Understanding how cells turn genes on and off is one of biology’s most enduring mysteries. Now, a new technology developed by chemist Brian Liau and his collaborators at Harvard offers an unprecedented window into this activity, an advance that has the potential to transform our understanding of the basic science as well as the treatment of genetic diseases.

In a paper published in Nature Methods, the authors unveil a powerful genome mapping tool that reveals how tiny changes in DNA can reshape the way genes are controlled.

This new platform, called TDAC-seq (Targeted Deaminase Accessible Chromatin sequencing), allows researchers to see, at single-nucleotide resolution, how hundreds of genetic perturbations alter the structure of “chromatin”—the dynamic DNA packaging that determines which genes are accessible to the cell’s machinery.

Previously, scientists mostly focused on the tiny portion of DNA that directly creates proteins. Now, TDAC-seq helps them finally study the “dark matter” of our genetic code—the noncoding DNA, which makes up about 98% of the genome and helps regulate gene activity.

“This new and innovative method is a tour de force, offering an unprecedented view into the DNA elements that govern our genome,” said David Liu, Thomas Dudley Cabot Professor of the Natural Sciences, whose earlier work on base-editing enzymes helped make this technology possible.

“This work will not only speed up our basic understanding of how these switches work but also show us how they could be targeted to benefit patients in the future.”

This research was performed by members of Liau’s lab, including Heejin Roh and Simon Shen, Ph.D. students at the Kenneth C. Griffin Graduate School of Arts and Sciences, and Hui Si Kwok, a postdoctoral scholar. The group collaborated with Jason D. Buenrostro, professor of stem cell and regenerative biology, and his former graduate student Yan Hu, who helped with computational analysis.

The researchers began with a big question: Can we find a way to test hundreds of changes to genetic switches at once and measure their effects in real cells?

“We wanted to develop a strategy where we can systematically mutate these noncoding elements using CRISPR to figure out how they work,” Liau said. “The problem was that we didn’t have the tools to do it, so we had to invent them.”

The Liau Lab’s innovation centered on an enzyme called DddA, found in bacteria, which marks open DNA by converting a single base, cytosine, into thymine—without breaking the DNA strand. By layering these DddA-induced mutations on top of CRISPR-edited DNA, the team developed a new way to read DNA accessibility in cells after CRISPR-genome editing.

“When we started the project, DddA was new and very little was known about it, so boosting its mutation rate in the genome was a big challenge,” Roh said. “We tried different DddA variants and optimized the reaction conditions until we achieved a mutation rate high enough to measure chromatin accessibility at single-molecule resolution.”

Shen, who helped handle the massive amounts of data the new technique generated, noted that innovation was a key to their success.

“Because this is a fundamentally new kind of data set that we’re collecting, it required a fundamentally new way to analyze the data,” Shen said. “Our approach was really good for getting us long, high-coverage reads in the targeted regions and pinpointing key elements within noncoding DNA.”

To demonstrate the power of their tool, the scientists applied it to several regulatory regions, including one that controls fetal hemoglobin—a hotbed for genetic disorders such as sickle cell disease.

By engineering DNA variants in human blood stem cells and applying TDAC-seq, the team tracked exactly how each change affected the surrounding chromatin. Buenrostro, a pioneer in technologies used to map chromatin accessibility, provided invaluable input enabling the team’s success.

“We were able to increase the fetal globin through genome editing, which is the therapeutic strategy to treat sickle cell disease, and then measure the resulting changes in chromatin accessibility to get at the underlying molecular mechanism.” Roh said.

“We also showed that this method can be applied to pooled CRISPR screens in primary cells, unlike other existing long-read sequencing methods.”

TDAC-seq’s importance goes well beyond sickle cell disease. Liau envisions the platform being used in the future to screen potential gene therapy strategies, guide the design of more precise treatments, and even help explain mysterious links between DNA variations and disease risks.

“This can be very impactful because most disease-associated variants are in noncoding regions of the genome,” Liau said, who plans to hone TDAC-seq so it works in even more cell types and situations.

“This tool is generalizable, so you can use it to study any kind of switch or a gene that is altered by disease.”

Scientists at UC San Diego have moved one step closer to unlocking a superpower held by some of nature’s greatest “masters of disguise.” Octopuses, squids, cuttlefish and other animals in the cephalopod family are well known for their ability to camouflage, changing the color of their skin to blend in with the environment. This remarkable display of mimicry is made possible by complex biological processes involving xanthommatin, a natural pigment.

Because of its color-shifting capabilities, xanthommatin has long intrigued scientists and even the military, but has proven difficult to produce and research in the lab—until now.

In a new study published in Nature Biotechnology, a team led by UC San Diego’s Scripps Institution of Oceanography describes a major breakthrough in understanding nature’s ability to camouflage, as they successfully develop a new way to produce large amounts of xanthommatin pigment.

Their nature-inspired method massively over-produced the pigmented material for the first time in a bacterium, opening new possibilities for the pigment’s use in a wide range of materials and cosmetics—from photoelectronic devices and thermal coatings to dyes and UV protectants. The new approach produces up to 1,000 times more material than traditional methods.

“We’ve developed a new technique that has sped up our capabilities to make a material, in this case xanthommatin, in a bacterium for the first time,” said Bradley Moore, the study’s senior author and a marine chemist with joint appointments at Scripps Oceanography and UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences.

“This natural pigment is what gives an octopus or a squid its ability to camouflage—a fantastic superpower—and our achievement to advance production of this material is just the tip of the iceberg.”

The authors say their discovery is significant, not just for understanding this unique pigment—which sheds light on the biology and chemistry of the animal kingdom—but also because the technique they used could be applied to many other chemicals, potentially helping industries move away from fossil fuel-based materials toward nature-based alternatives.

A promising pigment

Beyond cephalopods, xanthommatin is also found in insects within the arthropod group, contributing to the brilliant orange and yellow hues of monarch butterfly wings and the bright reds seen in dragonfly bodies and fly eyes.

Despite xanthommatin’s fantastic color properties, it is poorly understood due to a persistent supply challenge. Harvesting the pigment from animals isn’t scalable or efficient, and traditional lab methods are labor intensive, reliant on chemical synthesis that is low yielding.

Researchers in the Moore Lab at Scripps Oceanography sought to change that, working with colleagues across UC San Diego and at the Novo Nordisk Foundation Center for Biosustainability in Denmark to design a solution, a sort of growth feedback loop they call “growth coupled biosynthesis.”

The way in which they bioengineered the octopus pigment, a chemical, in a bacterium represents a novel departure from typical biotechnological approaches. Their approach intimately connected the production of the pigment with the survival of the bacterium that made it.

“We needed a whole new approach to address this problem,” said Leah Bushin, lead author of the study, now a faculty member at Stanford University and formerly a postdoctoral researcher in the Moore Lab at Scripps Oceanography, where her work was conducted. “Essentially, we came up with a way to trick the bacteria into making more of the material that we needed.”

Typically, when researchers try to get a microbe to produce a foreign compound, it creates a major metabolic burden. Without significant genetic manipulation, the microbe resists diverting its essential resources to produce something unfamiliar.

By linking the cell’s survival to the production of their target compound, the team was able to trick the microbe into creating xanthommatin. To do this, they started with a genetically engineered “sick” cell, one that could only survive if it produced both the desired pigment, along with a second chemical called formic acid.

For every molecule of pigment generated, the cell also produced one molecule of formic acid. The formic acid, in turn, provides fuel for the cell’s growth, creating a self-sustaining loop that drives pigment production.

“We made it such that activity through this pathway, of making the compound of interest, is absolutely essential for life. If the organism doesn’t make xanthommatin, it won’t grow,” said Bushin.

To further enhance the cells’ ability to produce the pigment, the team used robots to evolve and optimize the engineered microbes through two high-throughput adaptive laboratory evolution campaigns, which were developed by the lab of study co-author Adam Feist, professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering and senior scientist at the Novo Nordisk Foundation Center for Biosustainability.

The team also applied custom bioinformatics tools from the Feist Lab to identify key genetic mutations that boosted efficiency and enabled the bacteria to make the pigment directly from a single nutrient source.

“This project gives a glimpse into a future where biology enables the sustainable production of valuable compounds and materials through advanced automation, data integration and computationally driven design,” said Feist.

“Here, we show how we can accelerate innovation in biomanufacturing by bringing together engineers, biologists and chemists using some of the most advanced strain-engineering techniques to develop and optimize a novel product in a relatively short time.”

Traditional approaches yield around five milligrams of pigment per liter “if you’re lucky,” said Bushin, while the new method yields between one to three grams per liter.

Getting from the planning stages to the actual experimentation in the lab took several years of dedicated work, but once the plan was put into motion, the results were almost immediate.

“It was one of my best days in the lab,” Bushin recalled of the first successful experiment. “I’d set up the experiment and left it overnight. When I came in the next morning and realized it worked and it was producing a lot of pigment, I was thrilled. Moments like that are why I do science.”

Next steps

Moore anticipates that this new biotech methodology, which is fully nature-inspired and non-invasive, will transform the way in which biochemicals are produced.

“We’ve really disrupted the way that people think about how you engineer a cell,” he said. “Our innovative technological approach sparked a huge leap in production capability. This new method solves a supply challenge and could now make this biomaterial much more broadly available.”

While some applications for this material are far-out, the authors noted active interest from the U.S. Department of Defense and cosmetics companies.

According to the researchers, collaborators are interested in exploring the material’s natural camouflage capabilities, while skincare companies are interested in using it in natural sunscreens. Other industries see potential uses ranging from color-changing household paints to environmental sensors.

“As we look to the future, humans will want to rethink how we make materials to support our synthetic lifestyle of 8 billion people on Earth,” said Moore. ” … we’ve unlocked a promising new pathway for designing nature-inspired materials that are better for people and the planet.”

Pictures of DNA often look very tidy—the strands of the double helix neatly wind around each other, making it seem like studying genetics should be relatively straightforward. In truth, these strands aren’t often so perfectly picturesque. They are constantly twisting, bending, and even being repaired by minuscule proteins. These are movements on the nanoscale, and capturing them for study is extremely challenging. Not only do they wriggle about, but the camera’s fidelity must be high enough to focus on the tiniest details.

Researchers from the University of Illinois Urbana-Champaign (U. of I.) have been working on resolving a grand challenge for molecular biology, and more specifically, genetic research: how to take a high-resolution image of DNA to facilitate study.

Using a number of compute resources, including NCSA’s Delta, Aleksei Aksimentiev, a professor of physics at U. of I, and Dr. Kush Coshic, formerly a graduate research assistant in the Center for Biophysics and Quantitative Biology and the Beckman Institute for Advanced Science and Technology at U. of I., and currently a postdoctoral fellow at the Max Planck Institute of Biophysics, recently made significant contributions to solving this challenge. They did it by focusing on two specific problems: creating a “camera” that could capture the molecular movement of DNA, and by creating an environment in which they could predictably direct the movement of the DNA strands.

“The fundamental problem we try to address is the gap between our ability to engineer DNA structures and our ability to predict and control their motion on 2D surfaces, a challenge which requires a deeper, molecular-level understanding to lay the groundwork for future biosensors and structural biology tools,” said Aksimentiev.

The team relied on massive, microsecond-long Molecular Dynamics (MD) simulations to computationally model the atomic interactions and validate their experimental setup, a task that demanded the immense parallel compute power that Delta and DeltaAI provide.

Creating a nanoscale camera

When you imagine trying to take a photo of a DNA strand on a camera, you might think the best way to keep it still would be to place it on its side when trying to capture an image. However, researchers discovered that DNA can stand up straight on certain surfaces—a breakthrough for those attempting to capture high-quality images.

It’s essential to recognize that these breakthroughs result from highly collaborative efforts, often building upon the foundational work of scientists and researchers worldwide. In this case, Aksimentiev’s team was able to conduct their research due to the discovery made by researchers at Tinnefeld Lab at Ludwig Maximilian University (LMU) in Munich, Bavaria, Germany. That team created a “DNA camera” using a single, atomic-layer-thick sheet of graphene. They called this method GETvNA. Aksimentiev’s team built upon the work at LMU by exploring the atomic-level workings of this “DNA camera.”

“The GETvNA method builds on a discovery by our collaborators (Tinnefeld Lab, LMU, Germany) that double-stranded DNA adopts a vertical orientation on graphene, enabling detection of subtle conformational changes via energy transfer between a dye-labeled DNA and the graphene surface,” explained Coshic.

“Like a car’s suspension system, this configuration allows the DNA to flex and fluctuate freely while remaining vertically positioned on the surface, capturing its structural dynamics with Angstrom-level spatial and subsecond temporal resolution.”

Aksimentiev’s team was able to achieve a resolution down to the Angstrom scale (less than a billionth of a meter) and capture events in real-time. This is essential for observing processes such as DNA damage repair or protein translocation as they occur.

Capturing those images is a significant achievement in itself, but the team’s research has an even greater impact: their discovery means that even labs lacking access to expensive resources can study DNA at this scale.

“A key strength of GETvNA is its accessibility. It enables high-resolution single-molecule studies using a standard fluorescence microscope, removing the need for costly facilities to host cryogenic electron microscopy or nuclear magnetic resonance equipment,” said Aksimentiev.

Guiding DNA

What if you could also control where DNA moved? If you were able to get DNA to move along a selected path, you could sort and manipulate individual strands of DNA easily, but you could also start to build a “molecular machine” of sorts. Aksimentiev’s team discovered that by using a 2D material, hexagonal boron nitride (hBN), they could direct single-stranded DNA (ssDNA) along selected paths.

In a previous study published in Nature Nanotechnology, the team discovered that step defects can be used to guide biomolecules. A step defect is essentially a nanoscale stair-step or ledge on the surface of a material, such as graphene. These nano-sized, naturally occurring “stairs” can create channels through which biomolecules will move.

Initially, experiments performed with a team of collaborators, which included researchers Chirlmin Joo and Peter Steeneken, both from the Delft University of Technology (TU Delft), showed the DNA diffusing thousands of times slower than predicted. The team’s computational analysis solved this mystery, revealing that atomic defects on the hBN surface act as temporary trapping sites that intermittently slow the molecules, allowing for predictable control over their movement.

“Understanding the molecular interactions and how surface defects influence biomolecular motion on 2D surfaces, our ACS Nano work paves the way for designing 2D nanofluidic devices with precisely confined channels,” said Aksimentiev. “These can guide biomolecules directionally, via diffusion or external cues, for high-resolution sensing and without relying on complex nanofabrication protocols. GETvNA complements this by offering a novel, low-cost pipeline that achieves Angstrom-level localization precision for single-molecule measurements.”

The combination of these two breakthroughs allows for a wide range of impactful applications in biomolecular medicine.

“While our work is fundamental, focusing on understanding the rules to build new tools, it lays essential groundwork for the precise control and guiding of biomolecules for next-generation medical diagnostics,” said Aksimentiev.

“The GETvNA method serves as a powerful and low-cost platform for studying how single DNA molecules interact with proteins, a fundamental process in both health and disease. Its accessibility unlocks a wide range of applications, from enabling deeper biological research to offering a practical way to quantify the specific molecular interactions that are crucial for designing and testing new drugs.”

This research would have been impossible without the resources available at centers like NCSA. For research of this resource-intensive nature, Aksimentiev’s team had to utilize numerous resources. To get those resources, his team turned to the U.S. National Science Foundation ACCESS program. Through ACCESS, Aksimentiev was able to qualify for a “Maximize” allocation, granting him access to hundreds of thousands of compute hours on resources nationwide.

“NCSA resources, including Delta, were instrumental in enabling our microsecond-long simulations, currently the state-of-the-art, by reducing computation time from several months on personal machines to just a few days using high-performance computing,” said Aksimentiev.

In addition to obtaining allocations on NCSA’s Delta and DeltaAI machines, the team utilized resources from the Pittsburgh Supercomputing Center (PSC), the Texas Advanced Computing Center (TACC), the San Diego Supercomputer Center (SDSC), and Purdue’s Rosen Center for Advanced Computing (RCAC).

“For many years, the ACCESS, and its predecessor (XSEDE), program has been enabling our lab to perform computational discovery at the interface of biology and nanotechnology,” said Aksimentiev. “Being able to use these state-of-the-art resources is pivotal to ensuring global leadership of U.S. science and the emergence of breakthrough technological innovations.”

Building on a breakthrough

The team has published results of their work in two papers: Diffusion of DNA on Atomically Flat 2D Material Surfaces in ACS Nano, and Single-molecule dynamic structural biology with vertically arranged DNA on a fluorescence microscope in Nature Methods. However, a researcher’s work is never truly over. Aksimentiev and his team will continue to expand upon their results.

“We would like to better understand from a molecular standpoint the milliseconds-to-seconds dynamics of the vertical standing DNA on the graphene surface,” said Aksimentiev.

“Atomistic simulations cannot be used to probe such timescales, and instead, we will use our microsecond-long atomistic trajectories to calibrate coarser resolution models such as our in-house mrDNA method that we previously used to unravel the physical process of viral genome packaging inside the virus’ protein capsid.”

While grapes are being harvested throughout Italy, the Politecnico di Milano is looking to the future of viticulture with an innovative approach that combines mechanics, IT and digital simulation. A team of researchers from the Departments of Mechanical Engineering and Electronics, Information and Bioengineering at the Politecnico di Milano has developed a system to test and optimize self-driving strategies for agricultural tractors in a virtual environment.

The study, published in AgriEngineering, presents a complete methodology for creating realistic vineyard scenarios and evaluating control algorithms for autonomous driving. The goal is not simply to reduce the human presence, but to provide a high-fidelity digital environment in which to develop, verify and safely improve agricultural automation solutions based on sensors and predictive algorithms.

The research has made it possible to create a “digital twin” of the vineyard, capable of reproducing slopes, soil irregularities and row layout. Tractors equipped with low-cost GNSS and IMU sensors and guided by advanced algorithms have been tested in this virtual environment, vehicles capable of moving autonomously between rows and of performing off-field turning maneuvers with the utmost precision.

“Our approach combines terrain modeling, advanced control and realistic sensors in a single simulation environment. This speeds up research and reduces the risks and costs of real field tests,” says Federico Cheli, professor at the Politecnico di Milano, Department of Mechanical Engineering, and project coordinator.

According to the researchers, the use of realistic simulations not only reduces the risks and costs of field tests, but can also become a useful tool for operator training. It can accelerate the adoption of new agricultural technologies.

The project stems from the partnership between researchers at the Politecnico di Milano and the company Soluzioni Ingegneria s.r.l. that develops software for dynamic vehicle simulation. It is part of a broader context of cooperation with industrial companies engaged in research on automation and sustainability in agriculture.

A team led by University of Pittsburgh’s Graham Hatfull has developed a method to construct bacteriophages with entirely synthetic genetic material, allowing researchers to add and subtract genes at will. The findings open the field to new pathways for understanding how these bacteria-killing viruses work, and for potential therapy of bacterial infections.

The work is published in the journal Proceedings of the National Academy of Sciences.

As phages’ secrets are revealed, researchers will be able to engineer them with genomes tailor-made to attack specific bacteria, leading to new ways to combat the worsening problem of antibacterial resistance.

“This will speed up discovery,” Hatfull said. There is massive variation among phages, but researchers don’t know the roles played by many individual genes. “How are the genes regulated? If a phage has 100 genes, does it need all 100? What happens if we remove this one or that one? We don’t have the answers to those questions,” he said, “but now we can ask—and answer—almost any question we have about phages.”

For this research, the team reconstructed two naturally occurring phages that attack mycobacterium (which include the pathogens responsible for tuberculosis and leprosy, among others) using synthetic material. They then added and removed genes, successfully editing the synthetic genomes of both.

“And now, the sky’s the limit,” Hatfull said. “You can make any genome you want. You’re only limited by what you can imagine would be useful and interesting to make.”

Graham collaborated with Ansa Biotech and New England Biolabs, combining their unique techniques for synthesizing and assembling DNA with his expertise in phages and mycobacterium.

Researchers at University of Tsukuba have achieved high-resolution visualization of cellular organelles, such as nuclei and mitochondria, using an external apodized phase contrast (ExAPC) microscope. By effectively suppressing halo artifacts—false images caused by light diffraction—the technique reveals the tightly regulated and remarkably stable movement, spatial arrangement, and morphology of these organelles. The team also observed unlabeled biomolecular condensate-like structures whose molecular components remain unidentified.

Cells contain various organelles, including the nucleus, which stores genetic information, and mitochondria, which generate the energy essential for biological processes. While these are “membranous organelles” enclosed by lipid bilayers, cells also contain “nonmembranous organelles” formed through molecular assembly without membrane encapsulation. The morphology, quantity, and spatial distribution of these organelles are crucial for maintaining cellular functions and determining cell fate.

Traditionally, fluorescence-based imaging has been the principal approach for visualizing organelles. However, this method has inherent limitations, including phototoxicity from intense illumination, photobleaching of fluorescent dyes, and restrictions on the number of structures that can be simultaneously observed.

To overcome these challenges, phase contrast microscopy—which enables the visualization of transparent structures without the need for staining—has regained attention. Yet, conventional phase contrast techniques are prone to halo artifacts caused by diffraction.

In their study published in The FEBS Journal, the researchers used ExAPC microscopy, which incorporates an optical mechanism to suppress halo formation. This enabled high-resolution, label-free observation of multiple organelles, including nuclei, nucleoli, and mitochondria, during dynamic cellular events such as the cell cycle.

Notably, for the first time, the researchers clearly visualized biomolecular condensate-like structures of unknown composition. Examination of lipid droplet growth, mitochondrial fission and fusion, and cellular responses to drugs revealed that while individual organelles display diverse behaviors (heterogeneity), the overall system maintains a high degree of order and stability (robustness).

These findings highlight ExAPC microscopy as a powerful tool for capturing biological dynamics in their native state. The technology holds significant potential for elucidating pathological conditions associated with altered organelle morphology, quantity, and spatial organization—such as cancer, metabolic disorders, and neurodegenerative diseases—and may contribute to the development of novel diagnostic and therapeutic strategies.

Genetic engineers can design and assemble sophisticated gene circuits to program cells with new functions, but important signaling molecules can become diluted as these cells grow and divide, causing the synthetic gene circuits to lose their new functions.

Xiaojun Tian, an associate professor in the School of Biological and Health Systems Engineering, part of the Ira A. Fulton Schools of Engineering at Arizona State University, and his team have discovered a way to protect these fragile genetic programs using a principle borrowed straight from nature.

The project is powered by interdisciplinary expertise in synthetic biology, modeling and metabolic engineering, as provided by David Nielsen, a chemical engineering professor in the School for Engineering of Matter, Transport and Energy, part of the Fulton Schools at ASU, and Wenwei Zheng, an associate professor of chemistry in the School of Applied Sciences and Arts, also part of ASU’s Fulton Schools.

In a new paper published in Cell, the researchers have outlined a technique that can stabilize synthetic gene circuits by forming small, droplet-like compartments inside cells through a process called liquid-liquid phase separation.

These microscopic droplets, called transcriptional condensates, act like molecular safe zones around key genes, shielding synthetically engineered modifications from being washed away by the tide of cell growth.

“When we try to program cells to perform useful tasks, such as diagnostics or therapeutic production, the genetic programs often fail because cell growth dilutes the key molecules needed to keep them running,” Tian says. “We addressed this challenge by tapping into the cell’s own strategy of phase separation to protect engineered systems.”

Borrowing from nature’s playbook

Cells use phase separation to organize their inner environment, creating compartments for essential biochemical reactions without the use of membranes. Tian’s team realized that by engineering similar condensates around synthetic genes, they could mimic this natural organization and maintain genetic stability across various cell generations.

“We discovered that by forming tiny droplets called transcriptional condensates around genes, we can protect genetic programs and keep them stable even as cells grow,” Zheng says. “It’s a simple physical solution that prevents dilution and keeps circuits running reliably.”

This approach represents a major shift from traditional strategies in synthetic biology, which have largely focused on tweaking DNA sequences or regulatory feedback loops to keep engineered systems functioning.

Instead of more complex control systems, Tian’s team introduced a physical design principle that leverages the existing spatial organization of molecules inside cells.

A new design for self-stabilizing, programmable cells

While natural cells have evolved to use condensates as a built-in protective system for regulating gene circuit activity, this study is among the first to show how it can be repurposed to stabilize synthetic programs.

“Cells already use these droplets to regulate themselves,” Tian says. “We’re now harnessing the same strategy for synthetic biology.”

Adopting this methodology could help researchers build more reliable biological systems that maintain predictable, productive functions.

“This opens a new way to build more reliable living systems, from stable cell factories to future medical applications,” Tian says. “Our strategy can become a new design principle for researchers who need their engineered cells to work consistently.”

Images taken via microscope from the study show bright, glowing clusters of transcriptional condensates inside cells, which serve as visual proof that droplets can form precisely where needed to stabilize gene activity.

“It’s exciting to see how these droplets can be used to boost bioproduction yields,” Nielsen says. “This kind of collaboration bridges fundamental biological insights with real metabolic engineering applications.”

Sourcing stability through collaboration

Tian’s group is already exploring how to engineer different kinds of condensates to control different genes, effectively turning them into programmable control hubs inside cells.

“We want to program different condensates to control different genes, creating smart cells that can adapt and function long-term,” he says. “We’re learning how to design with the cell, not against it.”

This approach to designing in accordance with nature rather than trying to override it represents a key turning point in the field. The next step is to demonstrate the technique’s applications for more diverse implementations to determine resilience and scalability, though researchers see no shortage in potential applications.

“Researchers in synthetic biology who struggle with unstable circuits will see this as a new way to make their systems more reliable,” Zheng says. “Bioprocess engineers who want a consistent yield can also use it. For biophysicists like me, it’s exciting to see physical principles like phase separation turned into practical engineering tools.”

“This work reflects a new direction in synthetic biology,” Tian says. “By using the cell’s own organizing principles, we can build systems that are both powerful and inherently stable.”

Children and bacteria—normally they’re a parental nightmare, a cocktail of late-night pediatrician calls and ruined weekends.

The idea of a toy filled with bacteria probably sounds like a recipe for disaster. This team of designers says otherwise.

Meet SquidKid, a prototype toy designed by Northeastern University students that is, essentially, an organic Tamagotchi. Children take care of the bioluminescent bacterial culture in this squid-shaped toy, keeping it alive and glowing. The hope for SquidKid, which earned a finalist spot in the international Biodesign Challenge, is to create not only a lasting friend but a lasting connection between children and the natural world.

“Our real goal was to create a bioreactor that would be ongoing, so you would keep a bacterial culture alive for an extended period of time like you would keep a fish tank or something,” says Deirdre Ni Chonaill, an experience design master’s student and associate director of creative and experience design at Northeastern’s Bouvé College of Health Sciences. “Kids don’t always treat their toys very well. With Tamagotchi, there are times where if you ignored it, it died. In this case, you’re actually killing something.”

Children must maintain the bacteria housed in SquidKid, providing oxygen, the right “broth,” or food, and consistent agitation. The toy is even designed with a squeezable tentacle that injects oxygen into the system and moves the bacteria, prompting them to glow.

Blending art, science, and hands-on learning

SquidKid began life in the classroom. The team of students designed it as part of their Critical Making for Adaptive Futures class taught by Katia Zolotovsky, an assistant professor of design and biotechnology.

“SquidKid, it’s not only microbiology,” Zolotovsky says. “It’s also teaching kids how to take care of the environment and then learn biology, mutualism and environmental interdependence.”

The class bridges the divide between the arts and sciences. Zolotovsky’s focus is how to leverage biotechnologies in playful yet impactful ways. In a single semester, her students learn about the basics of biotechnologies before getting their hands dirty and actually designing with biomaterials.

The tangible aspect of biomaterials helps even students who arrive with just a high school understanding of biology get by.

“When you work with materials, you immediately see results,” Zolotovsky says.

Her students have designed clothes made out of bioplastics, algae-based dining experiences, and menstrual cycle trackers made out of biomaterials. Then, there is SquidKid.

From classroom concept to competition finalist

Inspired by the Hawaiian bobtail squid and its symbiotic relationship with bioluminescent bacteria, one team of students set out to bring bioluminescence into the home.

“We just wanted to combine these spectacular bioluminescent materials with our daily life, more intimate [uses],” says Motong Shi, who graduated from Northeastern with an interaction and experience design degree in 2025.

However, as a team of four designers with mostly a high school level of biology knowledge, they had to quickly learn bacteria 101. Using Northeastern’s Wet Lab Makerspace, they conducted some disastrous early experiments.

“We went to look at an electron microscope,” says Ni Chonaill. “We wanted to see if our bacteria were alive and kicking, and we weren’t sure if they were contaminated E. coli.”

With the help of Ezri Abraham, a biology student they pulled in from another team in class, and an ecotoxicologist, they settled on a design that was compelling enough to get them a spot in the 2025 Biodesign Challenge in New York City.

Ni Chonaill and Shi were both shocked when they heard SquidKid was a finalist in the internationally-renowned design competition. Many of the other biodesign challengers had developed their ideas for much longer and with much more science or engineering expertise.

Despite their surprise, they never doubted the power of SquidKid. It might seem small, but it’s packed with big ideas and even bigger ambitions.

“What would it mean for a generation to grow up seeing bacteria as collaborators, not as threats, to recognize care as a form of intelligence and a skill, one that responds, adapts to and sustains life?” Ni Chonaill says. “We believe toys can spark that shift.”

Research led by the University of Washington reports on an AI-guided method that designs epitope-specific antibodies and confirms atomically precise binding using high-resolution molecular imaging, then strengthens those designs so the antibodies latch on much more tightly.

Why epitope targeting matters

Antibodies dominate modern therapeutics, with more than 160 products on the market and a projected value of US$445 billion in 5 years. Antibodies protect the body by locking onto a precise spot—an epitope—on a virus or toxin.

That pinpoint connection determines whether an antibody blocks infection, marks a pathogen for removal, or neutralizes a harmful protein. When a drug antibody misses its intended epitope, treatment can lose power or trigger side effects by binding the wrong target.

In medical development, knowing exactly where an antibody lands on a molecule can decide whether it succeeds in patients or fails in trials. Researchers design epitope-specific antibodies to target disease-critical regions, such as the receptor-binding tip of a virus spike or the toxic domain of a bacterial protein. Reaching that level of accuracy normally requires a slow, iterative process with years of lab work, involving animal immunization, multiple rounds of screening, and structural studies to confirm the binding site.

A reliable way to plan those interactions on a computer could make antibody creation faster and more focused, aiming at the precise molecular surfaces that control infection, toxicity, or cell signaling.

Computational efforts have largely optimized existing antibodies, and some deep learning models have proposed variants once a binder already exists. Recent generative approaches have needed a starting binder, leaving de novo, epitope-specific antibody creation as an unmet goal.

In the study, “Atomically accurate de novo design of antibodies with RFdiffusion,” published in Nature, researchers trained an AI system to build antibodies that recognize user-specified molecular sites.

The model, known as RFdiffusion, used information about antibody frameworks and target surface “hotspots” to shape new binding loops. A second network, RoseTTAFold2, predicted whether each design would fold and bind as intended, filtering out unstable or misaligned candidates.

Llama assisted research

Design efforts focused first on single-domain antibodies known as VHHs. These miniature antibodies come from animals such as llamas and alpacas and are prized in research for being stable, compact, and easy to engineer. Their small size allows them to reach crevices on viral or bacterial proteins that full-size antibodies cannot.

Researchers used a humanized VHH framework as the scaffold and aimed designs at influenza hemagglutinin, Clostridium difficile toxin B, RSV sites I and III, and the SARS-CoV-2 receptor-binding domain.

Laboratory screens used yeast surface display to test 9,000 designs per target and E. coli expression with single-concentration surface plasmon resonance to evaluate 95 designs per target. Each target posed a distinct structural challenge, from the smooth surface of influenza to the complex folds of C. difficile toxin.

Hitting the targets

Influenza designs produced several lab-made antibodies that attached to the virus protein in test tubes. High-resolution imaging showed one of those matches lining up with the computer’s plan at near-atomic detail, including how a key loop on the antibody reached the target site. Microscopic sugar on the virus shifted aside when the antibody settled in, a movement seen in the images and consistent with the planned approach.

C. difficile toxin work yielded a compact antibody that grabbed the intended site and blocked a previously designed competitor from landing there. Lab tests on cells showed protection against the toxin’s damage.

Follow-up imaging captured the same docking behavior before and after lab evolution, indicating that improvements in grip did not change where or how the antibody latched on.

Missing a few

SARS-CoV-2 tests produced a compact antibody that attached only when the virus protein moved into the “up” position and blocked a known competitor at that spot. Imaging placed the connection on the right site while revealing a different angle of approach than planned, a result labeled a design failure by the authors.

Designs aimed at a cancer-related peptide on human immune proteins showed on-target recognition in two separate assays, yet engineered T cells built from those designs did not kill tumor cell lines in lab tests.

A good start

Reported success rates remain low at 0% to 2% across targets, and authors point to improved filtering with AlphaFold3 ipTM as a route to enrichment. Prospects include faster and potentially more targeted antibody discovery as models and filters improve, with particular value for applications needing precise epitope engagement such as receptor–ligand blockade, conformational modulation, and conserved viral sites.

At the Vrije Universiteit Brussel (VUB)—Flanders Institute for Biotechnology (VIB), biologist Jessie Vandierendonck has been investigating new, alternative treatments to combat bacterial infections using (bacterio)phages, viruses that attack and destroy bacteria. The findings are published in the journal Microbiology Spectrum.

“Bacteriophages were discovered even before the first antibiotic, and today we are once again recognizing their enormous potential in the fight against antibiotic-resistant bacteria,” says Vandierendonck.

The global rise of bacteria that have become insensitive to antibiotics poses an increasing threat to public health. As conventional antibiotics are losing their effectiveness, there is an urgent need for new ways to combat bacterial infections. One of the bacteria identified by the World Health Organization as critical in the search for new treatments is Escherichia coli. While this gut bacterium is usually harmless, certain strains can cause severe infections such as intestinal diseases, urinary tract infections, and sepsis.

A bacteriophage can be compared to a kind of lunar lander that attaches itself to specific bacteria using bacterial receptors on the cell wall. Once attached, the phage injects its genetic material into the bacterial host. From that point, there are two possible pathways for reproduction.

The phage may either exploit the bacterial “machinery” to produce new phages, which eventually burst the bacterial cell and kill it, or it may integrate its genetic material into the bacterial genome in a dormant state as a “temperate” phage. The former makes bacteriophages a promising and natural tool to selectively eliminate bacteria as an alternative to antibiotics. Temperate phages, by contrast, do not necessarily kill the bacterial cells, and this is where Vandierendonck’s research comes in.

In addition to phage therapy, she also explored the use of bacterial toxin–antitoxin systems, which consist of a toxin that induces cell death and an antitoxin that counteracts its effect. By combining phages and toxins, Vandierendonck developed an innovative approach to target pathogenic E. coli bacteria. In her research, temperate phages were genetically engineered to deliver bacterial toxins to harmful bacteria. Once inside the bacterial cell, the toxin is expressed, effectively neutralizing the bacterium.

“By using phages as a delivery vehicle for toxins, we can act with high precision, thereby reducing the risk of harming beneficial bacteria, unlike traditional antibiotics,” Vandierendonck explains.

Genetically manipulating toxin-bearing phages, however, proved challenging, as cloning toxin genes can halt the growth of the bacterial host cells. To overcome this obstacle, Vandierendonck developed new cloning strategies in which toxin expression is tightly controlled at multiple levels. She also isolated phages from enterohaemorrhagic E. coli and characterized them both genetically and morphologically, including the identification of the bacterial receptors involved in infection.

As a proof of concept, she combined one of these phages with toxin genes and demonstrated in the laboratory that this recombinant phage could effectively kill the target bacterium via the toxin.

Vandierendonck obtained her Master’s degree in Biology from VUB in 2020 and subsequently began her Ph.D. within the Structural Biology Brussels research group, under the supervision of Prof. Dr. Ir. Remy Loris. During her doctoral studies, she published two first-author scientific papers, supervised Master’s students, and participated in several international conferences on bacteriophages.

“We hope this research represents a step forward in developing targeted, sustainable, and safe treatments against multidrug-resistant bacteria,” Vandierendonck concludes.