Bailey Bowcutt investigated COVID-19 cases in rural Wyoming before coming to MIT for the summer and applying her knowledge to a new cellular invader.
Raleigh McElvery
July 23, 2021
The first time Bailey Bowcutt saw a lab it was nothing like she expected. Rather than a stark, sterile setting with sullen figures floating around like ghosts in white lab coats, the atmosphere was cordial and the dress casual. Some scientists even sported vibrant shirts with Marvel characters. A high school senior on a class field trip, Bowcutt couldn’t have predicted that the next time she’d set foot in the Wyoming Public Health Laboratory she’d no longer be a visitor, but a researcher performing diagnostic testing during a global pandemic. Now, as COVID-19 restrictions begin to lift, she’s taking the research tools she’s learned to Cambridge, Massachusetts to complete the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio) and investigate how other types of pathogens spread.
Growing up in rural Wyoming, Bowcutt had little exposure to science because there were few research institutes close by. But watching family members suffer from gastrointestinal illness and other infections spurred her to pursue a degree in microbiology at Michigan State University (MSU). Shortly after she arrived on campus in the fall of 2019, she joined Shannon Manning’s lab studying antibiotic resistance in cattle.
Cows are prone to contracting a bacterial infection of the udder called mastitis. (In humans, a similar inflammation can occur in breast tissue.) Manning’s lab is looking at how antibiotic treatments affect the bovine gut microbiome and emergence of antibiotic resistance genes. Bowcutt’s role was to help identify these super bugs inside the cows’ gastrointestinal tracts.
“I got to go to the farm to take samples, which involved a glove that goes all the way up to the shoulder and some invasive maneuvers inside cows,” she explains. “Luckily, I was just the bag holder!”
Intimate sample collection aside, Bowcutt was excited about the work because it combined agriculture and human health research to solve issues plaguing rural communities. But her time on the farm was cut short when COVID-19 cases climbed in early 2020. She headed back to her home in Wyoming to begin remote MSU classes and, reminiscing about her field trip to the Wyoming Public Health Laboratory, reached out to the director to see if there were any internship opportunities.
“I’d barely learned how to do science at that point, but they needed people who could handle a pipette, so they took me,” she says. “I ended up being one of the first people there helping with COVID research, and I stayed for about a year-and-a-half while I took online classes.”
The lab would receive nasopharyngeal swabs from COVID-19 patients, and Bowcutt’s first task was to help extract RNA from the samples. Later, she transitioned to another project, which required performing PCR on untreated wastewater samples to glean a population-level understanding of where COVID-19 outbreaks were occurring.
She began toying with the idea of pursuing a PhD, but wasn’t sure what it would entail. So, in early 2021, she started Googling summer science programs and stumbled on BSG-MSRP-Bio. She was accepted, and paired with one of the very labs that had caught her eye online: assistant professor Becky Lamason’s group.
Listeria monocytogenes (yellow) rocket around their host cells (outlined in cyan) before ramming through the host’s membrane and that of its neighbor, forming a protrusion that is engulfed by the recipient cell. Image by Cassandra Vondrak.
“If you’ve ever seen microscopy pictures from the Lamason lab, they’re just so beautiful,” Bowcutt explains. Beautiful, yes — but she would soon learn these snapshots capture a chilling cellular invasion and molecular heist.
The Lamason lab watches malicious bacteria as they hijack molecules in human host cells to build long tails, rocket around, and punch through the cell membrane to spread. Bowcutt’s mentor, graduate student Yamilex Acevedo-Sánchez, focuses on the food-borne bacterium Listeria monocytogenes, which targets the gastrointestinal tract. Acevedo-Sánchez’s research aims to understand the host cell pathways that Listeria commandeers to move from one cell to the next in a process called cell-to-cell spread.
Together, Acevedo-Sánchez and Bowcutt are investigating several proteins in the human host cell involved in cellular transport and membrane remodeling (Caveolin-1, Pacsin2, and Fes), which could regulate Listeria’s spread. Over the summer, the duo has been adjusting the levels of these proteins and observing what happens to Listeria’s ability to move from cell-to-cell.
Bowcutt spends most of her days doing Western blots; growing Listeria and mammalian cells; and combining immunofluorescence assays with fixed and live cell microscopy to take her own striking microscopy images and movies of the parasites.
“I expected the work environment at MIT to be very intense, but everyone has been really friendly and willing to answer questions,” she says. “Some of my favorite experiences have just been in the lab while everyone is bustling around. It’s a welcome change after so much COVID-19 isolation.”
Now that the COVID-era occupancy restrictions have lifted, Bowcutt’s lab bench neighbor is Lamason herself. “She’s next to me doing experiments all the time,” Bowcutt explains, “which is cool because she’s really engaging with the research in the same way we are.”
Bowcutt says her summer experience has given her some much-needed practice designing research questions and devising the experiments to answer them. She’s also acquired a new skill she didn’t anticipate: interpreting ambiguous results and developing follow-up experiments to clarify them.
These days, the prospect of a PhD seems much less intimidating. In fact, the Lamason lab has done more than simply pique Bowcutt’s interested in fundamental biology research. She’s now considering ways to combine her microbiology skills with her interest in rural health care.
“I didn’t expect to see this much growth in myself,” she says, “and I know it’s making me a better scientist. I’m excited to return to MSU in the fall because I feel like I can do so much more now — and I would totally do it again.”
Merrill Meadow | Whitehead Institute
July 13, 2021
The American Society of Hematology (ASH), will honor Whitehead Institute Founding Member Harvey Lodish with its Wallace H. Coulter Award for Lifetime Achievement in Hematology.
The Coulter Award—ASH’s highest honor—recognizes an individual who has demonstrated a lasting commitment to the field of hematology through outstanding contributions to education, research, and practice.
Lodish is being honored for his six decades of key contributions to hematology, including his studies of the structure and biogenesis of red blood cells and his use of those cells as vehicles for delivering therapeutics. His research has provided important insights into several red cell diseases, including beta thalassemia and polycythemia vera; and he identified a new family of growth factor receptors, now known as the cytokine receptor superfamily. Lodish is also being recognized for his mentorship of more than 200 students and fellows, including two Nobel Prize recipients.
He will formally receive the Award at the 2021 ASH Annual Meeting in December.
Greta Friar | Whitehead Institute
July 12, 2021
Messenger RNAs (mRNAs) are our cells’ intermediaries as genes become proteins. In order for the instructions in our genes to be carried out, first their DNA sequences are copied into mRNA, and then that mRNA is used as a template to create proteins that do the work of the cell. Early in development, eggs and embryos use mRNA supplied by the mother until the embryo starts making enough mRNA from its own genes. Usually, mRNAs are short lived, constantly being created and degraded to help regulate how much protein is made from a gene at any given time. However, in the earliest stages of development, before the embryo can make enough of its own mRNAs, they are a limited resource and the embryo cannot afford to destroy them. Whitehead Institute Member David Bartel’s lab discovered in 2014 ways in which cells regulate protein production differently during this early developmental period, using processes that modulate how efficiently existing mRNAs are translated into proteins, rather than destroying mRNAs to decrease the protein level.
In new research, published in eLife on July 2, Bartel, who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute, and Bartel lab member Kehui Xiang, a CRI Irvington Postoctoral Fellow, have now discovered how cells establish this early gene regulatory regime and what conditions prompt a switch as the embryos mature. The researchers have observed the same regulatory switch in fish, frogs, and flies, and because the switch occurs across the animal kingdom, they would expect to see that the mechanism applies in other species including mammals.
“When I joined the lab, they had discovered that egg cells and early embryos had this different regulatory regime, and I wanted to know why,” Xiang says. “There must be fundamental changes to the cell, or to the molecules in the cell, that define this.”
The difference in how mRNAs are regulated during and after early development has to do with the length of their tails. mRNAs have tails made up of strings of adenines, one of the building blocks of RNA. Tail length varies between mRNAs from different genes and even between mRNAs from the same gene. Usually, the length of this “poly(A)-tail” corresponds to how long an mRNA lasts before getting degraded. An mRNA with a long tail is more stable, and will generally last longer. However, researchers had also observed that in some cases mRNA tail length corresponds to how readily an mRNA is used to make protein. Bartel’s earlier research had helped define when each of these connections occurs: mRNA tail length affects translational efficiency only in immature eggs and early embryos, and in other stages, it affects mRNA stability or lifespan.
In their new research, Xiang and Bartel uncovered three conditions that are required for the mRNA regulatory regime that exists in early development.
A competitive environment
The first condition is that there has to be a limited availability of a protein that binds to mRNA tails called cytoplasmic poly(A)-binding protein (PABPC). PABPC is known to help activate the translation of mRNA into protein. It binds to the mRNA tail and—in embryos—helps to increase translational efficiency; the researchers propose that it may do this by promoting a more favorable structure for translation. When PABPC is in limited supply, as it is in early embryos, then short-tailed mRNAs are less likely to bind any of the protein, as they will be outcompeted by long-tailed mRNAs, explaining the correlation between tail length and translational efficiency. Later in development, PABPC is in such ready supply that all of the mRNAs are able to bind at least one, decreasing the competitive edge of long-tailed mRNAs.
Early durability
However, the researchers observed that reducing the amount of PABPC in adult cells so that it becomes limiting in these cells did not cause mRNAs with longer tails to be translated more efficiently, which showed that other conditions must also contribute to early embryos’ unique regulation. The second condition that Xiang identified is that mRNAs must be relatively stable in spite of their inability to compete for PABPC. In adult cells, RNAs without PABPC bound to their tails are very unstable, and so are likely to degrade. If the same were true in early embryos, then the short-tailed mRNAs would degrade quickly because they are outcompeted for binding PABPC, and so one would again see a link between tail length and stability, rather than between tail length and translational efficiency—short-tailed mRNAs would be eliminated rather than poorly translated. However, the processes that would normally degrade mRNAs without PABPC have not yet started occurring in early embryos, allowing the short-tailed mRNAs to survive.
Big fish in a small pond
Finally, Xiang discovered that in order for tail length and translational efficiency to be linked, PABPC has to be able to affect translational efficiency. He found that in adult cells PABPC does not appear to boost translational efficiency the way it does in embryos. The researchers hypothesize that this is because the process of translating mRNAs in adult cells is already so efficient that the small boost from binding PABPC does not make a significant difference. However, in early embryos PABPC is more of a big fish in a small pond. The cells do not have all of the machinery to maximize translational efficiency, so every bit of improvement, such as the benefit of binding PABPC, makes a noticeable difference.
Together, these three conditions enable early eggs and embryos to regulate their mRNA in a unique fashion that can control how much protein is made from each gene without destroying the limited pool of mRNA available. In the future, the researchers hope to recreate the three conditions in non-embryonic cells to confirm that the conditions Xiang identified are not only necessary but also sufficient to cause the switch in regulatory regimes.
“Knowing which function the poly(A)-tail is performing in a specific cell or scenario—providing mRNA stability or translational efficiency—is really critical for understanding how genes are regulated in the different cells,” Bartel says. “And understanding that is important for answering all kinds of questions about cells, from their functions to what can go wrong with them in diseases.”
Ken Shulman
July 9, 2021
There were only 625 undergraduate women on campus—and far fewer Latina women—when Arlyn García-Pérez ’79 arrived at MIT in 1975. But her experience wasn’t unlike that of many other first-year students: used to being at the top of her class, she found herself failing some of her first MIT courses. “It was a terrible shock,” says García-Pérez, who was born in Cuba and grew up in Peru and Puerto Rico. “But it turned out to be an invaluable lesson. I learned that failure is inevitable, and that the important thing is knowing how to lift yourself up and get on with your work.”
García-Pérez, who is now director of policy and analysis at the National Institutes of Health (NIH) Office of Intramural Research, lifted herself up deftly after her first-semester stumble. She’d come to MIT thinking she’d go to medical school. Instead, she fell in love with research after her first biology lab. “I knew right then I wanted to be involved in discovery,” she says. “To make the sort of inquiries my professors were making.”
She graduated with a biology degree and enrolled in a biochemistry PhD program at Michigan State University, where she studied the human kidney. With a PhD and a fellowship in hand, she began a postdoc at the Laboratory of Kidney and Electrolyte Metabolism at NIH in Bethesda, Maryland. There she studied how organic osmolytes protect the kidney medulla—the inner part of the kidney—from the high levels of salt there that would otherwise destroy DNA and proteins in its cells. Organisms all along the evolutionary spectrum use the same compounds to protect themselves in high-salt environments.
In 1992, García-Pérez was awarded tenure at NIH as an independent senior investigator. And in 1999, she accepted an invitation to join the administration at the Office of Intramural Research—the office that oversees all research conducted in-house at NIH. Since then, she has focused on creating programs and policies that facilitate other scientists’ discoveries. For example, she established a 12-year pilot for the since-expanded NIH Academy, a post-baccalaureate research program supporting work that contributes to eliminating domestic health disparities.
García-Pérez has also made it a priority to advocate for inclusivity in recruitment and advancement at NIH, eager to pay forward the mentorship and support she received there throughout her career. “We have to make a conscious effort to think of people who may not be like us,” she says.
This article also appears in the July/August 2021 issue of MIT News magazine, published by MIT Technology Review.
Carnegie Corporation
July 1, 2021
The daughter of a teacher and an engineer, Lehmann won a Fulbright Fellowship in ecology in 1977 that brought her to Seattle, where she discovered her passion for developmental genetics. She has since been using flies to study germ cells, precursors of eggs and sperm, which play an essential role in our survival.
Lehmann, who calls herself a dog and data lover, is professor of biology and the director of the Whitehead Institute at MIT. Her research on the origins of germ cells — the only cells in the human body that have immortality — is shedding light on how they lead to reproduction, on the role of RNA regulation in germ cells, and on how harmful mutations are eliminated during oogenesis. She believes it is critical for scientists to push the envelope, following their instincts to pursue research on topics about which not much is known.
Lehmann’s long list of achievements includes membership in the National Academy of Sciences and the American Academy of Arts and Sciences, and in 2021 she was awarded the Vilcek Prize in Biomedical Science.
“It means so much to me to be recognized as an immigrant and a researcher,” Lehmann said upon receiving the Vilcek Prize. “In these days, immigrants don’t feel as welcomed as I did when I came to this country. For me, coming to the U.S. meant to be given a chance to live the dream of being a scientist.”
Eva Frederick | Whitehead Institute
June 27, 2021
More corn is grown in the United States than any other crop, but we only use a small part of the plant for food and fuel production; once people have harvested the kernels, the inedible leaves, stalks and cobs are left over. If this plant matter, called corn stover, could be efficiently fermented into ethanol the way corn kernels are, stover could be a large-scale, renewable source of fuel.
“Stover is produced in huge amounts, on the scale of petroleum,” said Whitehead Institute Member and Massachusetts Institute of Technology (MIT) biology professor Gerald Fink. “But there are enormous technical challenges to using it cheaply to create biofuels and other important chemicals.”
And so, year after year, most of the woody corn material is left in the fields to rot.
Now, a new study from Fink and MIT chemical engineering professor Gregory Stephanopolous led by MIT postdoctoral researcher Felix Lam offers a way to more efficiently harness this underutilized fuel source. By changing the growth medium conditions surrounding the common yeast model, baker’s yeast Saccharomyces cerevisiae, and adding a gene for a toxin-busting enzyme, they were able to use the yeast to create ethanol and plastics from the woody corn material at near the same efficiency as typical ethanol sources such as corn kernels.
Sugarcoating the issue
For years, the biofuels industry has relied on microorganisms such as yeast to convert the sugars glucose, fructose and sucrose in corn kernels to ethanol, which is then mixed in with traditional gasoline to fuel our cars.
Corn stover and other similar materials are full of sugars as well, in the form of a molecule called cellulose. While these sugars can be converted to biofuels too, it’s more difficult since the plants hold onto them tightly, binding the cellulose molecules together in chains and wrapping them in fibrous molecules called lignins. Breaking down these tough casings and disassembling the sugar chains results in a chemical mixture that is challenging for traditional fermentation microorganisms to digest.
To help the organisms along, workers in ethanol production plants pretreat high-cellulose material with an acidic solution to break down these complex molecules so yeast can ferment them. A side effect of this treatment, however, is the production of molecules called aldehydes, which are toxic to yeast. Researchers have explored different ways to reduce the toxicity of the aldehydes in the past, but solutions were limited considering that the whole process needs to cost close to nothing. “This is to make ethanol, which is literally something that we burn,” Lam said. “It has to be dirt cheap.”
Faced with this economic and scientific problem, industries have cut back on creating ethanol from cellulose-rich materials. “These toxins are one of the biggest limitations to producing biofuels at a low cost.” said Gregory Stephanopoulos, who is the Willard Henry Dow Professor of Chemical Engineering at MIT.
Lending yeast a helping hand
To tackle the toxin problem, the researchers decided to focus on the aldehydes produced when acid is added to break down tough molecules. “We don’t know the exact mechanism by which aldehydes attack microbes, so then the question was, if we don’t really know what it attacks, how do we solve the problem?” Lam said. “So we decided to chemically convert these aldehydes into alcohol forms.”
The team began looking for genes that specialized in converting aldehydes to alcohols, and landed on a gene called GRE2. They optimized the gene to make it more efficient through a process called directed evolution, and then introduced it into the yeast typically used for ethanol fermentation, Saccharomyces cerevisiae. When the yeast cells with the evolved GRE2 gene encountered aldehydes, they were able to convert them into alcohols by tacking on extra hydrogen atoms.
The resultant high levels of ethanol and other alcohols produced from the cellulose might have posed a problem in the past, but at this point Lam’s past research came into play. In a 2015 paper from Lam, Stephanopoulos and Fink, the researchers developed a system to make yeast more tolerant to a wide range of alcohols, in order to produce greater volumes of the fuel from less yeast. That system involved measuring and adjusting the pH and potassium levels in the yeast’s growth media, which chemically stabilized the cell membrane.
By combining this method with their newly modified yeast, “we essentially channeled the aldehyde problem into the alcohol problem, which we had worked on before,” Lam said. “We changed and detoxified the aldehydes into a form that we knew how to handle.”
When they tested the system, the researchers were able to efficiently make ethanol and even plastic precursors from corn stover, miscanthus and other types of plant matter. “We were able to produce a high volume of ethanol per unit of material using our system,” Fink said. “That shows that there’s great potential for this to be a cost-effective solution to the chemical and economic issues that arise when creating fuel from cellulose-rich plant materials.”
Scaling up
Alternative fuel sources often face challenges when it comes to implementing them on a nationwide scale; electric cars, for example, require a nationwide charging infrastructure in order to be a feasible alternative to gas vehicles.
An essential feature of the researchers’ new system is the fact that the infrastructure is already in place; ethanol and other liquid biofuels are compatible with existing gasoline vehicles so require little to no change in the automotive fleet or consumer fueling habits. “Right now [the US produces around] 15 billion gallons of ethanol per year, so it’s on a massive scale,” he said. “That means there are billions of dollars and many decades worth of infrastructure. If you can plug into that, you can get to market much faster.”
And corn stover is just one of many sources of high-cellulose material. Other plants, such as wheat straw and miscanthus, also known as silvergrass, can be grown extremely cheaply. “Right now the main source of cellulose in this country is corn stover,” Lam said. “But if there’s demand for cellulose because you can now make all these petroleum-based chemicals in a sustainable fashion, then hopefully farmers will start planting miscanthus, and all these super dense straws.”
In the future, the researchers hope to investigate the potential of modifying yeasts with these anti-toxin genes to create diverse types of biofuels such as diesel that can be used in typical fuel-combusting engines. “If we can [use this system for other fuel types], I think that would go a huge way toward addressing sectors such as ships and heavy machinery that continue to pollute because they have no other electric or non-emitting solution,” Lam said.
Scaling up
Alternative fuel sources often face challenges when it comes to implementing them on a nationwide scale; electric cars, for example, require a nationwide charging infrastructure in order to be a feasible alternative to gas vehicles.
An essential feature of the researchers’ new system is the fact that the infrastructure is already in place; ethanol and other liquid biofuels are compatible with existing gasoline vehicles so require little to no change in the automotive fleet or consumer fueling habits. “Right now [the US produces around] 15 billion gallons of ethanol per year, so it’s on a massive scale,” he said. “That means there are billions of dollars and many decades worth of infrastructure. If you can plug into that, you can get to market much faster.”
And corn stover is just one of many sources of high-cellulose material. Other plants, such as wheat straw and Miscanthus, also known as silvergrass, can be grown extremely cheaply. “Right now the main source of cellulose in this country is corn stover,” Lam said. “But if there’s demand for cellulose because you can now make all these petroleum-based chemicals in a sustainable fashion, then hopefully farmers will start planting Miscanthus, and all these super dense straws.”
In the future, the researchers hope to investigate the potential of modifying yeasts with these anti-toxin genes to create diverse types of biofuels such as diesel that can be used in typical fuel-combusting engines. “If we can [use this system for other fuel types], I think that would go a huge way toward addressing sectors such as ships and heavy machinery that continue to pollute because they have no other electric or non-emitting solution,” Lam said.
Patterns of myosin and F-actin proteins across developing embryos promote tissue folding and shape new life.
Raleigh McElvery
June 14, 2021
Virtually all multicellular organisms, including humans, begin as a single cell that rapidly divides and begets trillions of others. These cells work together, stretching, squishing, and migrating to sculpt organs and tissues. In the case of the fruit fly embryo, it only takes a few hours for life to take shape. First, the multiplying cells form an oblong sphere akin to a football. Then, mechanical forces cause a band of cells along the “belly” side of the developing fly to furrow inwards. These “mesoderm” cells form a new layer that will later give rise to muscles. Although the folding process transpires in less than 20 minutes, it’s crucial for determining where the cells will go and what roles they will assume.
Scientists previously identified two important proteins that generate the force needed to fold the tissue. The first, myosin, has a characteristic rod shape with feet hanging off both ends. It can “walk” along the cell’s inner scaffolding, composed of a second, rope-like protein called filamentous actin (F-actin). As it walks, myosin tugs on the F-actin and constricts the tissue. Researchers are probing the distribution of myosin and F-actin across the developing embryo, an important step towards understanding how these proteins drive constriction in the proper places to fold the tissue.
Myosin appears in a gradient across the belly and back of the developing fly. Since myosin and F-actin work together, many scientists assumed they would display the same pattern. However, new work from MIT’s Department of Biology and Department of Mathematics suggests otherwise. The study, published in the journal Development, shows how gene expression patterns dictate a unique distribution of F-actin across the mesoderm, which exhibits peaks and valleys. In combination with the myosin present, this F-actin pattern causes the cells to stretch, squish, or maintain their shape in just the right places to bend the tissue.
“We’ve known for decades that mechanical proteins like myosin and F-actin regulate tissue curvature during development,” says Adam Martin, an associate professor of biology and the study’s senior author. “But what hasn’t been appreciated is the extent to which these two proteins are intricately patterned during the tissue folding process. Our finding that F-actin has a different pattern than myosin was quite surprising.”
The researchers, led by graduate student Marlis Denk-Lobnig, began by focusing on two well-known transcription factor proteins, Twist and Snail, which bind to DNA to control gene expression. These transcription factors are known to dictate cell shape and fate during tissue folding, and Denk-Lobnig wondered how they affected F-actin levels.
By imaging live and fixed cells, the researchers observed that Snail and Twist drove a different pattern of F-actin density across the mesoderm compared to previously described myosin gradients. Two to three hours after the fruit fly eggs are laid, Snail depletes F-actin levels across the mesoderm. But, as Twist activates its transcriptional targets, F-actin and myosin levels rise in a subset of the mesoderm cells along the belly of the developing fly — constricting them and folding that swath of the tissue. The more F-actin and myosin a cell contains, the more compressed and wedge-shaped it becomes.
Denk-Lobnig also targeted another protein, RhoA, that tunes F-actin and myosin levels. RhoA activation is ultimately controlled by the ratio of two other molecules, C-GAP and RhoGEF2. The researchers adjusted the levels of C-GAP and RhoGEF2 in live cells, and watched the subsequent changes in myosin and F-actin distribution in real time.
To continue disentangling the effects of each protein on tissue curvature, they leveraged a computer simulation of a developing embryo designed by Associate Professor of Mathematics Jörn Dunkel, former grad student Pearson Miller PhD ’20, and postdoctoral researcher Jan Totz. The model allowed the team to adjust patterns of force and protein activity, in order to determine how the changes that they’d witnessed in real embryos affected tissue shape.
“The main takeaway is that you need this elegant coordination between cells during development,” Denk-Lobnig says. “We’ve shown how force generation patterns change the shape of individual cells — and how this leads to shape changes across entire tissues.”
Top image: Cross sections of three fruit fly embryos undergoing tissue folding. Nuclei are in blue, the transcription factor Snail is in red, and the junctional protein Armadillo is in green. Credit: Marlis Denk-Lobnig.
Video: An early stage fruit fly embryo has a band of cells on its surface that furrows inward to form a fold. Credit: Marlis Denk-Lobnig.
Citation: “Combinatorial patterns of graded RhoA activation and uniform F-actin depletion promote tissue curvature”
Development, online June 14, DOI: 10.1242/dev.199232
Marlis Denk-Lobnig, Jan F. Totz, Natalie C. Heer, Jörn Dunkel, and Adam C. Martin
Posted: 6.14.21
MIT experts outline issues, offer hope for climate action
June 12, 2021
Across the Institute, work is underway to understand and address Earth’s changing climate and to mitigate the impacts of these changes on human populations. Spectrum asked three MIT faculty members who have engaged deeply with this work to provide insight into the challenges that lie ahead and suggest paths forward.
Sallie (Penny) Chisholm is an Institute Professor with a joint appointment in the Department of Civil and Environmental Engineering and the Department of Biology. Her award-winning research explores the biology, ecology, and evolution of marine phytoplankton, photosynthetic microbes that shape aquatic ecosystems.
Kerry A. Emanuel ’76, PhD ’78 is the Cecil and Ida Green Professor of Atmospheric Science in the Department of Earth, Atmospheric and Planetary Sciences (EAPS), and co-director of the Lorenz Center at MIT, an advanced climate research center. A prominent meteorologist and climate scientist, Emanuel is best known for his research on hurricanes and atmospheric convection.
Susan Solomon is the Lee and Geraldine Martin Professor of Environmental Studies in EAPS and a professor of chemistry. Solomon, who researches interactions between chemistry and climate, is renowned for her work advancing the understanding of the global ozone layer.
What are the biggest scientific challenges we face in addressing climate change?
SOLOMON: One of the biggest scientific challenges is understanding how much and how fast biological processes will be affected by a warmer world. For example, we need to better understand the drivers of wildfires in the North American West, the roles of ocean acidification and warming in damaging marine life, and how climate change will affect the spread of diseases. The coupling between biology and the physical and chemical system is well recognized as important, but a lot more needs to be done. Another key challenge is better understanding extreme events, because neither humans nor ecosystems have sufficient ability to deal with them.
EMANUEL: In my view, the greatest scientific challenge we face is quantifying the risks of climate change. We spend too much time calculating and talking about global mean temperature and sea level when in fact the most serious problems are bound to arise from extreme events, such as storms, droughts, and wildfires. There is much evidence that the risk of such events, which are also the main source of insurance payouts involving naturally occurring phenomena, has already evolved well beyond historical levels, rendering obsolete the financial basis of the global insurance and reinsurance markets. It is absolutely essential that science help the world come to grips with current levels of natural hazard risk and with how such risks are likely to evolve.
CHISHOLM: It appears to me that the biggest immediate challenge is in the social sciences. Broadly speaking, natural scientists know what causes global warming and what is needed to curb it. But until the public at large accepts that anthropogenic climate change is real and the consequences dramatic, it will be impossible to implement solutions.
How do we rise to this challenge and get the public to feel the urgency? I am reminded of the popularized wisdom of Baba Dioum, a Senegalese forester: “In the end, we will conserve only what we love; we will love only what we understand; and we will understand only what we are taught.” I too like to think that if people understood how our planet functions as a living system and how the climate system is embedded in that system, it would help move the needle.
Kerry Emanuel has produced a compelling climate primer, for example, that beautifully displays the essence of what one must understand to fully appreciate the climate challenge. I am so impressed by it that I have put a link to it in my email signature line. For my part, I have coauthored a series of children’s picture books—The Sunlight Series—that describe how our planet functions as a living system and the role of fossil fuels and climate in that system. These efforts are just drops in a bucket. What is needed is a global educational movement to bring Earth system science to the forefront.
What are you working on that gives you hope for the future?
EMANUEL: I have been working on a method for downscaling tropical cyclones from climate models in a way that allows one easily to generate hundreds of thousands of storms in a given climate. The important step was applying a rigorous understanding of tropical cyclone physics to the problem so as to achieve maximum computational speed with minimum loss of fidelity. This could not have been accomplished by machine learning. My work has already been applied by the nonprofit First Street Foundation to estimate flood risk, including from tropical cyclones, for every single piece of private property in the United States. Flood-risk estimates resulting from this work are communicated to current and prospective property owners through websites such as those used to shop for real estate.
By bringing quantitative measures of climate risk right down to the level of our homes, this work promises to make people much more aware of their current climate risk and how it is evolving over time. My hope is that this work will make the impact of climate change personal, and citizens will agitate for action.
SOLOMON: I’ve been doing a lot of work on fully understanding the sources and sinks of fluorochemicals, including chlorofluorocarbons and their substitutes, the hydrochlorofluorocarbons and hydrofluorocarbons. The fluorochemicals are potent greenhouse gases, so phasing them out has great benefits for climate. Some of my group’s recent work has shown that there are “banks” of old chlorofluorocarbons (for example, in old building chillers or even home freezers) that are still leaking and contributing to global warming. Additionally, there is some evidence that the continuing use of certain fluorochemicals as feedstocks to make other chemicals is far more problematic for the environment than it should be and could be.
What makes me hopeful is that the governments of the world are taking notice of these issues, in part because they’ve been so successful at dealing with these chemicals in the past. For example, concerns about damage to the stratospheric ozone layer that shields all life on Earth from damaging ultraviolet light from the sun led to the 1987 Montreal Protocol, a globally agreed-upon phaseout of the production of the worst ozone-damaging gases. There is evidence that the ozone layer is slowly starting to heal so that is a tremendous success story. Today, there is much more policy attention on what could be done to curb emissions and address global warming, so I’m optimistic that we can make improvements.
CHISHOLM: My lab does not work on climate science directly. We study marine phytoplankton, photosynthetic microbes at the base of aquatic food webs. Like plants on land, they use solar energy to draw CO2 out of the atmosphere and fix it into the organic carbon, feeding the rest of life in the sea. This so-called “invisible pasture” is responsible for nearly half of the annual flow of CO2 from the atmosphere into the global biosphere. More importantly, the planktonic food web functions as a “biological pump,” securing an enormous cache of CO2 in the deep sea. Like so many other biospheric processes, this “ecosystem service” is something we take for granted. But if the oceans were not alive—if the pump did not function—CO2 concentrations in the atmosphere would be dramatically higher.
But you asked what gives me hope. The short answer is: the wisdom and commitment of the younger generation to fight for their future. I can see a passion and commitment for change in young people that has been lacking for a few generations. Because my lab works on photosynthesis and I have written some children’s books about it, I frequently get emails from K–12 students looking for answers.
Recently, a 14-year-old wrote to ask, “What’s stopping usfrom mass adoption of ‘CO2 bioreactors’ to offset carbon emissions? Cost? Efficiency? Another factor?” That a 14-year-old is thinking along these lines is just one small example of things that give me hope.
What role do you think MIT and other research universities have to play in addressing climate change?
SOLOMON: MIT and other research universities have fantastic potential to help move the needle. For one thing, we have relevant experts in the physics, chemistry, and biology related to climate change under one roof. We also have key experts in the engineering and policy aspects of climate change. In short, we have all the research expertise needed to make progress. The problem is that it’s tough to get funding for interdisciplinary work via the traditional national funding mechanisms. Fortunately, that’s slowly changing.
EMANUEL: Universities can play a crucial role in bringing the dangers of climate change right to the front doors of ordinary people by catalyzing a revolution in the risk-modeling industry. We need to produce a new stream of talent that has a deep understanding of the physics of weather hazards; of numerical modeling; and of risk, risk-affected industries and government entities, and the risk-modeling industry. Such talent could then be employed to bring physical modeling to bear on weather hazard risk assessment. At the moment, almost all global risk modeling is done by just two firms and is extrapolated from historical records that are grossly insufficient for estimating long-term risk.
Fortunately, the insurance and reinsurance industries are rapidly coming to understand the woeful state of risk modeling and are eager to catalyze change. They are ready and willing to help fund positions in universities (e.g., postdoctoral research positions) that would produce the stream of new talent that’s badly needed to revolutionize the way we quantify and respond to climate risks.
CHISHOLM: Climate change, as well as most of the environmental challenges we face today, has emerged because we have accelerated dramatically the natural flows of energy and materials through the biosphere. The weight of human-made components on Earth now equals that of natural components, and we have appropriated roughly one-quarter of the Earth’s net plant production—the foundation of life for all other species. How has this human footprint changed the way the planet functions, and how will it change it as we move forward in the Anthropocene? And what about the unintended consequences of potential climate intervention through geoengineering? Clearly, we have a planet that is shifting dramatically from its natural self-assembling trajectory. There is little hope of making rational plans for our future until we begin to study the biosphere—and all the functions it mediates—with the same intensity as we study human biology.
So, what role should MIT play? Our late colleague Henry Kendall, a Nobel Laureate in Physics, once advised me to “never make small plans,” so here is my wish for MIT: Lead the equivalent of a Manhattan Project for the development of renewable energy and CO2-removal technologies. Create a College of Biocomplexity to consolidate and greatly expand the environmental research and education that is scattered throughout the Institute. Ensure that all new campus construction is a showcase for energy efficiency and the use of sustainable materials. Finally, advance economic frameworks that assign value to ecosystem services in the world economy. As one of the premier education and research institutions in the world, we should be leading the way.
A lifelong interest in teaching brought Mandana Sassanfar to MIT, where she has established programs to engage diverse students and forged partnerships with institutes across the country.
Raleigh McElvery
May 25, 2021
Of all the offices in Building 68, Mandana Sassanfar’s is perhaps the most colorful. Her walls are lined with photos of students past and present, each of whom completed one or more of the six outreach programs she heads as the Department of Biology’s director of outreach. Over the last two decades, Sassanfar has forged partnerships with communities across the country, in an effort to engage historically underrepresented groups in science — and increase access to MIT’s on-site and online resources.
Although she was born in Switzerland, Sassanfar spent most of her childhood moving between France and Iran for her father’s job. No matter where her family lived, she always attended French-speaking schools. As early as fourth grade, she remembers analyzing her instructors’ teaching strategies, and practicing how she would explain the same concepts to make them clearer. While this interest in education continued to percolate, she also discovered that her favorite subjects were chemistry and math.
By 1983, she’d earned a master’s in biochemistry from Pierre and Marie Curie University in Paris, and moved to the US to start a PhD at Cornell University. Although she nearly switched tracks to study plant science, she ultimately stuck with biochemistry in the hopes of studying under well-known scientist Jeffery Roberts. Although Roberts was not taking new students at the time, Sassanfar convinced him to let her complete an eight-week rotation in his lab.
“I scheduled that rotation as my last, so I would have made every mistake before working with Jeff’s group,” she says. “At the end of the eight weeks, I literally told him, ‘If you don’t take me, I’m going back to France.’ And he took me in.”
While everyone else was probing various aspects of transcription antitermination, Sassanfar was an outlier investigating the role of DNA replication in the bacterial SOS repair pathway following DNA damage. She was among the first researchers to design a quantitative western blot assay to measure the level of LexA and RecA proteins in vivo. “Jeff’s lab was a wonderful place to work and I received a rigorous scientific training,” she recalls. “He was an excellent mentor.”
After graduating from Cornell in 1988, Sassanfar completed two postdocs: one with Leona Samson at the Harvard School of Public Health, and another with Jack Szostak at Massachusetts General Hospital (MGH). Szostak later went on to earn a Nobel Prize in Physiology or Medicine for discovering how chromosomes are protected by telomeres and telomerase enzymes. While Sassanfar was in his lab, she overlapped with many prominent scientists, including David Bartel, Jennifer Doudna, Rachel Green, and John Lorsch.
Sassanfar (back row, left) planting a tree with the 2017 MSRP-Bio cohort.
As Sassanfar’s time at MGH drew to a close, Szostak introduced her to Paul Schimmel, a long-time faculty member at the MIT Department of Biology, who was hiring research scientists for his new biotech startup, Cubist, which he had co-founded with chemistry professor Julius Rebek. The company intended to explore aminoacyl-tRNA synthetases as potential antibiotic targets. Sassanfar already knew Schimmel as the co-author of one of her favorite books, Biophysical Chemistry. But working with him for nearly four years taught her additional skills that she couldn’t have gleaned from a book.
“I came to understand a tremendous amount about the biotech culture while I was at Cubist,” she says. “Paul was a great mentor, and I learned a lot from him about writing papers, and watching the even-keeled way he interacts with people.”
When Schimmel eventually moved to The Scripps Research Institute, Sassanfar joined Harvard University’s Department of Molecular and Cellular Biology as a teaching fellow. There, professor Stephen Harrison, a Howard Hughes Medical Institute (HHIM) Investigator, offered her a chance to become involved in her first outreach program — a week-long workshop for high school teachers that she continues to run today from MIT. She was also charged with coordinating a summer program that placed non-Harvard undergraduates in campus labs each summer. But, in 2002, just a couple months before a student cohort was slated to arrive, the program was abruptly canceled and Sassanfar resigned.
“I had to transfer six undergraduates to other summer programs and find a space for the teacher’s summer workshop,” she remembers. “I just needed some lab space for two weeks.”
She called the MIT Department of Biology, and within a few days she not only had lab spaces for the teachers workshop, but a job offer as well. She accepted, and teamed up with professor Graham Walker. Together, they worked to expand the department’s pre-college and undergraduate outreach programs, creating a pipeline to graduate school in the process.
While many graduate institutions are quick to recruit students from Ivy League schools, Sassanfar saw an opportunity to widen the applicant pool. “If you decide that all the top students are from the Ivies — which is not true — then you’re missing out on many phenomenal applicants,” she says. “So I started reaching out to undergraduate institutions with limited research resources that serve diverse student bodies. Graham and I wanted to offer these students a comprehensive summer research experience, which would inspire them to apply to rigorous PhD programs like MIT Biology.”
MIT already offered some programs in this vein — such as the MIT Summer Research Program (now called “MSRP General”) — but none of them focused specifically on the life sciences. However, MSRP General was not specifically designed to be a recruiting tool for the Department of Biology. As a result, Walker and Sassanfar decided to establish the MIT Summer Research Program in Biology (MSRP-Bio), which would offer additional, biology-specific programming to help these trainees succeed and prepare them for the next stage of their careers.
Walker was the long-time program director of the HHMI Undergraduate Science Education Program at MIT, and was also named an HHMI professor the year Sassanfar arrived. He and Sassanfar used some of the accompanying funds to establish synergetic programs focused on education outreach and diversity. These included MSRP-Bio, the Quantitative Biology Workshop, the HHMI special seminar series, and a summer mini-sabbatical for faculty at institutions serving students from disadvantaged backgrounds and minority groups.
At first, Sassanfar says, she didn’t know much about the MIT Biology philosophy or the graduate program. “I spent a lot of time just talking to the grad students. And I realized that if we were going to use MSRP-Bio as a recruiting tool, then we had to set admission standards similar to those of the graduate program.”“When Mandana began at MIT, she realized that to compete for the most talented students we needed to strengthen the biology component of MIT’s summer research programs, by increasing our outreach efforts and developing an enriched summer experience,” Walker recalls. “Since then, her leadership, energy, enthusiasm, and humanity have helped MSRP-Bio develop into the strikingly successful, high-impact program that it is today.”
She began by tweaking the admissions process, raising the minimum GPA and requiring additional letters of recommendation. That first summer, Sassanfar and Walker had only a few months to prepare, so the inaugural 2003 cohort was just 11 students.
Today, the program is known as the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio), and hosts up to 20 students. Participants perform full-time research for 10 weeks between June and August. They also attend academic seminars and weekly meetings with faculty. They visit biotech labs, take tours of Boston, learn about the grad school application process, practice their presentation skills, and share their research projects at the MSRP poster session and other conferences around the country.
In order to attract applicants from across the country, Sassanfar began traveling annually to schools with large populations of under-represented minority students, such as historically black colleges and universities; Hispanic-serving institutions; and large state schools in Texas, Florida, New York, Maryland, and Puerto Rico. She often relied on MSRP-Bio alumni to introduce her to science faculty during her campus visits.
At first it was difficult to connect with administrators and meet students. But Sassanfar slowly built sturdy relationships, and even started inviting faculty to join their students at MIT for seminars and summer sabbaticals. In 2004, the biotechnology program at the University Puerto Rico at Mayagüez honored Sassanfar with an award to celebrate her work.
“It’s really important to create opportunities that allow diverse students and faculty to benefit from MIT, rather than the other way around,” she says. “You have to show that you are doing this because you care, and not because you want something in return.”
Since 2003, over 400 students from 39 countries have participated in MSRP-Bio. Over 75% have gone on to graduate school (including 87 at MIT), 12 have become professors, and many others are leading successful careers in industry or medicine. One alumnus from the 2005 cohort, Eliezer Calo, is now a faculty member in the Department of Biology, and another from the 2007 cohort, Francisco Sánchez-Rivera, will start his own lab at the Koch Institute in 2022. Many of the MSRP-Bio alumni who complete their PhDs and postdocs at MIT stay actively engaged in outreach programs until they graduate, and help Sassanfar with many of the programs she coordinates.
Sassanfar (left) and Lee (right) at Lee’s graduation from MIT in 2010.
Mary Lee, a member of MSRP-Bio’s inaugural cohort who later completed her PhD at MIT, says she applied to the program in hopes of experiencing cutting-edge biology research in a new city. “Mandana was an integral part of my experience in MSRP-Bio,” she explains. “From my first encounter with her to even now, 20 years later, it is clear how committed she is to connecting students like myself to MIT and the research community. It was a short summer but the experience unlocked opportunities for me that I would not have had otherwise.”
Sassanfar also serves as the director of diversity and science outreach for the Department of Brain and Cognitive Sciences, as well as the diversity coordinator for the Center for Brains, Minds and Machines. These additional roles have allowed her to expand MSRP-Bio and the Quantitative Biology Workshop, now known as the Quantitative Methods Workshop. In addition, she’s spearheaded programs for local high school students, including field trips and the LEAH Knox Scholars Program.
Beyond her outreach work, each winter during MIT’s Independent Activities Period she teaches a class for first-year MIT undergraduates to introduce them to biology lab techniques. “My favorite thing is seeing the looks on students’ faces when they have been working so hard to learn and apply techniques, and they finally can see and interpret the results of their experiments,” she says. “That’s what I love.”
Although Sassanfar has mentored hundreds of students over the past 20 years, she works hard to connect with each while they’re on campus, and has stayed in touch with many of them. She enjoys getting visits and emails from summer program alums who share their successes and thank her for the role she’s played.
“The fact that we have so many students who have finished their PhDs and gone on to become postdocs, faculty, doctors and important players in industry is, I think, truly where the success lies,” she says. “My hope is to build a strong network of alums who are excited to meet current students and create a community.”
Most recently, Sassanfar has teamed up with students, staff, and faculty from the Department of Biology to begin a new initiative, which provides research training opportunities to local community college students.
“What has really worked for me is that the Biology Department gives me free rein,” she says. “They provide their full support, and let me take it from there.”
Computer Science + Biology — and powerful insights from a Women's & Gender Studies minor
MIT School of Humanities, Arts, and Social Sciences
May 21, 2021
When graduating senior Natasha Joglekar ’21 faced some serious medical issues in the fall of 2018, she found comfort in one particular class that term: WGS.229 / Race, Culture, and Gender in the US and Beyond: A Psychological Perspective. “I think that class was sometimes the only time I talked to people all week,” she recalls.
Following a medical leave, Joglekar was able to return to MIT full-time in the fall of 2020, and soon took another class in Women’s and Gender Studies (WGS): WGS.250 HIV/AIDS in American Culture. “That’s the class that made me want to be a WGS minor,” she says. “It was nice to get a broader perspective on illness, one that was not rooted in medicine, treatment, and doctors.”
Insight into societal outcomes
A Computer Science + Biology major (Course 6-7), Joglekar found that her WGS coursework provided her with meaningful insight into the human factors that drive so many societal outcomes. “WGS studies helped give me a framework for understanding the world,” she says, “in the same way that my Physics and Math classes did.” She adds that WGS classes helped her understand myths about various minority groups, as well as the ways children are socialized to believe them.
Joglekar, who was named a Burchard Scholar in 2019 for excellence in her humanistic WGS classes, says she always knew she wanted to study the humanities, as well as the STEM fields, in college. But she didn’t choose MIT only because the Institute pairs extraordinary technical and scientific education with a world-class School of Humanities, Arts, and Social Sciences. She was also impressed by the gender parity she saw on a visit to campus.
Support for women in tech
While at high school in a Boston suburb, her techie classes were predominantly male; at MIT, she saw both men and women pursuing science, technology, and math. “You come here and see, omigod, here are all these girls doing all these cool things,” she says. “I knew I would go into a technical field, and I wanted to go to a place with a lot of women in tech and a support system for women in tech.”
One of the supportive networks Joglekar found at the Institute was the lab of Tyler Jacks, a leader in the field of cancer genetics, the David H. Koch Professor of Biology, and Director of the Koch Institute for Integrative Cancer Research. Working through MIT’s Undergraduate Research Opportunities Program (UROP), Joglekar conducted cancer research in the Jacks lab, investigating the combination therapy potential of a small molecule inhibitor on tumor heterogeneity.
“The lab was a wonderful place to learn,” she says. “They were the community I needed.”
Detail, “The Ties That Bind,” artwork by Ekua Holmes; emblem for MIT Women’s & Gender Studies
Joglekar plans to work as a research assistant in a hospital, and says she expects her experience in Women and Gender Studies will help her understand patients better — and perhaps even address some of the social determinants of health.
Friendship and community
Community is of central important to Joglekar, whose family always emphasized the importance of friendship. That’s why she has spent much of her extracurricular time at MIT supporting community-building efforts. She is on the Executive Council of the Biology Undergraduate Student Association, which runs departmental study breaks and faculty dinners. She also serves on the Undergraduate Student Advisory Group for the Department of Electrical Engineering and Computer Science (EECS), which works to improve systemic issues, such as departmental communications.
The latter experience in particular gave Joglekar the chance to work directly with leaders in the EECS department. “That has been one of the highlights of my undergraduate experience,” she notes. “They’re all so good at listening and taking feedback, and they have influenced how I want to be one day if ever I’m in a leadership position.”
Leadership
In fact, Joglekar has served in several leadership roles already. In addition to her committee work, she serves as editor in chief of the MIT Undergraduate Research Journal, the Institute’s only peer-reviewed scientific journal serving the undergraduate population. And, like a good leader she is candid about her journey. “I don’t want people to think, ‘look at this person who’s flying through life.’ Far from it. I struggled at different times for different reasons,” she says. “But I’d still do it all over again!”
Joglekar is now planning to work as a research assistant in a hospital, and expects her experience in WGS will help her understand patients better — and perhaps even address some of the social determinants of health. “WGS gives you the tools to understand so many things, including underlying biases,” she says. “I think everybody should take a WGS class for this reason. it’s relevant regardless of what you do.”
