Author: mantulin

Department of Biology hosts 2017 Massachusetts Junior Academy of Science Symposium

High school students present research projects to build communication skills while earning membership to the American Junior Academy of Science.

Raleigh McElvery | Department of Biology
October 24, 2017

On Oct. 14, 22 school students from across the state presented their research projects at the annual Massachusetts Junior Academy of Science (MassJAS) Symposium.

The talks were split into two concurrent sessions based on subject: biological and environmental sciences; and engineering, chemistry, mathematics, and physics. Participants were selected based on merit and ranking in this year’s Massachusetts State Science and Engineering Fair.

Judges nominated three students from the biology session and four from physics and engineering as American Junior Academy of Science (AJAS) delegates. Delegates are invited to attend the AJAS Convention, which will be held in Austin, Texas this coming February. The AJAS is a national honor society that meets annually in conjunction with the American Association for the Advancement of Science — the world’s largest science organization and the publisher of Science. All participants were inducted as AJAS fellows.

The sessions took place in adjacent lecture rooms in Building 68. The event was organized by Mandana Sassanfar, director of diversity and science outreach for MIT’s Department of Biology and Department of Brain and Cognitive Sciences, as well as the director of MassJAS. During the event, delegates toured local research institutions, shared their projects with others in the field, and attended conference sessions.

At this year’s MassJAS symposium, the jury for the biological and environmental science session was composed of three graduate students and postdoc from the MIT Department of Biology.

“I really enjoyed hearing how these projects came to be, and what inspired students to ask their respective research questions,” said Sora Kim, a third year graduate student in Tania Baker’s lab and a returning judge. “Some students did these projects at home, while others had collaborations with researchers at local universities. In many cases, these were their first science projects, so being able to understand their own projects and also convey their ideas to a more general audience is really important.”

First-time judge Summer Morrill, a third year graduate student in Angelika Amon’s lab, agreed that learning to present ideas clearly in ways that inspire others is key to the scientific process. “I was excited to hear what people at the high school level think is important in science, because they’re the next generation of scientists,” she said.

Each participant had ten minutes to present, followed by an audience question-and-answer session. The biology-related talks ranged from antimicrobial resistance to gene editing techniques to the effects of wifi router radiation.

Joshua Powers and Natalia Huynh, both juniors at the Everett High School STEM Academy, presented first, describing the results of their summer research project at MIT as part of the LEAH Knox Scholars pilot program. Powers and Huynh pooled their findings, isolating and characterizing bacterial specimens from the Charles River.

“We’re friends and we both go to the same high school, so it was easy to collaborate with both our ideas and our data,” said Powers. “The LEAH Knox Scholars program was intense in that we had the chance to perform more advanced procedures with equipment we’ve never used before in school.”

Huynh also enjoyed tackling larger research questions with more refined tools, adding, “We practiced explaining our results this summer, so today’s presentation was similar to what we’d already done — but a little more intense because it was a competition.”

Nancy Cianchetta, who teaches biotechnology at Everett High School and serves as the coordinator for the STEM Academy, said Powers and Huynh will be part of the very first class to graduate from the Academy. She and many of her students have participated in MIT biology outreach programs over the years.

“I’ve taken my classes here for field trips and career exploration days, and many of my students come for the spring lecture series at the Whitehead Institute,” she said. “The kids get so excited to come to MIT.”

While some participants shared data they’d only just begun to analyze, others had been tackling the same research question for over a year.

Evan Mizerak, a returning MassJAS Symposium winner and senior at Wachusett Regional High School, has spent the past two-and-a-half years collaborating with researchers at the University of Massachusetts Medical School on his project related to heritable infertility in fruit flies.

Mizerak attended last year’s AJAS Convention in Boston, as well as the MIT-sponsored Breakfast with Scientists. This year, delegates met with esteemed faculty, including Institute Professor Phillip Sharp, the winner of the 1993 Nobel Prize in physiology or medicine and a member of the Department of Biology and the Koch Institute for Integrative Cancer Research.

“The AJAS Convention was incredible last year, because we had the chance to meet researchers from around the country — not just in and around Massachusetts,” he said. “At the Breakfast with Scientists, we met with Nobel Prize winners. Being introduced to people I consider celebrities was just amazing.”

“You wouldn’t expect anyone that famous to be interested in our work,” added Emma Kelly, a junior from Newton Country Day School and also a returning presenter. “But these professionals were genuinely curious, and often gave us ideas for new projects and things like that. It was such an incredible opportunity.”

MIT neuroscientists build case for new theory of memory formation

Existence of “silent engrams” suggests that existing models of memory formation should be revised.

Anne Trafton | MIT News Office
October 23, 2017

Learning and memory are generally thought to be composed of three major steps: encoding events into the brain network, storing the encoded information, and later retrieving it for recall.

Two years ago, MIT neuroscientists discovered that under certain types of retrograde amnesia, memories of a particular event could be stored in the brain even though they could not be retrieved through natural recall cues. This phenomenon suggests that existing models of memory formation need to be revised, as the researchers propose in a new paper in which they further detail how these “silent engrams” are formed and re-activated.

The researchers believe their findings offer evidence that memory storage does not rely on the strengthening of connections, or “synapses,” between memory cells, as has long been thought. Instead, a pattern of connections that form between these cells during the first few minutes after an event occurs are sufficient to store a memory.

“One of our main conclusions in this study is that a specific memory is stored in a specific pattern of connectivity between engram cell ensembles that lie along an anatomical pathway. This conclusion is provocative because the dogma has been that a memory is instead stored by synaptic strength,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, the director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, and the study’s senior author.

The researchers also showed that even though memories held by silent engrams cannot be naturally recalled, the memories persist for at least a week and can be “awakened” days later by treating cells with a protein that stimulates synapse formation.

Dheeraj Roy, a recent MIT PhD recipient, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Oct. 23. Other authors are MIT postdoc Shruti Muralidhar and technical associate Lillian Smith.

Silent memories

Neuroscientists have long believed that memories of events are stored when synaptic connections, which allow neurons to communicate with each other, are strengthened. Previous studies have found that if synthesis of certain cellular proteins is blocked in mice immediately after an event occurs, the mice will have no long-term memory of the event.

However, in a 2015 paper, Tonegawa and his colleagues showed for the first time that memories could be stored even when synthesis of the cellular proteins is blocked. They found that while the mice could not recall those memories in response to natural cues, such as being placed in the cage where a fearful event took place, the memories were still there and could be artificially retrieved using a technique known as optogenetics.

The researchers have dubbed these memory cells “silent engrams,” and they have since found that these engrams can also be formed in other situations. In a study of mice with symptoms that mimic early Alzheimer’s disease, the researchers found that while the mice had trouble recalling memories, those memories still existed and could be optogenetically retrieved.

In a more recent study of a process called systems consolidation of memory, the researchers found engrams in the hippocampus and the prefrontal cortex that encoded the same memory. However, the prefrontal cortex engrams were silent for about two weeks after the memory was initially encoded, while the hippocampal engrams were active right away. Over time, the memory in the prefrontal cortex became active, while the hippocampal engram slowly became silent.

In their new PNAS study, the researchers investigated further how these silent engrams are formed, how long they last, and how they can be re-activated.

Similar to their original 2015 study, they trained mice to fear being placed in a certain cage, by delivering a mild foot shock. After this training, the mice freeze when placed back in that cage. As the mice were trained, their memory cells were labeled with a light-sensitive protein that allows the cells to be re-activated with light. The researchers also inhibited the synthesis of cellular proteins immediately after the training occurred.

They found that after the training, the mice did not react when placed back in the cage where the training took place. However, the mice did freeze when the memory cells were activated with laser light while the animals were in a cage that should not have had any fearful associations. These silent memories could be activated by laser light for up to eight days after the original training.

Making connections

The findings offer support for Tonegawa’s new hypothesis that the strengthening of synaptic connections, while necessary for a memory to be initially encoded, is not necessary for its subsequent long-term storage. Instead, he proposes that memories are stored in the specific pattern of connections formed between engram cell ensembles. These connections, which form very rapidly during encoding, are distinct from the synaptic strengthening that occurs later (within a few hours of the event) with the help of protein synthesis.

“What we are saying is that even without new cellular protein synthesis, once a new connection is made, or a pre-existing connection is strengthened during encoding, that new pattern of connections is maintained,” Tonegawa says. “Even if you cannot induce natural memory recall, the memory information is still there.”

This raised a question about the purpose of the post-encoding protein synthesis. Considering that silent engrams are not retrieved by natural cues, the researchers believe the primary purpose of the protein synthesis is to enable natural recall cues to do their job efficiently.

The researchers also tried to reactivate the silent engrams by treating the mice with a protein called PAK1, which promotes the formation of synapses. They found that this treatment, given two days after the original event took place, was enough to grow new synapses between engram cells. A few days after the treatment, mice whose ability to recall the memory had been blocked initially would freeze after being placed in the cage where the training took place. Furthermore, their reaction was just as strong as that of mice whose memories had been formed with no interference.

Sheena Josselyn, an associate professor of psychology and physiology at the University of Toronto, said the findings run counter to the longstanding idea that memory formation involves strengthening of synapses between neurons and that this process requires protein synthesis.

“They showed that a memory formed during protein-synthesis inhibition may be artificially (but not naturally) recalled. That is, the memory is still retained in the brain without protein synthesis, but this memory cannot be accessed under normal conditions, suggesting that spines may not be the key keepers of information,” says Josselyn, who was not involved in the research. “The findings are controversial, but many paradigm-shifting papers are.”

Along with the researchers’ previous findings on silent engrams in early Alzheimer’s disease, this study suggests that re-activating certain synapses could help restore some memory recall function in patients with early stage Alzheimer’s disease, Roy says.

The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.

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.”

New target for treating “undruggable” lung cancer

Drug already in clinical trials may be effective on some aggressive adenocarcinomas.

Becky Ham | MIT News correspondent
October 2, 2017

Mutations in the KEAP1 gene could point the way to treating an aggressive form of lung cancer that is driven by “undruggable” mutations in the KRAS gene, according to a new study by MIT researchers.

KEAP1 mutations occur alongside KRAS mutations in about 17 percent of lung adenocarcinoma cases. Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and co-senior author of the study, and his colleagues found that cancer cells with nonfunctioning KEAP1 genes are hungry for glutamine, an amino acid essential for protein synthesis and energy use. Starving these cells of glutamine may thus offer a way to treat cancers with both KRAS and KEAP1 mutations.

Indeed, small-molecule-based inhibitors of glutaminase, an enzyme crucial to glutamine metabolism, slowed cancer cell growth and led to smaller tumors overall in human lung adenocarcinoma cell lines and in tumors in mice with KEAP1 mutations, the researchers found.

The study offers a way to identify lung cancer patients who might respond well to drugs that block the work of glutaminase, says MIT graduate student Rodrigo Romero, a first author on the paper that appears in the Oct. 2 online edition of Nature Medicine.

“All cell lines that we have currently tested that are KEAP1-mutant — independent of their KRAS status — appear to be exquisitely sensitive to glutaminase inhibitors,” says Romero, a graduate student in Jacks’ lab, who participated in the MIT Summer Research Program (MSRP) as an undergraduate.

Hyperactivating the antioxidant response

Lung adenocarcinoma accounts for about 40 percent of U.S. lung cancers, and 15 to 30 percent of those cases contain a KRAS mutation. KRAS has been “notoriously difficult to inhibit” because the usual ways of blocking the KRAS protein’s interactions or interfering with the protein’s targets have fallen short, says Romero.

Lung cancers containing KRAS mutations often harbor other mutations, including KEAP1, which is the third most frequently mutated gene in lung adenocarcinoma. To find out more about how these co-mutations affect lung cancer progression, the MIT research team created KEAP1 mutations in mouse models of lung adenocarcinoma, using the CRISPR/Cas9 gene-editing system to target the gene.

The KEAP1 protein normally represses another protein called NRF2, which controls the activation of an antioxidant response that removes toxic, reactive oxygen species from cells. When the researchers disabled KEAP1 with loss-of-function mutations, NRF2 was able to accumulate and contribute to a “hyperactivation” of the antioxidant response.

Lung adenocarcinomas bearing the KEAP1 mutation may “take advantage of this [hyper-activation] to promote cellular growth or detoxify intracellular damaging agents,” Romero says.

In fact, when the researchers examined genes targeted by NRF2 across a sample of human lung adenocarcinoma tumors, they concluded that the expression of these genes was greater in advanced stage IV tumors, and that patients with such “up-regulated” NRF2 tumors had significantly worse survival rates than other lung adenocarcinoma patients.

Tumors hungry for glutamine

Romero and colleagues used CRISPR/Cas9 to learn more about other genetic interactions with KEAP1 mutants. Their screening demonstrated that lung cancer cells with KRAS and KEAP1 loss-of function mutations were more dependent than other cells on increased amounts of glutamine.

To learn whether this glutamine hunger could be a therapeutic vulnerability, the researchers tested two glutaminase inhibitors against the cancer cells, including one compound called CB-839 that is in phase I clinical trials for KRAS-mutant lung cancer. CB-839 slowed growth and kept tumors smaller than normal in lung adenocarcinoma with KEAP1 mutations, the researchers found.

Phase I clinical trials that treat KEAP1-mutant lung adenocarcinoma patients with a combination of CB-839 and the cancer immunotherapy drug nivolumab (Opdivo) are also underway, says Romero, who notes the MIT study might help identify patients who would be good candidates for these trials.

“There are also many clinical trials testing the efficacy of glutaminase inhibition in a variety of cancer types, independent of KRAS status. However, the results from these studies are still unclear,” Romero says.

Jacks emphasizes that his laboratory has and will continue to study several mutations beyond KEAP1 that may cooperate with KRAS in their mouse models of human lung adenocarcinoma. “The complexity of human cancer can be quite daunting,” he notes. “The genetic tools that we have assembled allow us to create models of many individual subtypes of the disease and in this way begin to define the exploitable vulnerabilities of each. The observed sensitivity of KEAP1 mutant tumors to glutaminase inhibitors is an important example of this approach. There will be more.”

Co-authors on the Nature Medicine paper include former Koch Institute postdoc Thales Papagiannakopoulos, now at New York University, and MIT professor of biology Matthew Vander Heiden. The research was funded by the Laura and Isaac Perlmutter Cancer Support Grant, the National Institutes of Health, and the Koch Institute Support Grant from the National Cancer Institute.

Michael Rosbash PhD ’71 shares Nobel Prize in physiology or medicine

MIT alumnus and two others honored for discovering the molecular mechanisms of circadian rhythms.

Anne Trafton | MIT News Office
October 2, 2017

Michael Rosbash, who earned his PhD from MIT in 1971, will share the 2017 Nobel Prize in physiology or medicine, the Nobel Committee announced this morning in Stockholm.

Rosbash, now a professor of biology at Brandeis University, shares the prize with Jeffrey C. Hall of the University of Maine and Michael W. Young of Rockefeller University. The scientists were honored for “their discoveries of molecular mechanisms controlling the circadian rhythm.”

Circadian rhythms help living organisms adapt their biological activities to the normal 24-hour cycle of light and darkness. These rhythms influence behavior, sleep, metabolism, body temperature, and many other biological functions.

In 1984, Rosbash, Hall, and Young isolated a gene that regulates these daily rhythms in fruit flies. This gene, known as period, encodes a protein that accumulates during the night and is degraded during the day. Further work revealed that this protein inhibits the gene that encodes it, creating a negative feedback loop that is key to generating continuous oscillations.

Since then, the three scientists have discovered several other genes necessary for maintaining circadian cycles, and similar processes have been found in many other organisms, including humans.

Rosbash was born in Kansas City, Missouri, but grew up in Newton, Massachusetts. He earned his bachelor’s degree at Caltech before coming to MIT to pursue a PhD in biology. He has been on the faculty at Brandeis since 1974, and he is an investigator with the Howard Hughes Medical Institute and a member of the National Academy of Sciences. In 2013, Rosbash, Hall, and Young shared the Shaw Prize in Life Sciences and Medicine for their circadian clock research.

Rosbash is the 35th MIT alumnus to win a Nobel Prize, and the 88th MIT-connected winner of the prize.

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.”

Gene Brown, professor emeritus of biology, dies at 91

A pioneer in the field of intermediary metabolism and former dean of the School of Science, Brown’s deepest passion was teaching.

Vivian Siegel | Department of Biology
August 18, 2017

Gene M. Brown, MIT professor emeritus of biology, former department head, and former dean of the School of Science, passed away on Aug. 4 at the age of 91.

“He was really the heart and soul of the department for a very long time, devoted to undergraduates and to teaching,” says MIT Professor Lisa Steiner. Steiner, an expert in the evolution and development of the immune system, was hosted by Brown during her recruitment visit to MIT and became the first female faculty member hired in the Department of Biology. “The idea of the department without him is quite shocking.”

A pioneer in the field of intermediary metabolism, Brown’s research career focused on how living systems carry out chemical reactions in order to survive. He trained himself in enzymology after arriving at MIT, and he and his students and postdocs focused primarily on the enzymatic synthesis of several B vitamins, including thiamine, folic acid, riboflavin, and coenzyme A. He is best known for his work on the biosynthesis of folic acid and related compounds both in microorganisms and in the fruit fly Drosophila melanogaster, publishing over 100 research papers in his career.

“Gene was a wonderful research advisor and teacher,” says Linda Spremulli, professor emerita of chemistry at the University of North Carolina at Chapel Hill, who was a graduate student with Brown from 1969 to 1973. “He transformed my life, instilling in me a love for the beauty of metabolic pathways with their complex mechanisms.”

Growing up in rural Missouri and Idaho, Brown was the first member of his family to finish high school, and the only person in his graduating class to attend college. After a year as a college student in Idaho, Brown enlisted in the Army Air Forces, where he taught defensive measures against chemical warfare. After his term in the Army Air Forces, he returned to college at Colorado A & M College, where he majored in chemistry, graduating in 1949. He completed his graduate work at the University of Wisconsin in 1953 under the direction of Esmond Snell, isolating and characterizing the enzymatic synthesis of pantetheine, an analog of vitamin B5, and an intermediary in the production of coenzyme A.

Brown continued working with Snell as a postdoc at the University of Texas until he was recruited by Professor Jack Buchanan to join the newly forming biochemistry division of the MIT Department of Biology in 1954. Brown served as executive officer of the department from 1967 to 1972; as associate department head under Professor Boris Magasanik from 1972 to 1977; as department head from 1977 to 1985; and as dean of the School of Science from 1985 to 1991. While serving as dean of science, Brown closed his research program. He officially retired from MIT in 1996, but continued teaching until 2014.

Brown’s deepest passion was teaching. “As dean, he would leave meetings with the president of MIT to go teach,” recalls Professor Tom RajBhandary, who co-taught 7.05 (Introductory Biochemistry) with Brown for over 20 years. He was legendary for teaching intermediary metabolism without any notes, filling the boards of Room 10-250 with detailed pathways in meticulous handwriting. Brown got his first taste of teaching in high school, when his math and chemistry teachers would routinely call him to the board to explain the material. He was the first person in the Department of Biology to give open book and open note examinations, promoting the view that students should not have to memorize, but rather should be assessed for their ability to think and to solve problems. He was involved in teaching 7.05 for 60 years.

“I loved teaching with Gene and will miss him,” says Professor Matthew vander Heiden, who currently teaches 7.05. “The privilege to see how he taught the class has had a tremendous impact on my own approach to teaching. I think he would be pleased to know that the unique insights he provided continue to be passed on each spring, and will continue to be passed on as long as I am involved in the course.”

Teaching undergraduates was a value that extended throughout his career. As dean of science, he made it clear that the quality of teaching would be an important consideration for tenure decisions. He also co-chaired the committee that instituted the undergraduate communications requirement aimed at improving skills in both written and oral communications. The Department of Biology gives two teaching awards in his honor: The Gene Brown Prize, funded by Brown himself, recognizes teaching excellence among undergraduates; and the Gene Brown-Merck Teaching Award, funded by Merck and by Brown’s former graduate students and postdocs, recognizes teaching excellence among graduate students.

During Brown’s administrative tenure in biology, the MIT Center for Cancer Research (the predecessor of the Koch Institute for Integrative Cancer Research) and the Whitehead Institute were established with Department of Biology faculty leadership (Professor Salvador Luria for the Center for Cancer Research in 1974, and Professor David Baltimore for the Whitehead Institute in 1982).

A longtime resident of Concord, Massachusetts, Brown is survived by his children, James, Lindsey, and Holly, and his four grandchildren. He was predeceased by his wife, Shirley, and a brother, James.

Gifts in Brown’s name may be made to the Gene Brown Undergraduate Education Fund, fund No. 3839399. Donations in his memory will support undergraduates and undergraduate education in the MIT Department of Biology. For more information, contact Rebecca Chamberlain at 617-253-4729 or rchambe@mit.edu.