National Academy of Medicine, Member, 1991
  • American Association for the Advancement of Science, Fellow, 1987
  • American Academy of Arts and Sciences, Fellow, 1987
  • National Academy of Sciences, Member, 1983
Iain M. Cheeseman

Education

  • PhD, 2002, University of California, Berkeley
  • BS, 1997, Biology, Duke University

Research Summary 

Our lab is fascinated by the molecular machinery that directs core cellular processes, and in particular how these processes are modulated and rewired across different physiological contexts. Our work has focused on the proteins that direct chromosome segregation and cell division, including the macromolecular kinetochore structure that mediates chromosome-microtubule interactions. Although cell division is an essential cellular process, this machinery is remarkably flexible in its composition and properties, which can vary dramatically between species and are even modulated within the same organism — over the cell cycle, during development, and across diverse physiological situations. To define the basis by which the kinetochore and other core cellular structures are rewired to adapt to diverse situations and functional requirements, we are currently investigating diverse transcriptional, translational, and post-translational mechanisms that act to generate proteomic variability both within individual cells and across tissues, cell state, development, and disease.

Awards

  • Global Consortium for Reproductive Longevity and Equality (GCRLE) Scholar Award, 2020
  • MIT Undergraduate Research Opportunities Program (UROP) Outstanding Mentor – Faculty, 2019
  • American Society for Cell Biology (ASCB) Early Career Life Scientist Award, 2012
  • Searle Scholar Award, 2009-2012

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Of highways, engines, and chromosomes

Whitehead researchers unravel fundamental molecular machinery that propels chromosome movement

November 16, 2017

Each day, billions of cells in the human body undergo a vital ritual, wherein one cell divides to form two. This process, known as cell division, is as beautiful as it is essential, undergirding the body’s growth in times of both health and disease. Despite the fact that cell division (or “mitosis”) has been a basic topic in high school biology classes for the past 70 years, the mechanisms by which cells conduct this critical event remain poorly understood. In particular, there are lingering uncertainties about how chromosomes — large units of DNA that include our genes — get properly allocated so that both daughter cells receive intact, complete copies of their genetic blueprint.

“People have been watching chromosomes move, align, and segregate for more than a century — it’s such a fundamental aspect of biology,” says Iain Cheeseman, a member of the Whitehead Institute for Biomedical Research and an associate professor of biology at Massachusetts Institute of Technology. “It’s also much more elegant and complicated than we ever anticipated.”

Cheeseman and members of his Whitehead laboratory have discovered many of the molecular movers and shakers that ensure chromosomes get to the right place at the right time. These components assemble together — like the parts of an engine — to establish robust connections with chromosomes and ultimately power their movement within cells. “The most important unanswered question in the field is how do these components work together? That is, how do you build a machine that is more than the sum of its parts?” he says.

Now, in two recent papers in the journals eLife and Current Biology, Cheeseman and his colleagues help shed light on this central question.

Back to the drawing board

As recently as 15 years ago, scientists assumed that in dividing cells, chromosomes move the way many other cellular objects move — transported by tiny molecular motors. These mini-motors are specifically designed to travel along roads made from rod-like structures called microtubules. Like a car cruising on a highway, they can carry cargo over long distances. Although such microtubule-based vehicles seemed a logical suspect, when scientists inactivate them in human cells, chromosomes can still move and segregate just fine. So something else must contribute the necessary molecular muscle.

“We basically had to throw out the major hypothesis that was out there and go back to the drawing board,” says Cheeseman.

Over the last several years, he and other scientists in the field have helped develop a clearer view of how this process works and who the key players are that enable a very different type of movement. Consider a car sitting motionless on a highway. Rather than revving its own engine to generate motion, the highway itself moves, shrinking or growing while the car hangs on. “It is a radically different way of imagining this movement process,” says Cheeseman. “An important part of my lab’s mission has been to figure out how do you build a motor like that? What are the factors required and how do they act?”

Of course, the highway — or more precisely, the microtubule — must grow and shrink as needed. But even more important, there must also be an apparatus that can enable chromosomes to hold on to such a dynamic structure. As Cheeseman and his colleagues have uncovered, this coupling requires a suite of highly sophisticated molecular players.

Building an unusual machine

Cheeseman and his laboratory have focused on three key groups or complexes of proteins that play essential roles in chromosome segregation in human cells. These components assemble together to form a kind of molecular tether point on chromosomes (called the kinetochore) where microtubules attach.

Diagram of the kinetochore/microtube interface
Diagram of the kinetochore/microtube interface
Courtesy: David Kern/Whitehead Institute

Among this trio of parts, the most critical is the Ndc80 complex. “It is the major connection between the kinetochore and the microtubule,” says Cheeseman. As a postdoc, he discovered the biochemical properties that enable this Ndc80 complex to grab on to microtubules, research that sparked his lab’s quest to study the various pieces of the kinetochore machinery and how they work.

While Ndc80 forms a critical linkage, it lacks some key capabilities, like processivity — the ability to keep ahold of something while it moves. In a series of papers, one published in 2009, another in 2012, and a new one in Current Biology, Cheeseman’s team revealed that Ska1 can perform this crucial function. That is, it has the biochemical capacity to enable chromosomes to hang onto microtubules while they grow and as they shrink, an activity that it can impart to the Ndc80 complex. “These are pretty powerful properties,” says Cheeseman.

Diving even deeper into Ska1’s bag of tricks, Julie Monda and Ian Whitney, lead authors of the Current Biology paper, went on to decipher the precise molecular features that enable the complex’s dynamic capabilities, uncovering multiple surfaces that associate with microtubules and enable Ska1 to undergo something akin to molecular somersaults. These somersaults are what allow it to maintain its association with microtubules.

The third complex, Astrin-SKAP, also plays a unique role. As Cheeseman’s team described in their recent eLife paper, led by first author David Kern, it serves as a master stabilizer — like a final drop of superglue to secure everything in place. “It’s the last thing that comes in and helps lock down these interactions, so you can stabilize and maintain them,” says Cheeseman.

Uncovering its role was no easy feat. Astrin-SKAP proved to be rather temperamental biochemically, complicating Kern’s efforts to purify and manipulate it in the laboratory. Also, as he and his colleagues discovered, a tiny piece of the structure had previously gone undetected; it works alongside the rest of the complex and is required for its normal function. Perhaps the most important revelation was that Astrin-SKAP doesn’t just work alone — it also coordinates with Ndc80. “This is an important finding for how we think about these components as a whole,” saysCheeseman.

Although questions remain about how all of these parts work together and how other pieces may come into play, Cheeseman believes these studies provide an exciting start. “The first human kinetochore component wasn’t identified until 1987, when many of the other key processes in the cell had already been intensively studied,” he says. “There are so many exciting questions that are accessible now that we have these tools and knowledge.”

Now, he and his colleagues will continue to meld approaches in cell biology and biochemistry to decode the inner workings of the kinetochore. That includes understanding how the various components operate not only in individual cells, but also in multicellular organisms.

“We are currently thinking a lot about the physiological context— that is, what matters to cells and to an organism,” says Cheeseman. “The work that our lab and others have conducted over the past two decades has given us a molecular handle on this problem. I’m excited to be able to apply these finding to understanding the ways that cell division is altered in development and in disease states.”

Written by Nicole Davis
* * *
Iain Cheeseman’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 associate professor of biology at Massachusetts Institute of Technology.
* * *
Full citations:
“Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80”
eLife 2017;6:e26866 August 25, 2017. DOI: 10.7554/eLife.26866
David M Kern (1,2), Julie K Monda (1,2), Kuan-Chung Su (1), Elizabeth M Wilson-Kubalek (3), and Iain M Cheeseman (1,2).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
3. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
“Microtubule tip tracking by the spindle and kinetochore protein Ska1 requires diverse tubulin-interacting surfaces”
Current Biology, online November 16, 2017. DOI: 10.1016/j.cub.2017.10.018
Julie K. Monda (1,2,6), Ian P. Whitney (1,6), Ekaterina V. Tarasovetc (3,4), Elizabeth Wilson-Kubalek (5), Ronald A. Milligan (5), Ekaterina L. Grishchuk (3), and Iain M. Cheeseman (1,2).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
3. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
4. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia
5. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
6. These authors contributed equally
New player in cellular signaling

Researchers have identified a key nutrient sensor in the mTOR pathway that links nutrient availability to cell growth.

Nicole Giese Rura | Whitehead Institute
November 9, 2017

To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.

The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.

Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.

Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.

“There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”

Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.

“People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”

The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.

“It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”

This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.

A new workflow for natural product characterization comes ashore with red algae
October 30, 2017

CAMBRIDGE, Mass. – A few years ago while paddling off the coast near La Jolla, California, avid surfer Roland Kersten noticed a piece of red algae (Laurenica pacifica) bobbing alongside his surfboard. Kersten, whose background is in natural product chemistry, was intrigued.

Natural products—chemicals from living organisms such as plants and algae—represent a rich source of potential therapeutics. A majority of anti-cancer drugs are natural product-based or inspired. One such well-known natural product—the potent anti-cancer drug Taxol—was identified in the bark of a yew tree.

Marine algae, like the red algae Kersten found, are often rich in compounds called sesquiterpenes, some of which have been shown to have potential medicinal attributes. Since the 1970s, scientists identified many sesquiterpenes produced by Laurencia species with anti-cancer properties. The identification techniques usually required about tens of milligrams of purified compounds, which were obtained from more than a kilogram of algae. Because Laurencia and the reef ecosystems in which it thrives are protected, and such large-scale harvesting for scientific or medicinal purposes is no longer tenable, Kersten had to devise a different approach to analyze its sesquiterpenes.

Kersten received a collection permit to clamber over the rocky shore at deep low tide to collect a hand-sized sample of the red algae. Now a postdoctoral fellow in the lab of Whitehead Member and Massachusetts Institute of Technology assistant professor of biology Jing-Ke Weng, Kersten’s first task was to search the RNA sequences of all genes expressed in his red algae sample to find those whose product seemed likely to be enzymes that make sesquiterpenes.  In order to determine the product generated by these enzymes, he engineered them in yeast and isolated its sesquiterpene products.

In order to define the first step in the biogenesis of sesquiterpenes in red algae, Kersten wanted to see the precise 3-D structure of the isolated sesquiterpene. But the small handful of algae he had obtained produced only a fraction of the amount required for x-ray crystallography, the established method for determining a compound’s absolute structure. So Kersten tried a method recently developed by collaborator Makoto Fujita at the University of Tokyo that requires only a few nanograms of material: soaking extracted compounds into a special crystalline sponge, which supports the sample’s molecular shape while it is bombarded with x-rays to accurately determine the 3-D conformation of a molecule. A new combination of the crystalline sponge method and nuclear magnetic resonance spectroscopy by the Fujita group revealed the structure of prespatane.

With the compound’s structure in hand, Kersten is closer to understanding how Laurenciabiosynthesizes its sesquiterpenes and how to engineer yeast to produce the same molecules for medicinal research at scale—without touching the red algae flourishing on protected reefs. And the novel workflow—spanning genomics, metabolomics, synthetic biology, and x-ray crystallography with crystalline sponges—established by Weng, Kersten, and their collaborators may expedite the identification of other promising compounds produced by organisms from both land and sea.

Other contributors to this work include Shoukou Lee of Tokyo University, Daishi Fujita of Tokyo University and Whitehead Institute, Tomáš Pluskal of Whitehead Institute.  The team also collaborated with researchers from Scripps Institution of Oceanography and Salk Institute of Biological Sciences.

This work was supported by Howard Hughes Medical Institute, the Simons Foundation, the Helen Hay Whitney Foundation, the Pew Scholars Program in the Biomedical Sciences, the Searle Scholars Program, and the Japan Science and Technology Agency.

 Written by Nicole Giese Rura
* * *
Jing-Ke Weng’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:
“A Red Algal Bourbonane Sesquiterpene Synthase Defined by Microgram-scale NMR-coupled Crystalline Sponge XRD Analysis”
Journal of the American Chemical Society, online October 30, 2017.
Roland D. Kersten (1,6), Shoukou Lee (2,6) , Daishi Fujita (1,2) , Tomáš Pluskal (1) , Susan Kram (3), Jennifer E. Smith (3) , Takahiro Iwai (2) , Joseph P. Noel (4) , Makoto Fujita (2), Jing-Ke Weng (1,5).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, United States
2. Graduate School of Engineering, The University of Tokyo, JST-ACCEL, Tokyo, Japan
3. Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, United States
4. Howard Hughes Medical Institute, Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA, United States
5. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
6. These authors contributed equally
School of Science welcomes new faculty members

This fall brings 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

School of Science
October 10, 2017

This fall, the MIT School of Science has welcomed 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

Ian J. M. Crossfield focuses on the atmospheric characterization of exoplanets through all possible methods — transits, eclipses, phase curves, and direct imaging — from the ground and from space, with an additional interest in the discovery of new exoplanets, especially those whose atmospheres that can be studied in more detail. He joins the MIT Department of Physics as an assistant professor.

Joey Davis, an assistant professor in the Department of Biology, studies the molecular mechanisms underpinning autophagy using biochemical, biophysical, and structural biology techniques such as mass spectrometry and cryo-electron microscopy. This pathway is responsible for protein and organelle degradation and has been linked to a variety of aging associated disorders including neurodegeneration and cancer.

Daniel Harlow works on black holes and cosmology, viewed through the lens of quantum gravity and quantum field theory. He has joined the Department of Physics as assistant professor.

Philip Harris, a new assistant professor in the Department of Physics, searches for dark matter, seeking a deeper understanding of the petabytes of data collected at the Large Hadron Collider. Much of his research exploits new techniques to resolve the structure of quark and gluon decays, known as jet substructure.

Or Hen studies quantum chromodynamics effects in the nuclear medium, and the interplay between partonic and nucleonic degrees of freedom in nuclei, conducting experiments at the Thomas Jefferson and Fermi National Accelerator Laboratories, as well as other accelerators around the world. He has joined the faculty as an assistant professor in the Department of Physics and the Laboratory of Nuclear Science.

Laura Kiessling investigates how carbohydrates are assembled, recognized, and function in living cells, which is crucial to understanding key biological processes such as bacterial cell wall biogenesis, bacteria chemotaxis, enzyme catalysis and inhibition, immunity, and stem cell propagation and differentiation. She is the new Novartis Professor of Chemistry.

Rebecca Lamason investigates how intracellular bacterial pathogens hijack host cell processes to promote infection. In particular, she studies how Rickettsia parkeri and Listeria monocytogenes move through tissues via a process called cell-to-cell spread. She has joined the Department of Biology as an assistant professor.

Sebastian Lourido studies the molecular events that enable parasites in the phylum Apicomplexa to remain widespread and deadly infectious agents. Lourido uses Toxoplasma gondii to model processes conserved throughout the phylum, in order to expand our understanding of eukaryotic diversity and identify specific features that can be targeted to treat parasite infections. He has been welcomed into the Department of Biology as an assistant professor.

Ronald T. Raines, who has joined the faculty as the Firmenich Professor of Chemistry, uses techniques that range from synthetic chemistry to cell biology to illuminate in atomic detail both the chemical basis and the biological purpose for protein structure and protein function. He seeks insights into the relationship between amino-acid sequence and protein function (or dysfunction), as well as to the creation of novel proteins with desirable properties.

Giulia Saccà is an algebraic geometer with a focus on hyperkähler and Calabi-Yau manifolds, K3 surfaces, moduli spaces of sheaves, families of abelian varieties and their degenerations, and symplectic resolutions. She is now an assistant professor in the Department of Mathematics.

Stefani Spranger studies the interactions between cancer and the immune system, with the goal of improving existing immunotherapies or developing novel therapeutic approaches. Spranger seeks to understand how CD8 T cells, otherwise known as killer T cells, are excluded from the tumor microenvironment, with a focus on lung and pancreatic cancers. She has joined the Department of Biology as an assistant professor.

Daniel Suess works at the intersection of inorganic and biological chemistry, studying redox reactions that underpin global biogeochemical cycles, metabolism, and energy conversion. He develops chemical strategies for attaining precise, molecular-level control over the structures of complex active sites. In doing so, his research yields detailed mechanistic insight and enables the preparation of catalysts with improved function. Suess is an assistant professor in the Department of Chemistry.

Wei Zhang is a number theorist who works in arithmetic geometry, with special interest in fundamental objects such as L-functions, which appear in the Riemann hypothesis and its generalizations, and are central to the Langlands program. Zhang has joined the Department of Mathematics as a full professor.

Yufei Zhao, who has joined the Department of Mathematics as an assistant professor, works in combinatorics and graph theory, and is especially interested in problems with extremal, probabilistic, and additive flavors.

Department of Biology hosts its first Science Slam

Eight biology trainees had just three minutes to explain their research and earn favor with the judges and audience in new yearly event.

Raleigh McElvery | Department of Biology
October 5, 2017

Nearly 300 spectators crowded into a lecture hall at the Ray and Maria Stata Center on a recent Tuesday to witness the first annual Science Slam, hosted by MIT’s Department of Biology.

A science slam features a series of short presentations where researchers explain their work in a compelling manner and — as the name suggests — make an impact. The presentations aren’t just talks, they’re performances geared towards a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges.

The jury included Ellen Clegg, editorial page editor of The Boston Globe and co-author of two award-winning books, “ChemoBrain” and “The Alzheimer’s Solution;” Emilie Marcus, CEO of Cell Press and editor-in-chief of the flagship journal, Cell; and Ari Daniel, an independent science reporter who produces digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were five graduate students and three postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, the Broad Institute, the Koch Institute for Integrative Cancer Research, and the Picower Institute for Learning and Memory. The storytellers were:

  • Sahin Naqvi, from David Page’s lab, who spoke about the evolution of genetic sex differences in mammals, as well as how these differences impact the likelihood of developing certain diseases based on gender;
  • Sudha Kumari, from Darrell Irvine’s lab, who spoke about her work investigating immune cell interactions — specifically how T cells communicate using physical contact;
  • Deniz Atabay, from Peter Reddien’s lab, who spoke about the ways cells in flatworms self-organize during regeneration to re-form organs, tissues, and even neural circuits;
  • Emma Kowal, from Christopher Burge’s lab, who spoke about her goals to demystify the ways in which certain noncoding regions of genetic sequence, known as introns, contribute to protein production;
  • Xin Tang, from Rudolf Jaenisch’s lab, who spoke about a technique to illuminate the seemingly invisible changes in brain cells that trigger disease, using a glowing enzyme from a firefly;
  • Nicole Aponte, from Troy Littleton’s lab, who spoke about her ability to manipulate brain cell activity in the fruit fly, and study how defects in neuronal connections contribute to developmental disorders;
  • Karthik Shekhar, from Aviv Regev’s lab, who spoke about his efforts to identify and manipulate different types of brain cells, understanding how they assemble into complex networks to facilitate learning, memory, and — in some cases — disease; and
  • Monika Avello, from Alan Grossman’s lab, who spoke about “bacterial sexology,” that is, how and why these organisms choose to block unwanted sexual advances from fellow bacteria.

Vivian Siegel, who oversees the department’s communications efforts, moderated the event. Siegel and the Building 68 communications team joined forces with three members of the Building 68 MIT Postdoctoral Association — Ana Fiszbein, Isabel Nocedal, and Peter Sudmant — to publicize the event and to host two pre-slam workshops, as well as one-on-one training sessions with individual participants.

“Participating in a Science Slam seemed like a great way for our trainees to learn how to communicate to a nonspecialized audience, which is something they will need to be able to do throughout their careers,” Siegel said. “We really wanted to develop a camaraderie among the participants, and bring trainees together from across the department to help each other tell compelling stories about their science.”

Kowal — whose talk was titled “Gone but Not Forgotten: How Do Introns Enhance Gene Expression?”  — ultimately took home both the audience and jury cash prizes. Kowal completed her undergraduate degree in chemical and physical biology at Harvard before coming to MIT for graduate school. Her dream is to write science fiction, so she decided she’d better study science so she’d know what to write about.

“I really enjoyed seeing people get stoked about introns, and the fact that they enhance gene expression,” she said. “It’s a great way to get comfortable explaining your project in a compelling way to a broad audience. Since you’ll probably be telling people about your work for a while, I think it’s a very good use of time to practice doing that.”

Biologists identify possible new strategy for halting brain tumors

Cutting off a process that cancerous cells rely on can force them to stop growing.

Anne Trafton | MIT News Office
September 28, 2017

MIT biologists have discovered a fundamental mechanism that helps brain tumors called glioblastomas grow aggressively. After blocking this mechanism in mice, the researchers were able to halt tumor growth.

The researchers also identified a genetic marker that could be used to predict which patients would most likely benefit from this type of treatment. Glioblastoma is usually treated with radiation and the chemotherapy drug temozolamide, which may extend patients’ lifespans but in most cases do not offer a cure.

“There are very few specific or targeted inhibitors that are used in the treatment of brain cancer. There’s really a dire need for new therapies and new ideas,” says Michael Hemann, an associate professor of biology at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and a senior author of the study.

Drugs that block a key protein involved in the newly discovered process already exist, and at least one is in clinical trials to treat cancer. However, most of these inhibitors do not cross the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain. The MIT team hopes to develop drugs that can cross this barrier, possibly by packaging them into nanoparticles.

The study, which appears in Cancer Cell on Sept. 28, is a collaboration between the labs of Hemann; Jacqueline Lees, associate director of the Koch Institute and the Virginia and D.K. Ludwig Professor for Cancer Research; and Phillip Sharp, an MIT Institute Professor and member of the Koch Institute. The paper’s lead authors are former MIT postdoc Christian Braun, recent PhD recipient Monica Stanciu, and research scientist Paul Boutz.

Too much splicing

Several years ago, Stanciu and Braun came up with the idea to use a type of screen known as shRNA to seek genes involved in glioblastoma. This test involves using short strands of RNA to block the expression of specific genes. Using this approach, researchers can turn off thousands of different genes, one per tumor cell, and then measure the effects on cell survival.

One of the top hits from this screen was the gene for a protein called PRMT5. When this gene was turned off, tumor cells stopped growing. Previous studies had linked high levels of PRMT5 to cancer, but the protein is an enzyme that can act on hundreds of other proteins, so scientists weren’t sure exactly how it was stimulating cancer cell growth.

Further experiments in which the researchers analyzed other genes affected when PRMT5 was inhibited led them to hypothesize that PRMT5 was using a special type of gene splicing to stimulate tumor growth. Gene splicing is required to snip out portions of messenger RNA known as introns, that are not needed after the gene is copied into mRNA.

In 2015, Boutz and others in Sharp’s lab discovered that about 10 to 15 percent of human mRNA strands still have one to three “detained introns,” even though they are otherwise mature. Because of those introns, these mRNA molecules can’t leave the nucleus.

“What we think is that these strands are basically an mRNA reservoir. You have these unproductive isoforms sitting in the nucleus, and the only thing that keeps them from being translated is that one intron,” says Braun, who is now a physician-scientist at Ludwig Maximilian University of Munich.

In the new study, the researchers discovered that PRMT5 plays a key role in regulating this type of splicing. They speculate that neural stem cells utilize high levels of PRMT5 to guarantee efficient splicing and therefore expression of proliferation genes. “As the cells move toward their mature state, PRMT5 levels drop, detained intron levels rise, and those messenger RNAs associated with proliferation get stuck in the nucleus,” Lees says.

When brain cells become cancerous, PRMT5 levels are typically boosted and the splicing of proliferation-associated mRNA is improved, ultimately helping the cells to grow uncontrollably.

Predicting success

When the researchers blocked PRMT5 in tumor cells, they found that the cells stopped dividing and entered a dormant, nondividing state. PRMT5 inhibitors also halted growth of glioblastoma tumors implanted under the skin of mice, but they did not work as well in tumors located in the brain, because of the difficulties in crossing the blood-brain barrier.

Unlike many existing cancer treatments, the PRMT5 inhibitors did not appear to cause major side effects. The researchers believe this may be because mature cells are not as dependent as cancer cells on PRMT5 function.

The findings shed light on why researchers have previously found PRMT5 to be a promising potential target for cancer treatment, says Omar Abdel-Wahab, an assistant member in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, who was not involved in the study.

“PRMT5 has a lot of roles, and until now, it has not been clear what is the pathway that is really important for its contributions to cancer,” says Abdel-Wahab. “What they have found is that one of the key contributions is in this RNA splicing mechanism, and furthermore, when RNA splicing is disrupted, that key pathway is disabled.”

The researchers also discovered a biomarker that could help identify patients who would be most likely to benefit from a PRMT5 inhibitor. This marker is a ratio of two proteins that act as co-factors for PRMT5’s splicing activity, and reveals whether PRMT5 in those tumor cells is involved in splicing or some other cell function.

“This becomes really important when you think about clinical trials, because if 50 percent or 25 percent of tumors are going to have some response and the others are not, you may not have a way to target it toward those patients that may have a particular benefit. The overall success of the trial may be damaged by lack of understanding of who’s going to respond,” Hemann says.

The MIT team is now looking into the potential role of PRMT5 in other types of cancer, including lung tumors. They also hope to identify other genes and proteins involved in the splicing process they discovered, which could also make good drug targets.

Spearheaded by students and postdocs from several different labs, this project offers a prime example of the spirit of collaboration and “scientific entrepreneurship” found at MIT and the Koch Institute, the researchers say.

“I think it really is a classic example of how MIT is a sort of bottom-up place,” Lees says. “Students and postdocs get excited about different ideas, and they sit in on each other’s seminars and hear interesting things and pull them together. It really is an amazing example of the creativity that young people at MIT have. They’re fearless.”

The research was funded by the Ludwig Center for Molecular Oncology at MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Three MIT biologists receive NIH Outstanding Investigator Awards

Graham Walker, Michael Yaffe, and Robert Weinberg earn support from the National Institutes of Health to further their research endeavors.

Raleigh McElvery | Department of Biology
September 19, 2017

This fall, two faculty members from the MIT Department of Biology received R35 Outstanding Investigator Awards sponsored by the National Institute of Environmental Health Sciences (NIEHS), while a third garnered the same distinction from the National Cancer Institute (NCI). These awards provide long-term support to experienced investigators with outstanding records of research productivity as they undertake lengthy projects with unusual potential.

Graham Walker, the American Cancer Society Professor in the Department of Biology at MIT, a member of the Center for Environmental Health Sciences, and affiliate member of the Koch Institute for Integrative Cancer Research, is one of two biology faculty to earn the R35 Outstanding Investigator Award from the NIEHS.

This award is supported by the NIEHS through the Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program. The program recognizes outstanding investigators in the field of environmental health, potentially offering up to $750,000 per year over the next eight years.

The awardees include both mid-career and senior researchers, whose work spans many aspects environmental health science — including technology development, mechanistic, clinical, and epidemiological research. A total of eight investigators received the NIEHS RIVER R35 this year.

“The RIVER program is designed to fund people, not projects,” said David Balshaw, chief of the NIEHS Exposure, Response, and Technology Branch who leads the NIEHS team overseeing this initiative. “It gives outstanding environmental health scientists stable funding, time, and, importantly, flexibility to pursue creative scientific ideas, rather than constantly writing grants to support their research programs.”

Walker will use his award to continue investigating the fundamental mechanisms of mutagenesis and DNA repair, with a special emphasis on the Rev1/3/7-dependent pathway of mutagenic translation synthesis found in eukaryotes, including humans. He and his colleagues recently published evidence suggesting that inhibiting this pathway could potentially improve chemotherapy.

Michael Yaffe, the David H. Koch Professor of Science at MIT, a member of the Koch Institute and the Center for Environmental Health Sciences, and attending surgeon at the Beth Israel Deaconess Medical Center, also received a NIEHS RIVER R35 award.

Yaffe’s work concerns how cells respond to injury, including damage to DNA and RNA molecules arising because of the environment and in response to drugs used to treat cancer. He is also interested in the relationship between inflammation, blood clotting, and cancer. He employs multidisciplinary approaches harnessing techniques from biochemistry, structural and cell biology, computer science, and systems biology/engineering.

Yaffe will use his funds to further a project investigating the roles of protein kinases in coordinating cellular responses to damage to both DNA and RNA molecules.

Robert Weinberg, founding member of the Whitehead Institute, professor of biology at MIT, an affiliate member of the Koch Institute, and director of the MIT Ludwig Center for Molecular Oncology, has received his R35 Outstanding Investigator Award from the NCI.

The award provides up to $600,000 per year over seven years to accomplished cancer researchers, nominated by their institutions, who have served as principal investigators on an NCI grant for the last five years. A total of 18 investigators received the NCI Outstanding Investigator Award this year.

“The NCI Outstanding Investigator Award addresses a problem that many cancer researchers experience: finding a balance between focusing on their science while ensuring that they will have funds to continue their research in the future,” said Dinah Singer, director of NCI’s Division of Cancer Biology. “With seven years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs.”

Weinberg is a pioneer in cancer research, best known for his role in discovering the first human oncogene — a gene that, when activated, can spur tumor growth. His lab is also credited with isolating the first known tumor suppressor gene.

He will use his funds to delve into the mechanisms of metastasis — the process that allows cancer cells to spread. He aims to learn more about how these cells disseminate from primary tumors, as well as how they become established in distant tissues after they metastasize.

New faculty welcomed to Department of Biology

Assistant professors Joey Davis and Rebecca Lamason will spearhead research initiatives into fundamental cellular processes.

Raleigh McElvery | Department of Biology
September 11, 2017

MIT’s Department of Biology is welcoming two new assistant professors, Joey Davis and Rebecca Lamason, this September. The duo will augment the department’s efforts in basic research, probing fundamental facets of cellular processes like molecular degradation and bacterial infection.

“I am thrilled that Becky and Joey have joined our department,” says Alan Grossman, department head. “They bring new research areas and approaches that fit well with our overarching goals to help solve fundamental biological problems. I anticipate that their expertise and interests will enable collaborations within MIT and beyond.”

The arrival of Davis and Lamason brings the number of recent biology faculty additions to five since January.

Joey Davis

Joey Davis investigates how cells maintain a delicate internal balance of assembling and dismantling their own machinery, particularly macromolecules. A cell’s ability to keep the precarious balance of this process in check often diminishes with age, and when it goes awry, disease can ensue.

Born in Durango, Colorado, but raised in Long Beach, California, Davis became interested in how things were built by emulating his construction worker father. Assembling bicycles and other objects spurred Davis’ curiosity about the nuts and bolts of the natural world and he soon realized that, unlike bikes, biological systems were not so easily parsed.

Davis went on to earn dual bachelor’s degrees in biological engineering and computer science from the University of California at Berkeley. He arrived at MIT as a graduate student shortly thereafter, jointly advised by professors Robert Sauer and Tania Baker, both of whom are based in Building 68, where Davis will now run his own lab. He also served as a teaching assistant for 7.51 (Principles of Biochemical Analysis), and as an advisor to MIT’s team for the International Genetically Engineered Machines (iGEM) competition.

Davis became enthralled by molecular disassembly, particularly in bacteria. After a brief foray into the biotechnology sector, he returned to his California roots to pursue his postdoctoral training at the Scripps Research Institute in La Jolla. He brought with him his MIT-inspired fervor for large cellular machinery, and in doing so encountered his macromolecule of choice: the ribosome. Sometimes referred to by researchers as the “construction workers” of cells, ribosomes play a key role in building molecules from genetic blueprints. After three years, he was awarded a K99/R00 Pathway to Independence Award from the National Institute of Aging, which included an affiliation at the Sanford Burnham Prebys Medical Discovery Institute. The award will also help fund his first several years of research at MIT.

In his own lab, Davis seeks to determine how cells assemble and destroy ribosomes and other macromolecules, as well as how they remove harmful protein aggregates and dysfunctional organelles. These functions are often compromised due to age, genetic mutations, and environmental stresses, leading to diseases like cancer, diabetes, and neurodegenerative disorders. Davis says he is excited to further examine these processes at MIT.

“The questions I’m asking about how the degradation system is constructed and how it targets substrates are similar to those I pursued in graduate school — but the answers will likely be completely different,” Davis says. “The members of the MIT research community truly want to know how the natural world works, and that mindset draws me in today as much as it did 13 years ago.”

Davis has been hard at work developing a series of new research techniques, some involving cryo-electron microscopy, a method to image large macromolecules at high resolution. His discoveries could ultimately assist pharmaceutical development — improving antibiotics and anti-cancer therapeutics — and perhaps enabling scientists to one day engineer their own bigger and better molecules.

Rebecca Lamason

Rebecca Lamason investigates what happens when cellular functions are hijacked by unwanted interlopers — namely, the bacteria that cause diseases such as spotted fever and meningitis. Her interdisciplinary work spans multiple fields, including immunology, genetics, biochemistry, cell biology, and microbiology.

Growing up in a family that was interdisciplinary in its own right, composed of both artists and mechanics, Lamason has always sought to examine fundamental questions from multiple perspectives.

After earning a bachelor’s degree in molecular biology from Millersville University in Pennsylvania, she went on to graduate school at the Johns Hopkins University School of Medicine, where she immersed herself in the field of immunology. There she demonstrated how a molecule called CARD11 regulates immune cell activation, a discovery with potential applications for cancer therapeutics. She also served as a teaching assistant for the school’s graduate immunology course and co-founded the Immunology Student Journal Club.

It wasn’t until her postdoctoral training at the University of California at Berkeley, however, that Lamason found her model systems: two species of bacteria called Rickettsia parkeri and Listeria monocytogenes.

The two pathogens lay siege to cells in much the same way, entering and leveraging preexisting internal structures to build tails for rapid migration to neighboring cells. Lamason hypothesized that to do so, the intruders must also take over the complex communication systems between cells. Common scientific consensus held for years that Rickettsia, Listeria, and several other species of bacteria spread in a similar manner — using their tails to propel themselves and ram into the host’s cell wall to gain access to neighboring cells. Lamason, however, demonstrated this isn’t always the case and that Rickettsia tend to lose their tails and must then rely on the host cell’s internal machinery instead to invade neighboring cells.

Lamason was drawn to MIT by the diverse array of research efforts that are unified by a collaborative desire to explore the mechanistic details of cellular systems. Like Davis, she received a K99/R00 Pathway to Independence Award in 2015 — in her case from the National Institute of General Medical Sciences. Her lab will continue to investigate the interplay between invasive bacteria and their hosts, aiming to clarify how cell-to-cell spread varies between species. She plans to leverage advanced imaging platforms with tools from cell biology, microbiology, genetics, and biophysics to gain a deeper understanding of how these pathogens manipulate their hosts.

“My goal is to understand this virulence mechanism in order to prevent disease, and to use pathogens as tools to better understand host cell biology,” Lamason says. “This type of study lends itself naturally to interdisciplinary work. I love the challenge of learning new things and using multiple approaches to clarify important biological questions.”