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Sparse, small, but diverse neural connections help make perception reliable, efficient

First detailed mapping and modeling of thalamus inputs onto visual cortex neurons show brain leverages “wisdom of the crowd” to process sensory information.

David Orenstein | Picower Institute for Learning and Memory
February 2, 2023

The brain’s cerebral cortex produces perception based on the sensory information it’s fed through a region called the thalamus.

“How the thalamus communicates with the cortex in a fundamental feature of how the brain interprets the world,” says Elly Nedivi, the William R. and Linda R. Young Professor in The Picower Institute for Learning and Memory at MIT. Despite the importance of thalamic input to the cortex, neuroscientists have struggled to understand how it works so well given the relative paucity of observed connections, or “synapses,” between the two regions.

To help close this knowledge gap, Nedivi assembled a collaboration within and beyond MIT to apply several innovative methods. In a new study described in Nature Neuroscience, the team reports that thalamic inputs into superficial layers of the cortex are not only rare, but also surprisingly weak, and quite diverse in their distribution patterns. Despite this, they are reliable and efficient representatives of information in the aggregate, and their diversity is what underlies these advantages.

Essentially, by meticulously mapping every thalamic synapse on 15 neurons in layer 2/3 of the visual cortex in mice and then modeling how that input affected each neuron’s processing of visual information, the team found that wide variations in the number and arrangement of thalamic synapses made them differentially sensitive to visual stimulus features. While individual neurons therefore couldn’t reliably interpret all aspects of the stimulus, a small population of them could together reliably and efficiently assemble the overall picture.

“It seems this heterogeneity is not a bug; it’s a feature that provides not only a cost benefit, but also confers flexibility and robustness to perturbation” says Nedivi, corresponding author of the study and a member of MIT’s faculty in the departments of Biology and Brain and Cognitive Sciences.

Aygul Balcioglu, the research scientist in Nedivi’s lab who led the work, adds that the research has created a way for neuroscientists to track all the many individual inputs a cell receives as that input is happening.

“Thousands of information inputs pour into a single brain cell. The brain cell then interprets all that information before it communicates its own response to the next brain cell,” Balcioglu says. “What is new, and we feel exciting, is we can now reliably describe the identity and the characteristics of those inputs, as different inputs and characteristics convey different information to a given brain cell. Our techniques give us the ability to describe in living animals where in the structure of the single cell what kind of information gets incorporated. This was not possible until now.”

“MAP”ping and modeling

Nedivi and Balcioglu’s team chose layer 2/3 of the cortex because this layer is where there is relatively high flexibility, or “plasticity,” even in the adult brain. Yet, thalamic innervation there has rarely been characterized. Moreover, Nedivi says, even though the model organism for the study was mice, those layers are the ones that have thickened the most over the course of evolution, and therefore play especially important roles in the human cortex.

Precisely mapping all the thalamic innervation onto entire neurons in living, perceiving mice is so daunting it’s never been done.

To get started, the team used a technique established in Nedivi’s lab that enables observing whole cortical neurons under a two-photon microscope using three different color tags in the same cell simultaneously, except in this case they used one of the colors to label thalamic inputs contacting the labeled cortical neurons. Wherever the color of those thalamic inputs overlapped with the color labeling excitatory synapses on the cortical neurons, that revealed the location of putative thalamic inputs onto the cortical neurons.

Two-photon microscopes offer deep looks into living tissues, but their resolution is not sufficient to confirm that the overlapping labels are indeed synaptic contacts. To confirm their first indications of thalamic inputs, the team turned to a technique called MAP invented in the Picower Institute lab of MIT chemical engineering Associate Professor Kwanghun Chung. MAP physically enlarges tissue in the lab, effectively increasing the resolution of standard microscopes. Rebecca Gillani, a postdoc in the Nedivi lab, with help from Taeyun Ku, a Chung Lab postdoc, was able to combine the new labeling and MAP to definitely resolve, count, map, and even measure the size of all thalamic-cortical synapses onto entire neurons.

The analysis revealed that the thalamic inputs were rather small (typically presumed to also be weak and maybe temporary), and accounted for between 2 and 10 percent of the excitatory synapses on individual visual cortex neurons. The variance in thalamic synapse numbers was not just at a cellular level, but also across different “dendrite” branches of individual cells, accounting for anywhere between zero and nearly half the synapses on a given branch.

“Wisdom of the crowd”

These facts presented Nedivi’s team with a conundrum. If the thalamic inputs were weak, sparse, and widely varying, not only across neurons but even across each neuron’s dendrites, then how good could they be for reliable information transfer?

To help solve the riddle, Nedivi turned to colleague Idan Segev, a professor at Hebrew University in Jerusalem specializing in computational neuroscience. Segev and his student Michael Doron used the Nedivi lab’s detailed anatomical measurements and physiological information from the Allen Brain Atlas to create a biophysically faithful model of the cortical neurons.

Segev’s model showed that when the cells were fed visual information (the simulated signals of watching a grating go past the eyes) their electrical responses varied based on how their thalamic input varied. Some cells perked up more than others in response to different aspects of the visual information, such as contrast or shape, but no single cell revealed much about the overall picture. But with about 20 cells together, the whole visual input could be decoded from their combined activity — a so-called “wisdom of the crowd.”

Notably, Segev compared the performance of cells with the weak, sparse, and varying input akin to what Nedivi’s lab measured, to the performance of a group of cells that all acted like the best single cell of the lot. Up to about 5,000 total synapses, the “best” cell group delivered more informative results, but after that level the small, weak, and diverse group actually performed better. In the race to represent the total visual input with at least 90 percent accuracy, the small, weak, and diverse group reached that level with about 6,700 synapses, while the “best” cell group needed more than 7,900.

“Thus heterogeneity imparts a cost reduction in terms of the number of synapses required for accurate readout of visual features,” the authors wrote.

Nedivi says the study raises tantalizing implications regarding how thalamic input into the cortex works. One, she says, is that given the small size of thalamic synapses they are likely to exhibit significant “plasticity.” Another is that the surprising benefit of diversity may be a general feature, not just a special case for visual input in layer 2/ 3. Further studies, however, are needed to know for sure.

In addition to Nedivi, Balcioglu, Gillani, Ku, Chung, Segev and Doron, other authors are Kendyll Burnell and Alev Erisir.

The National Eye Institute of the National Institutes of Health, the Office of Naval Research, and the JPB Foundation funded the study.

New instrument lets MIT researchers combine previously disparate microscopy techniques

The first Live μ in the country will reveal fleeting sub-cellular events in high resolution

Saima Sidik
February 1, 2023

Inside cells, events can unfold quickly. Sub-cellular compartments constantly re-arrange while proteins move along structural fibers and membranes fuse and divide. By attaching fluorescent tags to sub-cellular structures, researchers can watch events unfold in real time using light microscopes. But to see the finest details of these processes, scientists need to shift from using light microscopy to using beams of electrons to generate even higher resolution images using a technique called electron microscopy. Using these techniques together is a powerful and rapidly growing strategy called correlative light electron microscopy (CLEM). In CLEM, light microscopy images are used to target regions of interest, and then the same sample is interrogated with electron microscopy to see the same areas at higher resolution.

The Peterson (1957) Nanotechnology Materials Core Facility in the Robert A. Swanson (1969) Biotechnology Center at the Koch Institute for Integrative Cancer Research at MIT recently acquired a high pressure freezer called the Live μ that will let researchers do just that. This instrument allows scientists to image the same biological sample using fluorescent light microscopy and electron microscopy in close succession. These two techniques are usually performed on separate samples, but with the Live μ, researchers will be able to identify fleeting sub-cellular events using light microscopy, then preserve cells and observe the same events in high resolution using electron microscopy — a combination that was not previously available to researchers at MIT. In fact, the Live μ, which is sold by the Paris-based company CryoCapCell, will be the first instrument of its kind in the country.

Although high-pressure freezers like the Live μ have been around for decades, integration with a light microscope is what makes the Live μ special. The instrument itself is a washing machine-sized freezing instrument, equipped with an arm to hold a biological sample under a nearby light microscope. When researchers observe an interesting biological event using the light microscope, they can quickly retract the arm and insert the sample into the Live μ’s inner chamber, exposing it to low temperature and high pressure and freezing it in less than two seconds. Cells must be preserved before they can be observed using an electron microscope, and by freezing samples faster than ice crystals can form, the Live μ creates pristine samples that accurately represent the state of cells before preservation. Superimposing pictures taken using the light microscope on top of images from an electron microscope allows researchers to use the fluorescent signals like a “treasure map,” says Abigail Lytton-Jean, the director of the Peterson Facility.

Exocytosis is a vital sub-cellular event that could be studied using the Live μ. In this cellular process, cells use bubble-like vesicles to ferry proteins from the internal compartments where they’re made to the cell’s surface, where they can sense the external environment, attach cells to one another, or carry information to other cells. Exocytosis is important for many aspects of biology, and a variety of scientists, from ecologists to cancer researchers to microbiologists, would benefit from a greater understanding of this process. With the Live μ, researchers may be able to use light microscopy to catch the vesicles that mediate exocytosis when they dock with the cell’s surface, then use electron microscopy to understand the details of this association.

Researchers creating artificial materials to replace human tissues could also benefit from the Live μ, Lytton-Jean says. These materials are thick and contain a lot of water, but the Live μ is capable of freezing them without generating ice crystals that change their structure. Using this instrument, scientists can examine the internal structure of these synthetic materials and assess their similarities to live tissue.

“People who want to use the Live μ are coming from all sorts of labs,” Lytton-Jean says.

The world of biology and electron microscopy is wildly exciting right now, she adds, thanks in part to instruments like this. “People who have worked with electron microscopes for decades have told me that this is the most exciting time they’ve ever lived in.”

The Live μ recently took its place in the back of the Peterson Facility, under a picture of the Eiffel Tower that Lytton-Jean brought back from Paris when she first went to test the Live μ at CryoCapCell’s headquarters years ago. The Live μ is only the latest addition to a vast suite of instrumentation focused on cutting-edge cryo-electron microscopy and CLEM workflows, expanding the facility’s unusually large portfolio of workflows.

“There aren’t many places in the country that can do all of the different workflows we offer, and all in one place,” said Lytton-Jean. “High pressure freezing is the first step in the preservation process, so having this instrument in our lab will further enable many new workflows with our existing instrumentation. Although these workflows are challenging and sophisticated, our team of dedicated scientists are familiar with conducting this work.”

Paying it forward

When she’s not analyzing data about her favorite biomolecule, senior Sherry Nyeo focuses on improving the undergraduate experience at MIT.

Phie Jacobs | School of Science
January 31, 2023

Since arriving at MIT in fall 2019, senior Sherry Nyeo has conducted groundbreaking work in multiple labs on campus, acted as a mentor to countless other students, and made a lasting mark on the Institute community. But despite her well-earned bragging rights, Nyeo isn’t one to boast. Instead, she takes every opportunity to express just how grateful she is to the professors, alumni, and fellow students who have helped and inspired her during her time at MIT. “I like helping people if I can,” says Nyeo, who is majoring in computer science and molecular biology, “because I got helped so much.”

Nyeo’s passion for science began when she applied for the Selective Science Program at Tainan First Senior High School, widely considered one of the most prestigious high schools in Taiwan. “Preparing for that process made me realize that biology was pretty cool,” she recalls.

When Nyeo was 16, her family moved from Taiwan to Colorado, where she continued to cultivate her interest in STEM. Although she excelled at biology, she initially struggled to master computer science. “[Programming] was really hard for me,” she says. “It was a completely different way of thinking.” When she arrived at MIT, she decided to pursue a degree in computer science precisely because she knew she would find it challenging and because she appreciates how vital data analysis is to the field of biology. After all, she says, when you’re working at the scale of cells and molecules, “you need a lot of data to describe what’s going on.”

In the winter of her first year at MIT, Nyeo began doing hands-on research in laboratories on campus through the Undergraduate Research Opportunities Program (UROP). Her work in the lab of Whitehead Fellow Silvi Rouskin sparked an enduring interest in RNA, which she has come to regard as her “favorite biomolecule.”

Nyeo’s work in the Rouskin lab focused on alternative RNA structures and the roles they play in human and viral biology. While DNA mostly exists as a double helix, RNA can fold itself into a huge variety of structures in order to fulfill different functions. During her time as a student researcher, Nyeo has demonstrated a similar ability to adapt to different circumstances. When MIT campus members evacuated due to the Covid-19 pandemic in March 2020, and her UROP became entirely remote, she treated her time away from the lab as an opportunity to explore the computational side of research. Her work was subsequently included in a Nature Communications paper on the SARS-CoV-2 genome, on which she is listed as a co-author.

Since returning to campus, Nyeo has often worked in multiple labs simultaneously, conducting innovative research while also juggling classes, internships, and several demanding extracurriculars. Through it all, she has continued to pursue her fascination with RNA, a tiny, somewhat unassuming molecule that nonetheless has a massive impact on practically every aspect of our biology. Nyeo, who has shown herself to be equally multifaceted, seems especially well-suited to the study of this remarkable biomolecule.

Although Nyeo’s work in the life sciences keeps her busy, she finds time to nurture a diverse set of other passions. She took a class on experimental ethics, is working on an original screenplay, and has even picked up a minor in German. Since her sophomore year, she has also been a part of the New Engineering Education Transformation (NEET) program, which provides students with multidisciplinary interests the opportunity to collaborate across departments. Through NEET, currently directed by professor of biological engineering Mark Bathe, Nyeo has been able to pursue her interest in bioengineering research and connect to a vast community of students and professors. Most recently, she has been working within the Bathe BioNano Lab to use DNA to engineer new materials at the nanometer scale.

Nyeo hopes to put her skills to use by pursuing a career in biotechnology. She is currently minoring in management and dreams of one day starting her own company. But she doesn’t want to leave academia behind just yet and has begun working on applications for PhD programs in biology. “I originally came in thinking that I would just go straight into the biotech industry,” Nyeo explains. “And then I realized that I don’t dislike research and that I actually enjoy it.”

As part of her current work in the lab of professor of biology David Bartel, Nyeo investigates how viral infection affects RNA metabolism, and she often finds herself using her computational skills to help postdocs with their data analysis. In fact, one of the things Nyeo has most enjoyed about working as a student researcher is the opportunity to join a network of people who provide one another with support and guidance.

Nyeo’s willingness to help others is perhaps the aspect of her personality that best suits her to the study of RNA. Over the past few decades, researchers have discovered an increasingly large number of therapeutic uses for RNA, including cancer immunotherapy and vaccine development. In the summer of 2022, Nyeo worked as an intern at Eli Lilly and Company, where she helped identify potential targets for RNA therapeutics. She may continue to explore this area of research when she eventually enters the biotech industry. In the meantime, however, she’s finding ways to help people closer to home.

Since her first year, Nyeo has been a part of the MIT Biotech Group. When she first joined, the group had a fairly small undergraduate presence, and most events were geared toward graduate students and postdocs. Nyeo immediately dedicated herself to making the group more welcoming for undergraduates. As the director of the Undergraduate Initiative and later the undergraduate student president, she was a leading architect of a new seminar series in which MIT alumni came to campus to teach undergraduates about biotechnology. “There are a lot of technical terms associated with [biotech],” Nyeo explains. “If you just come in as an undergrad, not knowing what’s happening, that can be a bit daunting.”

Between her research in the Bartel lab and her work with NEET and the MIT Biotech Group, Nyeo doesn’t have a lot of free time, but she dedicates most of it to making MIT a friendlier environment for new students. She promotes research opportunities as a UROP panelist and has worked as an associate advisor since her junior year. She helps first-year students choose and register for classes, works with faculty advisors, and provides moral support to students who are feeling overwhelmed with options. “When I came [to MIT], I also didn’t know what I wanted to do,” Nyeo explains. “Upperclassmen helped me a lot with that process, and I want to pay it forward.”

Compassion in the details

The late MIT Professor Angelika Amon was recognized as Committed to Caring for her generous and encompassing mentorship.

Daniel Korsun | Office of Graduate Education
January 17, 2023

The late MIT Professor Angelika Amon, renowned for her groundbreaking contributions to our understanding of how chromosomes are regulated and partitioned during cell division, was also beloved among the MIT community for her kind and supportive mentorship of students.

An engaged and valued member of the MIT community, Amon passed away in late 2020 after a difficult battle with ovarian cancer. She was the Kathleen and Curtis Marble Professor in Cancer Research within the Department of Biology at MIT, the associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT, a member of the Ludwig Center for Molecular Oncology at MIT, and a member of the Koch Institute for Integrative Cancer Research. Amon’s research focused on understanding the biological impacts of cell aneuploidy, or the presence of too many chromosomes, in both healthy and cancerous cells. Her research also touched upon the relationships between cell size, cell growth, and age.

Care and consideration

Amon’s nominators describe in detail how she placed a large emphasis on her students’ lives outside the classroom. She recognized that in order to be a productive scientist, it is important to prioritize self-care; one student wrote that Amon emphasized how important it was “to take care of [your] own mental health first, because as she put it, ‘the best data was produced by happy scientists.’”

However, Amon’s concern for her students’ well-being went far beyond her desire for them to be productive members of academia. Her nomination letters are filled with anecdotes demonstrating how much she truly cared about her students as colleagues and friends.

One nominator summed Amon up thusly: “At her core, Angelika was a tremendously generous human being, and she never displayed it more than in caring for her students.” She “opened her home” to celebrate the achievements of her mentees, welcomed students into her home for the holidays, and offered to take care of pets when some of her group members had to leave the country temporarily due to visa issues.

These touching acts demonstrate, without a doubt, that Amon’s care and consideration for her students knew no bounds. No matter the circumstances, “as her student, you knew that you were valued and cared for, and that she would be your safety net even when you were struggling.”

A dynamic mentorship style

In addition to making sure her students were cared for and healthy, Amon also recognized that her relationship with each student was not static, but instead needed to evolve and adjust depending on the current circumstances.

As one nominator wrote, “one of Angelika’s most impressive qualities was her ability to adjust her mentoring to what I needed at the time.” When meeting with her students one-on-one, Amon had a keen eye for identifying what they needed most; she could instinctively tell when it was appropriate to push them to complete an experiment, encourage them to change direction, or even to take a step back and take time for themselves.

This intuition was possible because of the unique, personal relationship she developed with each of her students. Amon was meticulous about understanding and keeping track of each student’s interests and goals, and made sure to provide each student with useful opportunities tailored to those goals. One nominator described how Amon “used all of her personal and professional connections (and made many new ones!) to ensure that her students ended up where they wanted to be.”

Even after she was diagnosed with ovarian cancer, Amon made it a priority to ensure the success and happiness of her students. She wrote out extensive plans for each of her students to use in the event of her passing, and she made sure to routinely check in with her students about their research and personal lives.

A brilliant scientist and a caring mentor, Amon never missed an opportunity to check in with her students and ensure their happiness, well-being, and success. MIT Professor Li-Huei Tsai, a collaborator of Amon’s, describes Amon as being “a champion for her female colleagues, fellow researchers, and students. She was very supportive in so many ways, but what struck me in particular was that she kept an eye out for those who might not be doing so well and would work to provide the help they needed.”

Amon’s students and the entire MIT community will miss her unrelenting enthusiasm and her kind, caring ways.

Daniel Lew

Education

  • Graduate: PhD, 1990, Rockefeller University
  • Undergraduate: BA, 1984, Genetics, Cambridge University

Research Summary

Different cells take on an astonishing variety of shapes, which are often critical to be able to perform specialized cell functions like absorbing nutrients or contracting muscles. We study how different cell shapes arise and how cells control the spatial distribution of their internal constituents. We take advantage of the tractability of fungal model systems, and address these questions using approaches from cell biology, genetics, and computational biology to understand molecular mechanisms. 

Honors and Awards

  • Fellow, American Academy of Microbiology, 2008
  • Fellow, American Association for the Advancement of Science, 2010
  • Duke Equity, Diversity, and Inclusion Award, 2019
Enzyme “atlas” helps researchers decipher cellular pathways

Biologists have mapped out more than 300 protein kinases and their targets, which they hope could yield new leads for cancer drugs.

Anne Trafton | MIT News Office
January 11, 2023

One of the most important classes of human enzymes are protein kinases — signaling molecules that regulate nearly all cellular activities, including growth, cell division, and metabolism. Dysfunction in these cellular pathways can lead to a variety of diseases, particularly cancer.

Identifying the protein kinases involved in cellular dysfunction and cancer development could yield many new drug targets, but for the vast majority of these kinases, scientists don’t have a clear picture of which cellular pathways they are involved in, or what their substrates are.

“We have a lot of sequencing data for cancer genomes, but what we’re missing is the large-scale study of signaling pathway and protein kinase activation states in cancer. If we had that information, we would have a much better idea of how to drug particular tumors,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

Yaffe and other researchers have now created a comprehensive atlas of more than 300 of the protein kinases found in human cells, and identified which proteins they likely target and control. This information could help scientists decipher many cellular signaling pathways, and help them to discover what happens to those pathways when cells become cancerous or are treated with specific drugs.

Lewis Cantley, a professor of cell biology at Harvard Medical School and Dana Farber Cancer Institute, and Benjamin Turk, an associate professor of pharmacology at Yale School of Medicine, are also senior authors of the paper, which appears today in Nature. The paper’s lead authors are Jared Johnson, an instructor in pharmacology at Weill Cornell Medical College, and Tomer Yaron, a graduate student at Weill Cornell Medical College.

“A Rosetta stone”

The human genome includes more than 500 protein kinases, which activate or deactivate other proteins by tagging them with a chemical modification known as a phosphate group. For most of these kinases, the proteins they target are unknown, although research into kinases such as MEK and RAF, which are both involved in cellular pathways that control growth, has led to new cancer drugs that inhibit those kinases.

To identify additional pathways that are dysregulated in cancer cells, researchers rely on phosphoproteomics using mass spectrometry — a technique that separates molecules based on their mass and charge — to discover proteins that are more highly phosphorylated in cancer cells or healthy cells. However, until now, there has been no easy way to interrogate the mass spectrometry data to determine which protein kinases are responsible for phosphorylating those proteins. Because of that, it has remained unknown how those proteins are regulated or misregulated in disease.

“For most of the phosphopeptides that are measured, we don’t know where they fit in a signaling pathway. We don’t have a Rosetta stone that you could use to look at these peptides and say, this is the pathway that the data is telling us about,” Yaffe says. “The reason for this is that for most protein kinases, we don’t know what their substrates are.”

Twenty-five years ago, while a postdoc in Cantley’s lab, Yaffe began studying the role of protein kinases in signaling pathways. Turk joined the lab shortly after, and the three have since spent decades studying these enzymes in their own research groups.

“This is a collaboration that began when Ben and I were in Lew’s lab 25 years ago, and now it’s all finally really coming together, driven in large part by what the lead authors, Jared and Tomer, did,” Yaffe says.

In this study, the researchers analyzed two classes of kinases — serine kinases and threonine kinases, which make up about 85 percent of the protein kinases in the human body — based on what type of structural motif they put phosphate groups onto.

Working with a library of peptides that Cantley and Turk had previously created to search for motifs that kinases interact with, the researchers measured how the peptides interacted with all 303 of the known serine and threonine kinases. Using a computational model to analyze the interactions they observed, the researchers were able to identify the kinases capable of phosphorylating every one of the 90,000 known phosphorylation sites that have been reported in human cells, for those two classes of kinases.

To their surprise, the researchers found that many kinases with very different amino acid sequences have evolved to bind and phosphorylate the same motifs on their substrates. They also showed that about half of the kinases they studied target one of three major classes of motifs, while the remaining half are specific to one of about a dozen smaller classes.

Decoding networks

This new kinase atlas can help researchers identify signaling pathways that differ between normal and cancerous cells, or between treated and untreated cancer cells, Yaffe says.

“This atlas of kinase motifs now lets us decode signaling networks,” he says. “We can look at all those phosphorylated peptides, and we can map them back onto a specific kinase.”

To demonstrate this approach, the researchers analyzed cells treated with an anticancer drug that inhibits a kinase called Plk1, which regulates cell division. When they analyzed the expression of phosphorylated proteins, they found that many of those affected were controlled by Plk1, as they expected. To their surprise, they also discovered that this treatment increased the activity of two kinases that are involved in the cellular response to DNA damage.

Yaffe’s lab is now interested in using this atlas to try to find other dysfunctional signaling pathways that drive cancer development, particularly in certain types of cancer for which no genetic drivers have been found.

“We can now use phosphoproteomics to say, maybe in this patient’s tumor, these pathways are upregulated or these pathways are downregulated,” he says. “It’s likely to identify signaling pathways that drive cancer in conditions where it isn’t obvious what the genetics that drives the cancer are.”

The research was funded by the Leukemia and Lymphoma Society, the National Institutes of Health, Cancer Research UK, the Brain Tumour Charity, the Charles and Marjorie Holloway foundation, the MIT Center for Precision Cancer Medicine, and the Koch Institute Support (core) grant from the National Cancer Institute.

The molecules behind metastasis
Greta Friar | Whitehead Institute
January 4, 2023

Many cancer cells never leave their original tumors. Some cancer cells evolve the ability to migrate to other tissues, but once there cannot manage to form new tumors, and so remain dormant. The deadliest cancer cells are those that can not only migrate to, but also thrive and multiply in distant tissues. These metastatic cancer cells are responsible for most of the deaths associated with cancer. Understanding what enables some cancer cells to metastasize—to spread and form new tumors—is an important goal for researchers, as it will help them develop therapies to prevent or reverse those deadly occurrences.

Past research from Whitehead Institute Member Robert Weinberg and others suggests that cancer cells are best able to form metastatic tumors when the cells are in a particular state called the quasi-mesenchymal (qM) state. New research from Weinberg and Arthur Lambert, once a postdoc in Weinberg’s lab and now an associate director of translational medicine at AstraZeneca, has identified two gene-regulating molecules as important for keeping cancer cells in the qM state. The research, published in the journal Developmental Cell on December 19, shows that these molecules, ΔNp63 and p73, enable breast cancer cells to form new tumors in mice, and illuminates important aspects of how they do so.

Most potent in the middle

Cells enter the qM state by undergoing the epithelial-mesenchymal transition (EMT), a developmental process that can be co-opted by cancer cells. In the EMT, cells transition from an epithelial state through a spectrum of more mesenchymal states, which allows them to become more mobile and aggressive. Cells in the qM state have only transitioned partway through the EMT, becoming more, but not fully, mesenchymal. This middle ground is perfect for metastasis, whereas cells on either end of the spectrum—cells that are excessively epithelial or excessively mesenchymal—lose their metastatic abilities.

Lambert and colleagues wanted to understand more about how cancer stem cells, which can seed metastases and recurrent tumors, remain in a metastasis-prone qM state. They analyzed how gene activity was regulated in those cells and identified two transcription factors—molecules that influence the activity of target genes—as important. One of the transcription factors, ΔNp63, appeared to most directly control cancer stem cells’ ability to maintain a qM state. The other molecule, p73, seemed to have a similar role because it can activate ΔNp63. When either transcription factor was inactivated, the cancer stem cells transitioned to the far end of the EMT spectrum and so were unable to metastasize.

Next, the researchers looked at what genes ΔNp63 regulates in cancer stem cells. They expected to find a pattern of gene regulation resembling what they would see in healthy breast stem cells. Instead they found a pattern closely resembling what one would see in cells involved in wound healing and regeneration. Notably, ΔNp63 stimulates EGFR signaling, which is used in wound healing to promote rapid multiplication of cells.

“Although this is not what we expected to see, it makes a lot of sense because the process of metastasis requires active proliferation,” Lambert says. “Metastatic cancer cells need both the properties of stem cells—such as the ability to self-renew and differentiate into different cell types—and the ability to multiply their numbers to grow new tumors.”

This finding may help to explain why qM cells are so uniquely good at metastasizing. Only in the qM state can the cells strongly stimulate EGFR signaling and so promote their own proliferation.

“This work gives us some mechanistic understanding of what it is about the quasi-mesenchymal state that drives metastatic tumor growth,” says Weinberg, who is also the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology.

The researchers hope that these insights could eventually contribute to therapies that prevent metastasis. They also hope to pursue further research into the role of ΔNp63. For example, this work illuminated a possible connection between ΔNp63 and the activation of dormant cancer cells, the cells that travel to new tissues but then cannot proliferate after they arrive there. Such dormant cells are viewed as ticking time bombs, as at any point they may reawaken. Lambert hopes that further research may reveal new insights into what causes dormant cancer cells to eventually gain the ability to grow tumors, adding to our understanding of the mechanisms of metastatic cancer.

Notes

Arthur W. Lambert, Christopher Fiore, Yogesh Chutake, Elisha R. Verhaar, Patrick C. Strasser, Mei Wei Chen, Daneyal Farouq, Sunny Das, Xin Li, Elinor Ng Eaton, Yun Zhang, Joana Liu Donaher, Ian Engstrom, Ferenc Reinhardt, Bingbing Yuan, Sumeet Gupta, Bruce Wollison, Matthew Eaton, Brian Bierie, John Carulli, Eric R. Olson, Matthew G. Guenther, Robert A. Weinberg. “ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.” Developmental Cell, Volume 57, Issue 24,
2022, 2714-2730.e8, https://doi.org/10.1016/j.devcel.2022.11.015.

Portraiture at the intersection of art, science, and society

Exhibit at MIT's Koch Institute attempts to make visible the luminary personalities behind major scientific and engineering advances.

Koch Institute
January 5, 2023

“For me, this project is about making science visible in society,” says Herlinde Koelbl, a renowned German photo artist whose portrait series, “Fascination of Science,” is now on display at MIT.

Koelbl set herself the goal to photograph scientists and to show their motivation, influences, and ways of thinking — through the eyes of an artist. The portraits juxtapose the subjects’ faces with scientific concepts, advice, or reflections playfully inscribed on their palms. Individually, each picture or phrase speaks to the researcher’s personal quest for knowledge — everything from nucleotide base pairings and “learn from failures!” to “make malaria history!” and a sailing vessel beset by sea creatures — but collectively, the broad sweep of disciplines and backgrounds represented in the portraits reveals the interconnectedness of the scientific endeavor across institutions, geography, and subject matter.

The MIT venue for Koelbl’s work is the Public Galleries of the Koch Institute for Integrative Cancer Research, a research center that combines MIT’s rich traditions of interdisciplinary inquiry and technological innovation with discovery-based biological research to develop new insights, tools, and technologies to fight cancer.

Through Koelbl’s lens, MIT’s “mind and hand” motto is made visible, along with the diversity of ideas that fuel society’s collective fascination with science. The exhibit includes portraits of MIT scientists Sangeeta Bhatia, Ed Boyden, Sallie “Penny” Chisholm, Wolfgang Ketterle, Robert Langer, and Robert Weinberg, along with other internationally acclaimed scientists such as George Church, Jennifer Doudna, Emmanuelle Charpentier, and 2022 Nobel laureate Carolyn Bertozzi.

Visitors are welcome to view Koelbl’s work at the Koch Institute’s Public Galleries (open to the public on weekdays 8 a.m. – 6 p.m.) through Jan. 27.

Scientists discover a new way of sharing genetic information in a common ocean microbe

Prochlorococcus, the world’s most abundant photosynthetic organism, reveals a gene-transfer mechanism that may be key to its abundance and diversity.

David L. Chandler | MIT News Office
January 5, 2023

From the tropics to the poles, from the sea surface to hundreds of feet below, the world’s oceans are teeming with one of the tiniest of organisms: a type of bacteria called Prochlorococcus, which despite their minute size are collectively responsible for a sizable portion of the oceans’ oxygen production. But the remarkable ability of these diminutive organisms to diversify and adapt to such profoundly different environments has remained something of a mystery.

Now, new research reveals that these tiny bacteria exchange genetic information with one another, even when widely separated, by a previously undocumented mechanism. This enables them to transmit whole blocks of genes, such as those conferring the ability to metabolize a particular kind of nutrient or to defend themselves from viruses, even in regions where their population in the water is relatively sparse.

The findings describe a new class of genetic agents involved in horizontal gene transfer, in which genetic information is passed directly between organisms — whether of the same or different species — through means other than lineal descent. The researchers have dubbed the agents that carry out this transfer “tycheposons,” which are sequences of DNA that can include several entire genes as well as surrounding sequences, and can spontaneously separate out from the surrounding DNA. Then, they can be transported to other organisms by one or another possible carrier system including tiny bubbles known as vesicles that cells can produce from their own membranes.

The research, which included studying hundreds of Prochlorococcus genomes from different ecosystems around the world, as well as lab-grown samples of different variants, and even evolutionary processes carried out and observed in the lab, is reported today in the journal Cell, in a paper by former MIT postdocs Thomas Hackl and Raphaël Laurenceau, visiting postdoc Markus Ankenbrand, Institute Professor Sallie “Penny” Chisholm, and 16 others at MIT and other institutions.

Chisholm, who played a role in the discovery of these ubiquitous organisms in 1988, says of the new findings, “We’re very excited about it because it’s a new horizontal gene-transfer agent for bacteria, and it explains a lot of the patterns that we see in Prochlorococcus in the wild, the incredible diversity.” Now thought to be the world’s most abundant photosynthetic organism, the tiny variants of what are known as cyanobacteria are also the smallest of all photosynthesizers.

Hackl, who is now at the University of Groningen in the Netherlands, says the work began by studying the 623 reported genome sequences of different species of Prochlorococcus from different regions, trying to figure out how they were able to so readily lose or gain particular functions despite their apparent lack of any of the known systems that promote/boost horizontal gene transfer, such as plasmids or viruses known as prophages.

What Hackl, Laurenceau, and Ankenbrand investigated were “islands” of genetic material that seemed to be hotspots of variability and often contained genes that were associated with known key survival processes such as the ability to    assimilate essential, and often limiting, nutrients such as iron, or nitrogen, or phosphates. These islands contained genes that varied enormously between different species, but they always occurred in the same parts of the genome and sometimes were nearly identical even in widely different species — a strong indicator of horizontal transfer.

But the genomes showed none of the usual features associated with what are known as mobile genetic elements, so initially this remained a puzzle. It gradually became apparent that this system of gene transfer and diversification was different from any of the several other mechanisms that have been observed in other organisms, including in humans.

Hackl describes what they found as being something like a genetic LEGO set, with chunks of DNA bundled together in ways that could almost instantly confer the ability to adapt to a particular environment. For example, a species limited by the availability of particular nutrients could acquire genes necessary to enhance the uptake of that nutrient.

The microbes appear to use a variety of mechanisms to transport these tycheposons (a name derived from the name of the Greek goddess Tyche, daughter of Oceanus). One is the use of membrane vesicles, little bubbles pouched off from the surface of a bacterial cell and released with tycheposons inside it. Another is by “hijacking” virus or phage infections and allowing them to carry the tycheposons along with their own infectious particles, called capsids. These are efficient solutions, Hackl says, “because in the open ocean, these cells rarely have cell-to-cell contacts, so it’s difficult for them to exchange genetic information without a vehicle.”

And sure enough, when capsids or vesicles collected from the open ocean were studied, “they’re actually quite enriched” in these genetic elements, Hackl says. The packets of useful genetic coding are “actually swimming around in these extracellular particles and potentially being able to be taken up by other cells.”

Chisholm says that “in the world of genomics, there’s a lot of different types of these elements” — sequences of DNA that are capable of being transferred from one genome to another. However, “this is a new type,” she says. Hackl adds that “it’s a distinct family of mobile genetic elements. It has similarities to others, but no really tight connections to any of them.”

While this study was specific to Prochlorococcus, Hackl says the team believes the phenomenon may be more generalized. They have already found similar genetic elements in other, unrelated marine bacteria, but have not yet analyzed these samples in detail. “Analogous elements have been described in other bacteria, and we now think that they may function similarly,” he says.

“It’s kind of a plug-and-play mechanism, where you can have pieces that you can play around with and make all these different combinations,” he says. “And with the enormous population size of Prochlorococcus, it can play around a lot, and try a lot of different combinations.”

Nathan Ahlgren, an assistant professor of biology at Clark University who was not associated with this research, says “The discovery of tycheposons is important and exciting because it provides a new mechanistic understanding of how Prochlorococcus are able to swap in and out new genes, and thus ecologically important traits. Tycheposons provide a new mechanistic explanation for how it’s done.” He says “they took a creative way to fish out and characterize these new genetic elements ‘hiding’ in the genomes of Prochlorococcus.”

He adds that genomic islands, the portions of the genome where these tycheposons were found, “are found in many bacteria, not just marine bacteria, so future work on tycheposons has wider implications for our understanding of the evolution of bacterial genomes.”

The team included researchers at MIT’s Department of Civil and Environmental Engineering, the University of Wuerzburg in Germany, the University of Hawaii at Manoa, Ohio State University, Oxford Nanopore Technologies in California, Bigelow Laboratory for Ocean Sciences in Maine, and Wellesley College. The work was supported by the Simons Foundation, the Gordon and Betty Moore Foundation, the U.S. Department of Energy, and the U.S. National Science Foundation.

Uncovering how cells control their protein output

Gene-Wei Li investigates the rules that cells use to maintain the correct ratio of the proteins they need to survive.

Anne Trafton | MIT News Office
January 4, 2023

A typical bacterial genome contains more than 4,000 genes, which encode all of the proteins that the cells need to survive. How do cells know just how much of each protein they need for their everyday functions?

Gene-Wei Li, an MIT associate professor of biology, is trying to answer that question. A physicist by training, he uses genome-wide measurements and biophysical modeling to quantify cells’ protein production and discover how cells achieve such precise control of those quantities.

Using those techniques, Li has found that cells appear to strictly control the ratios of proteins that they produce, and that these ratios are consistent across cell types and across species.

“Coming from a physics background, it’s surprising to me that these cells have evolved to be really precise in making the right amount of their proteins,” Li says. “That observation was enabled by the fact that we are able to design measurements with a precision that matches what is actually happening in biology.”

From physics to biology

Li’s parents — his father, a marine biologist who teaches at a university in Taiwan, and his mother, a plant biologist who now runs a science camp for high school students — passed their affinity for science on to Li, who was born in San Diego while his parents were graduate students there.

The family returned to Taiwan when Li was 2 years old, and Li soon became interested in math and physics. In Taiwan, students choose their college major while still in high school, so he decided to study physics at National Tsinghua University.

While in college, Li was drawn to optical physics and spectroscopy. He went to Harvard University for graduate school, where after his first year, he started working in a lab that works on single-molecule imaging of biological systems.

“I realized there are a lot of really exciting fields at the boundary between disciplines. It’s something that we didn’t have in Taiwan, where the departments are very strict that physics is physics, and biology is biology,” Li says. “Biology is a lot messier than physics, and I had some hesitancy, but I was happy to see that biology does have rules that you can observe.”

For his PhD research, Li used single-molecule imaging to study proteins called transcription factors — specifically, how quickly they can bind to DNA and initiate the copying of DNA into RNA. Though he had never taken a class in biology, he began to learn more about it and decided to do a postdoc at the University of California at San Francisco, where he worked in the lab of Jonathan Weissman, a professor of cellular and molecular pharmacology.

Weissman, who is now a professor of biology at MIT, also trained as a physicist before turning to biology. In Weissman’s lab, Li developed techniques for studying gene expression in bacterial cells, using high-throughput DNA sequencing. In 2015, Li joined the faculty at MIT, where his lab began to work on tools that could be used to measure gene expression in cells.

When genes are expressed in cells, the DNA is first copied into RNA, which carries the genetic instructions to ribosomes, where proteins are assembled. Li’s lab has developed ways to measure protein synthesis rates in cells, along with the amount of RNA that is transcribed from different genes. Together, these tools can yield precise measurements of how much a particular gene is expressed in a given cell.

“We had the qualitative tools before, but now we can really have quantitative information and learn how much protein is made and how important those protein levels are to the cell,” Li says.

Precise control

Using these tools, Li and his students have discovered that different species of bacteria can have different strategies for making proteins. In E. coli, transcription of DNA and translation of RNA into proteins had long been known to be a coupled process, meaning that after RNA is produced, ribosomes immediately translate it into protein.

Many researchers assumed that this would be true for all bacteria, but in a 2020 study, Li found that Bacillus subtilis and hundreds of other bacterial species use a different strategy.

“A lot of other species have what we call runaway transcription, where the transcription happens really fast and the proteins don’t get made at the same time. And because of this uncoupling, these species have very different mechanisms of regulating their gene expression,” Li says.

Li’s lab has also found that across species, cells make the same proportions of certain proteins that work together. Many cellular processes, such as breaking down sugar and storing its energy as ATP, are coordinated by enzymes that perform a series of reactions in a specified sequence.

“Evolution, it turns out, gives us the same proportion of those enzymes, whether in E. coli or other bacteria or in eukaryotic cells,” Li says. “There are apparently rules and principles for designing these pathways that we didn’t know of before.”

Mutations that cause too much or too little of a protein to be produced can cause a variety of human diseases. Li now plans to investigate how the genome encodes the rules governing the correct quantities of each protein, by measuring how changes to genetic and regulatory sequences affect gene expression at each step of the process — from initiation of transcription to protein assembly.

“The next level that we’re trying to focus on is: How is that information stored in the genome?” he says. “You can easily read off protein sequences from a genome, but it’s still impossible to tell how much protein is going to be made. That’s the next chapter.”