PolyP and magnesium are involved in many biological processes. Thus, the findings could lead to new methods for tuning cellular responses, which could have impactful applications in translational medicine.

The ensuing study, published in Nature Communications on October 26, 2024, reveals a delicate “Goldilocks” zone — a specific magnesium concentration range — where DNA wraps around polyP-magnesium ion condensates. Similar to a thin eggshell covering a liquid-like interior, this seemingly simple structure may help cells organize and protect their genetic material.

This work began as a collaboration between co-senior authors Associate Professor Lisa Racki, PhD, and Professor Ashok Deniz, PhD, both in the Department of Integrative Structural and Computational Biology at Scripps Research. Racki had been studying these structures in bacterial cells, while Deniz’s next-door lab was exploring the physical chemistry of biomolecular condensates for the past decade. Collaboration, they realized, was the only way to unlock these ancient interactions.

“We knew that DNA was in close proximity to the magnesium-rich polyP condensates in cells, but we were totally surprised by the beautiful spheres of DNA that lit up under the microscope,” says Racki.

“Being molecular detectives, seeing these structures raised exciting questions for us about the physics and mathematics of the DNA shells and whether they influenced the polyP condensates,” adds Deniz.

Their microscopy images revealed that DNA wraps itself around a condensate, creating a thin eggshell-like barrier. This shell could affect molecule transportation and also slow down fusion: the process where two condensates merge into one. Without DNA shells, polyP-magnesium ion condensates readily fused — like how oil drops and vinegar fuse in a salad dressing bottle when shook.

However, careful examination showed that fusion overall slowed to varying extents, depending on DNA length. Longer DNA, the researchers suspected, caused greater entanglement on condensate surfaces — similar to how long hair tangles more than short hair.

DNA is more than 1,000 times thinner in diameter than condensates, making molecular details hard to visualize. Fortunately, infrastructure to capture such imaging has been developed by two other faculty members at Scripps Research: Assistant Professor Danielle Grotjahn, PhD, and Scripps Fellow Donghyun Raphael Park, PhD.

Teaming with Park, with help from Grotjahn, the researchers used cryo-electron tomography to closely examine the condensate surfaces. Using electrons instead of light, this technique captures three-dimensional, high-resolution images of samples that were rapidly frozen to preserve their structures. The new images revealed that DNA forms filaments protruding from condensate surfaces, resembling tangled hairs.

Another crucial discovery: DNA shell formation only occurred within a specific magnesium concentration range — too much or too little, and the shell wouldn’t materialize. This “Goldilocks” effect highlights how cells can regulate condensate structure, size and function simply by tuning control parameters.

“Although we think of cellular interfaces as boundaries, they also create a new landscape by providing a surface for molecules to organize,” notes Racki. “DNA may not actually be a tangled mess at the surface and is instead organized by these condensates.”

In this context, Deniz and Racki are particularly interested in understanding DNA supercoiling — how DNA twists like a spring to fit inside cells.

“Cells have to manage their DNA curls,” explains Racki. “Interestingly, the mathematics of DNA supercoiling results in ‘action-at-a-distance’ effects — like how twisting a rope can create coils far from where you’re holding it.”

The researchers suspect that DNA interactions with polyP condensates in cells might propagate local changes in DNA supercoiling over long distances, resulting in broader changes in gene expression and cell function. Investigating this effect is one of the team’s next goals.

“We’re excited by the prospects of leveraging these discoveries to develop new tools for cellular control — potentially simpler, more cost-effective approaches to manage biomatter for biomedicine,” says Deniz.

In addition to Deniz, Racki, Grotjahn and Park, authors of the study, “Reentrant DNA shells tune polyphosphate condensate size,” include co-first authors Ravi Chawla and Jenna K. A. Tom, and Tumara Boyd, Nicholas H. Tu and Tanxi Bai of Scripps Research.

This work was supported by funding from the National Institutes of Health (NIGMS Grant R35 GM130375, Grant DP2-GM-739-140918 and S10OD032467), Scripps Research start-up funds, a Postdoctoral Fellowship from the American Heart Association (Award #903967) and the Pew Scholars Program.

But sometimes, as in the corporate world, outright theft can be a quicker way to achieve dominance.

University of California, Berkeley biologists have shown that several species of fruit fly have stolen a successful defense from bacteria to survive predation by parasitic wasps, which in some flies can turn half of all fly larvae into surrogate wombs for baby wasps — a gruesome fate that inspired the creature in the 1979 movie “Alien.”

Bacteria and other microbes are famous for stealing genes from other microbes or viruses; this so-called horizontal gene transfer is the source of troublesome antibiotic resistance among disease-causing microbes. But it’s thought to be less common in multicellular organisms, such as insects and humans. Understanding how common it is in animals and how these genes are co-opted and shared can help scientists understand the evolution of animal immune defenses and could point the way to human therapies to fight parasitic or infectious diseases or cancer, itself a kind of parasite.

“It’s a model for understanding how immune systems evolve, including our immune system, which also contains horizontally transferred genes,” said Noah Whiteman, UC Berkeley professor of molecular and cell biology and of integrative biology and director of the campus’s Essig Museum of Entomology.

Last year, the researchers and their colleagues in Hungary used CRISPR genome editing to knock out the gene responsible for the defense in one widespread fly species, Drosophila ananassae, and found that nearly all the genetically modified flies died from predation by parasitic wasps.

In a new study published Dec. 20 in the journal Current Biology, the biologists demonstrated that this defense — a gene that encodes a toxin — can be edited into the genome of the common laboratory fruit fly, Drosophila melanogaster, to make them resistant to parasitoid wasps as well. The gene essentially becomes part of the fly’s immune system, one weapon in its armamentarium to fend off parasites.

The results demonstrate how crucial the stolen defense is to fly survival and highlights a strategy that may be more common in animals that scientists suspect.

“This shows that horizontal gene transfer is an underappreciated way that rapid evolution happens in animals,” said UC Berkeley doctoral student Rebecca Tarnopol, first author of the Current Biology paper. “People appreciate horizontal gene transfer as one of the major drivers of rapid adaptation in microbes, but these events were thought to be super uncommon in animals. But at least in insects, it seems like they’re fairly frequent.”

According to Whiteman, senior author of the paper, “The study shows that in order to keep up with the barrage of parasites that are continually evolving new ways to overcome host defenses, a good strategy for animals is to borrow genes from even more rapidly evolving viruses and bacteria, and that’s just what these flies have done.”

Gene flow from virus to bacteria to fly

Whiteman studies how insects evolve to resist the toxins that plants produce to prevent being eaten. In 2023, he published a book, “Most Delicious Poison,” about the plant toxins that humans have come to enjoy, such as caffeine and nicotine.

One plant-herbivore interaction he focuses on is that between the common fruit fly Scaptomyza flava and sour-tasting mustard plants, like the cresses that grow in streams throughout the world.

“The larvae, the immature stages of the fly, live in the leaves of the plant. They’re leaf miners, they leave little trails in the leaves,” Whiteman said. “They’re true parasites of the plant and the plant’s trying to kill them with its specialized chemicals. We study that arms race.”

What he’s learned, however, likely applies to many other insects, among the most successful herbivores on Earth.

“These are obscure little flies, but if you think about the fact that half of all living insect species are herbivores, it’s a very popular life history. Understanding the evolution of that is really important for understanding evolution in general in terms of how successful herbivores are,” he said.

Several years ago, after sequencing the fly’s genome in search of genes that allow it to resist mustard toxins, he discovered an unusual gene that he learned was widespread in bacteria. A search through earlier published genome sequences turned up the same gene in a related fly, Drosophila ananassae, as well as in a bacteria that lives inside an aphid. Researchers studying the aphid uncovered a complicated story: The gene actually comes from a bacterial virus, or bacteriophage, that infects the bacteria that live inside the aphid. The bacteriophage gene, expressed by the bacteria, makes the aphid resistant to a parasitic wasp that plagues it.

These wasps lay their eggs inside the larvae, or maggots, and remain there until the larvae turn into immobile pupae, at which point the wasp eggs mature into wasp larvae that consume the fly pupa, eventually emerging as adults.

When Tarnopol first used gene editing to express the toxin gene in all cells of D. melanogaster, all the flies died. But when Tarnopol expressed the gene only in certain immune cells, the fly became as resistant to parasites as its cousin, D. ananassae.

Whiteman, Tarnopol, and their colleagues subsequently discovered that the gene found in the genome of D. ananassae — a fusion between two toxin genes, cytolethal distending toxin B (cdtB) and apoptosis inducing protein of 56kDa (aip56), that the researchers called fusionB — codes for an enzyme that cuts up DNA.

To discover how this nuclease is able to kill a wasp egg, the UC Berkeley researchers reached out to István Andó at the Institute of Genetics of the HUN-REN Biological Research Centre in Szeged, Hungary, which had previously shown that these same flies have a cellular defense against wasp eggs that essentially walls off the eggs from the fly’s body and kills them. Andó and his lab colleagues created antibodies to the toxin that allowed them to track it through the fly’s body and found that the nuclease essentially floods the fly’s body to surround and kill the egg.

“We’ve been finding this huge untapped world of humoral immune factors that might be at play in the immune system of invertebrates,” Tarnopol said. “Our paper is one of the first ones to show, at least in Drosophila, that this type of immune response might be a common mechanism by which natural enemies like wasps and nematodes are dealt with. They are way more lethal in nature than some of the microbial infections that most people work with.”

Whiteman and his colleagues are still exploring the complexities of these interactions between fly and wasp, and the cellular and genetic changes that allowed the flies to synthesize a toxin without killing itself.

“If the gene is expressed in the wrong tissue, the fly is going to die. That gene is never going to sweep through populations through natural selection,” Whiteman said. “But if it lands in a place in the genome that’s near some enhancer or some regulatory component that expresses it a little bit in fat body tissue, then you can see how it can get this leg up really quickly, you get this amazing advantage.”

Horizontal gene transfer in any organism would pose similar problems, he said, but in the arms race between predator and prey, it may be worth it.

“When you’re a poor little fruit fly, how do you deal with these pathogens and parasites that are rapidly evolving to take advantage of you?” he said. “One way is to borrow genes from bacteria and viruses because they’re rapidly evolving. It’s an ingenious strategy — instead of waiting around for your own genes to help you, take them from other organisms that are more rapidly evolving than themselves. And that seems to have happened many times independently in insects, given that so many different ones have taken up this gene. It gives us a picture of a new kind of dynamism that is occurring even in animals that have just innate immune systems and don’t have adaptive immunity.”

Whiteman’s work was funded by the National Institute of General Medical Sciences of the National Institutes of Health (R35GM119816). Other co-authors of the paper are Josephine Tamsil, Ji Heon Ha, Kirsten Verster and Susan Bernstein of UC Berkeley, Gyöngyi Cinege, Edit Ábrahám, Lilla B. Magyar and Zoltán Lipinszki of Hungary and Bernard Kim of Stanford University.

Viruses are uniquely designed to encapsulate genetic material within spherical protein shells, enabling them to replicate and invade host cells, often causing disease. Inspired by these complex structures, researchers have been exploring artificial proteins modeled after viruses. These “nanocages” mimic viral behavior, effectively delivering therapeutic genes to target cells. However, existing nanocages face significant challenges: their small size restricts the amount of genetic material they can carry, and their simple designs fall short of replicating the multifunctionality of natural viral proteins.

To address these limitations, the research team used AI-driven computational design. While most viruses display symmetrical structures, they also feature subtle asymmetries. Leveraging AI, the team recreated these nuanced characteristics and successfully designed nanocages in tetrahedral, octahedral, and icosahedral shapes for the first time.

The resulting nanostructures are composed of four types of artificial proteins, forming intricate architectures with six distinct protein-protein interfaces. Among these, the icosahedral structure, measuring up to 75 nanometers in diameter, stands out for its ability to hold three times more genetic material than conventional gene delivery vectors, such as adeno-associated viruses (AAV), marking a significant advancement in gene therapy.

Electron microscopy confirmed the AI-designed nanocages achieved precise symmetrical structures as intended. Functional experiments further demonstrated their ability to effectively deliver therapeutic payloads to target cells, paving the way for practical medical applications.

“Advancements in AI have opened the door to a new era where we can design and assemble artificial proteins to meet humanity’s needs,” said Professor Sangmin Lee. “We hope this research not only accelerates the development of gene therapies but also drives breakthroughs in next-generation vaccines and other biomedical innovations.”

Professor Lee previously worked as a postdoctoral researcher in Professor Baker’s laboratory at the University of Washington for nearly three years, from February 2021 to late 2023, before joining POSTECH in January 2024.

This study was supported by the Republic of Korea’s Ministry of Science and ICT under the Outstanding Young Scientist Program, the Nano and Material Technology Development Program, and the Global Frontier Research Program, with additional funding provided by the Howard Hughes Medical Institute (HHMI) in the United States.

Lithium-ion batteries are indispensable in applications such as electric vehicles and energy storage systems (ESS). The lithium-rich layered oxide (LLO) material offers up to 20% higher energy density than conventional nickel-based cathodes by reducing the nickel and cobalt content while increasing the lithium and manganese composition. As a more economical and sustainable alternative, LLO has garnered significant attention. However, challenges such as capacity fading and voltage decay during charge-discharge cycles have hindered its commercial viability.

While previous studies have identified structural changes in the cathode during cycling as the cause of these issues, the exact reasons behind the instability have remained largely unclear. Additionally, existing strategies aimed at enhancing the structural stability of LLO have failed to resolve the root cause, hindering commercialization.

The POSTECH team focused on the pivotal role of oxygen release in destabilizing the LLO structure during the charge-discharge process. They hypothesized that improving the chemical stability of the interface between the cathode and the electrolyte could prevent oxygen from being released. Building on this idea, they reinforced the cathode-electrolyte interface by improving the electrolyte composition, which resulted in a significant reduction in oxygen emissions.

The research team’s enhanced electrolyte maintained an impressive energy retention rate of 84.3% even after 700 charge-discharge cycles, a significant improvement over conventional electrolytes, which only achieved an average of 37.1% energy retention after 300 cycles.

The research also revealed that structural changes on the surface of the LLO material had a significant impact on the overall stability of the material. By addressing these changes, the team was able to dramatically improve the lifespan and performance of the cathode while also minimizing unwanted reactions like electrolyte decomposition inside the battery.

Professor Jihyun Hong commented, “Using synchrotron radiation, we were able to analyze the chemical and structural differences between the surface and interior of the cathode particles. This revealed that the stability of the cathode surface is crucial for the overall structural integrity of the material and its performance. We believe this research will provide new directions for developing next-generation cathode materials.”

This research was supported by the Ministry of Trade, Industry and Energy through the Korea Institute for Advancement of Technology, and the Ministry of Science and ICT through the National Research Foundation of Korea, with funding for 2024.

“With many current drugs to prevent migraine, it takes time to find the right dosage for the individual and it can take weeks or even months for it to be most effective,” said study author Richard B. Lipton, MD, of Albert Einstein College of Medicine in the Bronx, New York, and a Fellow of the American Academy of Neurology. “Some people give up and stop taking the drugs before they reach this point. Plus, many people experience side effects with current treatments. Developing a drug that works both effectively and quickly is critical.”

In the study, people taking the drug atogepant were less likely to have a migraine on the first day of taking the drug compared to those taking a placebo. They also had fewer migraines per week during each of the first four weeks of the study and fewer migraines during the study overall than those taking a placebo.

For this study, researchers looked at the data from three trials on the safety and effectiveness of atogepant over 12 weeks to focus on how rapidly improvements appeared. The ADVANCE trial, which enrolled people with episodic migraine, had 222 people taking the drug and 214 taking placebo. The ELEVATE trial, which enrolled people with episodic migraine who had previously not responded well to other oral preventive treatments, had 151 on the drug and 154 on placebo. The PROGRESS trial, which enrolled people with chronic migraine, had 256 on the drug and 246 on placebo.

People with episodic migraine experience up to 14 migraine days per month. People with chronic migraine experience at least 15 days with headache per month, with at least eight days being characteristic of migraine.

On the first day of the study, 12% of those taking the drug in the first trial, the ADVANCE trial had a migraine, compared to 25% of those taking placebo. In the second trial, the ELEVATE trial, the numbers were 15% and 26%. For the third trial, the PROGRESS trial, the numbers were 51% and 61%.

When researchers adjusted for other factors that could affect the rate of migraine, they found that people taking the drug were 61% less likely to have a migraine in the first trial, 47% less likely in the second trial, and 37% less likely in the third trial.

For the first two trials, the people taking atogepant had an average of one fewer day with migraine per week, compared to an average of less than one-half day fewer per week for those taking the placebo. For the third trial, average migraine days per week declined by about 1.5 days for those taking the drug compared to about one day for those taking the placebo.

The people taking atogepant also showed improvement on assessments of how much migraine impaired their activities and their overall quality of life compared to people taking the placebo.

“Migraine is the second-leading cause of disability in the overall population and the leading cause of disability in young women, with people reporting negative effects on their relationships, parenting, career and finances,” Lipton said. “Having a treatment that can act quickly and effectively addresses a key need.”

A limitation of the study is that it involved mostly female and white participants, so the results may not apply to the overall population.

The study was supported by AbbVie, the maker of atogepant.

The application in live mice shows the improved efficiency of the tool, called SPLICER, over the current standard in gene editing technology, as well as the potential for application in other diseases, the researchers said. Led by Pablo Perez-Pinera, a professor of bioengineering at the U. of I., the researchers published their findings in the journal Nature Communications.

SPLICER uses a gene editing approach called exon skipping, which is of particular interest for health conditions caused by mutations that produce misfolded or toxic proteins, such as Duchenne’s muscular dystrophy or Huntington’s disease.

“DNA contains the instructions to build everything that is responsible for how cells function. So it’s like a book of recipes that contains very detailed instructions for cooking,” Perez-Pinera said. “But there are large regions of DNA that don’t code for anything. It’s like, you start the recipe for a turkey dinner, and then you hit a note that says, ‘continued on page 10.’ After page 10, it’s ‘continued on page 25.’ The pages between are gibberish.

“But say on one of the recipe pages — in genetics, an exon — there is a typo that makes the turkey inedible, or even poisonous. If we cannot correct the typo directly, we could amend the note before it to send you to the next page, skipping over the page with the error, so that at the end you could make an edible turkey. Though you might lose out on the gravy that was on the skipped page, you’d still have dinner. In the same way, if we can skip the piece of the gene with the toxic mutation, the resulting protein could still have enough function to perform its critical roles.”

SPLICER builds upon the popular CRISPR-Cas9 gene editing platform — with key changes. CRISPR-Cas9 systems require a specific DNA sequence to latch on, limiting which genes could be edited. SPLICER uses newer Cas9 enzymes that do not need that sequence, opening up the door to new targets like the Alzheimer’s-related gene that the Illinois group focused on.

“Another problem we address in our work is precision in what gets skipped,” said graduate student Angelo Miskalis, a co-first author of the paper. “With current exon-skipping techniques, sometimes not all of the exon gets skipped, so there’s still part of the sequence we don’t want expressed. In the cookbook analogy, it’s like trying to skip a page, but the new page starts in the middle of a sentence, and now the recipe doesn’t make sense. We wanted to prevent that.”

There are two key sequence areas surrounding an exon that tell the cellular machinery which parts of a gene to use for making proteins: one at the beginning and one at the end. While most exon-skipping tools target only one sequence, SPLICER edits both the starting and ending sequences. As a result, the targeted exons are skipped over more efficiently, Miskalis said.

The Illinois group chose to target an Alzheimer’s gene for the first demonstration of SPLICER’s therapeutic abilities because while the target gene has been well-studied, efficient exon skipping has remained elusive in living organisms. The researchers targeted a specific exon coding for an amino acid sequence within a protein that gets cleaved to form amyloid-beta, which accumulates to form plaques on neurons in the brain as the disease progresses.

In cultured neurons, SPLICER reduced the formation of amyloid-beta efficiently. When analyzing the DNA and RNA output of mouse brains, the researchers found that the targeted exon was decreased by 25% in the SPLICER-treated mice, with no evidence of off-target effects.

“When we originally tried to target this exon with older techniques, it didn’t work,” said graduate student Shraddha Shirguppe, also a co-first author of the study. “Combining the newer base editors with dual splice editing skipped the exon at a much better rate than we were previously able to with any of the available methods. We were able to show that not only could it skip the whole exon better, it reduced the protein that produces the plaque in these cells.”

“Exon skipping only works if the resulting protein is still functional, so it can’t treat every disease with a genetic basis. That’s the overall limitation of the approach,” Perez-Pinera said. “But for diseases like Alzheimer’s, Parkinson’s, Huntington’s or Duchenne’s muscular dystrophy, this approach holds a lot of potential. The immediate next step is to look at the safety of removing the targeted exons in these diseases, and make sure we aren’t creating a new protein that is toxic or missing a key function. We would also need to do longer term animal studies and see if the disease progresses over time.”

At Illinois, Perez-Pinera also is affiliated with the department of Molecular and Integrative Physiology, the Carle Illinois College of Medicine, the Cancer Center at Illinois and the Carl R. Woese Institute for Genomic Biology. U. of I. Bioengineering professors Sergei Maslov and Thomas Gaj were coauthors of the paper. The National Institutes of Health, the Muscular Dystrophy Association, the American Heart Association, the Parkinson’s Disease Foundation and the Simons Foundation supported this work.

This work was supported by the National Institutes of Health grants 1U01NS122102, 1R01NS123556, 1R01GM141296, 1R01GM127497, T32EB019944 and 1R01GM131272.

The research involved a bismuth complex synthesized in the group of Josep Cornella (MPI KOFO). This molecule has unique magnetic properties that a team led by Frank Neese (MPI KOFO) recently predicted in theoretical studies. So far, however, all attempts to measure the magnetic properties of the bismuth complex and thus experimentally confirm the theoretical predictions have failed.

This important step has now been achieved by using THz electron paramagnetic resonance spectroscopy (THz-EPR) at the synchrotron radiation source BESSY II, which is operated by the HZB in Berlin.

“The results show in a fascinating way that our method can be used to determine extremely high values of the magnetic anisotropy with high accuracy. Through our cooperation with scientists from fundamental research, we are thereby making a great step forward in the understanding of this class of materials,” says Tarek Al Said (HZB), first author of the study, which was recently published in the Journal of the American Chemical Society.