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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.
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.”
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.
The paths three graduate students forged to the same Picower Institute lab illustrate the value of participating in the MIT Summer Research Program in Biology and Neuroscience.
David Orenstein | The Picower Institute for Learning and Memory
August 16, 2023
Doctoral studies at MIT aren’t a calling for everyone, but they can be for anyone who has had opportunities to discover that science and technology research is their passion and to build the experience and skills to succeed. For Taylor Baum, Josefina Correa Menéndez and Karla Alejandra Montejo, three graduate students in just one lab of The Picower Institute for Learning and Memory, a pivotal opportunity came via the MIT Summer Research Program in Biology and Neuroscience (MSRP BIO). When a student finds MSRP-BIO, it helps them find their future in research.
In the program undergraduate STEM majors from outside MIT spend the summer doing full-time research in the Departments of Biology or Brain and Cognitive Sciences (BCS), or the Center for Brains, Minds and Machines (CBMM). They gain lab skills, mentoring, preparation for graduate school and connections that might last a lifetime. Over the last two decades, a total of 215 students from under-represented minority groups, who are from economically-disadvantaged backgrounds, first-generation or non-traditional college students, or students with disabilities have participated in research in BCS or CBMM labs.
Like Baum, Correa Menéndez, and Montejo, the vast majority go on to pursue graduate studies, said Diversity & Outreach Coordinator Mandana Sassanfar, who runs the program. For instance, among 91 students who have worked in Picower Institute labs, 81 have completed their undergraduate studies. Of those, 46 enrolled in PhD programs at MIT or other schools such as Cornell, Yale, Stanford, Princeton, and the University of California System. Another 12 have gone to medical school, another 7 are in MD/PhD programs and 3 have earned master’s degrees. The rest are studying as post-baccalaureates or went straight into the workforce after earning their bachelor’s.
After participating in the program, Baum, Correa Menéndez, and Montejo each became graduate students in the research group of Emery N. Brown, Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering in The Picower Institute and the Institute for Medical Engineering and Science. The lab combines statistical, computational and experimental neuroscience methods to study how general anesthesia affects the central nervous system to ultimately improve patient care and advance understanding of the brain. Brown said the students have each been doing “off the scale” work, in keeping with the excellence he’s seen from MSRP BIO students over the years.
“I think MSRP is fantastic. Mandana does this amazing job of getting students who are quite talented to come to MIT to realize that they can move their game to the next level. They have the capacity to do it. They just need the opportunities,” Brown said. “These students live up to the expectations that you have of them. And now as graduate students, they’re taking on hard problems and they’re solving them.”
Paths to PhD studies
Pursuing a PhD is hardly a given. Many young students have never considered graduate school or specific fields of study like neuroscience or electrical engineering. But Sassanfar engages students across the country to introduce them to the opportunity MSRP BIO provides to gain exposure, experience and mentoring in advanced fields. Every fall, after the program’s students have returned to their undergraduate institutions, she visits schools in places as far flung as Florida, Maryland, Puerto Rico, and Texas and goes to conferences for diverse science communities such as ABRCMS and SACNAS to spread the word.
When Baum first connected with the program in 2017, she was finding her way at Penn State University. She had been majoring in biology and music composition but had just switched the latter to engineering following a conversation over coffee exposing her to brain-computer interfacing technology, in which detecting of brain signals of people with full-body paralysis could improve their quality of life by enabling control of computers or wheelchairs. Baum became enthusiastic about the potential to build similar systems, but as a new engineering student, she struggled to find summer internships and research opportunities.
“I got rejected from every single progam except the MIT Center for Brains Minds and Machines MSRP,” she recalled with a chuckle.
Baum thrived in MSRP BIO, working in Brown’s lab for three successive summers. At each stage, she said, she gained more research skills, experience and independence. When she graduated, she was sure she wanted to go to graduate school and applied to four of her dream schools. She accepted MIT’s offer to join the Department of Electrical Engineering and Computer Science, where she is co-advised by faculty members there and by Brown. She is now working to develop a system grounded in cardiovascular physiology that can improve blood pressure management. A tool for practicing anesthesiologists, the system automates the dosing of drugs to maintain a patient’s blood pressure at safe levels in the operating room or intensive care unit.
More than that, Baum not only is leading an organization advancing STEM education in Puerto Rico, but also is helping to mentor a current MSRP BIO student in the Brown lab.
“MSRP definitely bonds everyone who has participated in it,” Baum said. “If I see anyone who I know participated in MSRP, we could have an immediate conversation. I know that most of us, if we needed help, we’d feel comfortable asking for help from someone from MSRP. With that shared experience, we have a sense of camaraderie, and community.”
In fact, a few years ago when a former MSRP BIO student named Karla Montejo was applying to MIT, Baum provided essential advice and feedback about the application process, Montejo said. Now as a graduate student, Montejo has become a mentor for the program in her own right, Sassanfar noted. For instance, Montejo serves on program alumni panels that advise new MSRP BIO students.
Montejo’s family immigrated to Miami from Cuba when she was a child. The magnet high school she attended was so new that students were encouraged to help establish the school’s programs. She forged a path into research.
“I didn’t even know what research was,” she said. “I wanted to be a doctor, and I thought maybe it would help me on my resume. I thought it would be kind of like shadowing, but no, it was really different. So I got really captured by research when I was in high school.”
Despite continuing to pursue research in college at Florida International University, Montejo didn’t get into graduate school on her first attempt because she hadn’t yet learned how to focus her application. But Sassanfar had visited FIU to recruit students and through that relationship Montejo had already gone through MIT’s related Quantitative Methods Workshop (QMW). So Montejo enrolled in MSRP BIO, working in the CBMM-affiliated lab of Gabriel Kreiman at Boston Children’s Hospital.
“I feel like Mandana really helped me out gave me a break, and the MSRP experience pretty much solidified that I really wanted to come to MIT,” Montejo said.
In the QMW, Montejo learned she really liked computational neuroscience and in Kreiman’s lab she got to try her hand at computational modeling of the cognition involved in making perceptual sense of complex scenes. Montejo realized she wanted to work on more biologically based neuroscience problems. When the summer ended, because she was off the normal graduate school cycle for now, she found a two-year postbaccalaurate program at Mayo Clinic studying the role a brain cell type called astrocytes might have in the Parkinson’s Disease treatment deep brain stimulation.
When it came time to re-apply to graduate schools (with the help of Baum and others in the BCS Application Assistance Program) Montejo applied to MIT and got in, joining the Brown lab. Now she’s working on modeling the role of metabolic processes in the changing of brain rhythms under anesthesia, , taking advantage of how general anesthesia predictably changes brain states. The effects anesthetic drugs have on cell metabolism and the way that ultimately affects levels of consciousness reveals important aspects of how metabolism affects brain circuits and systems. Earlier this month, for instance, Montejo co-led a paper the lab published in The Proceedings of the National Academy of Sciences detailing the neuroscience of a patient’s transition into an especially deep state of unconsciousness called “burst suppression.”
A signature of the Brown lab’s work is rigorous statistical analysis and methods, for instance to discern brain arousals states from EEG measures of brain rhythms. A PhD candidate in MIT’s Interdisciplinary Doctoral Program in Statistics, Correa Menéndez is advancing the use of Bayesian hierarchical models for neural data analysis. These statistical models offer a principled way of pooling information across datasets. One of her models can help scientists better understand the way neurons can “spike” with electrical activity when the brain is presented with a stimulus. The other’s power is in discerning critical features such as arousal states of the brain under general anesthesia from electrophysiological recordings.
Though she now works with complex equations and computations as a PhD candidate in Neuroscience and Statistics, Correa Menéndez was mostly interested in music art as a high school student at Academia María Reina in San Juan and then architecture in college at the University of Puerto Rico, Río Piedras campus. It was discussions at the intersection of epistemology and art during an art theory class that inspired Correa Menéndez to switch her major to biology and to take computer science classes, too.
When Sassanfar visited Puerto Rico in 2017, a computer science professor (Dr. Patricia Ordóñez) suggested that Correa Menéndez apply for a chance to attend the QMW. She did and that led her to also participate in MSRP BIO in the lab of Sherman Fairchild Professor Matt Wilson (a faculty member in BCS, CBMM and The Picower Institute). She joined in the lab’s studies of how spatial memories are represented in the hippocampus and how the brain makes use of those memories to help understand the world around it. With mentoring from then-postdoc Carmen Varela (now a faculty member at Florida State University), the experience not only exposed her to neuroscience, but also, she gained skills and experience with lab experiments, building research tools, and conducting statistical analyses. She ended up working in the Wilson lab as a research scholar for a year and began her graduate studies in September 2018.
Classes she took with Brown as a research scholar inspired her to join his lab as a graduate student.
“Taking the classes with Emery and also doing experiments made me aware of the role of statistics in the scientific process: from the interpretation of results to the analysis and the design of experiments,” she said. “More often than not, in science, statistics becomes this sort of afterthought—this ‘annoying’ thing that people need to do to get their paper published. But statistics as a field is actually a lot more than that. It’s a way of thinking about data. Particularly, Bayesian modeling provides a principled inference framework for combining prior knowledge into a hypothesis that you can test with data.”
To be sure, no one starts out with such inspiration about scientific scholarship, but MSRP BIO helps students find that passion for research and the paths it opens up.
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.
August 2, 2023
Greta Friar | Whitehead Institute
August 4, 2023
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.”
New Professor of Biology Daniel Lew uses budding yeast to address fundamental questions in cell biology
Lillian Eden | Department of Biology
August 3, 2023
Sipping a beer on a warm summer evening, one might not consider that humans and yeast have been inextricably linked for thousands of years; winemaking, baking, and brewing all depend on budding yeast. Outside of baking and fermentation, researchers also use Saccharomyces cerevisiae, classified as a fungus, to study fundamental questions of cell biology.
Budding yeast gets its name from the way it multiplies. A daughter cell forms first as a swelling, protruding growth on the mother cell. The daughter cell projects further and further from the mother cell until it detaches as an independent yeast cell.
How do cells decide on a front and back? How do cells decode concentration gradients of chemical signals to orient in useful directions, or sense and navigate around physical obstacles? New Department of Biology faculty member Daniel “Danny” Lew uses the model yeast S. cerevisiae, and a non-model yeast with an unusual pattern of cell division, to explore these questions.
Q: Why is it useful to study yeast, and how do you approach the questions you hope to answer?
A: Humans and yeast are descended from a common ancestor, and some molecular mechanisms developed by that ancestor have been around for so long that yeast and mammals often use the same mechanisms. Many cells develop a front and migrate or grow in a particular direction, like the axons in our nervous system, using similar molecular mechanisms to those of yeast cells orienting growth towards the bud.
When I started my lab, I was working on cell cycle control, but I’ve always been interested in morphogenesis and the cell biology of how cells change shape and decide to do different things with different parts of themselves. Those mechanisms turn out to be conserved between yeast and humans.
But some things are very different about fungal and animal cells. One of the differences is the cell wall and what fungal cells have to do to deal with the fact that they have a cell wall.
Fungi are inflated by turgor pressure, which pushes their membranes against the rigid cell wall. This means they’ll die if there is any hole in the cell wall, which would be expected to happen often as cells remodel the wall in order to grow. We’re interested in understanding how fungi sense when any weak spots appear in the wall and repair them before those weak spots become dangerous.
Yeast cells, like most fungi, also mate by fusing with a partner. To succeed, they must do the most dangerous thing in the fungal lifecycle: get rid of the cell wall at the point of contact to allow fusion. That means they must be precise about where and when they remove the wall. We’re fascinated to understand how they know it is safe to remove the wall there, and nowhere else.
We take an interdisciplinary approach. We’ve used genetics, biochemistry, cell biology, and computational biology to try and solve problems in the past. There’s a natural progression: observation and genetic approaches tend to be the first line of attack when you know nothing about how something works. As you learn more, you need biochemical approaches and, eventually, computational approaches to understand exactly what mechanism you’re looking at.
I’m also passionate about mentoring, and I love working with trainees and getting them fascinated by the same problems that fascinate me. I’m looking to work with curious trainees who love addressing fundamental problems.
Q: How does yeast decide to orient a certain way—towards a mating partner, for example?
A: We are still working on questions of how cells analyze the surrounding environment to pick a direction. Yeast cells have receptors that sense pheromones that a mating partner releases. What is amazing about that is that these cells are incredibly small, and pheromones are released by several potential partners in the neighborhood. That means yeast cells must interpret a very confusing landscape of pheromone concentrations. It’s not apparent how they manage to orient accurately toward a single partner.
That got me interested in related questions. Suppose the cell is oriented toward something that isn’t a mating partner. The cell seems to recognize that there’s an obstacle in the way, and it can change direction to go around that obstacle. This is how fungi get so good at growing into things that look very solid, like wood, and some fungi can even penetrate Kevlar vests.
If they recognize an obstacle, they have to change directions and go around it. If they recognize a mating partner, they have to stick with that direction and allow the cell wall to get degraded. How do they know they’ve hit an obstacle? How do they know a mating partner is different from an obstacle? These are the questions we’d like to understand.
Q: For the last couple of years, you’ve also been studying a budding yeast that forms multiple buds when it reproduces instead of just one. How did you come across it, and what questions are you hoping to explore?
A: I spent several years trying to figure out why most yeasts make one bud and only one bud, which I think is related to the question of why migrating cells make one and only one front. We had what we thought was a persuasive answer to that, so seeing a yeast completely disobey that and make as many buds as it felt like was a shock, which got me intrigued.
We started working on it because my colleague,Amy Gladfelter, had sampled the waters around Woods Hole, Massachusetts. When she saw this specimen under a microscope, she immediately called me and said, “You have to look at this.”
A question we’re very intrigued by is if the cell makes five, seven, or 12 buds simultaneously, how do they divide the mother cell’s material and growth capacity five, seven, or 12 ways? It looks like all of the buds grow at the same rate and reach about the same size. One of our short-term goals is to check whether all the buds really get to exactly the same size or whether they are born unequal.
And we’re interested in more than just growth rate. What about organelles? Do you give each bud the same number of mitochondria, nuclei, peroxisomes, and vacuoles? That question will inevitably lead to follow-up questions. If each bud has the same number of mitochondria, how does the cell measure mitochondrial inheritance to do that? If they don’t have the same amount, then buds are each born with a different complement and ratio of organelles. What happens to buds if they have very different numbers of organelles?
As far as we can tell, every bud gets at least one nucleus. How the cell ensures that each bud gets a nucleus is a question we’d also very much like to understand.
We have molecular candidates because we know a lot about how model yeasts deliver nuclei, organelles, and growth materials from the mother to the single bud. We can mutate candidate genes and see if similar molecular pathways are involved in the multi-budding yeast and, if so, how they are working.
It turns out that this unconventional yeast has yet to be studied from the point of view of basic cell biology. The other thing that intrigues me is that it’s a poly-extremophile. This yeast can survive under many rather harsh conditions: it’s been isolated in Antarctica, from jet engines, from all kinds of plants, and of course from the ocean as well. An advantage of working with something so ubiquitous is we already know it’s not toxic to us under almost any circumstances. We come into contact with it all the time. If we learn enough about its cell biology to begin to manipulate it, then there are many potential applications, from human health to agriculture.