biochemistry

Tiny, 45 base long RNA can make copies of itself

biochemistry, Biology, evolution, origin of life, ribozymes, RNA, Science / Shannon Garcia / February 13, 2026

Self-copying RNAs may have been a key stop along the pathway to life.

By base pairing with themselves, RNAs can form complex structures with enzymatic activity. Credit: Laguna Design

There are plenty of unanswered questions about the origin of life on Earth. But the research community has largely reached consensus that one of the key steps was the emergence of an RNA molecule that could replicate itself. RNA, like its more famous relative DNA, can carry genetic information. But it can also fold up into three-dimensional structures that act as catalysts. These two features have led to the suggestion that early life was protein-free, with RNA handling both heredity and catalyzing a simple metabolism.

For this to work, one of the reactions that the early RNAs would need to catalyze is the copying of RNA molecules, without which any sort of heritability would be impossible. While we’ve found a number of catalytic RNAs that can copy other molecules, none have been able to perform a key reaction: making a copy of themselves. Now, however, a team has found an incredibly short piece of RNA—just 45 bases long—that can make a copy of itself.

Finding an RNA polymerase

We have identified a large number of catalytic RNAs (generically called ribozymes, for RNA-based enzymes), and some of them can catalyze reactions involving other RNAs. A handful of these are ligases, which link together two RNA molecules. In some cases, they need these molecules to be held together by a third RNA molecule that base pairs with both of them. We’ve only identified a few that can act as polymerases, which add RNA bases to a growing molecule, one at a time, with each new addition base pairing with a template molecule.

Black on white image showing 3 different enzymatic activities. One links any two nucleic acid strands, the other only links base paired strands, and the third links one base at a time. — Some ligases can link two nucleic acid strands (left), while others can link the strands only if they’re held together by base pairing with a template (center). A polymerase can be thought of as a template-dependent ligase that adds one base at a time. The newly discovered ribozyme sits somewhere between a template-directed ligase and a polymerase. Credit: John Timmer

Obviously, there is some functional overlap between them, as you can think of a polymerase as ligating on one base at a time. And in fact, at the ribozyme level, there’s some real-world overlap, as some ribozymes that were first identified as ligases were converted into polymerases by selecting for this new function.

While this is fascinating, there are a few problems with these known examples of polymerase ribozymes. One is that they’re long. So long, in fact, that they’re beyond the length of the sort of molecules that we’ve observed forming spontaneously from a mix of individual RNA bases. This length also means they’re largely incapable of making copies of themselves—the reactions are slow and inefficient enough that they simply stop before copying the entire molecule.

Another factor related to their length is that they tend to form very complex structures, with many different areas of the molecule base-paired to one another. That leaves very little of the molecule in a single-stranded form, which is needed to make a copy.

Based on past successes, a French-UK team decided to start a search for a polymerase by looking for a ligase. And they limited that search in an important way: They only tested short molecules. They started with pools of RNA molecules, each with a different random sequence, ranging from 40 to 80 bases. Overall, they estimated that they made a population of 10¹³ molecules out of the total possible population of 10²⁴ sequences of this type.

These random molecules were fed a collection of three-base-long RNAs, each linked to a chemical tag. The idea was that if a molecule is capable of ligating one of these short RNA fragments to itself, it could be pulled out using the tag. The mixtures were then placed in a salty mixture of water and ice, as this can promote reactions involving RNAs.

After 11 rounds of reactions and tag-based purification, the researchers ended up with three different RNA molecules that could each ligate three-base-long RNAs to existing molecules. Each of these molecules was subjected to mutagenesis and further rounds of selection. This ultimately left the researchers with a single, 51-base-long molecule that could add clusters of three bases to a growing RNA strand, depending on their ability to base-pair with an RNA template. They called this “polymerase QT-51,” with QT standing for “quite tiny.” They later found that they could shorten this to QT-45 without losing significant enzyme activity.

Checking its function

The basic characterization of QT-45 showed that it has some very impressive properties for a molecule that, by nucleic acid standards, is indeed quite tiny. While it was selected for linking collections of molecules that were three bases long, it could also link longer RNAs, work on shorter two-base molecules, or even add a single base at a time, though this was less efficient. While it worked slowly, the molecule’s active half-life was well over 100 days, so it had plenty of time to get things done before it degraded.

It also didn’t need to interact with any specific RNA sequences to work, suggesting it had a general affinity for RNA molecules. As a result, it wasn’t especially picky about the sequences it could copy.

As you might expect from such a small molecule, QT-45 didn’t tolerate changes to its own sequence very well—nearly the entire molecule was important in one way or another. Tests that involved changing every single individual base one at a time showed that almost all the changes reduced the ribozyme’s activity. There were, however, a handful of changes that improved things, suggesting that further selection could potentially yield additional improvements. And the impact of mutations near the center of the sequence was far more severe, suggesting that region is critical for QT-45’s enzymatic activity.

The team then started testing its ability to synthesize copies of other RNA molecules when given a mixture of all possible three-base sequences. One of the tests included a large stretch in which one end of the sequence base-paired with the other. To copy that, those base pairs need to somehow be pried apart. But QT-45 was able to make a copy, meaning it synthesized a strand that was able to base pair with the original.

It was also able to make a copy of a template strand that would base pair with a small ribozyme. That copying produced an active ribozyme.

But the key finding was that it could synthesize a sequence that base-pairs with itself, and then synthesize itself by copying that sequence. This was horribly inefficient and took months, but it happened.

Throughout these experiments, the fidelity averaged about 95 percent, meaning that, in copying itself, it would make an average of two to three errors. While this means a fair number of its copies wouldn’t be functional, it also means the raw materials for an evolutionary selection for improved function—random mutations—would be present.

What this means

It’s worth taking a moment to consider the use of three-base RNA fragments by this enzyme. On the surface, this may seem a bit like cheating, since current RNA polymerases add sequence one base at a time. But in reality, any chemical environment that could spontaneously assemble an RNA molecule 45 bases long will produce many fragments shorter than that. So in many ways, this might be a more realistic model of the conditions in which life emerged.

The authors note that these shorter fragments may be essential for QT-45’s activity. The short ribozyme probably doesn’t have the ability to enzymatically pry base-paired strands of RNA apart to copy them. But in a mixture of lots of small fragments, there’s likely to be an equilibrium, with some base-paired sequences spontaneously popping open and temporarily base pairing with a shorter fragment. Working with these base-paired fragments is probably essential to the ribozyme’s overall activity.

Right now, QT-45 isn’t an impressive enzyme. But the researchers point out that it has only been through 18 rounds of selection, which isn’t much. The most efficient ribozyme polymerases we have at present have been worked on by multiple labs for years. I expect QT-45 to receive similar attention and improve significantly over time.

Also notable is that the team came up with three different ligases in a test of just a small subset of the possible total RNA population of this size. If that frequency holds, there are on the order of 10¹¹ ligating ribozymes among the sequences of this size. Which raises the possibility that we could find far more if we do an exhaustive search. That suggests the first self-copying RNA might not be as improbable as it seems at first.

Science, 2026. DOI: 10.1126/science.adt2760 (About DOIs).

John is Ars Technica’s science editor. He has a Bachelor of Arts in Biochemistry from Columbia University, and a Ph.D. in Molecular and Cell Biology from the University of California, Berkeley. When physically separated from his keyboard, he tends to seek out a bicycle, or a scenic location for communing with his hiking boots.

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Fungus could be the insecticide of the future

biochemistry, Biology, fungus, insecticides, pine beetles, Science / Kelly Newman / February 1, 2026

Exterminators keep getting calls for a reason. Wood-devouring insects, such as beetles, termites, and carpenter ants, are constantly chewing through walls or infecting trees and breaking them down. The fight against these insects usually involved noxious insecticides; but now, at least some of them can be eliminated using a certain species of fungus.

Infestations of bark beetles are the bane of spruce trees. Eurasian spruce bark beetles (Ips typographus) ingest bark high in phenolic compounds, organic molecules that often act as antioxidants and antimicrobials. They protect spruce bark from pathogenic fungi—and the beetles take advantage. Their bodies boost the antimicrobial power of these compounds by turning them into substances that are even more toxic to fungi. This would seem to make the beetles invulnerable to fungi.

There is a way to get past the beetles’ borrowed defenses, though. Led by biochemist Ruo Sun, a team of researchers from the Max Planck Institute for Chemical Ecology in Jena, Germany, found that some strains of the fungus Beauveria bassiana are capable of infecting and killing the pests.

“Insect herbivores have long been known to accumulate plant defense metabolites from their diet as defenses against their own enemies,” she said in a study recently published in PNAS. “However, as shown here for B. bassiana, fungal pathogens are able to circumvent the toxicity of these dietary defenses and cause disease.”

First line of defense

Populations of bark beetles have recently exploded in temperate forests because of climate change. One species they feed on is the Norway spruce (Picea abies), which makes organic phenolic compounds known as stilbenes and flavonoids. Stilbenes are hydrocarbons that function as secondary metabolites for plants, and flavonoids, which are polyphenols, are also secondary plant metabolites that are often antioxidants. The spruce links both classes of compounds with sugars and relies on their antibacterial and antifungal activity.

When metabolized by the beetles, the spruce sugars are removed through hydrolysis, converting them into aglycones that are even more toxic to microscopic invaders. Despite that, some fungi appear to be able to deactivate these compounds. Strains of the fungal insect pathogen B. bassiana have been documented as killing some of these beetles in the wild.

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Neural network finds an enzyme that can break down polyurethane

AI, biochemistry, Biology, chemistry, enzymes, neural networks, polymers, polyurethane, protein design, proteins, Science / Beth Washington / November 1, 2025

You’ll often hear plastic pollution referred to as a problem. But the reality is that it’s multiple problems. Depending on the properties we need, we form plastics out of different polymers, each of which is held together by a distinct type of chemical bond. So the method we use to break down one type of polymer may be incompatible with the chemistry of another.

That problem is why, even though we’ve had success finding enzymes that break down common plastics like polyesters and PET, they’re only partial solutions to plastic waste. However, researchers aren’t sitting back and basking in the triumph of partial solutions, and they’ve now got very sophisticated protein design tools to help them out.

That’s the story behind a completely new enzyme that researchers developed to break down polyurethane, the polymer commonly used to make foam cushioning, among other things. The new enzyme is compatible with an industrial-style recycling process that breaks the polymer down into its basic building blocks, which can be used to form fresh polyurethane.

Breaking down polyurethane

Image of a set of chemical bonds. From left to right there is an X, then a single bond to an oxygen, then a single bond to an oxygen that's double-bonded to carbon, then a single bond to a nitrogen, then a single bond to another X. — The basics of the chemical bonds that link polyurethanes. The rest of the polymer is represented by X’s here.

The new paper that describes the development of this enzyme lays out the scale of the problem: In 2024, we made 22 million metric tons of polyurethane. The urethane bond that defines these involves a nitrogen bonded to a carbon that in turn is bonded to two oxygens, one of which links into the rest of the polymer. The rest of the polymer, linked by these bonds, can be fairly complex and often contains ringed structures related to benzene.

Digesting polyurethanes is challenging. Individual polymer chains are often extensively cross-linked, and the bulky structures can make it difficult for enzymes to get at the bonds they can digest. A chemical called diethylene glycol can partially break these molecules down, but only at elevated temperatures. And it leaves behind a complicated mess of chemicals that can’t be fed back into any useful reactions. Instead, it’s typically incinerated as hazardous waste.

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New pathway engineered into plants lets them suck up more CO₂

biochemistry, Biology, carbon dioxide, metabolism, photosynthesis, plants, Science / Shannon Garcia / September 12, 2025

And, well, it worked remarkably well. The plants carrying all the genes for the McG cycle weighed two to three times as much as control plants that only had some of the genes. They had more leaves, the leaves themselves were larger, and the plants produced more seeds. In a variety of growing conditions, the plants with an intact McG cycle incorporated more carbon, and they did so without increasing their water uptake.

Having a two-carbon output also worked as expected. By feeding the plants radioactive bicarbonate, they were able to trace the carbon showing up in the expected molecules. And imaging confirmed that the plants were making so many lipids that their cells formed internal pockets containing nothing but fatty materials. Triglyceride levels increased by factors of 100 or more.

So, by a variety of measures, the plants actually did better with an extra pathway for fixing carbon. There are a number of cautions, though. For starters, it’s not clear whether what we’re learning using a small weed will also apply to larger plants or crops, or really anything much beyond Arabidopsis at the moment. It could be that having excess globs of fat floating around the cell has consequences for something like a tree. Plants grown in a lab also tend to be provided with a nutrient-rich soil, and it’s not clear whether all of this would apply to a range of real-world conditions.

Finally, we can’t say whether all the excess carbon these plants are sucking in from the atmosphere would end up being sequestered in any useful sense. It could be that all the fat would just get oxidized as soon as the plant dies. That said, there are a lot of approaches to making biofuel that rely on modifying the fats found in plants or algae. It’s possible that this can eventually help make biofuels efficient so they actually have a net positive effect on the climate.

Regardless of practical impacts, however, it’s pretty amazing that we’ve now reached the point where we can fundamentally rewire a bit of metabolism that has been in operation for billions of years without completely messing up plants.

Science, 2025. DOI: 10.1126/science.adp3528 (About DOIs).

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Researchers engineer bacteria to produce plastics

biochemistry, bioengineering, Biology, chemistry, plastics, Science / Shannon Garcia / March 18, 2025

Image of a series of chemical reactions, with enzymes driving each step forward. — One of the enzymes used in this system takes an amino acid (left) and links it to Coenzyme A. The second takes these items and links them into a polymer. Credit: Chae et. al.

Normally, PHA synthase forms links between molecules that run through an oxygen atom. But it’s also possible to form a related chemical link that instead runs through a nitrogen atom, like those found on amino acids. There were no known enzymes, however, that catalyze these reactions. So, the researchers decided to test whether any existing enzymes could be induced to do something they don’t normally do.

The researchers started with an enzyme from Clostridium that links chemicals to Coenzyme A that has a reputation for not being picky about the chemicals it interacts with. This worked reasonably well at linking amino acids to Coenzyme A. For linking the amino acids together, they used an enzyme from Pseudomonas that had four different mutations that expanded the range of molecules it would use as reaction materials. Used in a test tube, the system worked: Amino acids were linked together in a polymer.

The question was whether it would work in cells. Unfortunately, one of the two enzymes turns out to be mildly toxic to E. coli, slowing its growth. So, the researchers evolved a strain of E. coli that could tolerate the protein. With both of these two proteins, the cells produced small amounts of an amino acid polymer. If they added an excess of an amino acid to the media the cells were growing in, the polymer would be biased toward incorporating that amino acid.

Boosting polymer production

However, the yield of the polymer by weight of bacteria was fairly low. “It was reasoned that these [amino acids] might be more efficiently incorporated into the polymer if generated within the cells from a suitable carbon source,” the researchers write. So, the researchers put in extra copies of the genes needed to produce one specific amino acid (lysine). That worked, producing more polymer, with a higher percentage of the polymer being lysine.

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Small charges in water spray can trigger the formation of key biochemicals

biochemistry, Biology, chemistry, origin of life, Physics, Science / Beth Washington / March 16, 2025

Once his team nailed how droplets become electrically charged and how the micro-lightning phenomenon works, they recreated the Miller-Urey experiment. Only without the spark plugs.

Ingredients of life

After micro-lightnings started jumping between droplets in a mixture of gases similar to that used by Miller and Urey, the team examined their chemical composition with a mass spectrometer. They confirmed glycine, uracil, urea, cyanoethylene, and lots of other chemical compounds were made. “Micro-lightnings made all organic molecules observed previously in the Miller-Urey experiment without any external voltage applied,” Zare claims.

But does it really bring us any closer to explaining the beginnings of life? After all, Miller and Urey already demonstrated those molecules could be produced by electrical discharges in a primordial Earth’s atmosphere—does it matter all that much where those discharges came from? Zare argues that it does.

“Lightning is intermittent, so it would be hard for these molecules to concentrate. But if you look at waves crashing into rocks, you can think the spray would easily go into the crevices in these rocks,” Zare suggests. He suggests that the water in these crevices would evaporate, new spray would enter and evaporate again and again. The cyclic drying would allow the chemical precursors to build into more complex molecules. “When you go through such a dry cycle, it causes polymerization, which is how you make DNA,” Zare argues. Since sources of spray were likely common on the early Earth, Zare thinks this process could produce far more organic chemicals than potential alternatives like lightning strikes, hydrothermal vents, or impacting comets.

But even if micro-lightning really produced the basic building blocks of life on Earth, we’re still not sure how those combined into living organisms. “We did not make life. We just demonstrated a possible mechanism that gives us some chemical compounds you find in life,” Zare says. “It’s very important to have a lot of humility with this stuff.”

Science Advances, 2025. DOI: 10.1126/sciadv.adt8979

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AI used to design a multi-step enzyme that can digest some plastics

AI, biochemistry, Biology, catalysts, chemistry, Computer science, enzymes, Science / Mike M. / February 16, 2025

And it worked. Repeating the same process with an added PLACER screening step boosted the number of enzymes with catalytic activity by over three-fold.

Unfortunately, all of these enzymes stalled after a single reaction. It turns out they were much better at cleaving the ester, but they left one part of it chemically bonded to the enzyme. In other words, the enzymes acted like part of the reaction, not a catalyst. So the researchers started using PLACER to screen for structures that could adopt a key intermediate state of the reaction. This produced a much higher rate of reactive enzymes (18 percent of them cleaved the ester bond), and two—named “super” and “win”—could actually cycle through multiple rounds of reactions. The team had finally made an enzyme.

By adding additional rounds alternating between structure suggestions using RFDiffusion and screening using PLACER, the team saw the frequency of functional enzymes increase and eventually designed one that had an activity similar to some produced by actual living things. They also showed they could use the same process to design an esterase capable of digesting the bonds in PET, a common plastic.

If that sounds like a lot of work, it clearly was—designing enzymes, especially ones where we know of similar enzymes in living things, will remain a serious challenge. But at least much of it can be done on computers rather than requiring someone to order up the DNA that encodes the enzyme, getting bacteria to make it, and screening for activity. And despite the process involving references to known enzymes, the designed ones didn’t share a lot of sequences in common with them. That suggests there should be added flexibility if we want to design one that will react with esters that living things have never come across.

I’m curious about what might happen if we design an enzyme that is essential for survival, put it in bacteria, and then allow it to evolve for a while. I suspect life could find ways of improving on even our best designs.

Science, 2024. DOI: 10.1126/science.adu2454 (About DOIs).

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Researchers use AI to design proteins that block snake venom toxins

AI, anti-toxin, biochemistry, Computer science, protein design, Science, snakes, venom / Mike M. / January 15, 2025

Since these two toxicities work through entirely different mechanisms, the researchers tackled them separately.

Blocking a neurotoxin

The neurotoxic three-fingered proteins are a subgroup of the larger protein family that specializes in binding to and blocking the receptors for acetylcholine, a major neurotransmitter. Their three-dimensional structure, which is key to their ability to bind these receptors, is based on three strings of amino acids within the protein that nestle against each other (for those that have taken a sufficiently advanced biology class, these are anti-parallel beta sheets). So to interfere with these toxins, the researchers targeted these strings.

They relied on an AI package called RFdiffusion (the RF denotes its relation to the Rosetta Fold protein-folding software). RFdiffusion can be directed to design protein structures that are complements to specific chemicals; in this case, it identified new strands that could line up along the edge of the ones in the three-fingered toxins. Once those were identified, a separate AI package, called ProteinMPNN, was used to identify the amino acid sequence of a full-length protein that would form the newly identified strands.

But we’re not done with the AI tools yet. The combination of three-fingered toxins and a set of the newly designed proteins were then fed into DeepMind’s AlfaFold2 and the Rosetta protein structure software, and the strength of the interactions between them were estimated.

It’s only at this point that the researchers started making actual proteins, focusing on the candidates that the software suggested would interact the best with the three-fingered toxins. Forty-four of the computer-designed proteins were tested for their ability to interact with the three-fingered toxin, and the single protein that had the strongest interaction was used for further studies.

At this point, it was back to the AI, where RFDiffusion was used to suggest variants of this protein that might bind more effectively. About 15 percent of its suggestions did, in fact, interact more strongly with the toxin. The researchers then made both the toxin and the strongest inhibitor in bacteria and obtained the structure of their interactions. This confirmed that the software’s predictions were highly accurate.

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How can you write data to DNA without changing the base sequence?

biochemistry, Biology, DNA storage, epigenetics, Science, Storage / Beth Washington / October 29, 2024

The developers of the system call each of these potentially modifiable spots on the template an epi-bit, with the modified version corresponding to a 1 in a conventional computer bit and the unmodified version corresponding to a 0. Because no synthesis is required, multiple bits can be written simultaneously. To read the information, the scientists rigged the system so that 1s fluoresce and 0s don’t. The fluorescence, along with the sequences of bases, was read as the DNA was passed through a tiny pore.

Pictures in a meta-genome

Using this system, Zhang et al. created five DNA templates and 175 bricks to record 350 bits at a time. Using a collection of tagged template molecules, the researchers could store and read roughly 275,000 bits, including a color picture of a panda’s face and a rubbing of a tiger from the Han dynasty, which ruled China from 202 BCE to 220 CE.

They then had 60 student volunteers “with diverse academic backgrounds” store texts of their choice in epi-bits using a simple kit in a classroom. Twelve of the 15 stored texts were read successfully.

We’re not quite ready for your cat videos yet, though. There are still errors in the printing and reading steps, and since these modifications don’t survive when DNA is copied, making additional versions of the stored information may get complicated. Plus, the stability of these modifications under different storage conditions remains unknown, although the authors note that their epi-bits stayed stable at temperatures of up to 95o° C.

But once these and a few other problems are solved—and the technology is scaled up, further optimized and automated, and/or tweaked to accommodate other types of epigenetic modifications—it will be a clever and novel way to harness natural data storage methods for our needs.

Nature, 2024. DOI: 10.1038/s41586-024-08040-5

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Mice made transparent with a dye used in Doritos

biochemistry, Biology, optics, refractive index, Science, transparency / DJ Henderson / September 16, 2024

Under the skin —

Matching refractive indexes lets some wavelengths pass cleanly through the skin.

Jacek Krywko – Sep 16, 2024 4: 58 pm UTC

Enlarge / Zihao Ou, who helped develop this solution, holds a tube of it.

One key challenge in medical imaging is to look past skin and other tissue that are opaque to see internal organs and structures. This is the reason we need things like ultrasonography, magnetic resonance, or X-rays. There are chemical clearing agents that can make tissue transparent, like acrylamide or tetrahydrofuran, but they are almost never used in living organisms because they’re either highly toxic or can dissolve away essential biomolecules.

But now, a team of Stanford University scientists has finally found an agent that can reversibly make skin transparent without damaging it. This agent was tartrazine, a popular yellow-orange food dye called FD&C Yellow 5 that is notably used for coloring Doritos.

Playing with light

We can’t see through the skin because it is a complex tissue comprising aqueous-based components such as cell interiors and other fluids, as well as protein and lipids. The refractive index is a value that indicates how much light slows down (on average, of course) while going through a material compared to going through a vacuum. The refractive index of those aqueous components is low, while the refractive index of the proteins and lipids is high. As a result, light traveling through skin constantly bends as it endlessly crosses the boundary between high and low refractive index materials.

This scatters the light—once it penetrates the skin, it never gets back. What we see is just the light that bounces off the skin’s surface. The trick to making things transparent is mostly about making their refractive index uniform, so light, or at least some part of the spectrum, doesn’t bend all the time and doesn’t get scattered. This is exactly where the Doritos dye came in.

“The most surprising part of this study is that we usually expect dye molecules to make things less transparent,” says Guosong Hong, an assistant professor of materials science and engineering at Stanford and senior author of the paper. “For example, if you mix blue pen ink in water, the more ink you add, the less light can pass through the water. However, in our experiment, when we dissolve tartrazine in an opaque material like muscle or skin, which normally scatters light, the more tartrazine we add, the clearer the material becomes. This goes against what we typically expect with dyes.”

Transparency lotion

Hong’s team simply dissolved the dye in an aqueous solution and created a transparency-inducing lotion of sorts. It worked, because the dye reduced the difference in refractive index between water and lipids in the skin. Then the team started massaging it gently into a bit of polymer gel that emulated the light-scattering properties of tissue. From there, they moved to thinly sliced chicken breasts and to live mice.

The “transparency lotion” needed just a few minutes to start working when applied to a mouse’s skin. Massaged into a shaven scalp, it lets the scientists see the cerebral blood vessels with laser speckle contrast imaging, a technique that normally requires removal of the scalp to work. When applied to the mouse’s abdomen, it made all the internal organs, including the liver, bladder, and small intestine, visible to the naked eye. All that was needed to reverse the effect and make the skin opaque again was washing the lotion off with water.

There were some problems, though. One of them was that tartrazine absorbed most light at wavelengths around 257 and 428 nanometers, which let us see shades of violet and blue. On the other hand, it had minimal absorption above 600 nanometers, which meant that the transparent skin tinted everything red. The second issue was the depth of penetration. The lotion worked well only at spots where the skin was thin, and couldn’t penetrate deep enough where the skin was thicker.

Finally, its formulation was not universal. It relied on finding a chemical that could match the refractive index of lipids when dissolved in water, but the exact composition of the lotion was determined through trial and error. If there’s a lot of mouse-to-mouse variation, it might make it hard to come up with a one-size-fits-all solution.

Tattoos and needles

The problem of penetrating deeper into thick skin was partially solved by making the application a bit more painful. “Using microneedle patch applicators or subcutaneous injections could help deliver the molecules through thicker layers of skin,” Hong explains. The red tint issue, he suggested, might be handled by testing different dyes. “The research in my lab is currently focused on identifying molecules with sharp absorption in the near-ultraviolet region, minimizing spectral tailing into the visible range to ensure tissue transparency without the presence of a red tone,” Hong said.

“This study has only been conducted on animals. However, if the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics,” Hong suggests. The benefits he is focusing on include evaluating deep-seated tumors without relying on biopsies, making blood tests less stressful by making locating the veins easier, and even things like improved laser tattoo removals by allowing the pigment beneath the skin to be targeted precisely.

But there is some bad news. Even though the FD&C Yellow 5 dye is widely available, replicating Hong’s results at home and making the transparency lotion on your own is not the brightest idea. “We strongly discourage attempting this on the human skin, as the toxicology of dye molecules in humans, particularly when applied topically, has not been fully evaluated,” Hong says.

And, in the end, it might not even work. “The human skin is significantly thicker than mouse skin, with the stratum corneum, the outermost layer of the epidermis, serving as a substantial barrier that prevents effective delivery of molecules into the dermis,” Hong explains

Science, 2024. DOI: 10.1126/science.adm6869

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A single peptide helps starfish get rid of a limb when attacked

biochemistry, Biology, muscles, Science, signaling, Starfish / Mike M. / September 14, 2024

You can have it —

A signaling molecule that’s so potent injected animals may drop more than one limb.

Elizabeth Rayne – Sep 14, 2024 11: 07 am UTC

A five-armed starfish, with orange and yellow colors, stretched out across a coral.

For many creatures, having a limb caught in a predator’s mouth is usually a death sentence. Not starfish, though—they can detach the limb and leave the predator something to chew on while they crawl away. But how can they pull this off?

Starfish and some other animals (including lizards and salamanders) are capable of autonomy (shedding a limb when attacked). The biology behind this phenomenon in starfish was largely unknown until now. An international team of researchers led by Maurice Elphick, professor of Animal Physiology and Neuroscience at Queen Mary University of London, have found that a neurohormone released by starfish is largely responsible for detaching limbs that end up in a predator’s jaws.

So how does this neurohormone (specifically a neuropeptide) let the starfish get away? When a starfish is under stress from a predatory attack, this hormone is secreted, stimulating a muscle at the base of the animal’s arm that allows the arm to break off.

The researchers confirmed this neuropeptide “acts as an autotomy-promoting factor in starfish and such it is the first neuropeptide to be identified as a regulator of autotomy in animals,” as they said in a study recently published in Current Biology.

Holding on

Elphick’s team studied how the neuropeptide known as ArSK/CCK1 facilitates autonomy in the European Starfish, Asterias rubens. ArSK/CCK1 is already known to inhibit feeding behavior in A. rubens by causing the stomach to contract, and muscle contraction plays a role in limb loss. The researchers found that its ability to trigger contractions goes beyond feeding.

Starfish underwent an experiment that simulated conditions where a predator’s jaw clamped down on one arm. Clamps were placed on one of three sections on a single arm, either on the end, middle, or at the site in the base where autotomy is known to occur, also known as the autotomy plane. The starfish were then suspended by these clamps above a glass bowl of seawater. During the first part of the experiment, the starfish were left to react naturally, but during the second part, they were injected with ArSK/CCK1.

Without the injection, autotomy was seen mostly in animals that had arms that were clamped closest to the autotomy plane. There was not nearly as much of a reaction from starfish when the arms were clamped in the middle or end.

In the second half of the experiment, the clamping used before was combined with an injection of ArSK/CCK1. For comparison, some were injected with the related neuropeptide ArSK/CCK2. A staggering 85 percent of ArSK/CCK1-injected animals that were clamped in the middle of the arm or closer to the autotomy plane exhibited autonomy, and some autotomized additional arms. This only happened in about 27 percent of those injected with ArSK/CCK2.

Letting go

While ArSK/CCK1 proved to be the most effective chemical trigger for autotomy, its activity in the autotomy plane depends on certain aspects of a starfish’s anatomy.

Like all echinoderms, starfish have endoskeletons built of tiny bones, or ossicles, linked by muscles and collagen fibers that allow the animals to change posture and move. Two exclusive features only found in the autotomy plane allow this structure to break. Under the skin of the autotomy plane, there is a region where bundles of collagen fibers are positioned far apart to make breakage easier. The second of these features is a band of muscle close to the region of collagen bundles. Known as the tourniquet muscle, this muscle is responsible for the constriction that allows an arm in danger to fall off.

Analyzing starfish arm tissue while it was undergoing autotomy gave the scientists a new perspective on this process. Right after a starfish has its arm seized by a predator, ArSK/CCK1 tells nerves in the tourniquet muscle to start constricting in the region right by the autonomy plane. While this is happening, the collagen in the body wall in that region softens and breaks, and so do the muscles and ligaments that hold together ossicles. It is now thought that ArSK/CCK1 is also involved in the softening of this tissue that prepares it for breakage.

After starfish autotomize a limb, that limb eventually regenerates. The same happens in other animals that can use autotomy to their advantage (such as lizards, which also grow their tails back). In the future, finding out why some animals have the ability to regenerate may tell us why we either never evolved it or some of our ancestors lost the ability. Elphick acknowledged that there might still be other unidentified factors working together with ArSK/CCK1, but further insight could someday give us a clearer picture of this process.

“Autotomy is a key adaptation for survival that has evolved in several animal taxa,” the research team said in the same study, “[and] the findings of this study provide a seminal insight into the neural mechanisms that control this remarkable biological process,”

Current Biology, 2024. DOI: 10.1016/j.cub.2024.08.003

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DNA-based bacterial parasite uses completely new DNA-editing method

biochemistry, Biology, DNA, gene editing, molecular biology, RNA, Science / Kelly Newman / June 26, 2024

Enlarge / Top row: individual steps in the reaction process. Bottom row: cartoon diagram of the top, showing the position of each DNA and RNA strand.

Hiraizumi, et. al.

While CRISPR is probably the most prominent gene-editing technology, there are a variety of others, some developed before, others since. And people have been developing CRISPR variants to perform more specialized functions, like altering specific bases. In all of these cases, researchers are trying to balance a number of competing factors: convenience; flexibility; specificity and precision for the editing; low error rates; and so on.

So, having additional options for editing can be a good thing, enabling new ways of balancing those different needs. On Wednesday, a pair of papers in Nature describe a DNA-based parasite that moves itself around bacterial genomes through a mechanism that hasn’t been previously described. It’s nowhere near ready for use in humans, but it may have some distinctive features that make it worth further development.

Going mobile

Mobile genetic elements, commonly called transposons, are quite common in many species—they make up nearly half the sequences in the human genome, for example. They are indeed mobile, showing up in new locations throughout the genome, sometimes by cutting themselves out and hopping to new locations, other times by sending a copy out to a new place in the genome. For any of this to work, they need to have an enzyme that cuts DNA and specifically recognizes the right transposon sequence to insert into the cut.

The specificity of that interaction, needed to ensure the system only inserts new copies of itself, and the cutting of DNA, are features we’d like for gene editing, which places a value on better understanding these systems.

Bacterial genomes tend to have very few transposons—the extra DNA isn’t really in keeping with the bacterial reproduction approach of “copy all the DNA as quickly as possible when there’s food around.” Yet bacterial transposons do exist, and a team of scientists based in the US and Japan identified one with a rather unusual feature. As an intermediate step in moving to a new location, the two ends of the transposon (called IS110) are linked together to form a circular piece of DNA.

In its circular form, the DNA sequences at the junction act as a signal that tells the cell to make an RNA copy of nearby DNA (termed a “promoter”). When linear, each of the two bits of DNA on either side of the junction lacks the ability to act as a signal; it only works when the transposon is circular. And the researchers confirmed that there is in fact an RNA produced by the circular form, although the RNA does not encode for any proteins.

So, the research team looked at over 100 different relatives of IS110 and found that they could all produce similar non-protein-coding RNAs, all of which shared some key features. These included stretches where nearby sections of the RNA could base-pair with each other, leaving an unpaired loop of RNA in between. Two of these loops contained sequences that either base-paired with the transposon itself or at the sites in the E. coli genome where it inserted.

That suggests that the RNA produced by the circular form of the transposon helped to act as a guide, ensuring that the transposon’s DNA was specifically used and only inserted into precise locations in the genome.

Editing without precision

To confirm this was right, the researchers developed a system where the transposon would produce a fluorescent protein when it was properly inserted into the genome. They used this to show that mutations in the loop that recognized the transposon would stop it from being inserted into the genome—and that it was possible to direct it to new locations in the genome by changing the recognition sequences in the second loop.

To show this was potentially useful for gene editing, the researchers blocked the production of the transposon’s own RNA and fed it a replacement RNA that worked. So, you could potentially use this system to insert arbitrary DNA sequences into arbitrary locations in a genome. It could also be used with targeting RNAs that caused specific DNA sequences to be deleted. All of this is potentially very useful for gene editing.

Emphasis on “potentially.” The problem is that the targeting sequences in the loops are quite short, with the insertion site targeted by a recognition sequence that’s only four to seven bases long. At the short end of this range, you’d expect that a random string of bases would have an insertion site about once every 250 bases.

That relatively low specificity showed. At the high end, various experiments could see an insertion accuracy ranging from a close-to-being-useful 94 percent down to a positively threatening 50 percent. For deletion experiments, the low end of the range was a catastrophic 32 percent accuracy. So, while this has some features of an interesting gene-editing system, there’s a lot of work to do before it could fulfill that potential. It’s possible that these recognition loops could be made longer to add the sort of specificity that would be needed for editing vertebrate genomes, but we simply don’t know at this point.

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