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In search of nature’s winning recipe

Graduate student Darren Parker aims to understand the ratio of ingredients that constitutes the optimal cell.

Raleigh McElvery
May 31, 2019

Fifth-year graduate student Darren Parker is as much a baker as he is a biologist — at least metaphorically speaking. He’s on a mission to understand the ratio of ingredients required to concoct nature’s winning recipe for the optimal cell. Researchers have a solid understanding of which components are essential for cellular function, but they have yet to determine whether it’s critical for cells to generate exactly the right amount of protein.

“In that way, my graduate work is actually pretty simple,” Parker says. “I just want to know if changing the amounts of a specific ingredient has an effect on the overall product.”

The oldest of four brothers, Parker grew up in a suburb just outside of Chicago. When he enrolled in the University of Illinois Urbana-Champaign for his undergraduate studies in 2009, he was considering a major in environmental science. “My high school biology classes were mostly rote memorization,” he explains, “so the molecular aspects just didn’t resonate with me. I was more interested in studying life on a larger scale.”

After his first year, he entered the Integrated Biology program, which essentially “encompassed all biology that wasn’t molecular biology.” He was still required to take an introductory molecular biology course, though, as part of the major. But this time around, something clicked.

He remembers performing his first genetic knockdown experiment, decreasing the level of dopamine receptors in roundworms and witnessing the behavioral ramifications in real time. “I finally had a handle on the molecular concepts enough to really get what was going on,” he says.

He attributed his newfound appreciation for the basic mechanisms underlying life to his fortified chemistry skills. At the beginning of his third year, he officially declared a biochemistry major, and joined a lab in the Department of Chemistry studying nucleic acid enzymes.

Parker’s job was to sift through trillions of short DNA strands, selecting only those that could act like enzymes and cut RNA. He would then home in on the nucleotide sequences within those strands that were best suited to carry out the reaction. After a year-and-a-half, he’d successfully identified a few DNA sequences that could cut RNA molecules with a distinct chemistry. After this point he was excited to try “studying life” as opposed to synthetic reactions.

Mid-way through his fourth year, he joined a biology lab in the College of Medicine probing alternative splicing in liver and heart development. It was a new group with only a few members, and Parker had more experience as an undergraduate than some of the first-year graduate students, so he hit the ground running. His last-minute switch to biochemistry meant he had five years of studies instead of the usual four — totaling six full semesters (and several summers) in lab.

After identifying a key splicing protein required for the liver to fully mature in mice and humans, Parker became even more fascinated by molecular biology and determined to pursue a career in science with bigger picture applications.

At the urging of his advisor, Parker sent in his graduate school applications. He was primarily interested in microbiology and infectious disease research — although he had no prior experience working in bacteria, only a longstanding interest in the intersection of science and society. He ultimately chose MIT Biology because of the breadth of labs. He could join a microbiology lab, or pursue an entirely different path, all within the same department. Gene-Wei Li’s lab seemed like “the perfect mix.”

“Gene was asking questions in molecular biology from the unique perspective of a physicist, looking at biological questions in a way I had never even considered before,” he says. “Gene had also just joined the department and wasn’t tied to a specific field or model organism yet, so I had the chance to build my own projects from the bottom up; I wasn’t just slotting in somewhere.”

Best of all, the Li lab was all about drilling down into to the mechanics of protein production in order to understand the cell as a whole — the bigger picture perspective that Parker was longing for.

Parker began by exploring ways to modify high-throughput RNA sequencing. He aimed to make this popular method cheaper and more scalable, in hopes of knocking out many individual genes in E. coli to test the genome-wide effects. He then pivoted his project and applied his new technique to study the effects of reducing essential genes in B. subtilis, another model bacterium. The family of enzymes that was the most interesting to him from these experiments were the aminoacyl-tRNA synthetases.

tRNAs, or transfer RNAs, carry amino acids to the ribosome so that the cell can produce proteins. This process requires the help of enzymes — tRNA synthetases — to “charge” the tRNAs with an amino acid. Only then can the ribosome transfer the amino acid from the tRNAs to the growing chain of amino acids that eventually forms the protein. Like an inquisitive baker, Parker wanted to know what would happen if he added more or less tRNA synthetase to the recipe of a bacterial cell.

His results would make Goldilocks proud. Over the past few years, he’s shown that too much or too little tRNA synthetase prevents the cell from growing at a normal rate. The amount must be just right.

“It turns out that what’s most important to the cell is maintaining the ratios of those very conserved ingredients,” Parker says. “The cell will actively use less of those ingredients if the synthetase is limiting, and this leads to a much slower growing cell. Adding too much tRNA synthetase is just a waste because the cell already has as much as it needs to sustain translation.”

This same family of tRNA synthetase proteins, he adds, are also implicated in some neurological diseases in humans, which gives him further impetus to study them.

At this point, Parker has taste-tested his fair share of biological areas, and he’s found his niche. “It was a long process,” he says. “That was probably best, though, because it gave me more time to explore.”

Once he graduates, he plans to go into industry, perhaps continuing to tweak the list of ingredients in order to engineer cells to do new things.

“The next time you’re in the kitchen and you want to add more or less of your favorite ingredient,” he urges, “just think about how the cell might feel if you did so with your favorite gene.”

Photo credit: Raleigh McElvery
Posted 5.30.19
Drug-resistant cancer cells create own Achilles heel
Nicole Giese Rura | Whitehead Institute
May 28, 2019

Cambridge, MA — The cells of most patients’ cancers are resistant to a class of drugs, called proteasome inhibitors, that should kill them. When studied in the lab, these drugs are highly effective, yet hundreds of clinical trials testing proteasome inhibitors have failed. Now scientists may have solved the mystery of these cells’ surprising hardiness. The key: Resistant cancer cells have shifted how and where they generate their energy. Using this new insight, researchers have identified a drug that resensitizes cancer cells to proteasome inhibitors and pinpointed a gene that is crucial for that susceptibility.

As cancer cells develop, they accrue multiple genetic alterations that allow the cells to quickly reproduce, spread and survive in distant parts of the body, and recruit surrounding cells and tissues to support the growing tumor. To perform these functions, cancer cells must produce high volumes of the proteins that support these processes. The increased protein production and numerous mutated proteins of cancer cells make them particularly dependent on the proteasome, which is the cell’s protein degradation machine. These huge protein complexes act as recycling machines, gobbling up unwanted proteins and dicing them into their amino acid building blocks, which can be reused for the production of other proteins.

Previously, researchers exploited cancer cells’ increased dependency on their proteasomes to develop anti-cancer therapies that inhibit the proteasomes’ function. Several distinct proteasome inhibitors have been developed, and when used in the lab, these proteasome inhibitor drugs are indeed highly effective at eradicating tumor cells. However, when administered to animal models or patients with cancer, such as multiple myeloma, proteasome inhibitors have limited efficacy and even initially vulnerable cancer cells quickly develop resistance to them. How do cancer cells so adroitly sidestep drugs that should kill them?

Exploring the gene expression of thousands of tumors and hundreds of cancer cell lines, Peter Tsvetkov, a former postdoc in the lab of late Whitehead Institute Member Susan Lindquist, has determined that the answer may lie with how and where the cells produce their energy. According to his analysis of the active genes and metabolism products generated in proteasome inhibitor-resistant cancer cells and tumors, Tsvetkov, who is currently a postdoc in the lab of Broad Institute Founding Core Member, director of the Cancer Program, and oncologist at the Dana-Farber Cancer Institute Todd Golub, concluded that such cells have shifted how they produce energy — away from breaking down the sugar glucose toward a dependency on processes within the mitochondria, the “powerhouse” part in the cell. In fact, when Tsvetkov pushed cancer cells’ metabolism to depend on the mitochondria, that change alone was sufficient to make cancer cells immune to proteasome inhibitors. Tsvetkov’s findings are described online this week in the journal Nature Chemical Biology.

In order to understand how a metabolic shift could link to proteasome inhibitor resistance, Tsvetkov screened proteasome inhibitor-resistant breast cancer cells with thousands of small molecules to identify the ones that hamper the cells’ growth or even kill the cells. One stood out in the screen: elesclomol, a small molecule that that researchers had previously evaluated as an anti-cancer agent in phase 3 clinical trials without knowing with what the drug interacts in cancer cells. To identify how elesclomol preferentially targets the proteasome inhibitor resistant cells, Tsvetkov did genome-wide CRISPR-Cas9 screens to find out which genes elesclomol requires to incapacitate resistant cancer cells. Only the gene FDX1, which encodes an enzyme in the mitochondria, came to the fore.

In collaboration with John Markley from the Department of Biochemistry at the University of Wisconsin-Madison, Tsvetkov used biochemical and biophysical systems to demonstrate that elesclomol directly binds to the mitochondrial enzyme FDX1 and impedes its natural function. In the presence of copper, elesclomol can also be altered by the FDX1 enzyme, which increases the drug’s anti-cancer toxicity. These findings led the researchers to determine that as cancer cells become overly reliant on their mitochondrial metabolism, they ramp up the FDX1 protein’s activity. Also, when the FDX1 protein interacts with copper-bound elesclomol, the protein enhances the drug’s copper-dependent toxicity. Thus, copper appears to play an essential role — when Tsvetkov removed copper, elesclomol was no longer effective.

Having established that a metabolic shift and resistance to proteasome inhibitors are linked, Tsvetkov is now interested in understanding how a change in metabolism allows cancer cells to adapt to other anti-cancer therapies and how copper-binding molecules such as elesclomol can be developed as effective anticancer agents.

This work was supported by the National Institutes of Health (NIH grant P41GM103399), University of Wisconsin-Madison Biochemistry Department, EMBO (Fellowship ALTF 739-2011), the Charles A. King Trust Postdoctoral Fellowship Program, and Howard Hughes Medical Institute (HHMI).

Written by Nicole Giese Rura

***

Susan Lindquist’s primary affiliation was with Whitehead Institute for Biomedical Research, where her laboratory was located and all her research was conducted. She was also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

***

Citation:

“Mitochondrial metabolism promotes adaptation to proteotoxic stress”

Nature Chemical Biology, online May 27, 2019, DOI: 10.1038/s41589-019-0291-9

Peter Tsvetkov, Alexandre Detappe, Kai Cai, Heather R. Keys, Zarina Brune, Weiwen Ying, Prathapan Thiru, Mairead Reidy, Guillaume Kugener, Jordan Rossen, Mustafa Kocak, Nora Kory, Aviad Tsherniak, Sandro Santagata, Luke Whitesell, Irene M. Ghobrial, John L. Markley , Susan Lindquist, and Todd R. Golub.

Merging machine learning and the life sciences

Through computing, senior and Marshall Scholar Anna Sappington seeks answers to biological questions.

Gina Vitale | MIT News correspondent
May 22, 2019

Anna Sappington’s first moments of fame came when she was a young girl, living in a home so full of pets she calls it a zoo. She grew up on the Chesapeake Bay, surrounded by a lush environment teeming with wildlife, and her father was an environmental scientist. One day, when she found a frog in a skip laurel bush, she named him Skippy and built him a habitat. Later on, she and Skippy appeared on the Animal Planet TV special “What’s to Love About Weird Pets?”

Now a senior majoring in computer science and molecular biology, Sappington has been chosen for another prestigious honor: She’s one of five MIT students selected this year to be Marshall Scholars. She chose to study computer science because she wanted to have a role in pulling apart and understanding data, and she chose biology because of her lifelong fascination with nature, cells, genetic inheritance — and, of course, Skippy.

“My interests have grown and expanded in different ways, but they’re still kind of rooted in this natural dual passion that I have for both of these fields,” she says.

An eye for genomic research

When Sappington came to MIT, it was right after her first summer internship at the National Institutes of Health, where she examined genes that could be related to increased risk of cardiovascular disease. It was her first experience working with data on human patients, and it inspired her to continue working in medical research.

When she was a first-year student, Sappington spent the year at the Koch Institute, working with a graduate student to determine how liver cells respond to infection by hepatitis B virus. The summer after that, she went back to the NIH to contribute to a different project. This one still involved human health data, but it was more focused on building a computational tool. Sappington helped develop an algorithm that would quickly calculate how similar two genomes or proteins were to each other, a technology that could be used to screen for different bacteria strains in real-time.

“I wanted to kind of get my feet wet in all the different kinds of ways computer science and biology and human health can interact,” she says.

Since her return from the NIH at the beginning of her sophomore year, Sappington has been working in Aviv Regev’s lab in the Broad Institute of MIT and Harvard. She says Regev, a professor in the MIT Department of Biology, has been nothing short of an inspiration.

“She herself is just an incredible role model for the world of computational biology,” Sappington says.

The main initiative of Regev’s lab is an initiative called the Human Cell Atlas, which was recently named Science’s Breakthrough of the Year. It’s like a layer on top of the Human Genome Project, she says. They are working to identify and catalogue the different types of cells, such as skin cells and lung cells. The need for the cataloging comes from the fact that even though these cells have the exact same DNA genome, they have different specialized functions, and therefore can’t be identified by genome alone.

“Within a given tissue, like your skin tissue, cells are actually like a whole collage of different molecular profiles in how they express their genes,” she says. “So while the underlying genome is the same, there’s all sorts of other factors that make your cells express those genes — which turn into proteins — differently.”

Because the human body contains so many different types of cells, teams of researchers work on different pieces. Sappington works on data analysis as part of a team that is classifying retinal cells. It’s a unique challenge, she says, because the retina has more than 40 different types of cells, all of which respond to disease in different ways. While still chipping away at human retinal cell types, her team contributed to a recently published retinal cell atlas for the macaque monkey. For her undergraduate research career, Sappington was named a 2018-2019 Goldwater Scholar.

Dancing, speaking, leading

Before coming to MIT, Sappington had never been involved in dancing. But after she saw a showcase by the Asian Dance Team her first year, she decided to give it a try. After a few semesters dancing with ADT, Sappington also joined MIT DanceTroupe, where she found the culture to be creative, supportive, and incredibly fun.

“[I] just really fell in love with the community, and the general community of dancers at MIT,” she says.

Dance wasn’t the only aspect of the arts and humanities at MIT that she loved. She is also a part of the Burchard Scholars program, which allows students with a particular interest in the humanities to explore that topic. After she took a linguistics class with Professor David Pesetsky her first year, that field became her official humanities concentration. She ended up taking the next level of that class, which centered around syntax, and then she and five other students later created their own special subject class on linguistics.

“Essentially linguistics is the study of how language as a whole works, and the underlying rules that govern it,” she says. “It interfaces with brain and cognitive science, and even computer science, and how language is learned and acquired.”

Outside of class, Sappington has also been involved with TechX, a student-run organization that is responsible for many of MIT’s tech-related events, including HackMIT. Events also include the makeathon MakeMIT, the spring career fair and technology demo xFair, and high school mentoring program THINK. After serving on and running an event committee, Sappington served as the overall director for TechX in her junior year. While she’s no longer in charge, she’s still grateful to be part of the team.

“The whole thing was like one big family. … Each committee has its own intercommittee pride with the event that they run, but then everyone also has to rely on each other,” she says.

Machine learning across the pond

After graduation, Sappington will be heading off to University College London to earn her MS in machine learning. Her goal is to explore machine learning in a context that isn’t biology, so that she can learn new and different approaches that she might later be able to apply to biological challenges. The second year of her Marshall Scholarship will be spent at Cambridge University, where she will do a full year of research, likely involving machine learning applied to health care or other biological questions.

Her ultimate goal is to find new and better ways to use machine learning and technology to improve the health care system. To that end, she aims to get her MD/PhD after the next two years in England. After volunteering at the Massachusetts General Hospital and shadowing doctors in the Boston area, Sappington is pretty certain she wants a career where she can interact with patients while still being involved with computer science and biology. She’s excited to move forward with the next chapter of her life — but when it comes to leaving MIT, she’s got understandably mixed feelings.

“I think no matter where I would be going after graduation, it’s bittersweet to leave the incredible community that is the MIT community,” she says.

Eleven MIT students accept 2019 Fulbright Fellowships

Grantees will spend the 2019-2020 academic year pursuing research and teaching opportunities abroad.

Julia Mongo | Office of Distinguished Fellowships
May 17, 2019

Eleven MIT graduating seniors and current graduate students have been named winners in the 2019-2020 Fulbright U.S. Student Fellowship Program. In addition to the 11 students accepting their awards, three applicants from MIT were selected as finalists but decided to decline their grants.

MIT’s newest Fulbright Students will engage in independent research and English teaching assignments in Brazil, the Netherlands, Spain, Russia, Taiwan, and Senegal.

Sponsored by the U.S. Department of State’s Bureau of Educational and Cultural Affairs, the mission of Fulbright is to promote cultural exchange, increase mutual understanding, and build lasting relationships among people of the world. The Fulbright U.S. Student Program offers grants in over 140 countries.

The MIT students were supported in the application process by the Presidential Committee on Distinguished Fellowships, chaired by professors Rebecca Saxe and Will Broadhead, and by MIT’s Distinguished Fellowships Office within Career Advising and Professional Development. The MIT winners are:

Annamarie “Anna” Bair ’18 earned a bachelor of science in computer science and engineering in June 2018 and will receive her master of engineering degree in computer science later this year. In Barcelona, Spain, Bair will engage in complex systems research.

Abigail “Abby” Bertics will graduate in June with a bachelor of science in electrical engineering and computer science. Her research in Yekaterinburg, Russia, will focus on natural language processing methods for understanding English second language acquisition by Russian speakers.

Hope Chen is a senior graduating with a bachelor of science in mechanical engineering. She will be going to Taiwan as an English Teaching Assistant in primary school classrooms. After completing her Fulbright program and returning to the U.S., Chen will matriculate in medical school.

Alexis D’Alessandro will graduate this spring with a bachelor of science in mechanical engineering. For her research in Aracaju, Brazil, she will develop an educational program and chemical sensing tool to promote water safety awareness among children.

Sarah DiIorio will earn her bachelor of science in biological engineering in June. She is headed to Eindhoven, the Netherlands, to conduct medical research related to cartilage regeneration for osteoarthritis.

Katie Fisher is a senior in MIT’s Scheller Teaching Education Program graduating with a bachelor of science in urban studies and planning with a concentration in education. As an English teaching assistant in the Netherlands, Fisher will work with students at a vocational college in Amsterdam.

Miranda McClellan ’18 received a bachelor of science in computer science and engineering in June 2018 and will earn her master of engineering degree in computer science this spring. McClellan will research automated scaling of 5G computer network resources in Barcelona, Spain.

Samira Okudo will graduate in June with a joint bachelor of science in computer science and comparative media studies. As an English teaching assistant in Brazil, she will work with university students training to be English-language instructors.

James Pelletier is a PhD candidate in physics. For his Fulbright research in Madrid, Spain, he will develop biophysical models to investigate how plants process information for cellular resource allocation and agricultural efficiency.

Jonars Spielberg is a third-year doctoral student in the Department of Urban Studies and Planning’s international development program. In Senegal, he will examine how the personal interactions of bureaucrats and farmers shape agricultural policy implementation in the country’s main irrigated regions.

Catherine Wu will graduate in June with a bachelor of science in biology. She will be working with university students in Brazil as a Fulbright English Teaching Assistant.

MIT students interested in applying to the Fulbright U.S. Student Program should contact Julia Mongo in Distinguished Fellowships.

Catalyzing new approaches in research and education to meet the climate challenge
MIT Energy Initiative
May 16, 2019

Catherine Drennan says nothing in her job thrills her more than the process of discovery. But Drennan, a professor of biology and chemistry, is not referring to her landmark research on protein structures that could play a major role in reducing the world’s waste carbons.

“Really the most exciting thing for me is watching my students ask good questions, problem-solve, and then do something spectacular with what they’ve learned,” she says.

For Drennan, research and teaching are complementary passions, both flowing from a deep sense of “moral responsibility.” Everyone, she says, “should do something, based on their skill set, to make some kind of contribution.”

Drennan’s own research portfolio attests to this sense of mission. Since her arrival at MIT 20 years ago, she has focused on characterizing and harnessing metal-containing enzymes that catalyze complex chemical reactions, including those that break down carbon compounds.

She got her start in the field as a graduate student at the University of Michigan, where she became captivated by vitamin B12. This very large vitamin contains cobalt and is vital for amino acid metabolism, the proper formation of the spinal cord, and prevention of certain kinds of anemia. Bound to proteins in food, B12 is released during digestion.

“Back then, people were suggesting how B12-dependent enzymatic reactions worked, and I wondered how they could be right if they didn’t know what B12-dependent enzymes looked like,” she recalls. “I realized I needed to figure out how B12 is bound to protein to really understand what was going on.”

Drennan seized on X-ray crystallography as a way to visualize molecular structures. Using this technique, which involves bouncing X-ray beams off a crystallized sample of a protein of interest, she figured out how vitamin B12 is bound to a protein molecule.

“No one had previously been successful using this method to obtain a B12-bound protein structure, which turned out to be gorgeous, with a protein fold surrounding a novel configuration of the cofactor,” says Drennan.

Carbon-loving microbes show the way

These studies of B12 led directly to Drennan’s one-carbon work. “Metallocofactors such as B12 are important not just medically, but in environmental processes,” she says. “Many microbes that live on carbon monoxide, carbon dioxide, or methane—eating carbon waste or transforming carbon—use metal-containing enzymes in their metabolic pathways, and it seemed like a natural extension to investigate them.”

Some of Drennan’s earliest work in this area, dating from the early 2000s, revealed a cluster of iron, nickel, and sulfur atoms at the center of the enzyme carbon monoxide dehydrogenase (CODH). This so-called C-cluster serves hungry microbes, allowing them to “eat” carbon monoxide and carbon dioxide (CO2).

Recent experiments by Drennan analyzing the structure of the C-cluster-containing enzyme CODH showed that in response to oxygen, it can change configurations, with sulfur, iron, and nickel atoms cartwheeling into different positions. Scientists looking for new avenues to reduce greenhouse gases took note of this discovery. CODH, suggested Drennan, might prove an effective tool for converting waste CO2 into a less environmentally destructive compound, such as acetate, which might also be used for industrial purposes.

Drennan has also been investigating the biochemical pathways by which microbes break down hydrocarbon byproducts of crude oil production, such as toluene, an environmental pollutant.

“It’s really hard chemistry, but we’d like to put together a family of enzymes to work on all kinds of hydrocarbons, which would give us a lot of potential for cleaning up a range of oil spills,” she says.

The threat of climate change has increasingly galvanized Drennan’s research, propelling her toward new targets. A 2017 study she co-authored in Science detailed a previously unknown enzyme pathway in ocean microbes that leads to the production of methane, a formidable greenhouse gas: “I’m worried the ocean will make a lot more methane as the world warms,” she says.

Drennan hopes her work may soon help to reduce the planet’s greenhouse gas burden. Commercial firms have begun using the enzyme pathways that she studies, in one instance employing a proprietary microbe to capture CO2 produced during steel production—before it is released into the atmosphere—and convert it into ethanol.

“Reengineering microbes so that enzymes take not just a little but a lot of CO2 out of the environment—this is an area I’m very excited about,” says Drennan.

Creating a meaningful life in the sciences

At MIT, she has found an increasingly warm welcome for her efforts to address the climate challenge. “There’s been a shift in the past decade or so, with more students focused on research that allows us to fuel the planet without destroying it,” she says.

In Drennan’s lab, a postdoc, Mary Andorfer, and a sophomore, Phoebe Li, are currently working to inhibit an enzyme present in an oil-consuming microbe whose unfortunate residence in refinery pipes leads to erosion and spills. “They are really excited about this research from the environmental perspective and even made a video about their microorganism,” says Drennan.

Drennan delights in this kind of enthusiasm for science. In high school, she thought chemistry was dry and dull, with no relevance to real-world problems. It wasn’t until college that she “saw chemistry as cool.”

The deeper she delved into the properties and processes of biological organisms, the more possibilities she found. X-ray crystallography offered a perfect platform for exploration. “Oh, what fun to tell the story about a three-dimensional structure—why it is interesting, what it does based on its form,” says Drennan.

The elements that excite Drennan about research in structural biology—capturing stunning images, discerning connections among biological systems, and telling stories—come into play in her teaching. In 2006, she received a $1 million grant from the Howard Hughes Medical Institute (HHMI) for her educational initiatives that use inventive visual tools to engage undergraduates in chemistry and biology. She is both an HHMI investigator and an HHMI professor, recognition of her parallel accomplishments in research and teaching, as well as a 2015 MacVicar Faculty Fellow for her sustained contribution to the education of undergraduates at MIT.

Drennan attempts to reach MIT students early. She taught introductory chemistry classes from 1999 to 2014, and in fall 2018 taught her first introductory biology class.

“I see a lot of undergraduates majoring in computer science, and I want to convince them of the value of these disciplines,” she says. “I tell them they will need chemistry and biology fundamentals to solve important problems someday.”

Drennan happily migrates among many disciplines, learning as she goes. It’s a lesson she hopes her students will absorb. “I want them to visualize the world of science and show what they can do,” she says. “Research takes you in different directions, and we need to bring the way we teach more in line with our research.”

She has high expectations for her students. “They’ll go out in the world as great teachers and researchers,” Drennan says. “But it’s most important that they be good human beings, taking care of other people, asking what they can do to make the world a better place.”

Tissue chip headed to International Space Station for osteoarthritis study

Successfully launched project aims to understand why some injuries result in develop post-traumatic osteoarthritis while others heal and recover.

Daniel J. Darling | Department of Biological Engineering
May 7, 2019

On May 4, a National Center for Advancing Translational Sciences (NCATS)-supported tissue-chip system with direct clinical applications to health conditions here on Earth was launched on the SpaceX CRS 17/Falcon 9 rocket.

Hundreds of millions of people worldwide suffer from osteoarthritis (OA), and there are currently no disease-modifying drugs that can halt or reverse the progression of OA — only painkillers for short-term symptomatic relief. Millions of healthy young to middle-aged individuals develop post-traumatic osteoarthritis (PTOA) as a result of a traumatic joint injury, like a tear of the anterior cruciate ligament or meniscus, especially in young women playing sports. Exercise-related injuries are also said to be frequent sources of joint injury for crew members living aboard the International Space Station (ISS), and pre-existing joint injuries may also affect astronaut performance in space. These conditions are compounded and worsened by exposure of crew members to weightlessness and radiation on the ISS.

After a traumatic joint injury, there is an immediate upregulation of inflammatory proteins called cytokines in the joint synovial fluid, proteins which are secreted mainly by cells in the joint’s synovial lining. When mechanical trauma to cartilage caused by the initial injury is accompanied by cytokine penetration into cartilage, degradation of cartilage and subchondral bone over weeks and months often progresses to full-blown, painful PTOA in 10-15 years.

To study PTOA on Earth and in space, investigators at MIT have developed a cartilage-bone-synovium micro-physiological system in which primary human cartilage, bone, and synovium tissues (obtained from donor banks) are co-cultured for several weeks. During culture, investigators can monitor intracellular and extracellular biomarkers of disease using quantitative experimental and computational metabolomics and proteomics analyses, along with detection of disease-specific fragments of tissue matrix molecules. In addition, this co-culture system allows investigators to test the effects of potential disease-modifying drugs to prevent cartilage and bone loss on Earth and in space.

Experiments aboard the ISS utilize a Multi-purpose Variable-G Platform, made by Techshot Inc., to study the effects of microgravity and ionizing radiations on a knee tissue chip prepared using cartilage-bone-synovium tissues secured on a biocompatible material. The platform enables automated nutrient media transfer and collection for test conditions with and without disease-modifying drugs, including tests using a one-gravity control system.

These investigations on Earth and in the ISS have the potential to lead to the discovery of treatments and treatment regimens that, if administered immediately after a joint injury, could halt the progression of OA disease before it becomes irreversible. The goal is to treat the root cause of PTOA and prevent permanent joint damage, rather than mask the symptoms with painkillers later in life, as is currently done. These studies are funded by the NIH National Center for Advancing Translational Sciences and the ISS-National Lab.

A new approach to targeting tumors and tracking their spread

Researchers develop nanosized antibodies that home in on the meshwork of proteins surrounding cancer cells.

Helen Knight | MIT News correspondent
May 6, 2019

The spread of malignant cells from an original tumor to other parts of the body, known as metastasis, is the main cause of cancer deaths worldwide.

Early detection of tumors and metastases could significantly improve cancer survival rates. However, predicting exactly when cancer cells will break away from the original tumor, and where in the body they will form new lesions, is extremely challenging.

There is therefore an urgent need to develop new methods to image, diagnose, and treat tumors, particularly early lesions and metastases.

In a paper published today in the Proceedings of the National Academy of Sciences, researchers at the Koch Institute for Integrative Cancer Research at MIT describe a new approach to targeting tumors and metastases.

Previous attempts to focus on the tumor cells themselves have typically proven unsuccessful, as the tendency of cancerous cells to mutate makes them unreliable targets.

Instead, the researchers decided to target structures surrounding the cells known as the extracellular matrix (ECM), according to Richard Hynes, the Daniel K. Ludwig Professor for Cancer Research at MIT. The research team also included lead author Noor Jailkhani, a postdoc in the Hynes Lab at the Koch Institute for Integrative Cancer Research.

The extracellular matrix, a meshwork of proteins surrounding both normal and cancer cells, is an important part of the microenvironment of tumor cells. By providing signals for their growth and survival, the matrix plays a significant role in tumor growth and progression.

When the researchers studied this microenvironment, they found certain proteins that are abundant in regions surrounding tumors and other disease sites, but absent from healthy tissues.

What’s more, unlike the tumor cells themselves, these ECM proteins do not mutate as the cancer progresses, Hynes says. “Targeting the ECM offers a better way to attack metastases than trying to prevent the tumor cells themselves from spreading in the first place, because they have usually already done that by the time the patient comes into the clinic,” Hynes says.

The researchers began developing a library of immune reagents designed to specifically target these ECM proteins, based on relatively tiny antibodies, or “nanobodies,” derived from alpacas. The idea was that if these nanobodies could be deployed in a cancer patient, they could potentially be imaged to reveal tumor cells’ locations, or even deliver payloads of drugs.

The researchers used nanobodies from alpacas because they are smaller than conventional antibodies. Specifically, unlike the antibodies produced by the immune systems of humans and other animals, which consist of two “heavy protein chains” and two “light chains,” antibodies from camelids such as alpacas contain just two copies of a single heavy chain.

Nanobodies derived from these heavy-chain-only antibodies comprise a single binding domain much smaller than conventional antibodies, Hynes says.

In this way nanobodies are able to penetrate more deeply into human tissue than conventional antibodies, and can be much more quickly cleared from the circulation following treatment.

To develop the nanobodies, the team first immunized alpacas with either a cocktail of ECM proteins, or ECM-enriched preparations from human patient samples of colorectal or breast cancer metastases.

They then extracted RNA from the alpacas’ blood cells, amplified the coding sequences of the nanobodies, and generated libraries from which they isolated specific anti-ECM nanobodies.

They demonstrated the effectiveness of the technique using a nanobody that targets a protein fragment called EIIIB, which is prevalent in many tumor ECMs.

When they injected nanobodies attached to radioisotopes into mice with cancer, and scanned the mice using noninvasive PET/CT imaging, a standard technique used clinically, they found that the tumors and metastases were clearly visible. In this way the nanobodies could be used to help image both tumors and metastases.

But the same technique could also be used to deliver therapeutic treatments to the tumor or metastasis, Hynes says. “We can couple almost anything we want to the nanobodies, including drugs, toxins or higher energy isotopes,” he says. “So, imaging is a proof of concept, and it is very useful, but more important is what it leads to, which is the ability to target tumors with therapeutics.”

The ECM also undergoes similar protein changes as a result of other diseases, including cardiovascular, inflammatory, and fibrotic disorders. As a result, the same technique could also be used to treat people with these diseases.

In a recent collaborative paper, also published in Proceedings of the National Academy of Sciences, the researchers demonstrated the effectiveness of the technique by using it to develop nanobody-based chimeric antigen receptor (CAR) T cells, designed to target solid tumors.

CAR T cell therapy has already proven successful in treating cancers of the blood, but it has been less effective in treating solid tumors.

By targeting the ECM of tumor cells, nanobody-based CAR T cells became concentrated in the microenvironment of tumors and successfully reduced their growth.

The ECM has been recognized to play crucial roles in cancer progression, but few diagnostic or therapeutic methods have been developed based on the special characteristics of cancer ECM, says Yibin Kang, a professor of molecular biology at Princeton University, who was not involved in the research.

“The work by Hynes and colleagues has broken new ground in this area and elegantly demonstrates the high sensitivity and specificity of a nanobody targeting a particular isoform of an ECM protein in cancer,” Kang says. “This discovery opens up the possibility for early detection of cancer and metastasis, sensitive monitoring of therapeutic response, and specific delivery of anticancer drugs to tumors.”

This work was supported by a Mazumdar-Shaw International Oncology Fellowship, fellowships for the Ludwig Center for Molecular Oncology Research at MIT, the Howard Hughes Medical Institute and a grant from the Department of Defence Breast Cancer Research Program, and imaged on instrumentation purchased with a gift from John S. ’61 and Cindy Reed.

The researchers are now planning to carry out further work to develop the nanobody technique for treating tumors and metastases.

Study reveals how glial cells may play key epilepsy role

Mutation in disease model flies undermines maintenance of key ion balance.

David Orenstein | Picower Institute
May 2, 2019

A new study provides potential new targets for treating epilepsy and new fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyperactivated by stress, leading to seizures.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, the Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses, such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions — for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance — and the way it is upset by the zydeco mutation — turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton, and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton says. “So this is a really important discovery linking an observation that’s been found in glia for a long time — these calcium oscillations that no one really understood — to a real biological function in glial cells, where it’s contributing to their ability to regulate ionic balance around neurons.”

Weiss’s work lays out a detailed sequence of events, implicating several specific molecular players and processes. That richly built knowledge meant that along the way, she and the team found multiple steps in which they could intervene to prevent seizures.

She started working the problem from the calcium end. With too much calcium afoot, she asked, what genes might be in a related pathway such that, if their expression was prevented, seizures would not occur? She interfered with expression in 847 potentially related genes and found that about 50 affected seizures. Among those, one stood out both for being closely linked to calcium regulation and also for being expressed in the key cortex glia cells of interest: calcineurin. Inhibiting calcineurin activity, for instance with the immunosuppressant medications cyclosprorine A or FK506, blocked seizures in zydeco mutant flies.

Weiss then looked at the genes affected by the calcineurin pathway and found several. One day at a conference where she was presenting a poster of her work, an onlooker mentioned that glial potassium channels could be involved. Sure enough, she found a particular one called “sandman” that, when knocked down, led to seizures in the flies. Further research showed that hyperactivation of calcineurin in zydeco glia led to an increase in a cellular process called endocytosis, in which the cell was bringing too much sandman back into the cell body. Without sandman staying on the cell membrane, the glia couldn’t effectively remove potassium from the outside.

When Weiss and her co-authors interfered to suppress endocytosis in zydeco flies, they also were able to reduce seizures, because that allowed more sandman to persist where it could reduce potassium. Sandman, notably, is equivalent to a protein in mammals called TRESK.

“Pharmacologically targeting glial pathways might be a promising avenue for future drug development in the field,” the authors wrote in eLife.

In addition to that clinical lead, the study also offers some new insights for more fundamental neuroscience, Littleton and Weiss said. While zydeco flies are good models of epilepsy, Drosophila’s cortex glia do have a property not found in mammals: They contact only the cell body of neurons, not the synaptic connections on their axon and dendrite branches. That makes them an unusually useful test bed to learn how glia interact with neurons via their cell body versus their synapses. The new study, for instance, shows a key mechanism for maintaining ionic balance for the neurons.

In addition to Weiss and Littleton, the paper’s other authors are Jan Melom, who helped lead the discovery of zydeco, postdoc Kiel Ormerod, and former postdoc Yao Zhang.

The National Institutes of Health and the JPB Foundation funded the research.

Three from MIT elected to the National Academy of Sciences for 2019

Faculty members Edward Boyden, Paula Hammond, and Aviv Regev recognized for “distinguished and continuing achievements in original research.”

Melanie Miller Kaufman | Department of Chemical Engineering
May 1, 2019

Three MIT professors — Edward Boyden, Paula Hammond, and Aviv Regev — are among the 100 new members and 25 foreign associates elected to the National Academy of Sciences on April 30. Forty percent of the newly elected members are women, the most ever elected in any one year to date.

Membership to the National Academy of Sciences is considered one of the highest honors that a scientist or engineer can receive. Current membership totals approximately 2,380 members and nearly 485 foreign associates.

Edward S. Boyden is the Y. Eva Tan Professor in Neurotechnology at MIT; leader of the Synthetic Neurobiology Group in the MIT Media Lab; associate professor of biological engineering and of brain and cognitive sciences; a McGovern Institute investigator; co-director of the MIT Center for Neurobiological Engineering; and a member of the MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute for Integrative Cancer Research at MIT.

Boyden develops new tools for probing, analyzing, and engineering brain circuits. He uses a range of approaches, including synthetic biology, nanotechnology, chemistry, electrical engineering, and optics to develop tools capable of revealing fundamental mechanisms underlying complex brain processes. He pioneered the development of optogenetics, a powerful method that enables neuronal activity to be controlled with light. He also led the team that invented expansion microscopy, in which a specimen is embedded in a gel that swells as it absorbs water, thereby expanding nanoscale features to a size where they can be seen using conventional microscopes. He is now seeking to systematically integrate these technologies to create detailed maps and models of brain circuitry.

Paula T. Hammond is the David H. Koch Chair Professor of Engineering and the head of the Department of Chemical Engineering; a founding member of the MIT Institute for Soldier Nanotechnology; and a member of the MIT Energy Initiative and Koch Institute.

Hammond’s research in nanomedicine encompasses the development of new biomaterials to enable drug delivery from surfaces with spatio-temporal control. She also investigates novel responsive polymer architectures for targeted nanoparticle drug and gene delivery, and has developed self-assembled materials systems for electrochemical energy devices. She has designed multilayered nanoparticles to deliver a synergistic combination of siRNA or inhibitors with chemotherapy drugs in a staged manner to tumors, leading to significant decreases in tumor growth and a great lowering of toxicity.

Aviv Regev is a professor of biology; a core member of the Broad Institute of Harvard and MIT; and aHoward Hughes Medical Institute investigator.

Regev studies the molecular circuitry that governs the function of mammalian cells in health and disease and has pioneered many leading experimental and computational methods for the reconstruction of circuits, including in single-cell genomics. Her work focuses on dissecting complex molecular networks to determine how they function and evolve in the face of genetic and environmental changes, as well as during differentiation, evolution and disease.

The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established in 1863 by an Act of Congress, signed by President Abraham Lincoln, the academy was charged with “providing independent, objective advice to the nation on matters related to science and technology.” Scientists are elected by their peers to membership for outstanding contributions to research. The NAS is committed to furthering science in America, and its members are active contributors to the international scientific community.

Department of Biology hosts second annual Science Slam

Eight biology contestants get one slide and three minutes to explain their research and impress their listeners.

Raleigh McElvery | Department of Biology
April 30, 2019

Trainees recently took over the Tuesday Biology Colloquium for the second annual Science Slam, hosted by MIT’s Department of Biology. Topics ranged from the science behind cancer metastasis to parasites, hangovers, and, notably, poop.

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. These 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 latter included Mary Carmichael, founder and CEO of the strategic communications consultancy Quark 4; John Pham, editor-in-chief of Cell; and Ari Daniel, an independent science reporter who crafts digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were six graduate students and two postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, and the Koch Institute for Integrative Cancer Research at MIT. In order of appearance:

  • Rebecca Silberman, from Angelika Amon’s lab, who spoke about how there is something special about cancer cells that allows them to thrive with the wrong number of chromosomes;
  • Tyler Smith, from Sebastian Lourido’s lab, who spoke about his organism of choice, Toxoplasma gondii, and how these parasites provide insights into fundamental biology that classic “model” organisms do not;
  • Jasmin Imran Alsous, from Adam Martin’s lab, who spoke about the coordinated cellular interactions required for fruit fly egg development;
  • Darren Parker, from Gene-Wei Li’s lab, who spoke about the ratio of ingredients needed to concoct nature’s winning recipe for the perfect cell;
  • Sophia Xu, from Jing-Ke Weng’s lab, who spoke about the molecules responsible for the kudzu flower’s capacity to alleviate hangovers;
  • Jay Thangappan, from Silvi Rouskin’s lab, who spoke about the importance of RNA structure in splicing and its consequences for many important biological processes;
  • Lindsey Backman, from Catherine Drennan’s lab, who spoke about the biochemical processes carried out by gut bacteria that make poop smell bad; and
  • Arish Shah, from Eliezer Calo’s lab, who spoke about how developing zebrafish clear maternally-contributed molecules and replace them with their own, thus becoming “independent from mom.”

The event was moderated by former Slammers, postdoc Monika Avello and graduate student Emma Kowal. The duo joined forces with the Building 68 communications team and Biology Graduate Student Council to publicize the event and host two pre-slam workshops and a practice session.

Kowal, last year’s winner, was motivated to mentor this year’s cohort because, as she puts it, most scientists either don’t recognize the importance of clear communication or don’t recognize the challenge of doing it well.

“It is rare to see graduate programs devote training time to this,” she says, “but I believe it’s worth the effort. Taking the time to distill what excites and motivates us in our research not only inspires people to value science and even become scientists, but also helps us connect with each other — and remember why we love doing science in the first place.”

Avello recalls signing up for last year’s slam at the last minute, and “loving the experience.”

“I wanted to facilitate the experience of thinking hard about science communication in a fun and inclusive way for other graduate students and postdocs,” she says. “I really enjoyed watching everyone wrestle with the challenge of presenting their science in such a tight, condensed format, and ultimately developing their own unique story and style.”

There were two prizes, one awarded by the three judges and another awarded by the audience. Silberman, a fifth-year graduate student whose talk was titled “Does Chromosome Imbalance Cause Cancer?,” took home the Judges’ Prize, while third-year graduate student Sophia Xu claimed the Audience Prize with her talk, “Plant Natural Products and Human Ethanol Metabolism.”

Silberman said her favorite part was watching her fellow participants’ talks develop over time during the consecutive practice sessions. “Getting the opportunity to workshop my ideas and get input from Emma, Moni, and the other participants made the final presentation much less terrifying than it would have been otherwise, and made my talk much better,” she says.

Xu saw the Slam as an opportunity to practice presenting her research in an engaging way, and take a small step toward conquering her fear of public speaking. “I was overwhelmed by the support I received, not only from the organizers, but also from the other speakers,” she says. “It felt much like what I imagine a collaborative, friendly British cooking show would be like.”

Silberman encourages Department of Biology trainees considering participating in next year’s slam to “go for it.” She adds: “As grad students, we often aren’t challenged to distill our research down to its simplest terms. It was both harder and more fun than I expected.”