Current genetic sequencing techniques can provide much information about the genetic makeup and activity in a sample, like a piece of tissue or a drop of blood. But they are unable to reveal where specific genetic sequences were located inside that sample, or their relationship to other genes and molecules, according to University of Chicago (UChicago) scientists, who say they are developing a novel method that overcomes these challenges.

By tagging each DNA or RNA molecule and allowing neighboring tags to interact, their approach constructs a molecular network that encodes their relative positions, creating a spatial map of genetic material. This technique, called volumetric DNA microscopy, creates a 3D image of an entire organism from the inside out, giving scientists an unprecedented view of genetic sequences and where they are located, down to individual cells, noted Joshua Weinstein, PhD, assistant professor of medicine and molecular engineering at UChicago.

In the article, “Spatial transcriptomic imaging of an intact organism using volumetric DNA microscopy” in Nature Biotechnology, Weinstein and postdoctoral scholar Nianchao Qian, PhD, used the technology to create a complete DNA image of a zebrafish embryo, a common model organism for studying development and neurobiology.

“It’s a level of biology that no one has ever seen before,” Weinstein said. “To be able to see that kind of a view of nature from within a specimen is exhilarating.”

Unlike traditional microscopes that use light or lenses, DNA microscopy creates images by calculating interactions among molecules, providing a new way to visualize genetic material in 3D. First, short DNA sequence tags called unique molecular identifiers (UMIs) are added to cells. They attach to DNA and RNA molecules and begin making copies of themselves. This starts a chemical reaction that creates new sequences, called unique event identifiers (UEIs), that are distinctive to each pairing.

It’s these pairings that help create the spatial map of where each genetic molecule is located. UMI pairs that are close together interact more frequently and generate more UEIs than those that are farther apart. Once the DNA and RNA are sequenced, a computational model reconstructs their original locations by analyzing the physical links between UMI tags, creating a spatial map of gene expression.
Weinstein compares the technique to using data from cell phones pinging each other to determine people’s location in a city. Knowing the cell phone number or IP address of each person is like knowing the genetic sequence of one molecule, but if you can layer on their interactions with other phones nearby, you can work out their locations too.

“We can do this with cell phones and people, so why not do that with molecules and cells,” he asked. “This turns the idea of imaging on its head. Rather than relying on an optical apparatus to shine light in, we can use biochemistry and DNA to form a massive network between molecules and encode their proximities to each other.”

DNA microscopy doesn’t rely on prior knowledge of the genome or shape of a specimen, so it could be useful for understanding genetic expression in unique, unknown contexts. Tumors generate countless new genetic mutations, for example, so the tool would be able to map out the tumor microenvironment and where it interacts with the immune system.

Immune cells interact with each other and respond to pathogens in context-specific ways, so DNA microscopy could help unravel those genetic mechanisms. Such applications could in turn guide more precise immunotherapy for cancer or tailor personalized vaccines.

“This is the critical foundation for being able to have truly comprehensive information about the ensemble of unique cells within the lymphatic system or tumor tissue,” pointed out Weinstein. “There has still been this major gap in technology for allowing us to understand idiosyncratic tissue, and that’s what we’re trying to fill in here.”

A preclinical study by researchers at Baylor College of Medicine has uncovered a mechanism that allows triple-negative breast cancer (TNBC) to develop resistance to immune checkpoint blockade (ICB) immunotherapy and to chemotherapy. The study, including tests in mouse models, showed that lipid accumulation in tumor cells and nearby immune cells promotes immune suppression. The results also indicated that disrupting lipid formulation reverses treatment resistance and the immunosuppressive microenvironment.

Xiang H.-F. Zhang, PhD, director of the Lester and Sue Smith Breast Center and professor of molecular and cellular biology at Baylor, is corresponding author of the team’s published study in Immunity, titled, “Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer,” in which the researchers concluded, “Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.”

Standard-of-care treatment for TNBC includes chemotherapy and immunotherapy, the authors explained. “For triple-negative breast cancer (TNBC), a combination of pembrolizumab (an anti-PD-1 antibody) and chemotherapies has been approved to treat advanced tumors in the neoadjuvant setting.” However, some initially responsive tumors still develop recurrences, “… suggesting acquired resistance mechanisms that remain poorly understood.”

Studying mouse models, Zhang and colleagues found that TNBC cells that survived treatment accumulated lipid droplets containing omega-6 fatty acids. Single-cell RNA sequencing revealed that neutrophils—a type of white blood cell—near the tumor cells also accumulated these lipids. “Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells,” the investigators stated. “Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming.”

First author Liqun Yu, PhD, a postdoctoral fellow in the Zhang lab at Baylor, further explained, “We found the tumor cells give the lipid droplets to surrounding neutrophils. This shifted the function of the neutrophils from antitumor to tumor promotion.” The team in addition found that they could reverse therapy resistance and the immunosuppressive tumor microenvironment (TME) by disrupting lipid droplet formation. Blocking dietary intake of omega-6 fatty acids also resensitized the tumors to chemotherapy and immunotherapy.

“The prevailing perspective in our field has focused on the role of fatty acid metabolism in regulating the immune response and therapeutic response,” said Zhang, who is the William T. Butler, MD, Endowed Chair for Distinguished Faculty, and co-leader of the Breast Cancer Program at the Dan L Duncan Comprehensive Cancer Center at Baylor. “We found in this study that not only can fatty acids serve as an energy source, but they also are precursors of immunosuppressive signals the cancer cells can use to fight against our immune system.”

In their report, the team concluded, “Our findings suggest that the intake, processing, and storage of specific fatty acid in TNBC could alter their response to combined treatments involving ICB and chemotherapy. Our preclinical study offers potential strategies for pharmacological and dietary intervention to overcome therapeutic resistance, especially the acquired resistance.”

Zhang added, “We can advise patients to consume a diet low in omega-6 fatty acids, which is not significantly different from the general advice to lower red meat, fat, and sodium intake. We also are exploring therapeutic options to block fatty acid accumulation and immunosuppressive signals between the cancer cells and the neutrophils.”

Four top research institutions have united under the Weill Cancer Hub East, a collaborative partnership that aims to transform cancer treatment. The initiative connects experts from Princeton University, the Rockefeller University, Weill Cornell Medicine, and the Ludwig Institute for Cancer Research to enhance immunotherapeutic strategies.

The Weill Cancer Hub East was established with a $50 million gift from the Weill Family Foundation, directed by Joan and Sanford I. Weill, and matched with philanthropy from each partner institution that together will total more than $125 million. The initiative seeks to break down institutional barriers and unite top experts in cancer biology, cancer clinical trials, immunology, nutrition, and metabolism to drive cross-field collaboration that pushes the boundaries of scientific discovery.

Over the next decade, the Weill Cancer Hub East will marshal multidisciplinary teams to explore the complex relationship between solid tumors and the environment in which they form and grow, according to a Weill Cornell Medicine spokesperson, adding that their investigations will leverage the complementary strengths of each research institution to illuminate how the food we eat and the beneficial microbes that help metabolize that food influence the effectiveness of cancer treatments such as immunotherapy.

Emerging therapeutics

The hub will evaluate how emerging therapeutics, including a class of diabetes and anti-obesity drugs (GLP-1 agonists), might impact cancer progression and treatment.

“The Weill Cancer Hub East will offer doctors and scientists a tremendous opportunity to revolutionize the treatment of cancer, a disease that complicates so many lives,” said Sandy Weill, founder of the Weill Family Foundation and chair emeritus of the Weill Cornell Medicine Board of Fellows.

“With the best minds in the field armed with the most advanced research techniques, the Weill Cancer Hub East will seek to elevate immunotherapy and improve patient care for people battling cancer.”

Using advances in metabolomics, immunology, computational analysis, and artificial intelligence, the Weill Cancer Hub East will explore how metabolism affects the immune system’s ability to recognize and control cancer.

“The hub will enable extraordinary biomedical scientists, leading clinicians, and the New York medical community to join forces in new ways and leverage our academic research with amazing translational and clinical expertise,” said Christopher L. Eisgruber, JD, president of Princeton University.

Seed funding will be available for funding basic, clinical, and translational scientists from Princeton University, the Rockefeller University, and Weill Cornell Medicine to allow them to pursue collaborative projects that focus on reprogramming the tumor microenvironment and augmenting cell function by modulating patients’ metabolisms and microbiomes.

In addition, the hub will make a portfolio of clinical trials available, including those that explore whether GLP-1 agonists, which are designed to modify a person’s metabolism, have downstream beneficial effects on a cancer patient’s immune response and outcome.

Findings gleaned from these investigations may have applications in cardiovascular, metabolic, and autoimmune conditions.

“Immune modulation and engineered immune effector cell therapies have transformed the treatment of a number of cancers, begging the question of how these and related therapies can be extended to many others,” said Richard Lifton, MD, PhD, president of the Rockefeller University. “The funding for this collaboration allows for a deep, mechanistic investigation into how one’s diet, metabolism, and microbiome can affect cancer immunotherapy. Promoting the integration of basic science and clinical investigation will promote discoveries that will improve patient outcomes.”

A scientific steering committee, comprising one scientific leader from each academic institution, will oversee the hub’s scientific activities. The committee members are:

• Joshua Rabinowitz, MD, PhD, professor in the department of chemistry and Lewis-Sigler Institute for Integrative Genomics at Princeton University, and director of the Princeton Branch of the Ludwig Institute for Cancer Research
• Sohail Tavazoie, MD, PhD, the Leon Hess Professor, head of the Meyer Laboratory of Systems Cancer Biology, and director of the Black Center for Metastasis Research at the Rockefeller University
• Jedd Wolchok, MD, PhD, the Meyer Director of the Sandra and Edward Meyer Cancer Center, co-director of the Ludwig Collaborative Laboratory, and co-director of the Parker Institute for Cancer Immunology at Weill Cornell Medicine

Genetic engineering in non-human primates has been challenged by the limitations of virus-based gene delivery methods. Recently, researchers in Japan successfully used a nonviral system to introduce a transgene into cynomolgus monkeys.

“Our research represents a milestone in the field of genetic engineering,” explained Tomoyuki Tsukiyama, PhD, associate professor in developmental engineering, reproductive and stem cell biology at the Institute for the Advanced Study of Human Biology (WPI-ASHBi) in Kyoto, Japan. “Our method provides a practical and efficient way to introduce transgenes into non-human primates, which we hope will unlock new insights into complex human diseases.”

This work is published in Nature Communications in the paper, “Non-viral generation of transgenic non-human primates via the piggyBac transposon system.”

Although non-human primates are an essential model for biomedical research, genetic modification of these animals has been challenging. For example, conventional virus-based methods (lentiviral methods have been used for generating transgenic monkeys) require specialized containment facilities and are limited in terms of the size of transgenes that the viruses can carry. Also, these methods do not allow for precise selection of modified embryos before implantation.

To overcome these challenges, the research team sought an alternative to using viruses to carry transgenes, instead opting for a nonviral piggyBac transposon system. The piggyBac transposon system offers several advantages over traditional virus-based approaches, including greater flexibility in terms of the size of transgenes that can be carried and the ability to confirm successful modifications at the early embryo stage. This allows for more efficient embryo screening before implantation, increasing the likelihood of producing genetically modified animals that carry the desired traits.

After optimizing the protocol in mice, the authors noted that “the co-injection of piggyBac components with sperm into metaphase II-stage oocytes successfully [generated] transgenic monkeys expressing transgenes throughout their whole bodies.” Transgene expression, they say, was observed in all examined tissue types, including germ cells, although the levels of expression vary.

More specifically, in the resulting cynomolgus monkeys, there was widespread expression of fluorescent reporter genes. Red fluorescent protein was localized to cell membranes, and green fluorescent protein was localized to cell nuclei. Expression was confirmed across all tissues examined, including germ cells, demonstrating that the transgene was stably introduced. These findings suggest that the piggyBac transposon system has significant potential for creating genetically modified primates, which could be used to study human disease in ways that traditional rodent models cannot replicate.

While the transgene integration pattern was consistent across different tissues, expression levels varied. This variability underscores the need in future applications to carefully select promoters based on the target tissue. For example, genes such as OCT3/4 and DDX4 play important roles in germ cell lineage differentiation, while SYN1 and THY1 are involved in neuronal lineage differentiation. By selecting appropriate promoters for specific tissues, researchers can fine-tune gene expression to achieve the desired effects, an essential step in advancing genetic models for disease research.

The team plans to expand the applications of this system to include multiplex gene expression and precise transgene control, thereby allowing for more sophisticated genetic models. In addition, the researchers are exploring the potential for integrating epigenetic data about how genes are turned on and off into their work in order to better understand how gene expression is regulated at the molecular level. By refining these techniques, the researchers aim to explore disease mechanisms that remain inaccessible in rodent models and ultimately improve our understanding of complex health conditions in humans.

For human health, prematurely aging cells are a big problem. When a cell ages and stops growing, its function changes, which can cause or worsen cardiovascular disease, Alzheimer’s disease and other chronic diseases. But these cells are also like needles in a haystack, difficult to identify by traditional scientific measures.

To find these problematic cells, a University of Illinois Chicago doctoral student has developed a powerful new software platform called SenePy. In a paper for Nature Communications, Mark Sanborn and co-authors from the College of Medicine announced the open-source tool to find aging — or senescent — cells in organs and tissues.

The tool will give researchers a boost for studying these biologically important cells to better understand and treat several diseases, according to the paper’s lead author, Dr. Jalees Rehman, Benjamin J. Goldberg Professor and head of the department of biochemistry and molecular genetics.

“Cellular senescence describes the premature aging of a cell where the cell stops growing, doesn’t die, but it stops functioning normally,” said Rehman, who is also a member of the University of Illinois Cancer Center. “That causes problems because the cell is not replaced by healthy cells. Instead, it persists and promotes inflammation, thus disrupting the function of its neighboring cells.”

To develop SenePy, Sanborn analyzed single-cell sequencing data from over 1.6 million human and mouse cells. On this large dataset, he used computational tools to find genetic signatures that distinguish aging cells from their healthier neighbors.

But it wasn’t as simple as finding one set of common markers for senescent cells everywhere in the body. In different tissues, such as the heart, lungs or brain, the genetic profile of aging cells also differs, the researchers found. In all, they identified 72 mouse and 64 human signatures.

SenePy helps make sense of that complexity, allowing researchers to analyze their own tissue samples and compare them to the database of signatures the UIC team discovered. The code for the platform is open-source and free to use.

“More people will use it and find value in it because, as an open-source tool, it is freely available to the scientific community,” said Sanborn, a doctoral student in the Graduate Education in Biomedical Sciences program. “If there’s more people using it, then there’s more potential for it to have a future therapeutic impact.”

In the Nature Communications paper, the researchers used SenePy to examine the role of senescent cells in cancer, heart attacks, COVID-19 and brain inflammation.

“We found that senescent cells are clustered together, because premature senescence in one cell promotes dysfunction and senescence in its neighbors,” Rehman said. “SenePy also allowed us to study how senescence acts as a natural brake which prevents tumor formation. High levels of activation of a cancer-promoting gene in cells also resulted in higher SenePy senescence scores.”

The team also looked at the effectiveness of drugs called senolytics that clear senescent cells from the body to fight or prevent disease and aging.

“Because we now have several markers for specific types of senescence and different cell types, we could generate new senolytics for potential new targets,” Sanborn said.

Additional UIC co-authors include Xinge Wang, Shang Gao and Yang Dai. The research was funded by grants from the National Institutes of Health.

Exposure to antibiotics during a key developmental window in infancy can stunt the growth of insulin-producing cells in the pancreas and may boost risk of diabetes later in life, new research in mice suggests.

The study, published this month in the journal Science, also pinpoints specific microorganisms that may help those critical cells proliferate in early life.

The findings are the latest to shine a light on the importance of the human infant microbiome — the constellation of bacteria and fungi living on and in us during our first few years. The research could lead to new approaches for addressing a host of metabolic diseases.

“We hope our study provides more awareness for how important the infant microbiome actually is for shaping development,” said first author Jennifer Hill, assistant professor in molecular, cellular and developmental biology at CU’s BioFrontiers Institute. “This work also provides important new evidence that microbe-based approaches could someday be used to not only prevent but also reverse diabetes.”

Something in the environment

More than 2 million U.S. adults live with Type 1 diabetes, an incurable disease in which the pancreas fails to make insulin (the hormone that turns glucose into energy) and the blood fills with sugar.

The disease typically emerges in childhood, and genetics play a strong role. But scientists have found that, while identical twins share DNA that predisposes them to Type 1 diabetes, only one twin usually gets the disease.

“This tells you that there’s something about their environmental experiences that is changing their susceptibility,” said Hill.

For years, she has looked to microbes for answers.

Previous studies show that children who are breastfed or born vaginally, which can both promote a healthy infant microbiome, are less likely to develop Type 1 diabetes than others. Some research also shows that giving babies antibiotics early can inadvertently kill good bugs with bad and boost diabetes risk.

The lingering questions: What microbes are these infants missing out on?

“Our study identifies a critical window in early life when specific microbes are necessary to promote pancreatic cell development,” said Hill.

A key window of opportunity

She explained that human babies are born with a small amount of pancreatic “beta cells,” the only cells in the body that produce insulin.

But some time in a baby’s first year, a once-in-a-lifetime surge in beta cell growth occurs.

“If, for whatever reason, we don’t undergo this event of expansion and proliferation, that can be a cause of diabetes,” Hill said.

She conducted the current study as a postdoctoral researcher at the University of Utah with senior author June Round, a professor of pathology.

They found that when they gave broad-spectrum antibiotics to mice during a specific window (the human equivalent of about 7 to 12 months of life), the mice developed fewer insulin producing cells, higher blood sugar levels, lower insulin levels and generally worse metabolic function in adulthood.

“This, to me, was shocking and a bit scary,” said Round. “It showed how important the microbiota is during this very short early period of development.”

Lessons in baby poop

In other experiments, the scientists gave specific microbes to mice, and found that several they increased their production of beta cells and boosted insulin levels in the blood.

The most powerful was a fungus called Candida dubliniensis.

The team used fecal samples from The Environmental Determinants of Diabetes in the Young (TEDDY) study to make what Hill calls “poop slushies” and fed them to the mice.

When the researchers inoculated newborn mice with poop from healthy infants between 7 to 12 months in age, their beta cells began to grow. Poop from infants of other ages did not do the same.

Notably, Candida dublineinsis was abundant in human babies only during this time period.

“This suggests that humans also have a narrow window of colonization by these beta cell promoting microbes,” said Hill.

When male mice that were genetically predisposed to Type 1 diabetes were colonized with the fungus in infancy, they developed diabetes less than 15% of the time. Males that didn’t receive the fungus got diabetes 90% of the time.

A joint team of professors—Hajun Kim, Taejoon Kwon, and Joo Hun Kang—from the Department of Biomedical Engineering at UNIST has unveiled a novel diagnostic technique that utilizes artificially designed polymers known as peptide nucleic acid (PNA) as probes. The research is published in the journal Biosensors and Bioelectronics.

The fluorescence in situ hybridization (FISH) technique works by detecting fluorescent signals generated when probe molecules bind to specific genetic sequences in bacteria. This innovative FISH method employs two PNA molecules simultaneously. By analyzing the genomic sequences of 20,000 bacterial species, the research team designed PNA sequences that specifically target the ribosomal RNA of particular species.

The method is significantly faster and more accurate than traditional bacterial culture and polymerase chain reaction (PCR) analysis, and it holds promise for reducing mortality rates in critical conditions such as sepsis, where timely administration of antibiotics is crucial.

PNA exhibits a higher sensitivity to sequence mismatches compared to conventional DNA-based probes and demonstrates superior penetration through bacterial cell walls.

Furthermore, the requirement for both PNA molecules to bind to their target site before generating a signal significantly reduces the likelihood of crosstalk, thereby enhancing accuracy in situations involving multiple overlapping bacterial strains.

In tests, the technology successfully detected seven bacterial species—including E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus—showing over 99% accuracy for all species except S. aureus, which was detected with an accuracy of 96.3%. The method’s effectiveness was further validated in mixed bacterial samples. Both Enterococcus and E. coli were detected with over 99% accuracy when tested together.

The approach utilizing two PNA molecules is based on Förster Resonance Energy Transfer (FRET). This principle involves energy transfer from one PNA molecule to another when they are in close proximity, allowing for the measurement of the fluorescence emitted by the recipient molecule.

Professor Kim noted, “This method will aid in the diagnosis of infections requiring immediate antibiotic treatment, such as sepsis, urinary tract infections, and pneumonia, while also helping to reduce unnecessary antibiotic usage.”

The research team plans to conduct further experiments using blood samples taken from actual patients to explore clinical applications.

New technology can separate the fibers in the sugar beet pulp left over after sugar production. Part of the fiber can be used as a nutritional supplement due to its anti-inflammatory properties and beneficial effects on our gut flora. Another part of the fiber, the cellulose, can be made into components to replace, for example, plastic.

Using residual products from the production of sugar from sugar beets will help fulfill one of Professor Anne S. Meyer’s visions—to transform our current food production to use raw materials for not just one, but several valuable products.

“We already know this from the production of cereals, for example, which we primarily grow to convert the kernels into flour. But we also utilize the rest of the plant, the straw, the husks, etc. for different purposes, so the whole plant is part of the cycle,” says Meyer.

A similar circular bioeconomic idea underlies the project to utilize the biomass that remains after sugar production.

“I call it my star project because our ambitions are high, but also because the perspectives are so great. Once we have demonstrated the possibilities of utilizing sugar beet for several valuable products, the vision is to expand our thinking to many other similar products on a global scale. These could be raw materials for food products that, due to climate change, will be the food of the future in, for example, Africa or Asia, where production conditions are changing dramatically in recent years and where it is obvious to consider using the entire crop for more than just food,” explains Meyer.

“By using a biologically inspired and enzyme-based technique to separate the fibers in food production residues, we take an important step towards ensuring profitable global utilization of raw materials to make multiple beneficial products. Products that are based on using specific fiber structures in the plant material,” she adds.

The first results

Not many weeks ago, Meyer’s research group succeeded in discovering new enzymes that act on the fibers in the residues from sugar beet production, the so-called sugar beet pulp. The burden of proof now lies in showing how quickly the enzymes penetrate the pulp, where they separate the cell wall components so that the different fibers can be gently separated from each other.

One group of interesting fibers in the sugar beet pulp are bioactive pectin elements, which in previous research projects have been shown to have a beneficial effect on the environment in our intestines. This effect must now be documented, and Professor Susanne Brix Pedersen, DTU, is at the forefront of this work. She researches immunology and the influence of microorganisms in the gut, and with her expertise and her team, she can map the anti-inflammatory effect of fiber and how it affects our immune system.

“As life expectancy increases, so does the interest in staying healthy for longer, and in this context, these health-promoting dietary fibers will be interesting. The goal of our work over the next few years is to both document their effect and define how it is most appropriate to consume these fibers—whether it should be in the form of a capsule to be swallowed, or whether the fibers should instead be added to a food, such as yogurt or a drink, or perhaps used for special nutrition,” says Meyer.

Replacement for plastic

The second group of fibers that can be utilized from the sugar beet pulp is cellulose. Although the cellulose structure is the same, the molecular environment of cellulose in the sugar beet and thus the sugar beet pulp is different from the cellulose we know from, for example, trees. In trees, the fibers are reinforced with lignin, among other things, to keep the plant upright and waterproof for years, whereas sugar beet is a tuber that grows extremely quickly in the soil and is harvested annually.

“Sugar beet cellulose fibers are therefore more malleable, so to speak, and not as stiff as cellulose from wood. We want to utilize this nanocellulose in materials that can be designed for many different purposes—typically to replace different types of plastic. The fibers will be used in composite materials, so-called composites, which can be hard, soft or flexible. At the same time, it is an important ambition that the material can be disassembled and reused again,” says Meyer.

This vision will be realized through collaboration with, among others, the EMPA research institution in Switzerland, which has extensive expertise in innovative applications and recycling of cellulose.

As a process and product is not necessarily sustainable just because it is based on natural materials, the project includes close collaboration with Professor Michael Z. Hauschild, Centre for Quantitative Research at EMPA. Hauschild, Centre for Quantitative Sustainability Assessment at DTU. He continuously assesses whether the project’s initiatives are sustainable. Researchers with detailed knowledge of plant cell wall structure from the Department of Plant and Environmental Sciences, Professor Peter Ulvskov from the University of Copenhagen, are also involved in the work.

The researchers’ initial results show that it is possible to form different types of material from the sugar beet cellulose and that the materials have desirable properties. Intensive work is now underway to show that these materials can be gently disassembled and recycled several times.

In addition, new enzymes and techniques have been developed that are expected to have a lasting impact on the gentle processing of plant materials into new products.

Life takes shape with the motion of a single cell. In response to signals from certain proteins and enzymes, a cell can start to move and shake, leading to contractions that cause it to squeeze, pinch, and eventually divide. As daughter cells follow suit down the generational line, they grow, differentiate, and ultimately arrange themselves into a fully formed organism.

Now MIT scientists have used light to control how a single cell jiggles and moves during its earliest stage of development. The team studied the motion of egg cells produced by starfish — an organism that scientists have long used as a classic model for understanding cell growth and development.

The researchers focused on a key enzyme that triggers a cascade of motion within a starfish egg cell. They genetically designed a light-sensitive version of the same enzyme, which they injected into egg cells, and then stimulated the cells with different patterns of light.

They found that the light successfully triggered the enzyme, which in turn prompted the cells to jiggle and move in predictable patterns. For instance, the scientists could stimulate cells to exhibit small pinches or sweeping contractions, depending on the pattern of light they induced. They could even shine light at specific points around a cell to stretch its shape from a circle to a square.

Their results, which will appear in the journal Nature Physics, provide scientists with a new optical tool for controlling cell shape in its earliest developmental stages. Such a tool, they envision, could guide the design of synthetic cells, such as therapeutic “patch” cells that contract in response to light signals to help close wounds, or drug-delivering “carrier” cells that release their contents only when illuminated at specific locations in the body. Overall, the researchers see their findings as a new way to probe how life takes shape from a single cell.

“By revealing how a light-activated switch can reshape cells in real time, we’re uncovering basic design principles for how living systems self-organize and evolve shape,” says the study’s senior author, Nikta Fakhri, associate professor of physics at MIT. “The power of these tools is that they are guiding us to decode all these processes of growth and development, to help us understand how nature does it.”

The study’s MIT authors include first author Jinghui Liu, Yu-Chen Chao, and Tzer Han Tan; along with Tom Burkart, Alexander Ziepke, and Erwin Frey of Ludwig Maximilian University of Munich; John Reinhard of Saarland University; and S. Zachary Swartz of the Whitehead Institute for Biomedical Research.

Cell circuitry

Fakhri’s group at MIT studies the physical dynamics that drive cell growth and development. She is particularly interested in symmetry, and the processes that govern how cells follow or break symmetry as they grow and divide. The five-limbed starfish, she says, is an ideal organism for exploring such questions of growth, symmetry, and early development.

“A starfish is a fascinating system because it starts with a symmetrical cell and becomes a bilaterally symmetric larvae at early stages, and then develops into pentameral adult symmetry,” Fakhri says. “So there’s all these signaling processes that happen along the way to tell the cell how it needs to organize.”

Scientists have long studied the starfish and its various stages of development. Among many revelations, researchers have discovered a key “circuitry” within a starfish egg cell that controls its motion and shape. This circuitry involves an enzyme, GEF, that naturally circulates in a cell’s cytoplasm. When this enzyme is activated, it induces a change in a protein, called Rho, that is known to be essential for regulating cell mechanics.

When the GEF enzyme stimulates Rho, it causes the protein to switch from an essentially free-floating state to a state that binds the protein to the cell’s membrane. In this membrane-bound state, the protein then triggers the growth of microscopic, muscle-like fibers that thread out across the membrane and subsequently twitch, enabling the cell to contract and move.

In previous work, Fakhri’s group showed that a cell’s movements can be manipulated by varying the cell’s concentrations of GEF enzyme: The more enzyme they introduced into a cell, the more contractions the cell would exhibit.

“This whole idea made us think whether it’s possible to hack this circuitry, to not just change a cell’s pattern of movements but get a desired mechanical response,” Fakhri says.

Lights and action

To precisely manipulate a cell’s movements, the team looked to optogenetics — an approach that involves genetically engineering cells and cellular components such as proteins and enzymes, such that they activate in response to light.

Using established optogenetic techniques, the researchers developed a light-sensitive version of the GEF enzyme. From this engineered enzyme, they isolated its mRNA — essentially, the genetic blueprint for building the enzyme. They then injected this blueprint into egg cells that the team harvested from a single starfish ovary, which can hold millions of unfertilized cells. The cells, infused with the new mRNA, then began to produce light-sensitive GEF enzymes on their own.

In experiments, the researchers then placed each enzyme-infused egg cell under a microscope and shone light onto the cell in different patterns and from different points along the cell’s periphery. They took videos of the cell’s movements in response.

They found that when they aimed the light in specific points, the GEF enzyme became activated and recruited Rho protein to the light-targeted sites. There, the protein then set off its characteristic cascade of muscle-like fibers that pulled or pinched the cell in the same, light-stimulated spots. Much like pulling the strings of a marionette, they were able to control the cell’s movements, for instance directing it to morph into various shapes, including a square.

Surprisingly, they also found they could stimulate the cell to undergo sweeping contractions by shining a light in a single spot, exceeding a certain threshold of enzyme concentration.

“We realized this Rho-GEF circuitry is an excitable system, where a small, well-timed stimulus can trigger a large, all-or-nothing response,” Fakhri says. “So we can either illuminate the whole cell, or just a tiny place on the cell, such that enough enzyme is recruited to that region so the system gets kickstarted to contract or pinch on its own.”

The researchers compiled their observations and derived a theoretical framework to predict how a cell’s shape will change, given how it is stimulated with light. The framework, Fakhri says, opens a window into “the ‘excitability’ at the heart of cellular remodeling, which is a fundamental process in embryo development and wound healing.”

She adds: “This work provides a blueprint for designing ‘programmable’ synthetic cells, letting researchers orchestrate shape changes at will for future biomedical applications.”

This work was supported, in part, by the Sloan Foundation, and the National Science Foundation.

Antibiotic-resistant bacteria is a serious public health threat. Understanding the biology of these bacteria — such as how they synthesise their protective capsules — is essential for developing new strategies to counter antibiotic resistance.

Streptococcus pneumoniae is a bacterium commonly found in the upper respiratory tract of humans. While it can exist harmlessly in some individuals, it is also a major pathogen responsible for severe illnesses, particularly in young children, the elderly, and people with weakened immune systems. Diseases caused by this bacterium, such as pneumonia and meningitis, are life-threatening. The bacterium’s ability to evade the immune system and cause disease is largely due to its capsule, which serves as a protective shield. As a result, this capsule is a primary target for vaccine development.

Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have made progress in uncovering how Streptococcus pneumoniae constructs its capsule. Their findings reveal that the adaptability of both the capsules and their transport mechanisms may play a crucial role in the bacteria’s ability to evolve and diversify, offering insights for managing pneumococcal diseases.

Cellular transporters

The results of their study, published in Science Advances, focus on these capsule transporters in this process. These transporters, which belong to the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) transporter family, help move sugar building blocks from inside the bacteria to the surface, where the capsule is formed. The capsule acts like a shield, protecting the bacteria from the body’s immune system. By blocking key immune defences — such as clearing bacteria from the airways or marking them for destruction — the capsule enables the bacteria to survive, multiply, and spread within the body. In addition, the ability to build a capsule that transports a wide range of sugar building blocks has potential applications in glycoengineering, a field that aims to modify sugar structures for various purposes, such as developing new drugs or improving the properties of biomaterials.

The study’s lead researcher, Assistant Professor Chris Sham Lok-To, from the Infectious Diseases Translational Research Programme (TRP) and Department of Microbiology and Immunology, NUS Medicine, highlighted the importance of understanding capsule synthesis for combating pneumococcal infections, “The capsule is critical for pneumococcus to cause disease. By examining how capsule transporters choose their substrates, we hope to open new avenues for research in bacterial evolution, antibiotic resistance, and vaccine development.”

Three categories of transporters identified

The researchers developed a large-scale method to study how bacteria transport sugars to build their protective capsules. They tested more than 6,000 combinations of transporters and sugar building blocks by inserting 80 different transporter genes into 79 strains of Streptococcus pneumoniae. Asst Prof Chris added, “Each transporter was marked with a unique genetic code (i.e., DNA barcode) for tracking. We then deleted the original transporter in each strain, creating a survival test: only bacteria with a functional replacement transporter could live. By analysing the barcodes of the surviving bacteria, we identified which transporters successfully carried the necessary sugars for capsule formation.”

The study found that transporters could be grouped into three categories based on how selective they were. The first group, strictly specific transporters, only worked with their original sugar building blocks. This ensures accuracy but limits flexibility. The second group, type-specific transporters, could handle sugars with certain common features, like specific chemical structures. These transporters could substitute for others within related capsule types but not beyond that. The third group, relaxed specificity transporters, could handle a variety of different sugars.

Dr Chua Wan Zhen, first author of the study, who is from the Infectious Diseases TRP and Department of Microbiology and Immunology, NUS Medicine, added, “However, this flexibility may sometimes cause problems by transporting incomplete or incorrect sugars, which disrupts bacterial growth. Transporters with relaxed specificity can cause issues because once they move incomplete building blocks across the cell membrane, there are no known mechanisms for the bacteria to send them back.” These unfinished precursors build up and interfere with important processes like cell wall construction, leading to stunted growth or even cell death. This explains why most bacteria have evolved to keep their transporters highly selective, despite the potential benefits of being able to transport a wider variety of sugars.

Key findings indicate that subtle modifications in transporter genes can alter specificity, potentially impacting bacterial adaptability and virulence. Understanding this process can help scientists develop new strategies for treating bacterial infections and explore ways to use these transport systems for engineering beneficial sugar-based materials.

Future research will focus on identifying specific amino acid residues responsible for transporter-substrate interactions and engineering transporters with optimised specificity for potential industrial and healthcare applications.