Category: Uncategorized
June 26, 2023
David Orenstein | The Picower Institute for Learning and Memory
June 23, 2023
Perhaps the most obvious feature of a neuron is the long branch called an axon that ventures far from the cell body to connect with other neurons or muscles. If that long, thin projection ever seems like it could be vulnerable, a new MIT study shows that its structural integrity may indeed require the support of a surrounding protein called perlecan. Without that protein in Drosophila fruit flies, researchers at The Picower Institute for Learning and Memory found axonal segments can break apart during development and the connections, or synapses, that they form end up dying away.
Perlecan helps make the extracellular matrix, the proteins and other molecules that surround cells, stable and flexible so that cells can develop and function in an environment that is supportive without being rigid.
“What we found was that the extracellular matrix around nerves was being altered and essentially causing the nerves to break completely. Broken nerves eventually led to the synapses retracting,” says study senior author Troy Littleton, the Menicon Professor in MIT’s departments of Biology and Brain and Cognitive Sciences.
Humans need at least some perlecan to survive after birth. Mutations that reduce, but don’t eliminate, perlecan can cause Schwartz-Jampel syndrome, in which patients experience neuromuscular problems and skeletal abnormalities. The new study may help explain how neurons are affected in the condition, Littleton says, and also deepen scientists’ understanding of how the extracellular matrix supports axon and neural circuit development.
Ellen Guss PhD ’23, who recently defended her doctoral thesis on the work, led the research published June 8 in eLife.
At first she and Littleton didn’t expect the study to yield a new discovery about the durability of developing axons. Instead, they were investigating a hypothesis that perlecan might help organize some of the protein components in synapses that fly nerves develop to connect with muscles. But when they knocked out the gene called “trol” that encodes perlecan in flies, they saw that the neurons appeared to “retract” many synapses at a late stage of larval development. Proteins on the muscle side of the synaptic connection remained, but the neuron side of the connection withered away. That suggested that perlecan had a bigger role than they first thought.
Indeed, the authors found that the perlecan wasn’t particularly enriched around synapses. Where it was pronounced was in a structure called the neural lamella, which surrounds axon bundles and acts a bit like the rubbery cladding around a TV cable to keep the structure intact. That suggested that a lack of perlecan might not be a problem at the synapse, but instead causes trouble along axons due to its absence in the extracellular matrix surrounding nerve bundles.
Littleton’s lab had developed a technique for daily imaging of fly neural development called serial intravital imaging. They applied it to watch what happened to the fly axons and synapses over a four-day span. They observed that while fly axons and synapses developed normally at first, not only synapses but also whole segments of axons faded away.
They also saw that the farther an axon segment was from the fly’s brain, the more likely it was to break apart, suggesting that the axon segments became more vulnerable the further out they extended. Looking segment by segment, they found that where axons were breaking down, synapse loss would soon follow, suggesting that axon breakage was the cause of the synapse retraction.
“The breakages were happening in a segment-wide manner,” Littleton says. “In some segments the nerves would break and in some they wouldn’t. Whenever there was a breakage event, you would see all the neuromuscular junctions (synapses) across all the muscles in that segment retract.”
When they compared the structure of the lamella in mutant versus healthy flies, they found that the lamella was thinner and defective in the mutants. Moreover, where the lamella was weakened, axons were prone to break and the microtubule structures that run the length of the axon would become misdirected, protruding outward and becoming tangled up in dramatic bundles at sites of severed axons.
In one other key finding, the team showed that perlecan’s critical role depended on its secretion from many cells, not just neurons. Blocking the protein in just one cell type or another did not cause the problems that total knockdown did, and enhancing secretion from just neurons was not enough to overcome its deficiency from other sources.
Altogether, the evidence pointed to a scenario where lack of perlecan secretion caused the neural lamella to be thin and defective, with the extracellular matrix becoming too rigid. The further from the brain nerve bundles extended, the more likely movement stresses would cause the axons to break where the lamella had broken down. The microtubule structure within the axons then became disorganized. That ultimately led to synapses downstream of those breakages dying away because the disruption of the microtubules means the cells could no longer support the synapses.
“When you don’t have that flexibility, although the extracellular matrix is still there, it becomes very rigid and tight and that basically leads to this breakage as the animal moves and pulls on those nerves over time,” Littleton says. “It argues that the extracellular matrix is functional early on and can support development, but doesn’t have the right properties to sustain some key functions over time as the animal begins to move and navigate around. The loss of flexibility becomes really critical.”
In addition to Littleton and Guss, the paper’s other authors are Yulia Akbergenova and Karen Cunningham.
Support for the study came from the National Institutes of Health. The Littleton Lab is also supported by The Picower Institute for Learning and Memory and The JPB Foundation.
It can be difficult to tell which of the many small genetic differences between us and chimps have been significant to our evolution. New research from Jonathan Weissman and colleagues narrowed in on the key differences in how humans and chimps rely on certain genes, including how humans became able to grow comparatively large brains.
Greta Friar | Whitehead Institute
June 22, 2023
Humans split away from our closest animal relatives, chimpanzees, and formed our own branch on the evolutionary tree about seven million years ago. In the time since—brief, from an evolutionary perspective—our ancestors evolved the traits that make us human, including a much bigger brain than chimpanzees and bodies that are better suited to walking on two feet. These physical differences are underpinned by subtle changes at the level of our DNA. However, it can be hard to tell which of the many small genetic differences between us and chimps have been significant to our evolution.
New research from Whitehead Institute Member Jonathan Weissman; University of California, San Francisco Assistant Professor Alex Pollen; Weissman lab postdoc Richard She; Pollen lab graduate student Tyler Fair; and colleagues uses cutting edge tools developed in the Weissman lab to narrow in on the key differences in how humans and chimps rely on certain genes. Their findings, published in the journal Cell on June 20, may provide unique clues into how humans and chimps have evolved, including how humans became able to grow comparatively large brains.
Studying function rather than genetic code
Only a handful of genes are fundamentally different between humans and chimps; the rest of the two species’ genes are typically nearly identical. Differences between the species often come down to when and how cells use those nearly identical genes. However, only some of the many differences in gene use between the two species underlie big changes in physical traits. The researchers developed an approach to narrow in on these impactful differences.
Their approach, using stem cells derived from human and chimp skin samples, relies on a tool called CRISPR interference (CRISPRi) that Weissman’s lab developed. CRISPRi uses a modified version of the CRISPR/Cas9 gene editing system to effectively turn off individual genes. The researchers used CRISPRi to turn off each gene one at a time in a group of human stem cells and a group of chimp stem cells. Then they looked to see whether or not the cells multiplied at their normal rate. If the cells stopped multiplying as quickly or stopped altogether, then the gene that had been turned off was considered essential: a gene that the cells need to be active–producing a protein product–in order to thrive. The researchers looked for instances in which a gene was essential in one species but not the other as a way of exploring if and how there were fundamental differences in the basic ways that human and chimp cells function.
By looking for differences in how cells function with particular genes disabled, rather than looking at differences in the DNA sequence or expression of genes, the approach ignores differences that do not appear to impact cells. If a difference in gene use between species has a large, measurable effect at the level of the cell, this likely reflects a meaningful difference between the species at a larger physical scale, and so the genes identified in this way are likely to be relevant to the distinguishing features that have emerged over human and chimp evolution.
“The problem with looking at expression changes or changes in DNA sequences is that there are many of them and their functional importance is unclear,” says Weissman, who is also a professor of biology at the Massachusetts Institute of Technology and an Investigator with the Howard Hughes Medical Institute. “This approach looks at changes in how genes interact to perform key biological processes, and what we see by doing that is that, even on the short timescale of human evolution, there has been fundamental rewiring of cells.”
After the CRISPRi experiments were completed, She compiled a list of the genes that appeared to be essential in one species but not the other. Then he looked for patterns. Many of the 75 genes identified by the experiments clustered together in the same pathways, meaning the clusters were involved in the same biological processes. This is what the researchers hoped to see. Individual small changes in gene use may not have much of an effect, but when those changes accumulate in the same biological pathway or process, collectively they can cause a substantive change in the species. When the researchers’ approach identified genes that cluster in the same processes, this suggested to them that their approach had worked and that the genes were likely involved in human and chimp evolution.
“Isolating the genetic changes that made us human has been compared to searching for needles in a haystack because there are millions of genetic differences, and most are likely to have negligible effects on traits,” Pollen says. “However, we know that there are lots of small effect mutations that in aggregate may account for many species differences. This new approach allows us to study these aggregate effects, enabling us to weigh the impact of the haystack on cellular functions.”
Researchers think bigger brains may rely on genes regulating how quickly cells divide
One cluster on the list stood out to the researchers: a group of genes essential to chimps, but not to humans, that help to control the cell cycle, which regulates when and how cells decide to divide. Cell cycle regulation has long been hypothesized to play a role in the evolution of humans’ large brains. The hypothesis goes like this: Neural progenitors are the cells that will become neurons and other brain cells. Before becoming mature brain cells, neural progenitors divide multiple times to make more of themselves. The more divisions that the neural progenitors undergo, the more cells the brain will ultimately contain—and so, the bigger it will be. Researchers think that something changed during human evolution to allow neural progenitors to spend less time in a non-dividing phase of the cell cycle and transition more quickly towards division. This simple difference would lead to additional divisions, each of which could essentially double the final number of brain cells.
Consistent with the popular hypothesis that human neural progenitors may undergo more divisions, resulting in a larger brain, the researchers found that several genes that help cells to transition more quickly through the cell cycle are essential in chimp neural progenitor cells but not in human cells. When chimp neural progenitor cells lose these genes, they linger in a non-dividing phase, but when human cells lose them, they keep cycling and dividing. These findings suggest that human neural progenitors may be better able to withstand stresses—such as the loss of cell cycle genes—that would limit the number of divisions the cells undergo, enabling humans to produce enough cells to build a larger brain.
“This hypothesis has been around for a long time, and I think our study is among the first to show that there is in fact a species difference in how the cell cycle is regulated in neural progenitors,” She says. “We had no idea going in which genes our approach would highlight, and it was really exciting when we saw that one of our strongest findings matched and expanded on this existing hypothesis.”
More subjects lead to more robust results
Research comparing chimps to humans often uses samples from only one or two individuals from each species, but this study used samples from six humans and six chimps. By making sure that the patterns they observed were consistent across multiple individuals of each species, the researchers could avoid mistaking the naturally occurring genetic variation between individuals as representative of the whole species. This allowed them to be confident that the differences they identified were truly differences between species.
The researchers also compared their findings for chimps and humans to orangutans, which split from the other species earlier in our shared evolutionary history. This allowed them to figure out where on the evolutionary tree a change in gene use most likely occurred. If a gene is essential in both chimps and orangutans, then it was likely essential in the shared ancestor of all three species; it’s more likely for a particular difference to have evolved once, in a common ancestor, than to have evolved independently multiple times. If the same gene is no longer essential in humans, then its role most likely shifted after humans split from chimps. Using this system, the researchers showed that the changes in cell cycle regulation occurred during human evolution, consistent with the proposal that they contributed to the expansion of the brain in humans.
The researchers hope that their work not only improves our understanding of human and chimp evolution, but also demonstrates the strength of the CRISPRi approach for studying human evolution and other areas of human biology. Researchers in the Weissman and Pollen labs are now using the approach to better understand human diseases—looking for the subtle differences in gene use that may underlie important traits such as whether someone is at risk of developing a disease, or how they will respond to a medication. The researchers anticipate that their approach will enable them to sort through many small genetic differences between people to narrow in on impactful ones underlying traits in health and disease, just as the approach enabled them to narrow in on the evolutionary changes that helped make us human.
MIT-Novo Nordisk Artificial Intelligence Postdoctoral Fellows Program will support up to 10 postdocs annually over five years.
Mary Beth Gallagher | School of Engineering
June 26, 2023
MIT’s School of Engineering and global health care company Novo Nordisk has announced the launch of a multi-year program to support postdoctoral fellows conducting research at the intersection of artificial intelligence and data science with life sciences. The MIT-Novo Nordisk Artificial Intelligence Postdoctoral Fellows Program will welcome its first cohort of up to 10 postdocs for a two-year term this fall. The program will provide up to $10 million for an annual cohort of up to 10 postdoc for two-year terms.
“The research being conducted at the intersection of AI and life sciences has the potential to transform health care as we know it,” says Anantha Chandrakasan, dean of the School of Engineering and Vannevar Bush Professor of Electrical Engineering and Computer Science. “I am thrilled that the MIT-Novo Nordisk Program will support early-career researchers who work in this space.”
The launch of the MIT-Novo Nordisk Program coincides with the 100th anniversary celebration of Novo Nordisk. The company was founded in 1923 and treated its first patients with insulin, which had recently been discovered in March of that year.
“The use of AI in the health care industry presents a massive opportunity to improve the lives of people living with chronic diseases,” says Thomas Senderovitz, senior vice president for data science at Novo Nordisk. “Novo Nordisk is committed to the development of new, innovative solutions, and MIT hosts some of the most outstanding researchers in the field. We are therefore excited to support postdocs working on the cutting edge of AI and life sciences.”
The MIT-Novo Nordisk Program will support postdocs advancing the use of AI in life science and health. Postdocs will join an annual cohort that participates in frequent events and gatherings. The cohort will meet regularly to exchange ideas about their work and discuss ways to amplify their impact.
“We are excited to welcome postdocs working on AI, data science, health, and life sciences — research areas of strategic importance across MIT,” adds Chandrakasan.
A central focus of the program will be offering postdocs professional development and mentorship opportunities. Fellows will be invited to entrepreneurship-focused workshops that enable them to learn from company founders, venture capitalists, and other entrepreneurial leaders. Fellows will also have the opportunity to receive mentorship from experts in life sciences and data science.
“MIT is always exploring opportunities to innovate and enhance the postdoctoral experience,” adds MIT Provost Cynthia Barnhart. “The MIT-Novo Nordisk Program has been thoughtfully designed to introduce fellows to a wealth of experiences, skill sets, and perspectives that support their professional growth while prioritizing a sense of community with their cohort.”
Angela Belcher, head of the Department of Biological Engineering, the James Mason Crafts Professor of Biological Engineering and Materials Science, and member of the Koch Institute for Integrative Cancer Research, and Asu Ozdaglar, deputy dean of academics for the MIT Schwarzman College of Computing and head of the Department of Electrical Engineering and Computer Science, will serve as co-faculty leads for the program.
The new program complements a separate postdoctoral fellowship program at MIT supported by the Novo Nordisk Foundation that focuses on enabling interdisciplinary research.
Biology graduate student Tong Zhang has spent the last two years learning the intricacies of how bacteria protect themselves.
Lillian Eden | Department of Biology
June 12, 2023
For the past two and a half years, graduate student Tong Zhang has been figuring out how bacteria protect themselves against phages — the viruses that infect them. All the while, doing so as a student far from her hometown of Beijing, China.
Phages and bacteria are in a constant arms race, which those in the field call the Red Queen Conflict: Alice in Wonderland running to stay in place, the queen making chase. Both the infector and the infected are constantly forced to adapt — the host and the parasite persistently co-evolving.
Perhaps the best-known anti-phage defense systems are called restriction modification systems, and much of the influential work on those systems was done by Salvador Luria, the longtime MIT professor and founding director of what is now called the Koch Institute for Integrative Cancer Research. Those anti-phage defense systems can distinguish self DNA from foreign DNA; they are always active, in surveillance mode, ignoring the host DNA but on the hunt for foreign DNA to slice up to protect the host.
Other anti-phage systems, however, require activation. Although researchers have characterized systems that protect bacteria from phage, many questions remain about how those systems become activated during infection.
Unlocking phage science
In an open-access paper published last year, Zhang, along with collaborators, found that during infection, the capsid protein that coats the outside of the phage directly triggers activation of a toxin-antitoxin system called CapRel, where the N-terminus of the protein is the toxin and the C-terminus is the antitoxin; the C-terminus works as both infection sensor and inhibitor of the toxic N-terminus. The capsid protein of some phages infecting Escherichia coli, the bacteria studied for the paper, will bind to the C-terminal domain, which triggers activation of the toxic N-terminus defense system to restrict infection by blocking phage replication.
“The capsid is essential for the phage and is the most abundant thing in the phage.” Zhang says. “The bacteria are sensing something that the phage cannot just get rid of and still be happy, so this really limits the possibility that the phage can overcome this defense system.”
Before Tong’s paper, it was unclear that phage proteins could directly activate this defense system.
Although the details and molecules are different for different immune systems, the concept of sensing foreign invaders and responding to infection is conserved across all domains of life.
“It’s a testament to how hard she works, how smart she is, and how dedicated she is, that this project resulted in a paper in just two years — and started during a pandemic,” Laub says.
From Beijing to MIT
Zhang has thought biology was “cool” since long before she arrived at MIT. She hails from Beijing and was an undergraduate at the University of California at Berkeley, where her mentor gave her the perfect mix of guidance and independence.
“I think that experience made me realize that trying to figure out a problem is like solving a puzzle,” she says. “What I’m interested in is understanding mechanisms, the details of how different systems work. In my current research, there are a lot of open questions like that, which is really exciting.”
Laub says Zhang was the driving force behind the project, but collaborations also helped move the project along.
Although the pandemic posed a lot of challenges for research, it also changed the scales of distance: certain things work well in a virtual format. Laub was able to participate in a thesis defense abroad from the comfort of his desk in Cambridge, for example, and Zhang’s project came about in part because Laub served as an outside examiner for a lab in Sweden that had been studying CapRel.
But some things just don’t work on Zoom — like going home.
“There have been some unique challenges for Tong — and for all of our international students. They’re a long way from home, a long way from family,” Laub says. “The courage and the tenacity that it takes to not only do this work but to thrive and to succeed the way she has is remarkable.”
Zhang, like many international students pursuing education in the United States, has not been home in more than three years; in contrast, as an undergraduate, she went home for extended periods at least twice a year.
“I think that’s the most challenging part,” she says of her time at MIT.
She arrived in the United States to attend UC Berkeley having never visited the campus before. Zhang, used to sitting in the same classroom with the same group of people all day, was surprised to find that not only did she have the flexibility to pick out her course schedule, she also had to go to different places to attend classes, each with their own group of people.
“I’m really glad I went to UC Berkeley. There were a ton of opportunities and the science there was amazing. Obviously there were difficulties navigating a huge university and overcoming language barriers, but I think that also trained me to be more proactive in finding resources, finding help, looking for opportunities, and working to get them,” she says.
Laub says she’s just the type of student that MIT’s graduate programs are a good fit for.
“Our graduate program attracts people like Tong who are super rigorous scientists that really want to push that deep mechanistic, incisive understanding of things.”
Zhang is currently hard at work on her next project with “cool data” already in hand, Laub says.
Now an assistant professor at UT Dallas, Nicole De Nisco draws on love of problem solving and interdisciplinary skills honed as an undergraduate and graduate student at MIT
Lillian Eden | Department of Biology
June 12, 2023
There were early signs that Nicole De Nisco, SB ‘07, PhD ‘13, might become a scientist. She ran out of science classes to take in high school and fondly remembers the teacher that encouraged her to pursue science instead of the humanities. But she ended up at MIT, in part, out of spite.
“I applied because my guidance counselor told me I wouldn’t get in,” she said. The rest, as they say, is history for the first-generation college student from Los Angeles.
Now, she’s an assistant professor of biological sciences at UT Dallas studying urinary tract infections (UTIs) and the urinary microbiome in postmenopausal women.
De Nisco has already made some important advancements in the field: she developed a new technique for visualizing bacteria in the bladder and used it to demonstrate that bacteria form reservoirs in human bladder tissue, leading to chronic or recurrent UTIs.
It was known that in mice, bacteria are able to create communities within the bladder tissue, forming reservoirs and staying there long term—but no one had shown that occurring in human tissue before.
De Nisco found that reservoirs of tissue-resident bacteria exist in human patients with recurring UTIs, a condition which may ultimately lead to women needing to have their bladder removed. De Nisco now mostly works with postmenopausal women who have been suffering from decades of recurring UTIs.
There was a big gap in the field, De Nisco explained, so entering the field of urology was also an opportunity to make new discoveries and find new ways to treat those recurring infections.
De Nisco said she’s in the minority, both as a woman studying urology and as someone studying diseases that affect female patients. Most researchers in the urology field are men, and most focus on the prostate.
But things are changing.
“I think there are a lot of women in the field who are now pushing back, and I actually collaborate with a lot of other female investigators in the field. We’re trying to support each other so that we can survive and, hopefully, actually advance the science—instead of it being in the same place it was 15 years ago,” De Nisco says.
De Nisco first fell in love with biomedical research as an undergrad doing a UROP in Catherine Drennan’s lab, back when Drennan was still located in the chemistry building.
“Cathy herself was incredibly encouraging, and is probably the main reason I decided to pursue a career in science—or felt that I could,” De Nisco said.
De Nisco became fascinated with the dialogue between a microbe and a host organism during an undergraduate course in microbial physiology with Graham Walker, which led to De Nisco’s decision to remain at MIT for her PhD work and to perform her doctoral research in rhizobia legume symbiosis in Walker’s lab.
De Nisco said during her time at MIT, Drennan and Walker gave her a lot of encouragement and “room to do my own thing,” fostering a love of discovery and problem solving. It’s a mentoring style she’s using now with her own graduate students; she currently has eight working in her lab.
“Every student is different: some just want a project and they want to know what they’re doing, and some want to explore,” she said. “I was the type that wanted to do my own thing and so they gave me the room and the patience to be able to explore and find something new that I was interested in and excited about.”
As a low-income student sending financial help home, she also pursued teaching opportunities outside of her usual duties; Walker was very supportive of pursuing other teaching opportunities. De Nisco was a graduate student tutor for Next House watching over 40 undergrads, served as a teaching fellow with the Harvard Extension School, and worked with Eric Lander to help launch the course 7.00x Introduction to Biology – The Secret of Life for EdX, one of the most highly rated MOOCs of all time.
She said MIT definitely prepared her for a life as a professor, teacher, and mentor; the most important thing about graduate school isn’t choosing “the most cutting-edge research project,” but making sure you have a good training experience and an advisor who can provide that.
“You don’t need to start building your name in the field when you’re a grad student. The lab environment is much more important than the topic. It’s easy to get burned out or to be turned off to a career in academia altogether if you have the wrong advisor,” she said. “You need to learn how to be a scientist, and you have plenty of time later in your career to follow whatever path you want to follow.”
She knows this from experience: her current research is somewhat parallel but unrelated to her previous research experience.
“I think my motivation for being a scientist is rooted in my desire to help people doing something I enjoy,” she said. “I was not doing this kind of research as a graduate student, and that doesn’t mean that I wasn’t able to end up at this point in my career where I’m doing research that is focused on improving the lives of women, specifically.”
She did her postdoctoral work at UT Southwestern Medical Center studying Vibrio parahaemolyticus, a human pathogen that causes gastroenteritis. The work was a marriage of her interests in biochemistry and host-microbiome interactions.
She said MIT prepared her well for the type of interdisciplinary work that she does every day: At UT Dallas, all the research buildings are fully integrated, with engineers, chemists, physicists, and biologists sharing lab spaces in the same building. Her closest collaborators are mathematicians, chemists, and engineers.
Although she may not be fully literate, she has a common language with the people she works with thanks to MIT’s undergraduate course requirements in many different topics and MIT’s focus on interdisciplinary research, which is “how real advancement is made.”
Ultimately, De Nisco said she is glad to this day that she attended MIT.
“Getting that acceptance letter to attend MIT probably changed the trajectory of my life,” she said. “You never know, on paper, what someone is going to achieve eventually, and what kind of force they’re going to be. I’m always grateful to whoever was on the admissions committees that made the decision to accept me—twice.”
Catalyst Symposium is part of an effort to bring outstanding postdocs from underrepresented backgrounds in science to engage with MIT community members.
Lillian Eden | Department of Biology
June 9, 2023
The MIT biology community recently welcomed eight postdocs — Catalyst Fellows — to campus as part of the inaugural Catalyst Symposium.
Catalysts speed up reactions, and the symposium aims to accelerate progress in inclusive diversity — not just at MIT, but at top research institutions across the country, according to Professor Amy Keating, head of the Department of Biology.
“To make new discoveries and expand our understanding of life, we seek colleagues and trainees who are curious, persistent, creative, ingenious, insightful, determined, collaborative, generous, and ambitious,” Keating says. “To find these exceptional people, we have to look broadly. We have to look further than we have in the past.”
The symposium is part of an effort to expose outstanding candidates from backgrounds traditionally underrepresented in academic research to the biology department. The three-day symposium included research talks by the Catalyst Fellows, one-on-one meetings with faculty members, panel discussions on the faculty search process and the experiences of junior faculty in the department, and social events. Each Catalyst Fellow was paired with a faculty mentor.
The research talks ranged from molecular to behavioral: Krishna Mudumbi from Yale School of Medicine presented “Probing the kinetics of EGFR signaling: Why timing is important;” Coral Yishan Zhou from the University of California at Berkeley presented “Mechanisms of mitotic chromosome scaling in Xenopus;” Andre Toussaint from Columbia University presented “Neurobiology of addiction and tactile sensation;” Sofia Quinodoz from Princeton University presented “Probing nuclear organization and functions of condensates at genome-wide scale;” Junior West from Johns Hopkins School of Medicine presented “Claudin 7 restricts cancer invasion and metastasis by suppressing smooth muscle actin networks;” Shan Meltzer from Harvard Medical School presented “Molecular and Cellular Mechanisms of Touch Circuit Formation;” José Reyes from Memorial Sloan Kettering Cancer Center presented “Catching p53 in the act of tumor suppression;” and Begüm Aydin from The Rockefeller University presented “Cellular Plasticity in the Enteric Nervous System.”
Iain Cheeseman, associate department head, Herman and Margaret Sokol Professor of Biology, and core member of the Whitehead Institute for Biomedical Research, says what stood out about the event was the “fantastic celebration of amazing science.”
“I loved the presentations as well as the beautiful range of different science approaches, research questions, and ideas,” he says. “These talks focused on research areas that are not currently represented in our department, so it was great to have this exposure to these new ways of thinking and to hear from these future leaders.”
Cheeseman was also a faculty mentor for Catalyst Fellow Yishan Zhou. Each Catalyst Fellow was paired with a faculty member based on shared scientific interests and matched with those who could provide support and feedback on the fellow’s academic journeys.
Fellows were selected based on nominations from current faculty and their scientific match within the department. They began their time at MIT connecting with their faculty mentors over dinner and then gave presentations about their research the following day. Lively Q&A sessions followed each talk, which formed the basis for further conversations and potential collaborations. The department also organized panels of junior and senior faculty. The fellows heard from junior faculty who recently experienced the job search process, and from senior faculty who were involved in deciding which candidates would be invited for interviews. The aim of both panels was to provide the fellows insights that would help them succeed in their own job searches.
“The Catalyst Symposium has been a great opportunity to bring incredibly talented postdocs from across the country to share their research with our community. Our long-term goal is to promote and support scientists from underrepresented groups in their transition to faculty positions — many of the connections and collaborations that emerge from these three days will hopefully help us realize this goal,” says associate professor of biology and core member of the Whitehead Institute Sebastian Lourido. Lourido was on the organizing committee for the event.
The event also provided an opportunity for current graduate students to interact with the Catalyst Fellows; some were curious about what factors went into the fellows’ selection of a postdoctoral position.
West says that during the course of a PhD, graduate students develop three things: a scientific question or questions; a specific system to address those questions; and specific methodology.
“The advice that I was given was that when you transition from a PhD to a postdoc, you should consider keeping two of those things and changing one,” West says. “It’s very important to start off with strong footing, but changing one thing also gives you the opportunity to grow as a scientist and extend your skill set.”
In his postdoc, West has been studying tumor metastasis and is hoping to dissect the signaling network of a gene whose loss is correlated with aggressive forms of breast cancer. West says that it’s important not to get so caught up in the endgame — the far-off paper or grant proposal — that one stops appreciating the triumph of everyday discoveries.
Quinodoz noted the importance of networking during graduate school, including at scientific conferences. Attending a conference helped her secure her own postdoc position: her current principal investigator heard her give a talk at a conference and invited her for an interview.
The 2022 Catalyst Symposium was planned and coordinated by diversity, equity, and inclusion (DEI) officer Hallie Dowling-Huppert; the DEI Faculty Committee, including organizing committee members Lourido, Jacqueline Lees, and Michael Laub; headquarters staff in the Department of Biology; Koch Institute for Integrative Cancer Research Director Matthew Vander Heiden; and Keating.
In future years, Dowling-Huppert says they will try fostering more of a cohort environment among the fellows, and also give the fellows more time to interact with current postdocs at MIT and others in the department, because building those relationships early in their careers will support them in the short and long terms.
Yadira Soto-Feliciano, an assistant professor of biology and intramural faculty at the Koch Institute who was paired with Reyes, says that building in some time for the fellows to explore MIT and the greater Boston area would be a welcome addition next year since some of the fellows were visiting the city for the first time. She says she’s planning to stay in contact with Reyes in the future.
“I think the Catalyst Symposium was a fantastic platform for these postdoctoral scholars to experience MIT in a more intimate fashion,” she says. “I’m certain that this experience will be beneficial in their short- and long-term success, and I would not be surprised if collaborations arose from these interactions.”
Approach opens the door to a greater understanding of protein-microbe interactions
Lillian Eden | Department of Biology
June 7, 2023
Your mouth is a crucial interface between the outside world and the inside of your body. Everything you breathe, chew or drink interacts with your oral cavity—the proteins and the microbes, including microbes that can harm us. When things go awry, the result can range from the mild, like bad breath, to the serious, like tooth and gum decay to more dire effects in the gut and other parts of the body.
Even though the oral microbiome plays a critical role as a front-line defense for human health and disease, we still know very little about the intricacies of host-microbe interactions in the complex physiological environment of the mouth; a better understanding of those interactions is key to developing treatments for human disease.
In a recent study published in PNAS, a collaborative effort revealed that one of the most abundant proteins found in our saliva binds to the surface of select microbes found in the mouth. The findings shed light on how salivary proteins and mucus play a role in maintaining the oral cavity microbiome.
The collaboration involved members of the Imperiali lab in the Department of Biology and the Kiessling lab in the Department of Chemistry at MIT, as well as the Ruhl group at the University at Buffalo School of Dental Medicine, and the Grimes group at the University of Delaware.
The paper is focused on an abundant oral cavity protein called zymogen granule protein 16 homolog B (ZG16B). Finding ZG16B’s interaction partners and gaining insight into its function were the overarching goals of the project. To accomplish this, Ghosh and colleagues engineered ZG16B to add reporter tags such as fluorophores. They called these modified proteins “microbial glycan analysis probes (mGAPs)” because they allowed them to identify ZG16B binding partners using complementary methods. They applied the probes to samples of healthy oral microbiomes to identify target microbes and binding partners.
The results excited them.
“ZG16B didn’t just bind to random bacteria. It was very focused on certain species including a commensal bacteria called Streptococcus vestibularis,” says first author Soumi Ghosh, a postdoctoral associate in the Imperiali lab.
Commensal bacteria are found in a normal healthy microbiome and do not cause disease.
Using the mGAPs, the team showed that ZG16B binds to cell wall polysaccharides of the bacteria, which indicates that ZG16B is a lectin, a carbohydrate-binding protein. In general, lectins are responsible for cell-cell interactions, signaling pathways, and some innate immune responses against pathogens. “This is the first time that it has been proven experimentally that ZG16B acts as a lectin because it binds to the carbohydrates on the cell surface or cell wall of the bacteria,” Ghosh highlights.
ZG16B was also shown to recruit Mucin 7 (MUC7), a salivary glycoprotein in the oral cavity, and, together the results suggest that ZG16B may help maintain a healthy balance in the oral microbiome by forming a complex with MUC7 and certain bacteria. The results indicate that ZG16B regulates the bacteria’s abundance by preventing overgrowth through agglutination when the bacteria exceed a certain level of growth.
The scale bar shown here represents a 3-micron (µm) length.
“ZG16B, therefore, seems to function as a missing link in the system; it binds to different types of glycans—the microbial glycans and the mucin glycans—and ultimately, maintains a healthy balance in our oral cavity,” Ghosh says.
Further work with this probe and samples of oral microbiome from healthy and diseased subjects could also reveal the lectin’s importance for oral health and disease.
Current attention is focused on developing and applying additional mGAPs based on other human lectins, such as those found in serum, liver, and intestine to reveal their binding specificities and their roles in host-microbe interactions.
“The research carried out in this collaboration exemplifies the kind of synergy that made me excited to move to MIT 5 years ago,” says senior co-author Laura Kiessling. “I’ve been able to work with outstanding scientists who share my interest in the chemistry and the biology of carbohydrates.”
The senior authors of the paper—Barbara Imperiali and Kiessling — came up with the term for the probes they’re creating: “mGAPS to fill in the gaps” in our understanding of the role of lectins in the human microbiome, according to Ghosh.
“If we want to develop therapeutics against bacterial infection, we need a better understanding of host-microbe interactions,” Ghosh says. “The significance of our study is to prove that we can make very good probes for microbial glycans, find out their importance in the frontline defense of the immune system, and, ultimately, come up with a therapeutic approach to disease.”
This research was supported by the National Institute of Health.
Omer Yilmaz’s work on how diet influences intestinal stem cells could lead to new ways to treat or prevent gastrointestinal cancers.
Anne Trafton | MIT News Office
May 25, 2023
Every three to five days, all of the cells lining the human intestine are replaced. That constant replenishment of cells helps the intestinal lining withstand the damage caused by food passing through the digestive tract.
This rapid turnover of cells relies on intestinal stem cells, which give rise to all of the other types of cells found in the intestine. Recent research has shown that those stem cells are heavily influenced by diet, which can help keep them healthy or stimulate them to become cancerous.
“Low-calorie diets such as fasting and caloric restriction can have antiaging effects and antitumor effects, and we want to understand why that is. On the other hand, diets that lead to obesity can promote diseases of aging, such as cancer,” says Omer Yilmaz, the Eisen and Chang Career Development Associate Professor of Biology at MIT.
For the past decade, Yilmaz has been studying how different diets and environmental conditions affect intestinal stem cells, and how those factors can increase the risk of cancer and other diseases. This work could help researchers develop new ways to improve gastrointestinal health, either through dietary interventions or drugs that mimic the beneficial effects of certain diets, he says.
“Our findings have raised the possibility that fasting interventions, or small molecules that mimic the effects of fasting, might have a role in improving intestinal regeneration,” says Yilmaz, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.
A clinical approach
Yilmaz’s interest in disease and medicine arose at an early age. His father practiced internal medicine, and Yilmaz spent a great deal of time at his father’s office after school, or tagging along at the hospital where his father saw patients.
“I was very interested in medicines and how medicines were used to treat diseases,” Yilmaz recalls. “He’d ask me questions, and many times I wouldn’t know the answer, but he would encourage me to figure out the answers to his questions. That really stimulated my interest in biology and in wanting to become a doctor.”
Knowing that he wanted to go into medicine, Yilmaz applied and was accepted to an eight-year, combined bachelor’s and MD program at the University of Michigan. As an undergraduate, this gave him the freedom to explore areas of interest without worrying about applying to medical school. While majoring in biochemistry and physics, he did undergraduate research in the field of protein folding.
During his first year of medical school, Yilmaz realized that he missed doing research, so he decided to apply to the MD/PhD program at the University of Michigan. For his PhD research, he studied blood-forming stem cells and identified new markers that allowed such cells to be more easily isolated from the bone marrow.
“This was important because there’s a lot of interest in understanding what makes a stem cell a stem cell, and how much of it is an internal program versus signals from the microenvironment,” Yilmaz says.
After finishing his PhD and MD, he thought about going straight into research and skipping a medical residency, but ended up doing a residency in pathology at Massachusetts General Hospital. During that time, he decided to switch his research focus from blood-forming stem cells to stem cells found in the gastrointestinal tract.
“The GI tract seemed very interesting because in contrast to the bone marrow, we knew very little about the identity of GI stem cells,” Yilmaz says. “I knew that once GI stem cells were identified, there’d be a lot of interesting questions about how they respond to diet and how they respond to other environmental stimuli.”
Dietary questions
To delve into those questions, Yilmaz did postdoctoral research at the Whitehead Institute, where he began investigating the connections between stem cells, metabolism, diet, and cancer.
Because intestinal stem cells are so long-lived, they are more likely to accumulate genetic mutations that make them susceptible to becoming cancerous. At the Whitehead Institute, Yilmaz began studying how different diets might influence this vulnerability to cancer, a topic that he carried into his lab at MIT when he joined the faculty in 2014.
One question his lab has been exploring is why low-calorie diets often have protective effects, including a boost in longevity — a phenomenon that has been seen in many studies in animals and humans.
In a 2018 study, his lab found that a 24-hour fast dramatically improves stem cells’ ability to regenerate. This effect was seen in both young and aged mice, suggesting that even in old age, fasting or drugs that mimic the effects of fasting could have a beneficial effect.
On the flip side, Yilmaz is also interested in why a high-fat diet appears to promote the development of cancer, especially colorectal cancer. In a 2016 study, he found that when mice consume a high-fat diet, it triggers a significant increase in the number of intestinal stem cells. Also, some non-stem-cell populations begin to resemble stem cells in their behavior. “The upshot of these changes is that both stem cells and non-stem-cells can give rise to tumors in a high-fat diet state,” Yilmaz says.
To help with these studies, Yilmaz’s lab has developed a way to use mouse or human intestinal stem cells to generate miniature intestines or colons in cell culture. These “organoids” can then be exposed to different nutrients in a very controlled setting, allowing researchers to analyze how different diets affect the system.
Recently, his lab adapted the system to allow them to expand their studies to include the role of immune cells, fibroblasts, and other supportive cells found in the microenvironment of stem cells. “It would be remiss of us to focus on just one cell type,” Yilmaz says. “We’re looking at how these different dietary interventions impact the entire stem cell neighborhood.”
While Yilmaz spends most of his time running his lab at MIT, he also devotes six to eight weeks per year to his work at MGH, where he is an associate pathologist focusing on gastrointestinal pathology.
“I enjoy my clinical work, and it always reminds me about the importance of the research we do,” he says. “Seeing colon cancer and other GI cancers under the microscope, and seeing their complexity, reminds me of the importance of our mission to figure out how we can prevent these cancers from forming.”