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MIT biologist Richard Hynes wins Lasker Award

Hynes and two other scientists will share the prize for their discoveries of proteins critical for cellular adhesion.

Anne Trafton | MIT News Office
September 28, 2022

MIT Professor Richard Hynes, a pioneer in studying cellular adhesion, has been named a recipient of the 2022 Albert Lasker Basic Medical Research Award.

Hynes, the Daniel K. Ludwig Professor for Cancer Research and a member of MIT’s Koch Institute for Integrative Cancer Research, was honored for the discovery of integrins, proteins that are key to cell-cell and cell-matrix interactions in the body. He will share the prize with Erkki Ruoslahti of Sanford Burnham Prebys and Timothy Springer of Harvard University.

“I’m delighted, and it’s a pleasure to be sharing it with them,” Hynes says. “It’s great for the field, and for the trainees who did much of the work.”

Hynes’ research focuses on proteins that allow cells to adhere to each other and to the extracellular matrix — a mesh-like network that provides structural support for cells. These proteins include integrins, a type of cell surface receptor, and fibronectins, a family of extracellular adhesive proteins. Integrins are the major adhesion receptors connecting the extracellular matrix to the intracellular cytoskeleton.

During embryonic development, cell adhesion is critical for cells to move to the correct locations in the embryo. Hynes’ work has also revealed that dysregulation of cell-to-matrix contact plays an important role in cancer cells’ ability to detach from a tumor and spread to other parts of the body, in a process known as metastasis.

“Professor Hynes’ contributions to the field of cancer biology, and more broadly, cellular biology, are numerous,” says Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics and the dean of the School of Science. “His investigations of fundamental biological questions — How do cells interact? How do they stick together? — changed how scientists approach cancer research and opened up avenues in developing potential therapeutics to disrupt metastatic disease.”

Born in Kenya, Hynes grew up in Liverpool, in the United Kingdom. Both of his parents were scientists: His father was a freshwater ecologist, and his mother a physics teacher. Hynes and all three of his siblings followed their parents into scientific fields.

“We talked science at home, and if we asked questions, we got questions back, not answers. So that conditioned me into being a scientist, for sure,” Hynes says.

After earning his bachelor’s and master’s degrees in biochemistry at Cambridge University, Hynes decided to head to the United States to continue graduate school. Colleagues at Cambridge suggested MIT, so he came to the Institute and earned his PhD in 1971. After doing a postdoc at the Imperial Cancer Research Fund Laboratories in London, he returned to MIT in 1975 as a faculty member in the Department of Biology and a founding member of MIT’s Center for Cancer Research (the predecessor of today’s Koch Institute).

Hynes began his career as a developmental biologist, studying how cells move to the correct locations during embryonic development. As a postdoc, he began studying the differences in the surface landscapes of healthy cells and tumor cells. This led to the discovery of a protein called fibronectin, which is often lost when cells become cancerous.

He and others found that fibronectin is part of the extracellular matrix, the network of proteins and other molecules that support cells and tissues in the body. When fibronectin is lost, cancer cells can more easily free themselves from their original location and metastasize to other sites in the body. Cells bind to the matrix through cell surface receptors known as integrins. In humans, 24 integrin proteins have been identified. These proteins help give tissues their structure, enable blood to clot, and are essential for embryonic development.

“These cell-matrix adhesion proteins hold us all together,” Hynes says. “If we didn’t have them, we’d be a pool of cells on the floor. And they’re contributors to lots of diseases: fibrosis, cancer, thrombosis, immune and autoimmune diseases. So, cell adhesion has become a huge field at both the basic science level and the therapeutic level.”

Since joining the MIT faculty, Hynes has also served as head and associate head of the Department of Biology, and as director of the Center for Cancer Research. He has also served as scientific governor of the Wellcome Trust in the United Kingdom, and as co-chair of National Academy committees establishing guidelines for stem cell and genome editing research.

His many awards include the Gairdner Foundation International Award, the Distinguished Investigator Award from the International Society for Matrix Biology, the Robert and Claire Pasarow Medical Research Award, the E.B. Wilson Medal from the American Society for Cell Biology and the Paget-Ewing Award, Metastasis Research Society. Hynes is also a member of the National Academy of Sciences, the National Academy of Medicine, the Royal Society of London, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.

The Lasker Award comes with a $250,000 prize, which will be shared between the three recipients.

Through mentorship, a deeper understanding of brain cancer metabolism grows

As an MSRP-Bio student in the Vander Heiden lab, Alejandra Rosario helped to reveal how cancer cells maintain access to materials they need to grow.

Grace van Deelen | Department of Biology
September 22, 2022

Alejandra Rosario’s enthusiasm for research is infectious. When she talks about studying cancer cells, or the possibility of getting a PhD, her face lights up. “It’s something I’m really passionate about,” she says.

As a Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio) student this past summer in the lab of Matt Vander Heiden, MIT’s Lester Wolfe (1919) Professor of Molecular Biology, Rosario worked to understand cancer metabolism. MSRP-Bio is a 10-week, research-intensive summer program intended to introduce non-MIT undergraduates to a research career. Rosario, who is a senior at the University of Puerto Rico at Cayey this fall, was one of two MSRP-Bio students this year who were the first from their campus to attend the program. “It’s a really great opportunity for us,” she says.

Rosario had always been interested in research and understanding natural systems. As a child growing up in San Lorenzo, Puerto Rico, she was surrounded by nature, and got involved at a young age in environmental activism. She also has a special passion for the beach, which contributed to her eventual interest in science and, more specifically, in biology.

Medical connections

When her mother developed thyroid cancer, she focused on cancer research. To support her mother, Rosario tried to learn as much as possible about the type of cancer she was fighting, as well as the treatments available. She noticed the impact of basic cancer research on the therapies her mother was receiving.

As a result of her experience watching her mother battle cancer, too, Rosario has a special interest in translational medicine: working to determine how fundamental discoveries can have specific relevance to human disease treatment. “In cancer research,” she says, “small strides can be huge strides.”

Delving into a career in cancer research became a focus for Rosario, who sought out opportunities to advance her connections to the field. During a virtual conference held by the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science, Rosario met MIT Department of Biology lecturer and science outreach director Mandana Sassanfar, who invited Rosario to visit MIT for a January workshop on computational skills. During the workshop, she met MIT professors, explored possible research ideas, and decided to apply to the MSRP-Bio program.

Rosario, who would like eventually to pursue a PhD or MD/PhD, was especially drawn to the Vander Heiden lab because of its focus on connecting research to medical applications. “I’m really fascinated about that connection, and how that works,” she says.

She especially liked the diversity of research happening in the lab, where projects range from cancer metabolism to genetics to stem cell research. “They’re all exploring different questions,” she says. “But at the end of the day, they all have conversations with each other and help each other out in a collaborative way.”

New insights into brain cancer

This summer, Rosario contributed to that diversity of research by continuing some of the core experiments of the Vander Heiden lab with a new cell line: glioblastoma, a type of brain cancer with a poor prognosis. The lab had never worked with this type of cancer before, so Rosario worked to understand its metabolism and process of cell division.

The main characteristic of cancer cells is that they divide very quickly. In order to do so, they need a lot of new material, like proteins, lipids, and nucleotides. A cancer cell has two options to obtain this new material: it can take it from the environment, or it can produce that new material itself. Glioblastoma occurs in the brain, a microenvironment that provides very little access to the materials necessary for cell division. In order to divide, then, glioblastoma cells must reprogram themselves in order to produce the materials necessary for growth.

Rosario’s research this summer sought to determine how glioblastoma cells survive in the environment of the brain by limiting the cells’ access to certain substances, like certain proteins or amino acids, and then measuring how the cells react. Understanding the cell’s reactions to such changes in the microenvironment could eventually inform cancer therapies.

“Our goal is to understand metabolically how these brain cancer cells are surviving everything we throw at them in order to possibly find a more specific target for treatment,” she says. Rosario presented her research in August in the MSRP-Bio poster session.

Shaped by mentorship

Overall, Rosario really enjoyed her experience as a summer researcher. The collaborative and open atmosphere in the lab, says Rosario, has helped her grow. For example, the lab holds occasional meetings called “Idea Club,” where researchers in the lab bring a question they’re struggling with or an idea they’re excited about, and other lab members give their input. “There’s a lot of scientific independence and curiosity,” says Rosario.

Rosario has especially enjoyed getting to know the graduate students in the lab, like Ryan Elbashir, a rising third-year doctoral student. Elbashir was also an MSRP-Bio student in 2018 and was one of the reasons Rosario chose the Vander Heiden lab. After a discussion with Elbashir about the importance of diversity in research, they formed a connection. “Alejandra is very inquisitive and comfortable around other people in the lab,” says Elbashir.

Rosario’s formal mentor, fourth-year MD/PhD student Sarah Chang, has also supported Rosario’s research goals by helping Rosario design research protocols and understand lab jargon. “Sarah’s been nothing but amazing,” says Rosario. “She’s teaching me how to think like a scientist.”

Rosario plans to build on the research she completed this summer in an MD/PhD program. She’d love to return to MIT or the Vander Heiden lab to carry out her future research and would like to continue to find ways to contribute to the development of cancer therapies. She’s very committed to studying cancer biology and wants to continue exploring the different sub-fields of cancer research during her senior year.

She plans to be a mentor to other young scientists, as well, and “pay it forward” to a new generation of underrepresented researchers. Mentoring, she says, creates a “chain reaction” of scientists supporting other scientists, which leads to better advances in research.

“By doing research and pursuing a question to the best of my abilities, I can impact as many people as possible,” she says.

Yami Acevedo ­Sánchez’s “go for it” attitude leads to MIT
Pamela Ferdinand
September 21, 2022

MIT PHD STUDENT YAMI ACEVEDO-SÁNCHEZ DISCOVERED SHE ENJOYED SCIENCE by watching television at home in Puerto Rico. While a strong student, encouraged by her mentors and parents to do well, she never imagined a science career would be in her future.

Acevedo-Sánchez is the second member of her extended family—her mother has 17 brothers and sisters; her father has 11—to earn a college degree. She didn’t learn about MIT until she began studying at the University of Puerto Rico, and attending the Institute felt like a very big step.

“I remember my thoughts were, ‘I’m never going to make it there.’ It felt really, really out of reach,” she says. “But I don’t say ‘no’ to myself. I just go for it.”

Today at MIT, Acevedo-Sánchez is pursuing her passion for biology, working to understand the basic processes that make all the complexity of life possible. “To me, it seems like a puzzle waiting for someone to assemble the pieces,” she says.

Her research focuses on a fundamental question: How do bacterial pathogens hijack a host? By studying how they travel between cells and spur infection, she hopes to discover more about the diseases they cause and potential therapies.

In particular, she is focused on Listeria monocytogenes, a widespread bacterium that can cause food poisoning. In high-risk populations, such as pregnant women or immunocompromised individuals, it can spread to the liver and then move through the bloodstream into the rest of the body. Listeria infection (listeriosis) has a high mortality rate, killing an estimated 20% to 30% of those infected, according to the US Food and Drug Administration.

Listeria hijacks molecular pathways as it spreads from cell to cell. It typically forces itself into neighboring cells by ramming into cell junctions (spots where cells connect). The force and speed Listeria uses to do this is about 0.2–1 microns per second—the equivalent of 50 feet per second if Listeria were the size of a submarine, Acevedo-Sánchez says: “It’s very impressive to watch!”

What is the mechanism of this action? Is it random, or programmed and regulated by the bacteria or our cells? Working with assistant professor of biology Rebecca Lamason and others in Lamason’s lab, Acevedo-Sánchez hopes to answer such questions through groundbreaking work that visualizes the cell membrane dynamics as Listeria spreads from cell to cell. To do this, the team uses a cellular line with a membrane marker (developed by Lamason) and a confocal microscope, which can capture high-resolution images deep inside cells.

Acevedo-Sánchez is especially interested in exploring how the mechanisms of two proteins, CAV1 and PACSIN2, promote cell-to-cell spread over long distances in a short amount of time. “These pathogens are constantly interacting with their host,” she says. “By understanding the key players that mediate those interactions from the bacteria side as well as the cell side, we can understand more about the microbiology of the bacteria and our own cell biology.”

Mentoring others

Outside the lab, Acevedo-Sánchez is working to support others like her who have not always believed they could pursue careers in science, technology, engineering, and mathematics. “There is tremendous power in having someone believe in your ability,” she says.

She has served as a mentor for the MIT Summer Research Program in Biology and supported first-year biology graduate students through the BioPals Program. Acevedo- Sánchez has also presented her work to middle school students around the world through the video series MIT Abstracts.

“Anyone can be a scientist, regardless of their background,” says Acevedo-Sánchez, who also has served as a graduate diversity ambassador at MIT. “You just need three things: be curious about the world that surrounds you, be willing to ask questions, and do the work yourself. Work smart and hard.”

Pamela Ferdinand is a 2003–2004 MIT Knight Science Journalism Fellow

Germ cells move like tiny bulldozers
Eva Frederick | Whitehead Institute
September 15, 2022

During fruit fly embryo formation, primordial germ cells — the stem cells that will later form eggs and sperm — must travel from the far end of the embryo to their final location in the gonads. Part of the primordial germ cell migration is passive; the cells are simply pushed into place by the movements of other cells. But at a certain point in development, the primordial germ cells must move on their own.

“A lot of the background in this field has been established by studying  how cells move in culture, and there’s this model that they move by using their cytoskeleton to push out their membranes to crawl,” said Benjamin Lin, a postdoctoral researcher in the lab of Whitehead Institute Director Ruth Lehmann. “We weren’t so sure they were actually moving that way in vivo.”

Now, in a new paper published September 14 in Science Advances, Lehmann who is also a professor of biology at the Massachusetts Institute of Technology, and researchers at Whitehead Institute and the Skirball Institute at New York University School of Medicine show that germ cells in growing fly embryos are in fact using a different method of movement which depends on a process called cortical flow, similar to the way bulldozers move on rotating treads. The research also reveals a new player in the pathway that governs this germ cell movement. “This work brings us one step closer to understanding the regulatory network that guides the germ cells on their long and complex journey across an ever-changing cellular landscape,” Lehmann said.

The research could also provide researchers with a new model for studying this type of cell movement in other situations — for example, cancer cells have been shown to move via cortical flow under certain conditions. ”We think there are more general implications for this mode of migratory behavior that go beyond primordial germ cells and apply to other migratory cells as well,” said Lin.

Balloon-shaped cells 

The first clue that Lehmann and Lin found that germ cells might not move the way scientists thought came from a simple observation. “When we began to study how these primordial germ cells move in the embryo, we saw that the cells actually remain shaped like a balloon while they’re moving and they don’t actually change their shape at all,” said Lin. “It’s really different from the crawling model.”

But if the cells weren’t moving by crawling, how were they moving through the embryo? To find out more, the researchers developed new techniques to image the germ cells in live fly embryos, and were able to watch clusters of a protein called actin moving backwards in each cell, as the cell itself was moving forward.

“There’s this thin layer of actin cytoskeleton just under the membrane of cells called the cortex, and they actually moved by making that cortex ‘flow,’” said Lin. “It’s like if you think of the tread of a bulldozer that’s moving backwards as the bulldozer is moving forward. The cells move that cortex backwards to generate friction to move the cell forward.”

Lin hypothesizes that this method of movement is especially well-suited to germ cells moving through a crowded embryo with many different cell types because instead of depending on recognizing specific proteins to “grab” in order to pull themselves through the embryo, it allows the germ cells to move independently. “Everything is pretty individualistic for primordial germ cells,” he said. “They don’t actually signal to each other at all, all the signaling is within each cell… And germ cells have to move through so many different tissues that they need a universal method of movement.”

A new role for a known protein

The researchers also found new information about how the cells control this form of motility. “We found that a protein called AMPK can control this pathway, which was really unexpected,” Lin said. “ Most people know it as a protein that senses energy. We found that this protein was important for helping these cells navigate. It’s one of these upstream players that can control how fast the cell goes, and in which direction.”

In the future, the researchers hope to map the entire pathway that allows germ cells to get to the right place at the right time in development. They also hope to learn more about the mechanisms behind cortical flow. “We want to figure out what is important for establishing these flows,” Lin said. “Our findings here could have implications not just for germ cells, but for other migrating cells as well.”

Notes

Benjamin Lin, Jonathan Luo, Ruth Lehmann. “An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo.” Science Advances, September 14, 2022. DOI: 10.1126/sciadv.abo0323

Biologists glean insight into repetitive protein sequences

A computational analysis reveals that many repetitive sequences are shared across proteins and are similar in species from bacteria to humans.

Anne Trafton | MIT News Office
September 13, 2022

About 70 percent of all human proteins include at least one sequence consisting of a single amino acid repeated many times, with a few other amino acids sprinkled in. These “low-complexity regions” are also found in most other organisms.

The proteins that contain these sequences have many different functions, but MIT biologists have now come up with a way to identify and study them as a unified group. Their technique allows them to analyze similarities and differences between LCRs from different species, and helps them to determine the functions of these sequences and the proteins in which they are found.

Using their technique, the researchers have analyzed all of the proteins found in eight different species, from bacteria to humans. They found that while LCRs can vary between proteins and species, they often share a similar role — helping the protein in which they’re found to join a larger-scale assembly such as the nucleolus, an organelle found in nearly all human cells.

“Instead of looking at specific LCRs and their functions, which might seem separate because they’re involved in different processes, our broader approach allows us to see similarities between their properties, suggesting that maybe the functions of LCRs aren’t so disparate after all,” says Byron Lee, an MIT graduate student.

The researchers also found some differences between LCRs of different species and showed that these species-specific LCR sequences correspond to species-specific functions, such as forming plant cell walls.

Lee and graduate student Nima Jaberi-Lashkari are the lead authors of the study, which appears today in eLife. Eliezer Calo, an assistant professor of biology at MIT, is the senior author of the paper.

Large-scale study

Previous research has revealed that LCRs are involved in a variety of cellular processes, including cell adhesion and DNA binding. These LCRs are often rich in a single amino acid such as alanine, lysine, or glutamic acid.

Finding these sequences and then studying their functions individually is a time-consuming process, so the MIT team decided to use bioinformatics — an approach that uses computational methods to analyze large sets of biological data — to evaluate them as a larger group.

“What we wanted to do is take a step back and instead of looking at individual LCRs, to try to take a look at all of them and to see if we could observe some patterns on a larger scale that might help us figure out what the ones that have assigned functions are doing, and also help us learn a bit about what the ones that don’t have assigned functions are doing,” Jaberi-Lashkari says.

To do that, the researchers used a technique called dotplot matrix, which is a way to visually represent amino acid sequences, to generate images of each protein under study. They then used computational image processing methods to compare thousands of these matrices at the same time.

Using this technique, the researchers were able to categorize LCRs based on which amino acids were most frequently repeated in the LCR. They also grouped LCR-containing proteins by the number of copies of each LCR type found in the protein. Analyzing these traits helped the researchers to learn more about the functions of these LCRs.

As one demonstration, the researchers picked out a human protein, known as RPA43, that has three lysine-rich LCRs. This protein is one of many subunits that make up an enzyme called RNA polymerase 1, which synthesizes ribosomal RNA. The researchers found that the copy number of lysine-rich LCRs is important for helping the protein integrate into the nucleolus, the organelle responsible for synthesizing ribosomes.

Biological assemblies

In a comparison of the proteins found in eight different species, the researchers found that some LCR types are highly conserved between species, meaning that the sequences have changed very little over evolutionary timescales. These sequences tend to be found in proteins and cell structures that are also highly conserved, such as the nucleolus.

“These sequences seem to be important for the assembly of certain parts of the nucleolus,” Lee says. “Some of the principles that are known to be important for higher order assembly seem to be at play because the copy number, which might control how many interactions a protein can make, is important for the protein to integrate into that compartment.”

The researchers also found differences between LCRs seen in two different types of proteins that are involved in nucleolus assembly. They discovered that a nucleolar protein known as TCOF contains many glutamine-rich LCRs that can help scaffold the formation of assemblies, while nucleolar proteins with only a few of these glutamic acid-rich LCRs could be recruited as clients (proteins that interact with the scaffold).

Another structure that appears to have many conserved LCRs is the nuclear speckle, which is found inside the cell nucleus. The researchers also found many similarities between LCRs that are involved in forming larger-scale assemblies such as the extracellular matrix, a network of molecules that provides structural support to cells in plants and animals.

The research team also found examples of structures with LCRs that seem to have diverged between species. For example, plants have distinctive LCR sequences in the proteins that they use to scaffold their cell walls, and these LCRs are not seen in other types of organisms.

The researchers now plan to expand their LCR analysis to additional species.

“There’s so much to explore, because we can expand this map to essentially any species,” Lee says. “That gives us the opportunity and the framework to identify new biological assemblies.”

The research was funded by the National Institute of General Medical Sciences, National Cancer Institute, the Ludwig Center at MIT, a National Institutes of Health Pre-Doctoral Training Grant, and the Pew Charitable Trusts.

Hot off the press: parasite researchers melt down proteins to understand their roles in infection
Eva Frederick | Whitehead Institute
August 31, 2022

Much like humans, plants, and bacteria, the single-celled parasite Toxoplasma gondii (T. gondii) uses calcium as a messenger to coordinate important cellular processes. But while the messenger is the same, the communication pathways that form around calcium differ significantly between organisms.

“Since Toxoplasma parasites are so divergent from us, they have evolved their own sets of proteins that are involved in calcium signaling pathways,”  said Alice Herneisen, a graduate student in the lab of Whitehead Institute Member Sebastian Lourido.

Lourido and his lab study the molecular mechanisms that allow the single-celled parasite T. gondii and related pathogens to be so widespread and potentially deadly — and calcium signaling is an important part of the parasite’s process of invading its hosts. “Calcium governs this very important transition from the parasites replicating inside of host cells to parasites leaving those cells and seeking out new ones to infect,” said Lourido. “We’ve been really interested in how calcium plays into the regulation of proteins inside the parasite.”

A paper published August 17 in eLife provides some insight. In the paper, Herneisen, Lourido and collaborators used an approach called thermal profiling to broadly survey which parasite proteins are involved in calcium signaling in T. gondii. The new work reveals that an unexpected protein plays a role in parasite calcium pathways, and provides new targets that scientists could potentially use to stop the spread of the parasite. The data will also serve as a resource that other Toxoplasma researchers can use to find out whether their own proteins of interest interact with calcium pathways in parasite cells.

The heat is on

When studying calcium pathways in humans, researchers can often draw parallels from work in mice. “But parasites are very different from us,” said Lourido. “All of the principles that we’ve learned about calcium signaling in humans or mice can’t be readily translated over to parasites.”

So to study these mechanisms in Toxoplasma, the researchers had to start from scratch to determine which proteins were involved. That’s where the thermal profiling method came in. The method is based on the observation that proteins are designed to work well at specific temperatures, and when it becomes too hot for them, they melt. Consider eggs: when the proteins in egg whites and egg yolks are heated in a frying pan, the proteins begin to melt and congeal. “When we think about a protein melting, what we mean is the proteins unraveling,” said Lourido. “When proteins unravel, they expose side chains that bind to each other. They stop being individual proteins that are well-folded, and become a mesh.”

Small changes to the chemical structure of a protein — such as the changes resulting from binding a small molecule such as calcium — can alter the melting point of a protein. Researchers can then trace these alterations using proteomic methods. “Proteins that are binding calcium are changing in response to calcium, and are ultimately changing their thermal stability,” Herneisen said. “That’s kind of the language of proteins, alterations in their thermal stability.”

The thermal profiling method works by applying heat to parasite cells and graphing how each of the parasite’s proteins responds to changes in temperature under different conditions (for example, the presence or absence of calcium). In a 2020 paper, the researchers used the thermal profiling method to investigate the role of a protein called ENH1 in calcium signaling.

In their new paper, Lourido and Herneisen investigated the effect of calcium on all proteins in the parasite using two approaches. The researchers combined parasites with specific amounts of calcium, applied heat, and then performed proteomics techniques to track how the calcium affected the melting behavior of each protein. If a protein’s melting point was higher or lower than usual, the researchers could deduce that that protein was changed either by calcium itself or by another player in a calcium signaling pathway.

They then treated the parasites with a chemical that caused them to release stored calcium in a controlled manner and measured how a protein modification called phosphorylation changed over time. Together, these methods allowed them to infer how proteins might sense and respond to calcium within the signaling network.

Their approach provided data on nearly every expressed protein in the parasite cells, but the researchers zeroed in on one particular protein called Protein Phosphatase 1 (or PP1). The protein is ubiquitous across many species, but has never previously been implicated in calcium signaling pathways. They found that the protein was concentrated at the front end of the parasite. This region of the parasite cell is involved in motility and host invasion.

The protein’s role in the parasites — and in the other organisms in which it appears — is to remove the small molecules called phosphates from phosphorylated proteins. “This is a modification that can often change the activity of individual proteins, because it’s this big charge that’s been covalently stuck onto the surface of the protein,” Lourido said. “This ends up being a principle through which many, many different biological processes are regulated.”

How exactly PP1 interacts with calcium remains to be seen. When the researchers depleted PP1 in parasite cells, they found that the protein is somehow involved in helping the parasite take in calcium necessary for movement. It’s unclear whether or not it actually binds calcium or is involved in the pathway through another mechanism.

Because parasites use calcium signaling to coordinate life cycle changes such as entering or leaving  host cells, insights into the key players in calcium pathways could be a boon to public health. “These are kind of the pressure points or the hubs that would be ideal to target in order to prevent the spread and pathogenesis of these parasites,” Herneisen said.

Herneisen and collaborators focused primarily on PP1, but there are many other proteins to investigate using the data from this project. “I think part of the reason why I wanted to release this paper is so that the field could take the next steps,” she said. “I’m just one person — it would be great if 20 other people find that the protein that they were studying is calcium responsive, and they can chase down the exact reason for that or how it is involved in this greater calcium signaling network. This was exciting for us with regards to PP1, and I’m sure other researchers will make their own connections.”

Notes

Alice L. Herneisen,  Zhu-Hong Li, Alex W. Chan, Silvia NJ Moreno, and Sebastian Lourido. “Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways”. eLife, August 17, 2022. DOI: https://doi.org/10.7554/eLife.80336

Scientists identify a plant molecule that sops up iron-rich heme

The peptide is used by legumes to control nitrogen-fixing bacteria; it may also offer leads for treating patients with too much heme in their blood.

Anne Trafton | MIT News Office
August 11, 2022

Symbiotic relationships between legumes and the bacteria that grow in their roots are critical for plant survival. Without those bacteria, the plants would have no source of nitrogen, an element that is essential for building proteins and other biomolecules, and they would be dependent on nitrogen fertilizer in the soil.

To establish that symbiosis, some legume plants produce hundreds of peptides that help bacteria live within structures known as nodules within their roots. A new study from MIT reveals that one of these peptides has an unexpected function: It sops up all available heme, an iron-containing molecule. This sends the bacteria into an iron-starvation mode that ramps up their production of ammonia, the form of nitrogen that is usable for plants.

“This is the first of the 700 peptides in this system for which a really detailed molecular mechanism has been worked out,” says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and the senior author of the study.

This heme-sequestering peptide could have beneficial uses in treating a variety of human diseases, the researchers say. Removing free heme from the blood could help to treat diseases caused by bacteria or parasites that need heme to survive, such as P. gingivalis (periodontal disease) or toxoplasmosis, or diseases such as sickle cell disease or sepsis that release too much heme into the bloodstream.

“This study demonstrates that basic research in plant-microbe interactions also has potential to be translated to therapeutic applications,” says Siva Sankari, an MIT research scientist and the lead author of the study, which appears today in Nature Microbiology.

Other authors of the paper include Vignesh Babu, an MIT research scientist; Kevin Bian and Mary Andorfer, both MIT postdocs; Areej Alhhazmi, a former KACST-MIT Ibn Khaldun Fellowship for Saudi Arabian Women scholar; Kwan Yoon and Dante Avalos, MIT graduate students; Tyler Smith, an MIT instructor in biology; Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator; Michael Yaffe, a David H. Koch Professor of Science and a member of MIT’s Koch Institute for Integrative Cancer Research; and Sebastian Lourido, the Latham Family Career Development Professor of Biology at MIT and a member of the Whitehead Institute for Biomedical Research.

Iron control

For nearly 40 years, Walker’s lab has been studying the symbiosis between legumes and rhizobia, a type of nitrogen-fixing bacteria. These bacteria convert nitrogen gas to ammonia, a critical step of the Earth’s nitrogen cycle that makes the element available to plants (and to animals that eat the plants).

Most of Walker’s work has focused on a clover-like plant called Medicago truncatula. Nitrogen-fixing bacteria elicit the formation of nodules on the roots of these plants and eventually end up inside the plant cells, where they convert to their symbiotic form called bacteroids.

Several years ago, plant biologists discovered that Medicago truncatula produces about 700 peptides that contribute to the formation of these bacteroids. These peptides are generated in waves that help the bacteria make the transition from living freely to becoming embedded into plant cells where they act as nitrogen-fixing machines.

Walker and his students picked one of these peptides, known as NCR247, to dig into more deeply. Initial studies revealed that when nitrogen-fixing bacteria were exposed to this peptide, 15 percent of their genes were affected. Many of the genes that became more active were involved in importing iron.

The researchers then found that when they fused NCR247 to a larger protein, the hybrid protein was unexpectedly reddish in color. This serendipitous observation led to the discovery that NCR247 binds heme, an organic ring-shaped iron-containing molecule that is an important component of hemoglobin, the protein that red blood cells use to carry oxygen.

Further studies revealed that when NCR247 is released into bacterial cells, it sequesters most of the heme in the cell, sending the cells into an iron-starvation mode that triggers them to begin importing more iron from the external environment.

“Usually bacteria fine-tune their iron metabolism, and they don’t take up more iron when there is already enough,” Sankari says. “What’s cool about this peptide is that it overrides that mechanism and indirectly regulates the iron content of the bacteria.”

Nitrogenase, the main enzyme that bacteria use to fix nitrogen, requires 24 to 32 atoms of iron per enzyme molecule, so the influx of extra iron likely helps those enzymes to become more active, the researchers say. This influx is timed to coincide with nitrogen fixation, they found.

“These peptides are produced in a wave in the nodules, and the production of this particular peptide is higher when the bacteria are preparing to fix nitrogen. If this peptide was secreted throughout the whole process, then the cell would have too much iron all the time, which is bad for the cell,” Sankari says.

Without the NCR247 peptide, Medicago truncatula and rhizobium cannot form an effective nitrogen-fixing symbiosis, the researchers showed.

“Many possible directions”

The peptide that the researchers studied in this work may have potential therapeutic uses. When heme is incorporated into hemoglobin, it performs a critical function in the body, but when it’s loose in the bloodstream, it can kill cells and promote inflammation. Free heme can accumulate in stored blood, so having a way to filter out the heme before the blood is transfused into a patient could be potentially useful.

A variety of human diseases lead to free heme circulating in the bloodstream, including sickle cell anemia, sepsis, and malaria. Additionally, some infectious parasites and bacteria depend on heme for their survival but cannot produce it, so they scavenge it from their environment. Treating such infections with a protein that takes up all available heme could help prevent the parasitic or bacterial cells from being able to grow and reproduce.

In this study, Lourido and members of his lab showed that treating the parasite Toxoplasma gondii with NCR427 prevented the parasite from forming plaques on human cells.

The researchers are now pursuing collaborations with other labs at MIT to explore some of these potential applications, with funding from a Professor Amar G. Bose Research Grant.

“There are many possible directions, but they’re all at a very early stage,” Walker says. “The number of potential clinical applications is very broad. You can place more than one bet in this game, which is an intriguing thing.”

Currently, the human protein hemopexin, which also binds to heme, is being explored as a possible treatment for sickle cell anemia. The NCR247 peptide could provide an easier to deploy alternative, the researchers say, because it is much smaller and could be easier to manufacture and deliver into the body.

The research was funded in part by the MIT Center for Environmental Health Sciences, the National Science Foundation, and the National Institutes of Health.

Brandon (Brady) Weissbourd

Education

  • Graduate: PhD, 2016, Stanford University
  • Undergraduate: BA, 2009, Human Evolutionary Biology, Harvard University

Research Summary

We use the tiny, transparent jellyfish, Clytia hemisphaerica, to ask questions at the interface of nervous system evolution, development, regeneration, and function. Our foundation is in systems neuroscience, where we use genetic and optical techniques to examine how behavior arises from the activity of networks of neurons. Building from this work, we investigate how the Clytia nervous system is so robust, both to the constant integration of newborn neurons and following large-scale injury. Lastly, we use Clytia’s evolutionary position to study principles of nervous system evolution and make inferences about the ultimate origins of nervous systems.

Awards

  • Searle Scholar Award, 2024
  • Klingenstein-Simons Fellowship Award in Neuroscience, 2023
  • Pathway to Independence Award (K99/R00), National Institute of Neurological Disorders and Stroke, 2020
  • Life Sciences Research Foundation Fellow, 2017
The blueprint of a body
Eva Frederick | Whitehead Institute
July 20, 2022

Multicellular organisms evolved over millennia into a dazzling array of differently adapted creatures. With each generation, tiny worms, lavishly plumed birds, and even humans must create themselves anew from a single cell. To do so, they require a plan.

“How that multifunctional body plan is created is one of the deepest questions in developmental biology,” said Zak Swartz, until recently a postdoctoral researcher in the lab of Whitehead Institute Member Iain Cheeseman. “How do you take a single cell and pattern into a body that has different functions and features along it?”

Whitehead Institute researchers are tackling this question through a variety of different lenses. Researchers in Iain Cheeseman’s lab, including Swartz, have delved into the mysterious forces that underlie the polarity of an organism’s first cell. For the lab led by Pulin Li, research comes in at a later stage of development, when multiple cells combine to form a tissue and must communicate with each other to become an organized whole. Work on regeneration in Peter Reddien’s lab shows how some creatures can access their body blueprint throughout their lives to repair nearly any injury, and Yukiko Yamashita’s group studies how organisms pass on their body blueprints to their offspring through germ cells. Jonathan Weissman and his lab have created a “map” which researchers can use to find the function of a given gene, allowing them access to an organism’s most fundamental plans. Read on to learn about these scientists’ work, and more.

Laying out the plan

All multicellular organisms begin with a single cell, the fertilized egg. This cell has an essential role in setting out the body plan for the rest of an organism. It all starts with establishing polarity — in other words, figuring out which side of the cell is the top, and which is the bottom. This polarity establishes an axis of symmetry for the growing organism, and sets the stage for other developmental processes to come.

In a 2021 study, Cheeseman and postdoctoral researcher Zak Swartz investigated how one protein in specific, called Disheveled, localizes in a cell to help create this polarity in sea star embryos. Swartz found that Disheveled started out uniformly distributed in small aggregations throughout the egg cell, or oocyte. As the cell prepared to divide, Disheveled aggregations dissolved and then reformed at what would become the “bottom” of the oocyte.

Once the initial polarity is established, the oocyte can divide, creating a bilaterally symmetric sea star larvae. The burgeoning cluster of cells must then undergo other processes to define the several axes of symmetry that adult sea stars are known for.

Talking through it 

If an organism’s developmental blueprints are to be followed as development progresses, cells must be able to effectively communicate with each other. That cell to cell communication is the area of expertise of Whitehead Institute Member Pulin Li.

During her postdoctoral fellowship at the California Institute of Technology, Li studied tissue patterning — the mechanisms by which an organism’s newly forming tissues are laid out. Specifically, she investigated a developmental mechanism called morphogen gradient formation.

These gradients, composed of chemicals present in developing embryos, function as spatial coordinate systems and help determine how various cell types will be arranged in the organism — for example which groups of cells will form the liver, or the bones, or the brain, and where they will be within the body.

Li was able to recreate these gradients in the lab, in a Petri dish, and then interpret their signals using time lapse imaging and mathematical modeling. Here at Whitehead Institute, she follows a “bottom-up” approach to studying these complex systems. The best way to understand how something works, she says, is to build it yourself.

A key process in asymmetric cell division preserves the immortality of the germline
Eva Frederick | Whitehead Institute
July 27, 2022

During cell division, chromosomes are replicated into two copies — one for each daughter cell. These copies, called sister chromatids, are usually considered identical. In fact, it’s the two pairs of sister chromatids that make up the symmetrical X shape usually shown when visualizing chromosomes.

A 2013 paper from the lab of Whitehead Institute Member Yukiko Yamashita showed that in the case of asymmetric cell division — such as when a stem cell is dividing into two different kinds of daughter cells (i.e. a stem cell and a differentiating daughter)  — sister chromatids of sex chromosomes actually may carry distinct information, and the dividing cell “chooses” which of the daughters receive a specific copy.

What that “choice” means, and how it’s executed, has been a mystery — until now. A new paper from Yamashita, who is also a professor of biology at the Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute, published in Science Advances on July 27, illuminates the mechanisms that underlie nonrandom sister chromatid segregation, and suggests that the whole process may serve as a way to maintain the amount of ribosomal DNA (or rDNA) that is passed on to subsequent generations. “Tying together these two processes — rDNA copy number maintenance and nonrandom chromatid segregation — is an unexpected and exciting advance in our understanding of how germ cells are able to maintain their immortality,” said Yamashita.

George Watase, a postdoctoral scholar in the Yamashita Lab, led the study. Watase began his research intent on discovering the genetic underpinnings of nonrandom segregation of X and Y chromosomes in the fruit fly Drosophila melanogaster. As he surveyed the genome for genes that were essential to nonrandom segregation, it became apparent that ribosomal DNA was key for the process.

When rDNA was left intact, the sister chromatid  with more rDNA was preferentially chosen by the daughter stem cell instead of the differentiating daughter cell. When rDNA was removed from X and Y chromosomes, however, Watase found that the sister chromatids segregated randomly to the daughter cells.

Ribosomal DNA, or rDNA, is composed of a long stretch of repeats of certain base pairs. The rDNA provides the instructions and material to make ribosomes, which are essential for cells to create proteins. “Most genes exist only as a single copy, but in the case of rDNA we have hundreds of copies in our genome,” Watase said. “The reason for this is that we need a massive amount of ribosomes to synthesize proteins to maintain our cells’ viability.”

As organisms age, most of their cells naturally lose some of those rDNA repeats, including germline stem cells.  However, germline cells are sometimes called “immortal” — while all other cells in the body are made anew with each generation and die when an organism dies, germline cells such as sperm and eggs must carry DNA between generations. THerefore, the stem cells that produce sperm and eggs thus cannot keep losing rDNA repeats, and must bypass the mortality of other cells, by maintaining  a high number of rDNA repeats over time.

By isolating proteins that bind to rDNA, Watase discovered one specific gene, the protein product of which bound to rDNA and somehow assigned the sister chromatid with more rDNA repeats to the daughter cell that was destined to remain a germline stem cell.

This particular gene had not been described before, and Watase and Yamashita were now tasked with naming it. Fruit fly genes are named after what happens to the animal when the gene is removed. When this new gene was knocked down, the germ cells of subsequent generations gradually lost the immortality that separates germline stem cells from their differentiated counterparts.

Watase wasn’t sure how to convey the intricacies of this outcome. In the end, it was Watase’s wife who came up with the perfect name: Indra. In Hindu scriptures, Indra, the lord of all deities, was given a garland of fragrant flowers by a sage called Durvasa. Indra placed the garland on the trunk of his elephant, but the animal was irritated by the smell of the flowers and threw the garland down, trampling it underfoot. When Durvasa saw this, he became enraged and cursed Indra, taking away his immortality.

The name also opened up a world of possibilities for naming future genes that are important in nonrandom sister chromatid segregation. “People sometimes pull from Roman or Greek myths when naming genes, but not as many people use names from Hindu myths,” he said. “And since this is new biology, if we identify additional related genes in the future, we can use names from Hindu myths again.”

Watase and Yamashita’s study opens new avenues for future research. For example, the paper focused primarily on male fruit flies and the production of sperm via asymmetric division. Indra is expressed in the female germline as well, and when the gene is knocked down in females, the resulting phenotype is much more severe. “There must be some mechanism in female germ cells to avoid rDNA copy number reduction,” said Watase. “We just don’t know what that mechanism is.”

In the future, Watase and Yamashita also hope to elucidate how exactly Indra is interacting with cell division machinery to influence which chromatid ends up in the stem cell and which in the differentiating cell, and beyond this mechanism, how the stem cell “selects” the longer chromatid.

“Many biologists study germ cells, but few specifically study how they maintain their immortality,” said Yamashita. “This study is a step towards understanding this fascinating property of germ cells. It’s a really fascinating area and we really have to keep digging deeper into this phenomenon.”