Author: mantulin

Individual neurons mix multiple RNA edits of key synapse protein, study finds

Neurons stochastically generated up to eight different versions of a protein-regulating neurotransmitter release, which could vary how they communicate with other cells.

David Orenstein | The Picower Institute for Learning and Memory
September 25, 2023

Neurons are talkers. They each communicate with fellow neurons, muscles, or other cells by releasing neurotransmitter chemicals at “synapse” junctions, ultimately producing functions ranging from emotions to motions. But even neurons of the exact same type can vary in their conversational style. A new open-access study in Cell Reports by neurobiologists at The Picower Institute for Learning and Memory highlights a molecular mechanism that might help account for the nuanced diversity of neural discourse.

The scientists made their findings in neurons that control muscles in Drosophila fruit flies. These cells are models in neuroscience because they exhibit many fundamental properties common to neurons in people and other animals, including communication via the release of the neurotransmitter glutamate. In the lab of Troy Littleton, Menicon Professor in MIT’s departments of Biology and Brain and Cognitive Sciences, which studies how neurons regulate this critical process, researchers frequently see that individual neurons vary in their release patterns. Some “talk” more than others.

In more than a decade of studies, Littleton’s lab has shown that a protein called complexin has the job of restraining spontaneous glutamate chatter. It clamps down on fusion of glutamate-filled vesicles at the synaptic membrane to preserve a supply of the neurotransmitter for when the neuron needs it for a functional reason, for instance to simulate a muscle to move. The lab’s studies have identified two different kinds of complexin in flies (mammals have four) and showed that the clamping effectiveness of the rare but potent 7B splice form is regulated by a molecular process called phosphorylation. How the much more abundant 7A version is regulated was not known, but scientists had shown that the RNA transcribed from DNA that instructs the formation of the protein is sometimes edited in the cell by an enzyme called ADAR.

In the new study from Littleton’s team, led by Elizabeth Brija PhD ’23, the lab investigated whether RNA editing of complexin 7A affects how it regulates glutamate release. What she discovered was surprising. Not only does RNA editing of complexin 7A have a significant impact on how well the protein prevents glutamate release, but also this can vary widely among individual neurons because they can stochastically mix and match up to eight different editions of the protein. Some edits were much more common than others on average, but 96 percent of the 200 neurons the team examined had at least some editing, which affected the structure of an end of the protein called its C-terminus. Experiments to test some of the consequences of this structural variation showed that different complexin 7A edits can dramatically affect the level of electrical current measurable at different synapses. That varying level of activity can also affect the growth of the synapses the neurons make with muscle. RNA editing of the protein might therefore endow each neuron with fine degrees of communication control.

“What this offers the nervous system is that you can take the same transcriptome and by alternatively editing various RNA transcripts, these neurons will behave differently,” Littleton says.

Moreover, Littleton and Brija’s team found that other key proteins involved in synaptic glutamate release, such as synapsin and Syx1A, are also sometimes edited at quite different levels among the same population of neurons. This suggests that other aspects of synaptic communication might also be tunable.

“Such a mechanism would be a robust way to change multiple features of neuronal output,” Brija, Littleton, and colleagues wrote.

The team tracked the different editing levels by meticulously extracting and sequencing RNA from the nuclei and cell bodies of 200 motor neurons. The work yielded a rich enough dataset to show that any of three adenosine nucleotides encoding two amino acids in the C-terminus could be swapped for another, yielding eight different editions of the protein. A slim majority of complexin 7A went unedited in the average neuron, while the seven edited versions composed the rest with widely varying degrees of frequency.

To investigate the functional consequences of some of the different editions, the team knocked out complexin and then “rescued” flies by adding back in unedited or two different edited versions. The experiments showed a stark contrast between the two edited proteins. One, which occurs more commonly, proved to be a less effective clamp than unedited complexin, barely preventing spontaneous glutamate release and upticks in electrical current. The other turned out to be more effective at clamping than the unedited version, keeping a tight lid on glutamate release and synaptic output. And while both of the edited versions showed a tendency to drift away from synapses and into the neuron’s axon, the long branch that extends from the cell body, the edition that clamped well prevented any overgrowth of synapses while the one that clamped poorly provided only a meager curb.

Because multiple editions are often present in neurons, Brija and the team did one more set of experiments in which they “rescued” complexin-less flies with a combination of unedited complexin and the weak-clamping edition. The result was a blend of the two: reduced spontaneous glutamate release than with just the weakly clamping edition alone. The findings suggest that not only does each edition potentially fine-tune glutamate release, but that combinations among them can act in a combinatorial fashion.

In addition to Brija and Littleton the paper’s other authors are Zhuo Guan and Suresh Jetti.

The National Institutes of Health, The JPB Foundation, and The Picower Institute for Learning and Memory supported the research.

School of Science welcomes new faculty in 2023

Sixteen professors join the departments of Biology; Chemistry; Earth, Atmospheric and Planetary Sciences; Mathematics; and Physics.

School of Science
September 25, 2023

Last spring, the School of Science welcomed seven new faculty members.

Erin Chen PhD ’11 studies the communication between microbes that reside on the surface of the human body and the immune system. She focuses on the largest organ: the skin. Chen will dissect the molecular signals of diverse skin microbes and their effects on host tissues, with the goal of harnessing microbe-host interactions to engineer new therapeutics for human disease.

Chen earned her bachelor’s in biology from the University of Chicago, her PhD from MIT, and her MD from Harvard Medical School, and she completed her medical residency at the University of California at San Francisco. Chen was also a Howard Hughes Medical Institute Hanna Gray Fellow at Stanford University and an attending dermatologist at UCSF and at the San Francisco VA Medical Center. Chen returns to MIT as an assistant professor in the Department of Biology, a core member of the Broad Institute of MIT and Harvard, and an attending dermatologist at Massachusetts General Hospital.

Robert Gilliard’s research is multidisciplinary and combines various aspects of organic, inorganic, main-group, and materials chemistry. The Gilliard group specializes in the chemical synthesis of new molecules that impact the development of new catalysts and reagents, including the discovery of unknown transformations of environmentally relevant small-molecules [e.g., carbon dioxide, carbon monoxide, and dihydrogen (H2)]. In addition, he investigates the design, characterization, and reactivity of boron-based luminescent and redox-active heterocycles for use in optoelectronic applications (e.g., stimuli-responsive materials, thermochromic materials, chemical sensors).

Gilliard earned his bachelor’s degree from Clemson University and his PhD from the University of Georgia. He completed joint postdoctoral studies at the Swiss Federal Institute of Technology (ETH Zürich) and Case Western Reserve University. He served on the faculty at the University of Virginia from 2017-22. Gilliard spent time in the MIT Department of Chemistry as a 2021-22 Dr. Martin Luther King Visiting Professor. He returns as the Novartis Associate Professor of Chemistry with tenure.

Sally Kornbluth is president of MIT and a professor of biology. Before she closed her lab to focus on administration, her research focused on the biological signals that tell a cell to start dividing or to self-destruct — processes that are key to understanding cancer as well as various degenerative disorders. She has published extensively on cell proliferation and programmed cell death, studying both phenomena in a variety of organisms. Her research has helped to show how cancer cells evade this programmed death, or apoptosis, and how metabolism regulates the cell death process; her work has also clarified the role of apoptosis in regulating the duration of female fertility in vertebrates.

Kornbluth holds bachelor’s degrees in political science from Williams College and in genetics from Cambridge University. She earned her PhD in molecular oncology from Rockefeller University in 1989 and completed postdoctoral training at the University of California at San Diego. In 1994, she joined the faculty of Duke University and served in the administration as vice dean for basic science at the Duke School of Medicine (2006-2014) and later as the university’s provost (2014-2022). She is a member of the National Academy of Medicine, the National Academy of Inventors, and the American Academy of Arts and Sciences.

Daniel Lew uses fungal model systems to ask how cells orient their activities in space, including oriented growth, cell wall remodeling, and organelle segregation. Different cells take on an astonishing variety of shapes, which are often critical to be able to perform specialized cell functions like absorbing nutrients or contracting muscles. Lew studies how different cell shapes arise and how cells control the spatial distribution of their internal constituents, taking advantage of the tractability of fungal model systems, and addressing these questions using approaches from cell biology, genetics, and computational biology to understand molecular mechanisms.

Lew received a bachelor’s degree in genetics from Cambridge University followed by a PhD in molecular biology from Rockefeller University. After postdoctoral training at the Scripps Research Institute, he joined the Duke University faculty in 1994. Lew joins MIT as a professor of biology with tenure.

Eluned Smith uses rare beauty decays measured with the LHCb detector at CERN to search for new fundamental particles at mass scales above the collision energy of the Large Hadron Collider (LHC). Her group leverages data to elucidate the physics of beauty quarks, whose behavior cannot be explained by the Standard Model of particle physics. In doing so, her work aims to resolve whether the anomalies are misunderstood quantum chromodynamics or the first sign of beyond-the-Standard-Model-physics at the LHC.

Smith joins MIT as an assistant professor in the Department of Physics and the Laboratory for Nuclear Science. She earned her undergraduate and doctoral degrees at Imperial College London, which she completed in 2017. She did her first postdoc at RWTH Aachen before winning an Ambizione Fellowship from the Swiss National Science Foundation at the University of Zürich.

Gaia Stucky de Quay explores topographic signals and landscape evolution, in order to both de-convolve and quantify primary driving forces such as tectonics, climate, and local geological processes. She integrates fieldwork, lab work, modeling, and remote sensing to improve our quantitative understanding of such processes at compelling geological sites such as Martian valleys and lakes, the surfaces of icy moons, and volcanic islands in the Atlantic Ocean.

Stucky de Quay joins the Department of Earth, Atmospheric and Planetary Sciences as an assistant professor. Most recently, she was a Daly Postdoctoral Fellow at Harvard University. Previously, she was a postdoc at the University of Texas at Austin and a visiting student at the University of Chicago. Stucky de Quay earned her MS from the University College of London and a PhD from Imperial College London.

Brandon “Brady” Weissbourd uses the jellyfish, Clytia hemisphaerica, to study nervous system evolution, development, regeneration, and function. With a foundation is in systems neuroscience, his lab uses genetic and optical techniques to examine how behavior arises from the activity of networks of neurons; they investigate how the Clytia nervous system is so robust; and they use Clytia’s evolutionary position to make inferences about the ultimate origins of nervous systems.

Weissbourd received a BA in human evolutionary biology from Harvard University in 2009 and a PhD from Stanford University in 2016. He then completed postdoctoral research at Caltech and The Howard Hughes Medical Institute. He joins MIT as an assistant professor in the Department of Biology and an investigator in The Picower Institute for Learning and Memory.

This fall, the School of Science welcomes nine new faculty members.

Facundo Batista studies the fundamental biology of the immune system to develop the next generation of vaccines and therapeutics. B lymphocytes are the fulcrum of immunological memory, the source of antibodies, and the focus of vaccine development. His lab has investigated how, where, and when B cell responses take shape. In recent years, the Batista group has expanded into preclinical vaccinology, targeting viruses including HIV, malaria, influenza, and SARS-CoV-2.

Batista is an MIT professor of biology with tenure as well as the associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard. He received his PhD from the International School of Advanced Studies in Trieste, Italy, and his undergraduate degree from the University of Buenos Aires, Argentina. Prior to MIT, Batista was a tenured member of the Francis Crick Institute, a professor at Imperial College London, and a professor of microbiology and immunology at Harvard Medical School.

Anna-Christina Eilers is an observational astrophysicist. Her research focuses on the formation of the first galaxies, quasars, and supermassive black holes in the early universe, during an era known as the Cosmic Dawn. In particular, Eilers is interested in the growth of the first supermassive black holes which reside in the center of luminous, distant galaxies known as quasars, to understand how black holes evolve from small stellar remnants to billion-solar-mass black holes within very short amounts of cosmic time.

Previously, Eilers received a bachelor’s degree in physics from the University of Goettingen, a master’s degree in astrophysics from the University of Heidelberg, and a PhD in astrophysics from the Max Planck Institute for Astronomy in Heidelberg. In 2019, she was awarded a NASA Hubble Fellowship and the Pappalardo Fellowship to continue her research at MIT. Eilers remains at MIT as an assistant professor in the Department of Physics and the MIT Kavli Institute for Astrophysics and Space Research.

Masha Elkin combines catalyst development, natural products synthesis, and machine learning to tackle important chemical challenges. Her group develops new transition metal catalysts that enable efficient bond disconnections and access to value-added compounds, leveraging these transformations for the synthesis of bioactive natural products that address outstanding needs in human health, and uses computational tools to explore all possible molecules and accelerate reaction discovery.

Elkin joins MIT as the D. Reid (1941) and Barbara J. Weedon Career Development Assistant Professor of Chemistry. She earned her bachelor’s degree in chemistry from Washington University in St. Louis in 2014, and her PhD from Yale University in 2019, then began as a postdoc at the University of California at Berkeley.

Mikhail Ivanov’s research has developed at the interface of theoretical physics and data analysis, bridging state-of-the-art theoretical ideas with observational data. The overarching aim of his research is to use Effective Field Theory in combination with astrophysical data in order to resolve fundamental challenges of modern physics, such as the nature of dark matter, dark energy, inflation, and gravity.

Ivanov joins MIT as an assistant professor in the Department of Physics and the Center for Theoretical Physics in the Laboratory for Nuclear Science. He obtained his PhD from the École Polytechnique Fédérale de Lausanne in 2019. During his PhD studies, he spent a year at the Institute for Advanced Study in Princeton, New Jersey, as a fellow of the Swiss National Science Foundation. Subsequently, he was a postdoc at New York University and a NASA Einstein Fellow at the Institute for Advanced Study.

Efforts to target pathogenic proteins with drugs or chemical probes can often be analogized to a lock and key, where the protein target is the “lock” and the molecule is the “key.” However, what happens when the target is flexible or lacks a defined structure? In all living things, molecular chaperone proteins have evolved to support proper folding of these moving targets. Yet, protein misfolding and aggregation is a hallmark of many myopathies and neurodegenerative diseases. Oleta Johnson uses chemical and biophysical tools to understand and tune the activity of molecular chaperone proteins in protein misfolding diseases. Thus, her research group will reveal the molecular underpinnings of molecular chaperone dysfunction in a broad array of disorders including Huntington’s disease and Parkinson’s disease. These tools and finding will be further developed to develop novel treatments for patients of these diseases.

Johnson joins the Department of Chemistry as an assistant professor. She earned her bachelor’s degree in biochemistry from Florida Agricultural and Mechanical University in 2013, and her PhD from the University of Michigan in 2018. Prior to MIT, Johnson completed postdoctoral research at the University of California at San Francisco.

Nicole Xike Nie is an isotope geo/cosmochemist using the chemical and isotopic compositions of extraterrestrial materials to understand the formation of our solar system. Her research is driven by fundamental questions about the origin and evolution of the early solar system. Leveraging geochemical methods, she wants to understand questions such as why all planetary bodies are depleted of volatile elements when their building block materials aren’t, and why the Earth’s chemical signatures are distinct from other planetary bodies.

Nie joins MIT as an assistant professor in the Department of Earth, Atmospheric and Planetary Sciences. Nie received a BS in geology from China University of Geosciences in 2010, an MS in geochemistry from Chinese Academy of Sciences in 2013, and a PhD in geo/cosmochemistry from the University of Chicago in 2019. After graduating she was a Carnegie Postdoc Fellow at Carnegie Institution for Science and a postdoc researcher at Caltech.

Tristan Ozuch works in the field of geometric analysis and focuses on Einstein manifolds and Ricci flows. His work has shed light on the moduli space of Einstein metrics in four dimensions, addressing questions that have lingered since the 1980s. These questions originated from the systematic study of Einstein’s equations and their degenerations since the 1970s, in both physics and mathematics.

After receiving a bachelor’s degree, master’s degree, and PhD from École Normale Supérieure, Tristan Ozuch joined MIT as a C.L.E. Moore Instructor of Mathematics. He continues in the Department of Mathematics as an assistant professor.

Climate scientist Talia Tamarin-Brodsky’s research is driven by questions on the interface between weather and climate. In her work, Tamarin-Brodsky combines theory, computational methods, and observational data to study Earth’s climate and weather and how they respond to climate change. Her interests include atmospheric dynamics, temperature variability, weather and climate extremes, and subseasonal-to-seasonal predictability. For example, she studies how nonlinear wave breaking events in the upper atmosphere influence surface weather and extremes, and the mechanisms shaping the spatial distribution of Earth’s near-surface temperature.

Tamarin-Brodsky received a bachelor’s degree in mathematics and geophysics as well as a master’s in physics from Tel Aviv University, Israel, before earning her PhD from the Weizmann Institute. She completed a postdoctoral project at the University of Reading, U.K., and a postdoctoral fellowship at Tel Aviv University. She joins the Department of Earth, Atmospheric and Planetary Studies as an assistant professor.

John Urschel PhD ’21 is a mathematician focused on matrix analysis and computations, with an emphasis on theoretical results and provable guarantees for practical problems. His research interests include numerical linear algebra, spectral graph theory, and topics in theoretical machine learning.

Urschel earned bachelor’s and master’s degrees in mathematics from Pennsylvania State University, then completed a PhD in mathematics at MIT in 2021. He was a member of the Institute for Advanced Study and a junior fellow at Harvard University before returning to MIT as an assistant professor of mathematics this fall.

Study explains why certain immunotherapies don’t always work as predicted

The findings could help doctors identify cancer patients who would benefit the most from drugs called checkpoint blockade inhibitors.

Anne Trafton | MIT News
September 14, 2023

Cancer drugs known as checkpoint blockade inhibitors have proven effective for some cancer patients. These drugs work by taking the brakes off the body’s T cell response, stimulating those immune cells to destroy tumors.

Some studies have shown that these drugs work better in patients whose tumors have a very large number of mutated proteins, which scientists believe is because those proteins offer plentiful targets for T cells to attack. However, for at least 50 percent of patients whose tumors show a high mutational burden, checkpoint blockade inhibitors don’t work at all.

A new study from MIT reveals a possible explanation for why that is. In a study of mice, the researchers found that measuring the diversity of mutations within a tumor generated much more accurate predictions of whether the treatment would succeed than measuring the overall number of mutations.

If validated in clinical trials, this information could help doctors to better determine which patients will benefit from checkpoint blockade inhibitors.

“While very powerful in the right settings, immune checkpoint therapies are not effective for all cancer patients. This work makes clear the role of genetic heterogeneity in cancer in determining the effectiveness of these treatments,” says Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT’s Koch Institute for Cancer Research.

Jacks; Peter Westcott, a former MIT postdoc in the Jacks lab who is now an assistant professor at Cold Spring Harbor Laboratory; and Isidro Cortes-Ciriano, a research group leader at EMBL’s European Bioinformatics Institute (EMBL-EBI), are the senior authors of the paper, which appears today in Nature Genetics.

A diversity of mutations

Across all types of cancer, a small percentage of tumors have what is called a high tumor mutational burden (TMB), meaning they have a very large number of mutations in each cell. A subset of these tumors has defects related to DNA repair, most commonly in a repair system known as DNA mismatch repair.

Because these tumors have so many mutated proteins, they are believed to be good candidates for immunotherapy treatment, as they offer a plethora of potential targets for T cells to attack. Over the past few years, the FDA has approved a checkpoint blockade inhibitor called pembrolizumab, which activates T cells by blocking a protein called PD-1, to treat several types of tumors that have a high TMB.

However, subsequent studies of patients who received this drug found that more than half of them did not respond well or only showed short-lived responses, even though their tumors had a high mutational burden. The MIT team set out to explore why some patients respond better than others, by designing mouse models that closely mimic the progression of tumors with high TMB.

These mouse models carry mutations in genes that drive cancer development in the colon and lung, as well as a mutation that shuts down the DNA mismatch repair system in these tumors as they begin to develop. This causes the tumors to generate many additional mutations. When the researchers treated these mice with checkpoint blockade inhibitors, they were surprised to find that none of them responded well to the treatment.

“We verified that we were very efficiently inactivating the DNA repair pathway, resulting in lots of mutations. The tumors looked just like they look in human cancers, but they were not more infiltrated by T cells, and they were not responding to immunotherapy,” Westcott says.

The researchers discovered that this lack of response appears to be the result of a phenomenon known as intratumoral heterogeneity. This means that, while the tumors have many mutations, each cell in the tumor tends to have different mutations than most of the other cells. As a result, each individual cancer mutation is “subclonal,” meaning that it is expressed in a minority of cells. (A “clonal” mutation is one that is expressed in all of the cells.)

In further experiments, the researchers explored what happened as they changed the heterogeneity of lung tumors in mice. They found that in tumors with clonal mutations, checkpoint blockade inhibitors were very effective. However, as they increased the heterogeneity by mixing tumor cells with different mutations, they found that the treatment became less effective.

“That shows us that intratumoral heterogeneity is actually confounding the immune response, and you really only get the strong immune checkpoint blockade responses when you have a clonal tumor,” Westcott says.

Failure to activate

It appears that this weak T cell response occurs because the T cells simply don’t see enough of any particular cancerous protein, or antigen, to become activated, the researchers say. When the researchers implanted mice with tumors that contained subclonal levels of proteins that normally induce a strong immune response, the T cells failed to become powerful enough to attack the tumor.

“You can have these potently immunogenic tumor cells that otherwise should lead to a profound T cell response, but at this low clonal fraction, they completely go stealth, and the immune system fails to recognize them,” Westcott says. “There’s not enough of the antigen that the T cells recognize, so they’re insufficiently primed and don’t acquire the ability to kill tumor cells.”

To see if these findings might extend to human patients, the researchers analyzed data from two small clinical trials of people who had been treated with checkpoint blockade inhibitors for either colorectal or stomach cancer. After analyzing the sequences of the patients’ tumors, they found that patients’ whose tumors were more homogeneous responded better to the treatment.

“Our understanding of cancer is improving all the time, and this translates into better patient outcomes,” Cortes-Ciriano says. “Survival rates following a cancer diagnosis have significantly improved in the past 20 years, thanks to advanced research and clinical studies. We know that each patient’s cancer is different and will require a tailored approach. Personalized medicine must take into account new research that is helping us understand why cancer treatments work for some patients but not all.”

The findings also suggest that treating patients with drugs that block the DNA mismatch repair pathway, in hopes of generating more mutations that T cells could target, may not help and could be harmful, the researchers say. One such drug is now in clinical trials.

“If you try to mutate an existing cancer, where you already have many cancer cells at the primary site and others that may have disseminated throughout the body, you’re going to create a super heterogeneous collection of cancer genomes. And what we showed is that with this high intratumoral heterogeneity, the T cell response is confused and there is absolutely no response to immune checkpoint therapy,” Westcott says.

The research was funded by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute, the Howard Hughes Medical Institute, and a Damon Runyon Fellowship Award.

Study explains how part of the nucleolus evolved

A single protein can self-assemble to build the scaffold for a biomolecular condensate that makes up a key nucleolar compartment.

Anne Trafton | MIT News
August 15, 2023

Inside all living cells, loosely formed assemblies known as biomolecular condensates perform many critical functions. However, it is not well understood how proteins and other biomolecules come together to form these assemblies within cells.

MIT biologists have now discovered that a single scaffolding protein is responsible for the formation of one of these condensates, which forms within a cell organelle called the nucleolus. Without this protein, known as TCOF1, this condensate cannot form.

The findings could help to explain a major evolutionary shift, which took place around 300 million years ago, in how the nucleolus is organized. Until that point, the nucleolus, whose role is to help build ribosomes, was divided into two compartments. However, in amniotes (which include reptiles, birds, and mammals), the nucleolus developed a condensate that acts as a third compartment. Biologists do not yet fully understand why this shift happened.

“If you look across the tree of life, the basic structure and function of the ribosome has remained quite static; however, the process of making it keeps evolving. Our hypothesis for why this process keeps evolving is that it might make it easier to assemble ribosomes by compartmentalizing the different biochemical reactions,” says Eliezer Calo, an associate professor of biology at MIT and the senior author of the study.

Now that the researchers know how this condensate, known as the fibrillar center, forms, they may be able to more easily study its function in cells. The findings also offer insight into how other condensates may have originally evolved in cells, the researchers say.

Former MIT graduate students Nima Jaberi-Lashkari PhD ’23 and Byron Lee PhD ’23 are the lead authors of the paper, which appears today in Cell Reports. Former MIT research associate Fardin Aryan is also an author of the paper.

Condensate formation

Many cell functions are carried out by membrane-bound organelles, such as lysosomes and mitochondria, but membraneless condensates also perform critical tasks such as gene regulation and stress response. In some cases, these condensates form when needed and then dissolve when they are finished with their task.

“Almost every cellular process that is essential for the functioning of the cell has been associated somehow with condensate formation and activity,” Calo says. “However, it’s not very well sorted out how these condensates form.”

In a 2022 study, Calo and his colleagues identified a protein region that seemed to be involved in forming condensates. In that study, the researchers used computational methods to identify and compare stretches of proteins known as low-complexity regions (LCRs), from many different species. LCRs are sequences of a single amino acid repeated many times, with a few other amino acids sprinkled in.

That work also revealed that a nucleolar protein known as TCOF1 contains many glutamate-rich LCRs that can help scaffold biomolecular assemblies.

In the new study, the researchers found that whenever TCOF1 is expressed in cells, condensates form. These condensates always include proteins usually found within a particular condensate known as the fibrillar center (FC) of the nucleolus. The FC is known to be involved in the production of ribosomal RNA, a key component of ribosomes, the cell complex responsible for building all cellular proteins.

However, despite its importance in assembling ribosomes, the fibrillar center appeared only around 300 million years ago; single-celled organisms, invertebrates, and the earliest vertebrates (fish) do not have it.

The new study suggests that TCOF1 was essential for this transition from a “bipartite” to “tripartite” nucleolus. The researchers found without TCOF1, cells form only two nucleolar compartments. Furthermore, when the researchers added TCOF1 to zebrafish embryos, which normally have bipartite nucleoli, they could induce the formation of a third compartment.

“More than just creating that condensate, TCOF1 reorganized the nucleolus to acquire tripartite properties, which indicates that whatever chemistry that condensate was bringing to the nucleolus was enough to change the composition of the organelle,” Calo says.

Scaffold evolution

The researchers also found that the essential region of TCOF1 that helps it form scaffolds is the glutamate-rich low-complexity regions. These LCRs appear to interact with other glutamate-rich regions of neighboring TCOF1 molecules, helping the proteins assemble into a scaffold that can then attract other proteins and biomolecules that help form the fibrillar center.

“What’s really exciting about this work is that it gives us a molecular handle to control a condensate, introduce it into a species that doesn’t have it, and also get rid of it in a species that does have it. That could really help us unlock the structure-to-function relationship and figure out what is the role of the third compartment,” Jaberi-Lashkari says.

Based on the findings of this study, the researchers hypothesize that cellular condensates that emerged earlier in evolutionary history may have originally been scaffolded by a single protein, as TCOF1 scaffolds the fibrillar center, but gradually evolved to become more complex.

“Our hypothesis, which is supported by the data in the paper, is that these condensates might originate from one scaffold protein that behaves as a single component, and over time, they become multicomponent,” Calo says.

The formation of certain types of biomolecular condensates has also been linked to disorders such as ALS, Huntington’s disease, and cancer.

“In all of these situations, what our work poses is this question of why are these assemblies forming, and what is the scaffold in these assemblies? And if we can better understand that, then I think we have a better handle on how we could treat these diseases,” Lee says.

The research was funded by the National Institutes of Health, the National Institute of General Medical Sciences, the Pew Charitable Trusts, and the National Cancer Institute.

Freeman Hrabowski encourages students to “hold fast to dreams” and take time for laughter

In a visit to MIT, the educator and author led a lively and inspiring Q&A with students.

Lillian Eden | Department of Biology
August 9, 2023

A group of more than 50 individuals recently had the pleasure of sitting down for an informal chat at MIT with distinguished educator, author, and mathematician Freeman Hrabowski. The group was predominantly composed of MIT Summer Research Program in Biology (MSRP-Bio) students and alumni and current students from the Meyerhoff Scholars Program and the University of Maryland, Baltimore County.

Hrabowski is widely credited for transforming UMBC into a world-renowned, innovative institution while serving as its president from 1992 to 2022. The educator also ushered in a generation of Black students to earn PhDs in science and engineering, co-founding the Meyerhoff Scholars Program at UMBC. Founded in 1988, the program has become a national model for increasing diversity in STEM. Hrabowski was also a member of the President’s Advisory Commission on Educational Excellence for African Americans during the Obama administration.

Hrabowski began by quoting poet William Carlos Williams: “It is difficult to get the news from poems yet men die miserable every day for lack of what is found there,” and leading a call-and-response recitation of the poem “Dreams,” by Langston Hughes, as well as a mantra encouraging students to use their words, actions, and habits to shape their character and their destiny. Afterward, the students asked Hrabowski about his life and experiences.

“The audience of high-achieving students asked terrific, insightful questions reflecting their contemplation of their own paths,” says Department of Biology head Amy Keating. “When students spoke up, Hrabowski engaged with them, and their ideas and perspectives were welcomed and respected. By the end of his time with them, almost everyone had their hand up and wanted to contribute to the lively discussion.”

Tobias Coombs, a Meyerhoff Scholars program alumnus and current graduate student in the Spranger Lab, says the event was an example of “classic Freeman Hrabowski:” Hrabowski injected the crowd with excitement and energy. Coombs also remarked that Hrabowski, named by Time as one of the world’s most influential people in 2012, acknowledged to the group that he’s shy, something Hrabowski is still pushing himself to overcome.

“He makes a point of being this down-to-earth person that you feel you can talk to about real issues and have real conversations with,” Coombs says. “He genuinely wants to motivate you to think science and math are cool.”

Before taking questions from the students in attendance, Hrabowski posed one to them: What do you think it takes to be successful in research in STEM? Among the responses were passion, curiosity, and a supportive community. After each response, Hrabowski encouraged a round of applause for each student brave enough to stand and give an answer because “everybody needs support.”

“The way that you think about yourselves, the language that you use, the way that you interact with each other, and the values that you hold, will be so important. You become like the things that you love,” Hrabowski says.

For his lifetime of accomplishments increasing diversity in STEM, the Howard Hughes Medical Institute recently announced a new program named after Hrabowski. The HHMI Freeman Hrabowski Scholars were selected for their potential to become leaders in their research fields and to foster diverse and inclusive lab environments. The inaugural class of 31 scholars includes MIT biology faculty members Seychelle Vos, the Robert A. Swanson Career Development Professor of Life Sciences, and Hernandez Moura Silva, an assistant professor and Ragon Institute of MGH, MIT and Harvard core member, as well as MIT biology and Cheeseman lab alumna Kara McKinley PhD ’16.

Vos and Moura Silva were among the faculty attending the event, and both say Hrabowski was an inspiring guest to have on campus.

“Dr. Hrabowski’s smile, energy, and words are a true force of nature,” Hernandez says. “His words of wisdom showed us that we can all make the impossible possible by bringing a positive attitude to build a strong, supportive, and diverse community. It was such an honor to have him here.”

Biology department undergraduate officer Adam Martin says he noticed the pride in Hrabowski’s eyes when Hrabowski discussed what his trainees and faculty in his programs have accomplished. Biology department graduate officer Mary Gehring said his visit made her remember why she wanted to be a professor: “to help others follow their passions to their full potential.”

Hrabowski reflected on many topics, including the recent Supreme Court ruling on affirmative action. He pointed out that this was not the first time the Supreme Court had ruled on a racially conscious initiative, namely the 1995 decision that a UMBC scholarship program was unconstitutional. To continue the Meyerhoff Scholars Program, which was affected by the Supreme Court decision at the time, Hrabowski worked with Maryland’s attorney general, found language and methods to encourage broad participation of diverse individuals, and focused on what the program was trying to achieve.

“My message to everyone was ‘where there’s a will, there’s a way.’ If the institution wants to continue to build diversity and broader participation, we can do it,” he says. “What we’re working to achieve in the Meyerhoff program and in the Freeman Hrabowski Scholars program is to have everybody included.”

Hrabowski also offered advice on more everyday challenges: good students, himself included, can focus too much, forgetting to make time for other important aspects of their lives. He has learned to make time for tai chi, acupuncture, and getting his steps in; he encouraged the students similarly to take time for themselves outside work or school.

“When you can have fun and laugh, you’re a much better person. You can be a better thinker if you take care of yourself overall,” he says. “It’s the healthy person who can be most effective.”

As for being intimidated or nervous to talk to a superior, Hrabowski had the room roaring with laughter at his advice: “Just remember they go to the bathroom, too.”

Keating noted that Hrabowski engaged with the audience with energy, compassion, and humor.

She also observed, “No one can hide in Dr. Hrabowski’s classroom.”

“He put students front and center in his presentation, and his emphasis on the joys and importance of learning, knowledge, and achievement inspired us all to go back to the lab and classroom and be our best selves,” Keating says. “He acknowledged that paths in STEM demand much of us, and he encouraged students to have the discipline needed to stay the course while also taking care of themselves.”

Fourteen MIT School of Science professors receive tenure for 2022 and 2023

Faculty members were recently granted tenure in the departments of Biology, Brain and Cognitive Sciences, Chemistry, EAPS, and Physics.

School of Science
August 8, 2023

In 2022, nine MIT faculty were granted tenure in the School of Science:

Gloria Choi examines the interaction of the immune system with the brain and the effects of that interaction on neurodevelopment, behavior, and mood. She also studies how social behaviors are regulated according to sensory stimuli, context, internal state, and physiological status, and how these factors modulate neural circuit function via a combinatorial code of classic neuromodulators and immune-derived cytokines. Choi joined the Department of Brain and Cognitive Sciences after a postdoc at Columbia University. She received her bachelor’s degree from the University of California at Berkeley, and her PhD from Caltech. Choi is also an investigator in The Picower Institute for Learning and Memory.

Nikta Fakhri develops experimental tools and conceptual frameworks to uncover laws governing fluctuations, order, and self-organization in active systems. Such frameworks provide powerful insight into dynamics of nonequilibrium living systems across scales, from the emergence of thermodynamic arrow of time to spatiotemporal organization of signaling protein patterns and discovery of odd elasticity. Fakhri joined the Department of Physics in 2015 following a postdoc at University of Göttingen. She completed her undergraduate degree at Sharif University of Technology and her PhD at Rice University.

Geobiologist Greg Fournier uses a combination of molecular phylogeny insights and geologic records to study major events in planetary history, with the hope of furthering our understanding of the co-evolution of life and environment. Recently, his team developed a new technique to analyze multiple gene evolutionary histories and estimated that photosynthesis evolved between 3.4 and 2.9 billion years ago. Fournier joined the Department of Earth, Atmospheric and Planetary Sciences in 2014 after working as a postdoc at the University of Connecticut and as a NASA Postdoctoral Program Fellow in MIT’s Department of Civil and Environmental Engineering. He earned his BA from Dartmouth College in 2001 and his PhD in genetics and genomics from the University of Connecticut in 2009.

Daniel Harlow researches black holes and cosmology, viewed through the lens of quantum gravity and quantum field theory. His work generates new insights into quantum information, quantum field theory, and gravity. Harlow joined the Department of Physics in 2017 following postdocs at Princeton University and Harvard University. He obtained a BA in physics and mathematics from Columbia University in 2006 and a PhD in physics from Stanford University in 2012. He is also a researcher in the Center for Theoretical Physics.

A biophysicist, Gene-Wei Li studies how bacteria optimize the levels of proteins they produce at both mechanistic and systems levels. His lab focuses on design principles of transcription, translation, and RNA maturation. Li joined the Department of Biology in 2015 after completing a postdoc at the University of California at San Francisco. He earned an BS in physics from National Tsinghua University in 2004 and a PhD in physics from Harvard University in 2010.

Michael McDonald focuses on the evolution of galaxies and clusters of galaxies, and the role that environment plays in dictating this evolution. This research involves the discovery and study of the most distant assemblies of galaxies alongside analyses of the complex interplay between gas, galaxies, and black holes in the closest, most massive systems. McDonald joined the Department of Physics and the Kavli Institute for Astrophysics and Space Research in 2015 after three years as a Hubble Fellow, also at MIT. He obtained his BS and MS degrees in physics at Queen’s University, and his PhD in astronomy at the University of Maryland in College Park.

Gabriela Schlau-Cohen combines tools from chemistry, optics, biology, and microscopy to develop new approaches to probe dynamics. Her group focuses on dynamics in membrane proteins, particularly photosynthetic light-harvesting systems that are of interest for sustainable energy applications. Following a postdoc at Stanford University, Schlau-Cohen joined the Department of Chemistry faculty in 2015. She earned a bachelor’s degree in chemical physics from Brown University in 2003 followed by a PhD in chemistry at the University of California at Berkeley.

Phiala Shanahan’s research interests are focused around theoretical nuclear and particle physics. In particular, she works to understand the structure and interactions of hadrons and nuclei from the fundamental degrees of freedom encoded in the Standard Model of particle physics. After a postdoc at MIT and a joint position as an assistant professor at the College of William and Mary and senior staff scientist at the Thomas Jefferson National Accelerator Facility, Shanahan returned to the Department of Physics as faculty in 2018. She obtained her BS from the University of Adelaide in 2012 and her PhD, also from the University of Adelaide, in 2015.

Omer Yilmaz explores the impact of dietary interventions on stem cells, the immune system, and cancer within the intestine. By better understanding how intestinal stem cells adapt to diverse diets, his group hopes to identify and develop new strategies that prevent and reduce the growth of cancers involving the intestinal tract. Yilmaz joined the Department of Biology in 2014 and is now also a member of Koch Institute for Integrative Cancer Research. After receiving his BS from the University of Michigan in 1999 and his PhD and MD from University of Michigan Medical School in 2008, he was a resident in anatomic pathology at Massachusetts General Hospital and Harvard Medical School until 2013.

In 2023, five MIT faculty were granted tenure in the School of Science:

Physicist Riccardo Comin explores the novel phases of matter that can be found in electronic solids with strong interactions, also known as quantum materials. His group employs a combination of synthesis, scattering, and spectroscopy to obtain a comprehensive picture of these emergent phenomena, including superconductivity, (anti)ferromagnetism, spin-density-waves, charge order, ferroelectricity, and orbital order. Comin joined the Department of Physics in 2016 after postdoctoral work at the University of Toronto. He completed his undergraduate studies at the Universita’ degli Studi di Trieste in Italy, where he also obtained a MS in physics in 2009. Later, he pursued doctoral studies at the University of British Columbia, Canada, earning a PhD in 2013.

Netta Engelhardt researches the dynamics of black holes in quantum gravity and uses holography to study the interplay between gravity and quantum information. Her primary focus is on the black hole information paradox, that black holes seem to be destroying information that, according to quantum physics, cannot be destroyed. Engelhardt was a postdoc at Princeton University and a member of the Princeton Gravity Initiative prior to joining the Department of Physics in 2019. She received her BS in physics and mathematics from Brandeis University and her PhD in physics from the University of California at Santa Barbara. Engelhardt is a researcher in the Center for Theoretical Physics and the Black Hole Initiative at Harvard University.

Mark Harnett studies how the biophysical features of individual neurons endow neural circuits with the ability to process information and perform the complex computations that underlie behavior. As part of this work, his lab was the first to describe the physiological properties of human dendrites. He joined the Department of Brain and Cognitive Sciences and the McGovern Institute for Brain Research in 2015. Prior, he was a postdoc at the Howard Hughes Medical Institute’s Janelia Research Campus. He received his BA in biology from Reed College in Portland, Oregon and his PhD in neuroscience from the University of Texas at Austin.

Or Hen investigates quantum chromodynamic effects in the nuclear medium and the interplay between partonic and nucleonic degrees of freedom in nuclei. Specifically, Hen utilizes high-energy scattering of electron, neutrino, photon, proton and ion off atomic nuclei to study short-range correlations: temporal fluctuations of high-density, high-momentum, nucleon clusters in nuclei with important implications for nuclear, particle, atomic, and astrophysics. Hen was an MIT Pappalardo Fellow in the Department of Physics from 2015 to 2017 before joining the faculty in 2017. He received his undergraduate degree in physics and computer engineering from the Hebrew University and earned his PhD in experimental physics at Tel Aviv University.

Sebastian Lourido is interested in learning about the vulnerabilities of parasites in order to develop treatments for infectious diseases and expand our understanding of eukaryotic diversity. His lab studies many important human pathogens, including Toxoplasma gondii, to model features conserved throughout the phylum. Lourido was a Whitehead Fellow at the Whitehead Institute for Biomedical Research until 2017, when he joined the Department of Biology and became a Whitehead Member. He earned his BS from Tulane University in 2004 and his PhD from Washington University in St. Louis in 2012.

Remembering Stephen Goldman, “an institution” at MIT

Faculty and staff recall Goldman’s unending commitment to his work for more than three decades.

Lillian Eden | Department of Biology
August 7, 2023

Last fall, Stephen “Steve” Goldman passed away at 59 after a courageous battle with amyotrophic lateral sclerosis (ALS). Prior to his passing, Goldman had worked at MIT for more than 30 years, first with Information Systems and Technology, then for the Computational and Systems Biology Initiative, and then in the Department of Biology.

“Steve was an institution,” says Stuart Levine, director of the BioMicro Center in the biology department and Goldman’s supervisor for more than a decade. According to Levine, Goldman was the type of person who had his “whole being” wrapped up in the job: “He did a little bit of everything, and that’s really hard to find these days.”

Steve Goldman was one of the first hires for the fledgling BioMicro Center, according to former supervisor Peter Sorger, whose is now the Otto Krayer Professor of Systems Pharmacology in the Department of Systems Biology at Harvard Medical School. Goldman, Sorger says, was essential for setting up the Department of Biology’s first server-based computing system.

“He brought great enthusiasm and skill to the role, and I also appreciated his sangfroid and sense of humor. This was essential because we were inventing the center’s infrastructure and mission on the fly and were often in the dark — and also down in the steam tunnels. Steve was a real pioneer,” Sorger says.

Before coming to MIT, Goldman lived in New York and worked on Wall Street. He met his wife of 32 years, Brenda Goldman (née Mahar), on a boat in the middle of the Caribbean Sea.

“He came up to me in a white tuxedo and asked me to have dinner,” Brenda Goldman recalls.

They clicked immediately. Around the time of their wedding two years later, Brenda had found a job in Cambridge, Massachusetts, and they were both eager for Steve to find work in the area, far from the high-stress environment of Wall Street.

“I found an ad at MIT and I said, ‘This sounds very much like you,’” Brenda says. After several interviews, he found out he’d gotten a job at MIT the day before their wedding — and the rest, as they say, is history.

Whether it was a weekend or a holiday, if Goldman got an alert that something was wrong, he would always try to follow up, fix the problem, or go in to offer hands-on help, according to Levine.

Brenda even accompanied him a few times, noticing that “there was always somebody around who waved or said hello. We couldn’t get out of the building without seeing someone, no matter which building it was,” she says.

Former department head Alan Grossman recalls many casual conversations about sports, especially baseball and softball.

“He always greeted me with a warm smile and ‘Hello, professor,’” Grossman says. “He truly loved working in our department, and we miss him.”

Goldman’s second love, according to Brenda Goldman, was refereeing sports. Steve would often get to work early so he could wrap up in time to referee or umpire games.

“He had something for almost every season of the year except winter,” Brenda says. “He liked it for the exercise, but he also liked it because it got him off his office chair and interacting with people.”

Steve Goldman was organized — but his workspace was notably less so. It was notorious for being filled with stuff — piles of memory sticks, CDs, cables, and devices open and in various stages of repair. However, Brenda says, “If you told him something broke, he knew what pile of things to pull the magic out of to make it work.”

Levine says Goldman’s death came as a bit of a shock: He had been answering emails just days before his passing.

“He always, always loved working for MIT,” Brenda Goldman says. “He loved computers, and the work gave his life purpose.”

Following his death, the Department of Biology made a contribution in Goldman’s memory to the ALS Association of Massachusetts. In addition to Brenda, his wife of 32 years, Goldman is survived by his children Kevin and Jason Goldman, in-laws, and many nieces and nephews.

A cool path to disease deceleration

MIT PhD student Kathrin Kajderowicz is studying how hibernation-like states could pave the way for new hypothermic therapies.

Department of Brain and Cognitive Sciences
August 4, 2023

In 2020, Kathrin “Kat” Kajderowicz’s father passed away from lung cancer. Kajderowicz was in charge of her father’s health care for as long as she can remember. While he suffered from various cardiovascular issues for several years, it wasn’t until the beginning of the Covid-19 pandemic that he was diagnosed with late-stage metastatic small-cell lung cancer. Jumping into a primary caregiver position, she closely monitored the treatments he received from doctors to no avail. “I was frustrated with the many medications he was prescribed without the doctors fully understanding how they interacted with each other,” she says. Even if a single physician had been overseeing his comprehensive treatment plan, she says, they still could not definitively say whether the medication combinations have adverse effects that outweigh any positive impact.

This frustration set her on a scientific journey that has now culminated in her research as a PhD student at MIT’s Department of Brain and Cognitive Sciences (BCS) and the Whitehead Institute for Biomedical Research. “My experience led me to a significant medical problem: How can we eventually shift the medical paradigm to develop treatments that consider not only one specific pathway or problem but contextualize systemic tissue or organ dysfunction?”

To engage with this problem, Kajderowicz studies animals uniquely adapted to handle different stressors and environments, possibly modeling human disease states. “Perhaps we can turn to nature and see how different organisms have adapted to overcome and mitigate similar challenges,” she says.

Kajderowicz now works in Professor Siniša Hrvatin’s lab at Whitehead, where she researches cold tolerance. “I’m interested in exploring the mechanisms underlying cellular cold tolerance in hibernating organisms.” Engineering cold tolerance and stasis has many potential revolutionary future applications. In the near term, her work could improve organ transplantation and cell or tissue preservation. In the longer term, she hopes her work could catalyze a shift in the medical field away from its current crisis-mode approach: “By slowing down bodily processes and disease progression, a lower metabolic state could pave the way for a new class of hypothermic therapies that induce human hibernation-like states for cells, organs, or even whole organisms.”

First-generation student and scientist

Kajderowicz’s clearheaded pursuit of fundamental, large-scale scientific questions has propelled her impressive career as a young scientist. Recently, she was awarded the Paul and Daisy Soros Fellowship for New Americans, recognizing her unique path as the daughter of immigrants from Soviet Poland. Her parents arrived in the United States without having completed higher education degrees, without any savings, knowledge of English, medical insurance, or immigration papers. They worked hard to make a living — her father was a construction worker and her mother a housekeeper — using much of their earnings to become naturalized citizens.

Kajderowicz developed an early interest in a scientific career. “My parents, who didn’t go to college, didn’t push me toward any specific profession,” she says. “This gave me the freedom to explore any field I wanted, and my curiosity naturally led me to science.”

As a teenager, she worked as a golf caddie to help her parents financially. Clients at the golf course assisted her in obtaining internships at biotech and tech companies. Having won Best in Category at the Illinois State Science Fair, Kajderowicz received a substantial scholarship to support her studies at Cornell University, but she continued working to pay for her expenses and tuition. At Cornell, Kajderowicz joined the renowned Lab of Ornithology, where she applied machine-learning techniques to study songbird communication and other behavioral patterns.

Kajderowicz’s journey as a neuroscientist began at Harvard Medical School in Professor Connie Cepko’s lab, where she studied the developmental trajectory of a population of retinal interneurons. “Learning how to identify cell signatures was a fascinating introduction to the complexity of life. But I ultimately realized I wanted to pursue the questions that kept me up at night — both how we process information and how and why these processes change during aging. For me, these are life’s biggest unanswered questions, and I believe neuroscience is the foundation for everything. This led me to MIT’s Department of Brain and Cognitive Sciences.”

Learning from hamsters

Kajderowicz applied and was admitted to over two dozen graduate programs — “but I knew I wanted to go to MIT BCS. That was a no-brainer,” she says. “The department has faculty members in all levels of neuroscience: the cellular and molecular, systems, computational, and cognitive levels. It’s amazing to have all these people under one roof.”

Shortly after starting her graduate work at MIT, Kajderowicz realized she wanted to focus on the cellular level. “I think it’s important first to understand how things work within cells before focusing on function and systems.” She also seeks a translational avenue connecting theory and therapy, bridging the gap between basic science and applied treatment.

Kajderowicz found what she sought at the Whitehead Institute’s Hrvatin Lab and Weissman Lab. “It’s truly unique to have access to two very different communities at MIT. In BCS, I am seen as a biologist, while at the Whitehead Institute, I am more of a neuroscientist. It’s great having folks from different training backgrounds challenging my ideas and work.”

Instead of working directly on how cognition is encoded at the cellular level, Kajderowicz decided to embark on a project that would allow her to figure out how different species survive extreme stressors and environments. She is now developing tools to study cold tolerance across several species on the cellular level.

“Hibernating hamsters can safely endure prolonged durations during which their body temperature drops to 4 degrees [Celsius]. By taking a comparative species approach, I want to identify whether hibernators are uniquely genetically programmed to withstand these conditions or whether non-hibernators don’t activate these genetic pathways,” she says. Next, Kajderowicz hopes to figure out how to transfer or activate cold-protective effects to human cells and, someday, whole humans. While she isn’t directly studying the root of cognition, she hopes her research will help maintain or enhance cognitive functioning throughout aging by pushing the boundaries of the types of medicines and therapeutics available.

Building a scientific community

Kajderowicz’s involvement in the scientific community extends beyond her immediate work. At the height of the pandemic, she initiated a digital platform facilitating conversations on biotechnology trends among researchers, biotech professionals, venture capitalists, and others interested in staying updated on cutting-edge developments. Known as “DNA Deviants,” the community she built consists of several thousand active members on several social media platforms.

“It started with an informal journal club I had with some friends, where we would meet over coffee and discuss new papers. Then, when the pandemic shut down everything, I started a real-time podcast on the Clubhouse app with a friend, discussing emerging biotech trends. Eventually, it became an online journal club, and people just kept joining. We got experts to serendipitously join conversations within their realm of expertise from around the world.” Today, almost a dozen PhD, MD-PhD, and motivated undergraduates worldwide take turns leading conversations with different paper authors.

“It’s been incredibly rewarding to remain connected not only to my work, but also to gain a comprehensive understanding of what’s happening in the world,” Kajderowicz says. “You always need to look beyond your immediate circle.”

Making sense of cell fate

MIT researchers find timing and dosage of DNA-damaging drugs are key to whether a cancer cell dies or enters senescence.

Bendta Schroeder | Koch Institute
July 31, 2023

Despite the proliferation of novel therapies such as immunotherapy or targeted therapies, radiation and chemotherapy remain the frontline treatment for cancer patients. About half of all patients still receive radiation and 60-80 percent receive chemotherapy.

Both radiation and chemotherapy work by damaging DNA, taking advantage of a vulnerability specific to cancer cells. Healthy cells are more likely to survive radiation and chemotherapy since their mechanisms for identifying and repairing DNA damage are intact. In cancer cells, these repair mechanisms are compromised by mutations. When cancer cells cannot adequately respond to the DNA damage caused by radiation and chemotherapy, ideally, they undergo apoptosis or die by other means.

However, there is another fate for cells after DNA damage: senescence — a state where cells survive, but stop dividing. Senescent cells’ DNA has not been damaged enough to induce apoptosis but is too damaged to support cell division. While senescent cancer cells themselves are unable to proliferate and spread, they are bad actors in the fight against cancer because they seem to enable other cancer cells to develop more aggressively. Although a cancer cell’s fate is not apparent until a few days after treatment, the decision to survive, die, or enter senescence is made much earlier. But, precisely when and how that decision is made has not been well understood.

In an open-access study of ovarian and osteosarcoma cancer cells appearing July 19 in Cell Systems, MIT researchers show that cell signaling proteins commonly associated with cell proliferation and apoptosis instead commit cancer cells to senescence within 12 hours of treatment with low doses of certain kinds of chemotherapy.

“When it comes to treating cancer, this study underscores that it’s important not to think too linearly about cell signaling,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. “If you assume that a particular treatment will always affect cancer cell signaling in the same way — you may be setting yourself up for many surprises, and treating cancers with the wrong combination of drugs.”

Using a combination of experiments with cancer cells and computational modeling, the team investigated the cell signaling mechanisms that prompt cancer cells to enter senescence after treatment with a commonly used anti-cancer agent. Their efforts singled out two protein kinases and a component of the AP-1 transcription factor complex as highly associated with the induction of senescence after DNA damage, despite the well-established roles for all of these molecules in promoting cell proliferation in cancer.

The researchers treated cancer cells with low and high doses of doxorubicin, a chemotherapy that interferes with the function with topoisomerase II, an enzyme that breaks and then repairs DNA strands during replication to fix tangles and other topological problems.

By measuring the effects of DNA damage on single cells at several time points ranging from six hours to four days after the initial exposure, the team created two datasets. In one dataset, the researchers tracked cell fate over time. For the second set, researchers measured relative cell signaling activity levels across a variety of proteins associated with responses to DNA damage or cellular stress, determination of cell fate, and progress through cell growth and division.

The two datasets were used to build a computational model that identifies correlations between time, dosage, signal, and cell fate. The model identified the activities of the MAP kinases Erk and JNK, and the transcription factor c-Jun as key components of the AP-1 protein likewise understood to involved in the induction of senescence. The researchers then validated these computational findings by showing that inhibition of JNK and Erk after DNA damage successfully prevented cells from entering senescence.

The researchers leveraged JNK and Erk inhibition to pinpoint exactly when cells made the decision to enter senescence. Surprisingly, they found that the decision to enter senescence was made within 12 hours of DNA damage, even though it took days to actually see the senescent cells accumulate. The team also found that with the passage of more time, these MAP kinases took on a different function: promoting the secretion of proinflammatory proteins called cytokines that are responsible for making other cancer cells proliferate and develop resistance to chemotherapy.

“Proteins like cytokines encourage ‘bad behavior’ in neighboring tumor cells that lead to more aggressive cancer progression,” says Tatiana Netterfield, a graduate student in the Yaffe lab and the lead author of the study. “Because of this, it is thought that senescent cells that stay near the tumor for long periods of time are detrimental to treating cancer.”

This study’s findings apply to cancer cells treated with a commonly used type of chemotherapy that stalls DNA replication after repair. But more broadly, the study emphasizes that “when treating cancer, it’s extremely important to understand the molecular characteristics of cancer cells and the contextual factors such as time and dosing that determine cell fate,” explains Netterfield.

The study, however, has more immediate implications for treatments that are already in use. One class of Erk inhibitors, MEK inhibitors, are used in the clinic with the expectation that they will curb cancer growth.

“We must be cautious about administering MEK inhibitors together with chemotherapies,” says Yaffe. “The combination may have the unintended effect of driving cells into proliferation, rather than senescence.”

In future work, the team will perform studies to understand how and why individual cells choose to proliferate instead of enter senescence. Additionally, the team is employing next-generation sequencing to understand which genes c-Jun is regulating in order to push cells toward senescence.

This study was funded, in part, by the Charles and Marjorie Holloway Foundation and the MIT Center for Precision Cancer Medicine.

Brady Weissbourd named Klingenstein-Simons Fellow

Three-year fellowship will support Weissbourd’s research on how the C. hemisphaerica jellyfish survives and thrives by constantly making new neurons.

David Orenstein | The Picower Institute for Learning and Memory
July 20, 2023

The Clytia hemisphaerica jellyfish is not only a hypnotically graceful swimmer, but also an amazing neuron-manufacturing machine with a remarkable ability to expand and regenerate its nervous system.

Now, thanks to a prestigious Klingenstein-Simons Fellowship Award in Neuroscience, MIT Assistant Professor Brady Weissbourd will study how the tiny, transparent animals use this ability to build, organize, and rebuild a stable, functional, and robust nervous system throughout their lives.

“As we look more broadly across the animal kingdom it is amazing to see how similar the basic biology is of animals that look completely different — even jellyfish have neurons similar to our own that generate their behavior,” says Weissbourd, a faculty member in MIT’s Department of Biology and The Picower Institute for Learning and Memory, whose work to engineer genetic access to C. hemisphaerica in 2021 established it as a new neuroscience model organism. “At the same time, it could be just as important to examine what is different across species, particularly when it comes to some of the incredible capabilities that have evolved.”

Weissbourd is just one of 13 researchers nationally to be recognized with this fellowship, which provides $300,000 over three years. It will enable Weissbourd’s lab to tackle several questions raised by the jellyfish’s prodigious production of neurons. Where does the constant stream of newborn neurons come from, and what guides them to their eventual places in the jellyfish’s mesh-like neural network? How does the jellyfish organize these ever-changing neural populations — for instance, into functional circuits — to enable its various behaviors?

Another question hails from the surprising results of an experiment in which Weissbourd ablated the entire class of the neurons that the jellyfish uses to fold up its umbrella-shaped body — about 10 percent of the 10,000 or so neurons that it has. He found that within a week enough new neurons had taken their place that the folding behavior was restored. Weissbourd’s studies will also seek to determine how the animal can so readily bounce back from the destruction of a whole major neural network and the behavior it produces.

“We were studying the neural control of a particular behavior and stumbled across this shocking observation that the subnetwork that controls this behavior is constantly changing size and can completely regenerate,” Weissbourd says. “We want to understand the mechanisms that allow this network to be so robust, including the ability to rebuild itself from scratch. I’m very grateful to the Klingenstein Fund and the Simons Foundation for supporting our work.”