The only Australian members of an international research team, scientists from Curtin’s WA-Organic and Isotope Geochemistry Centre (WA-OIGC) carried out controlled burnings of plants to produce PAHs.

ARC Laureate Fellow John Curtin Distinguished Professor Kliti Grice, director of WA-OIGC, said PAHs are organic compounds made up of carbon and hydrogen that are common on Earth but are also found in celestial bodies like asteroids and meteorites.

“We performed controlled burn experiments on Australian plants, which were isotopically compared to PAHs from fragments of the Ryugu asteroid that were returned to Earth by a Japanese spacecraft in 2020, and the Murchison meteorite that landed in Australia in 1969. The bonds between light and heavy carbon isotopes in the PAHs were analysed to reveal the temperature at which they were formed,” Professor Grice said.

“Select PAHs from Ryugu and Murchison were found to have different characteristics: the smaller ones likely in cold outer space, while bigger ones probably formed in warmer environments, like near a star or inside a celestial body.”

Study co-author Dr Alex Holman, also from WA-OIGC, said understanding the isotopic composition of PAHs helps unravel the conditions and environments in which these molecules were created, offering insights into the history and chemistry of celestial bodies like asteroids and meteorites.

“This research gives us valuable insights into how organic compounds form beyond Earth and where they come from in space,” Dr Holman said.

“The use of high-tech methods and creative experiments has shown that select PAHs on asteroids can be formed in cold space.”

The full research paper, ‘Polycyclic aromatic hydrocarbons in samples of Ryugu formed in the interstellar medium’ will be published in the journal Science.

To understand how a watch works, one might take it apart, piece by piece, and study the role played by each component in its timekeeping function. Similarly, in a protein such as a GPCR, each amino acid might play a different role in how the protein responds to an external signal. Researchers at St. Jude, in collaboration with scientists from Stanford University, the University of Montreal, the MRC Laboratory of Molecular Biology and Cambridge University, investigated the β2-adrenergic receptor (β2AR) by substituting one amino acid at a time to understand the contribution of each amino acid in this receptor to mediate a signaling response.

“Scientists learn how genes contribute to cell function by disrupting them one at a time. We asked, ‘Why don’t we take this one level deeper? Let’s understand how every amino acid contributes to the functioning of a receptor by mutating them, one amino acid at a time,'” said co-corresponding author M. Madan Babu, PhD, from St. Jude’s Department of Structural Biology, Center of Excellence for Data-Driven Discovery director and the George J. Pedersen Endowed Chair in Biological Data Science. “Through evolution, every amino acid in the receptor has been sculpted in some way or another to ensure that it binds the natural ligand, in this case adrenaline, and elicits the appropriate physiological response.”

Finding function in the form

GPCRs are proteins that span the cell’s membrane and connect the outside of the cell to its internal environment by transmitting external signals to the inside of the cell. In the case of the β2AR, adrenaline binds to the GPCR on the part outside of the cell, inducing a response inside the cell.

When a ligand binds, it causes changes in the shape of the receptor, especially in the intracellular region of the receptor where a G protein binds. The binding sites for the ligand and the G protein are on opposite sides of the protein but connect through a complex network of amino acid contacts that span the entire protein. Conformational (shape) changes within the GPCR activate the G protein to trigger a downstream signaling response within the cell. Through effects on multiple tissues and GPCRs, including the β2AR, adrenaline can trigger the fight-or-flight response, such as during an adrenaline surge.

To understand the role of each amino acid in a GPCR, Franziska Heydenreich, PhD, now of the Philipps University of Marburg, the lead and co-corresponding author of this project, mutated each of the 412 amino acids in the β2AR. She then evaluated each mutant’s response to the ligand adrenaline and determined the classical pharmacological properties of efficacy and potency. Efficacy measures the maximum response a ligand can elicit, and potency measures the amount of ligand required to elicit half of the maximum response. The aim was to reveal, on an atomic scale, how each amino acid contributes to these pharmacological properties.

“Surprisingly, only about 80 of the more than 400 amino acids contributed to these pharmacological properties. Of these pharmacologically relevant amino acids, only one-third were located within regions where the ligand or G protein bound to the receptor,” Heydenreich said.

“It was fascinating to observe that there are some amino acids that control efficacy, some that control potency and then there are others that affect both,” Babu said. “It means if you want to make a more potent or efficacious drug, you now know there are specific residues that the new ligand needs to influence.” The researchers also noted that the individual contribution of each residue to efficacy and potency was not equal, implying even more opportunities for fine-tuning drug responses while designing new therapeutic ligands.

“Efficacy and potency have been measured for numerous ligand-receptor signaling systems for several decades. Now we can understand how specific amino acids in a protein’s sequence can influence these pharmacological properties,” Babu explained.

“A fascinating aspect of the results is that potency and efficacy can be regulated independently of each other through distinct mechanisms. This provides a basis for understanding how genetic variation influences drug responses among individuals,” Michel Bouvier, PhD, co-corresponding author from the Department of Biochemistry and Molecular Medicine and General Director of the Institute for Research in Immunology and Cancer of the University of Montreal added.

A beautiful network

Prior research illustrated the structure of both the active and inactive states of the β2AR. Building on this knowledge, the researchers embarked on a new investigation. They explored whether the two-thirds of pharmacologically relevant amino acids previously demonstrated to be not involved in ligand or G-protein binding might play a role in the transition between the active and inactive states of the receptor.

“We systematically started looking at every residue contact unique to the active state,” Heydenreich said, “to understand whether all the amino acids that make an active-state contact are important.”

The researchers developed a data science framework to integrate pharmacological and structural data systematically and revealed the first comprehensive picture of GPCR signaling. “When we mapped the pharmacological data onto the structure, they formed a beautiful network,” said Babu.

“It provided new insights into the allosteric network linking the ligand binding pocket to the G protein binding site that governs efficacy and potency.” Added Brian Kobilka, co-corresponding author and the 2012 Nobel Prize winner in Chemistry from Stanford University School of Medicine.

By understanding GPCR signaling at the atomic level, the researchers are optimistic that they can begin probing even deeper — to see the transient sub-states between the active and inactive conformations and to explore the conformational landscape of proteins.

“We now know which mutants to go after, those that only affect efficacy, potency or both,” Heydenreich said.

“Now, we can perform molecular dynamics calculations and single-molecule experiments on those mutants to reveal the exact mechanisms by which the allosteric network influences efficacy and potency to mediate a signaling response. This is a direction we are pursuing through a St. Jude Research Collaborative on GPCRs that includes PIs from several institutions.” Babu explained.

Apart from these “driver” residues that are involved in mediating active state-specific contacts and affect pharmacology when mutated, Babu and his colleagues intend to probe other key findings revealed by this work. They aim to study “passenger” amino acids that, despite making contacts in the active state, do not affect efficacy or potency when mutated. They are also interested in “modulator” residues that don’t mediate active state-specific contacts but alter pharmacology when mutated. Their data science approach, integrating structural information and pharmacological measurements, isn’t limited to the β2AR. It can be extended to any GPCR to enhance our understanding of the mechanics governing this crucial class of drug targets.

At more than 12 billion years old, BRI 1335-0417 is the oldest and furthest known spiral galaxy in our universe.

Lead author Dr Takafumi Tsukui said a state-of-the-art telescope called ALMA allowed them to look at this ancient galaxy in much greater detail.

“Specifically, we were interested in how gas was moving into and throughout the galaxy,” Dr Tsukui said.

“Gas is a key ingredient for forming stars and can give us important clues about how a galaxy is actually fuelling its star formation.”

In this case, the researchers were able to not only capture the motion of the gas around BRI 1335-0417, but also reveal a seismic wave forming — a first in this type of early galaxy.

The galaxy’s disk, a flattened mass of rotating stars, gas and dust, moves in a way not dissimilar to ripples spreading on a pond after a stone is thrown in.

“The vertically oscillating motion of the disk is due to an external source, either from new gas streaming into the galaxy or by coming into contact with other smaller galaxies,” Dr Tsukui said.

“Both possibilities would bombard the galaxy with new fuel for star formation.

“Additionally, our study revealed a bar-like structure in the disk. Galactic bars can disrupt gas and transport it towards the galaxy’s centre. The bar discovered in BRI 1335-0417 is the most distant known structure of this kind.

“Together, these results show the dynamic growth of a young galaxy.”

Because BRI 1335-0417 is so far away, its light takes longer to reach Earth. The images seen through a telescope in the present day are a throwback to the galaxy’s early days — when the Universe was just 10 per cent of its current age.

“Early galaxies have been found to form stars at a much faster rate than modern galaxies. This is true for BRI 1335-0417, which, despite having a similar mass to our Milky Way, forms stars at rate a few hundred times faster,” co-author Associate Professor Emily Wisnioski said.

“We wanted to understand how gas is supplied to keep up with this rapid rate of star formation.

“Spiral structures are rare in the early Universe, and exactly how they form also remains unknown. This study also gives us crucial information on the most likely scenarios.

“While it is impossible to observe the galaxy’s evolution directly, as our observations only give us a snapshot, computer simulations can help piece the story together.”

This vast stellar nursery is located in the constellation Centaurus (the Centaur), at about 6500 light-years from Earth. Young stars within this nebula emit intense radiation that makes the surrounding hydrogen gas glow in shades of pink.

The Running Chicken Nebula actually comprises several regions, all of which we can see in this vast image that spans an area in the sky of about 25 full Moons [1]. The brightest region within the nebula is called IC 2948, where some people see the chicken’s head and others its rear end. The wispy pastel contours are ethereal plumes of gas and dust. Towards the centre of the image, marked by the bright, vertical, almost pillar-like, structure, is IC 2944. The brightest twinkle in this particular region is Lambda Centauri, a star visible to the naked eye that is much closer to us than the nebula itself.

There are, however, many young stars within IC 2948 and IC 2944 themselves — and while they might be bright, they’re most certainly not merry. As they spit out vast amounts of radiation, they carve up their environment much like, well, a chicken. Some regions of the nebula, known as Bok globules, can withstand the fierce bombardment from the ultraviolet radiation pervading this region. If you zoom in to the image, you might see them: small, dark, and dense pockets of dust and gas dotted across the nebula.

Other regions pictured here include, to the upper right, Gum 39 and 40, and to the lower right, Gum 41. Aside from nebulae, there are countless orange, white and blue stars, like fireworks in the sky. Overall in this image, there are more wonders than can be described — zoom in and pan across, and you’ll have a feast for the eyes.

This image is a large mosaic comprising hundreds of separate frames carefully stitched together. The individual images were taken through filters that let through light of different colours, which were then combined into the final result presented here. The observations were conducted with the wide-field camera OmegaCAM on the VST, a telescope owned by the National Institute for Astrophysics in Italy (INAF) and hosted by ESO at its Paranal site in Chile’s Atacama Desert that is ideally suited for mapping the southern sky in visible light. The data that went into making this mosaic were taken as part of the VST Photometric Hα Survey of the Southern Galactic Plane and Bulge (VPHAS+), a project aimed at better understanding the life cycle of stars.

Notes

[1] This image, edge to edge, is 270 light-years wide. It would take an average chicken almost 21 billion years to run across it. That’s much longer than our Universe has been around for.

Saturn’s spokes are transient features that rotate along with the rings. Their ghostly appearance only persists for two or three rotations around Saturn. During active periods, freshly-formed spokes continuously add to the pattern.

In 1981, NASA’s Voyager 2 first photographed the ring spokes. NASA’s Cassini orbiter also saw the spokes during its 13-year-long mission that ended in 2017.

Hubble continues observing Saturn annually as the spokes come and go. This cycle has been captured by Hubble’s Outer Planets Atmospheres Legacy (OPAL) program that began nearly a decade ago to annually monitor weather changes on all four gas-giant outer planets.

Hubble’s crisp images show that the frequency of spoke apparitions is seasonally driven, first appearing in OPAL data in 2021 but only on the morning (left) side of the rings. Long-term monitoring show that both the number and contrast of the spokes vary with Saturn’s seasons. Saturn is tilted on its axis like Earth and has seasons lasting approximately seven years.

“We are heading towards Saturn equinox, when we’d expect maximum spoke activity, with higher frequency and darker spokes appearing over the next few years,” said the OPAL program lead scientist, Amy Simon of NASA’s Goddard Space Flight Center in Greenbelt, Maryland.

This year, these ephemeral structures appear on both sides of the planet simultaneously as they spin around the giant world. Although they look small compared with Saturn, their length and width can stretch longer than Earth’s diameter!

“The leading theory is that spokes are tied to Saturn’s powerful magnetic field, with some sort of solar interaction with the magnetic field that gives you the spokes,” said Simon. When it’s near the equinox on Saturn, the planet and its rings are less tilted away from the Sun. In this configuration, the solar wind may more strongly batter Saturn’s immense magnetic field, enhancing spoke formation.

Planetary scientists think that electrostatic forces generated from this interaction levitate dust or ice above the ring to form the spokes, though after several decades no theory perfectly predicts the spokes. Continued Hubble observations may eventually help solve the mystery.

In 2019, astronomers announced the surprising find that a stellar explosion, or supernova, had occurred within MRG-M0138, as seen in images from NASA’s Hubble Space Telescope taken in 2016. When another group of astronomers examined the 2023 Webb images, they were astonished to find that seven years later, the same galaxy is home to a second supernova. Justin Pierel (NASA Einstein Fellow at the Space Telescope Science Institute) and Andrew Newman (staff astronomer at the Observatories of the Carnegie Institution for Science) tell us more about this first time that two gravitationally lensed supernovae were found in the same galaxy.

“When a supernova explodes behind a gravitational lens, its light reaches Earth by several different paths. We can compare these paths to several trains that leave a station at the same time, all traveling at the same speed and bound for the same location. Each train takes a different route, and because of the differences in trip length and terrain, the trains do not arrive at their destination at the same time. Similarly, gravitationally lensed supernova images appear to astronomers over days, weeks, or even years. By measuring differences in the times that the supernova images appear, we can measure the history of the expansion rate of the universe, known as the Hubble constant, which is a major challenge in cosmology today. The catch is that these multiply-imaged supernovae are extremely rare: fewer than a dozen have been detected until now.

“Within this small club, the 2016 supernova in MRG-M0138, named Requiem, stood out for several reasons. First, it was 10 billion light-years distant. Second, the supernova was likely the same type (Ia) that is used as a ‘standard candle’ to measure cosmic distances. Third, models predicted that one of the supernova images is so delayed by its path through the extreme gravity of the cluster that it will not appear to us until the mid-2030s. Unfortunately, since Requiem was not discovered until 2019, long after it had faded from view, it was not possible to gather sufficient data to measure the Hubble constant then.

“Now we have found a second gravitationally lensed supernova within the same galaxy as Requiem, which we call Supernova Encore. Encore was discovered serendipitously, and we are now actively following the ongoing supernova with a time-critical director’s discretionary program. Using these Webb images, we will measure and confirm the Hubble constant based on this multiply imaged supernova. Encore is confirmed to be a standard candle or type Ia supernova, making Encore and Requiem by far the most distant pair of standard-candle supernova ‘siblings’ ever discovered.

“Supernovae are normally unpredictable, but in this case we know when and where to look to see the final appearances of Requiem and Encore. Infrared observations around 2035 will catch their last hurrah and deliver a new and precise measurement of the Hubble constant.”

The study, published in the Zoological Journal of the Linnean Society, used DNA analysis and physical characteristics to describe two entirely new species of soft-furred hedgehogs and elevate three subspecies to the level of species.

The two new species, named Hylomys vorax and H. macarong, are endemic to the endangered Leuser ecosystem, a tropical rainforest in North Sumatra and Southern Vietnam, respectively. The museum specimens that were vital to describing these two new species came from the natural history collections of the Smithsonian and the Academy of Natural Sciences of Drexel University in Philadelphia where they had remained in drawers for 84 and 62 years, respectively, prior to identification.

The study — an international collaboration between researchers at the University of Seville and the Doñana Biological Station in Spain, George Mason University and the Smithsonian’s National Zoo and Conservation Biology Institute in the U.S., the Lee Kong Chian Natural History Museum in Singapore, the Natural History Museum of Geneva in Switzerland and the University of Malaya in Malaysia — highlights that even in well-studied animal groups like mammals there are still discoveries waiting to be made, showing what is possible when modern techniques such as DNA analysis are applied to museum collections.

Soft-furred hedgehogs or gymnures are small mammals that are members of the hedgehog family, but as their common name suggests they are furry rather than spiny. Like spiny hedgehogs, they are not rodents and they have a pointy snout. Without the spines of their more well-known cousins, soft-furred hedgehogs superficially look a bit like a mixture of a mouse and a shrew with a short tail, said Arlo Hinckley, the study’s lead author and a Margarita Salas Postdoctoral Fellow at the National Museum of Natural History and University of Seville. The five new species belong to a group of soft-furred hedgehogs called lesser gymnures (Hylomys) that live in Southeast Asia and previously was only recognized to have been represented by two known species.

“We were only able to identify these new hedgehogs thanks to museum staff that curated these specimens across countless decades and their original field collectors,” Hinckley said. “By applying modern genomic techniques like we did many years after these hedgehogs were first collected, the next generation will be able to identify even more new species.”

Hinckley said these small mammals are active during the day and night and are omnivorous, likely eating a diversity of insects and other invertebrates as well as some fruits as opportunities present themselves.

“Based on the lifestyles of their close relatives and field observations, these hedgehogs likely nest in hollows and take cover while foraging among tree roots, fallen logs, rocks, grassy areas, undergrowth and leaf litter,” Hinckley said. “But, because they’re so understudied, we are limited to speculate about the details of their natural history.”

Hinckley first became intrigued with the gymnure group Hylomys in 2016 during his doctoral studies, especially after he sampled them in Borneo with co-author Miguel Camacho Sánchez. Preliminary genetic data and studies of several known populations of Hylomys in Southeast Asia suggested to them there might be more species in the group than were currently recognized. This sent Hinckley combing through natural history collections searching for specimens assigned to the group, many of which were only preserved skins and skulls.

When he began his research at the Smithsonian in 2022, Hinckley leveraged the National Museum of Natural History’s collections to fill in geographic gaps in the specimens he had already studied with the help of Melissa Hawkins, the museum’s curator of mammals.

In the end, Hinckley, Hawkins and their collaborators assembled 232 physical specimens and 85 tissue samples for genetic analysis from across the entire Hylomys group from a combination of Hinckley and Hawkins’ own field collecting, as well as modern and historical museum specimens from no less than 14 natural history collections across Asia, Europe and the U.S.

Then Hinckley and his co-authors set about the lengthy process of conducting genetic analysis on the 85 tissue samples in Doñana Biological Station’s ancient DNA laboratory and the museum’s Laboratories of Analytical Biology. They also made rigorous physical observations and collected measurements to examine differences in the size and shape of skulls, teeth and fur on the 232 specimens.

The genetic results identified seven distinct genetic lineages in Hylomys, suggesting the number of recognized species in the group was about to increase by five, later confirmed by the team’s physical observations of the specimens.

“It might be surprising for people to hear that there are still undiscovered mammals out there,” Hawkins said. “But there is a lot we don’t know — especially the smaller nocturnal animals that can be difficult to tell apart from one another.”

H. macarong, which has dark brown fur and measures about 14 centimeters (5.5 inches) in length, was named after a Vietnamese word for vampire (Ma cà r?ng) because males of the species possess long, fang-like incisors. Hinckley said more field study would be required to figure out what purpose the fangs might serve, but that their larger size in males suggests they could have some role in sexual selection. Males also have rust-colored chest markings that Hawkins said could have been stained by scent glands.

H. vorax also has dark brown fur but is slightly smaller than H. macarong at 12 centimeters (4.7 inches) long; it has a completely black tail, a very narrow snout and is found only on the slopes of Mount Leuser in Northern Sumatra. Hinckley and Hawkins gave the species the Latin name H. vorax after a striking description of its behavior from mammologist Frederick Ulmer, who collected the specimens that led to the species description on an expedition to Sumatra in 1939. Ulmer described the creature in his field notes, incorrectly identifying it as a type of shrew: “They were voracious beasts often devouring the whole bait before springing the trap. Ham rind, coconut, meat, and walnuts were eaten. One shrew partially devoured the chicken head bait of a steel trap before getting caught in a nearby Schuyler trap baited with ham rind.”

The other three new species were all formerly considered to be subspecies of Hylomys suillus, but all showed sufficient genetic and physical divergence to merit the upgrade to species in their own right. They are named H. dorsalis, H. maxi and H. peguensis.

H. dorsalis hails from the mountains of Northern Borneo and features a conspicuous dark stripe that begins atop its head and bisects its back before fading around mid-body. It is about the same size as H. macarong. H. maxi is also on the larger end of the new species of soft-furred hedgehogs at 14 centimeters (5.5 inches). The species is found in mountainous regions on the Malay Peninsula and in Sumatra. H. peguensis is smaller, measuring 13 centimeters (5.1 inches), and is found in numerous countries in mainland Southeast Asia, especially Thailand, Laos and Myanmar. Its fur is a bit more yellow colored than that of the other new species, Hawkins said.

Describing new species expands humanity’s scientific understanding of the natural world can be a tool for boosting conservation in threatened habitats such as Northern Sumatra’s Leuser ecosystem.

“This kind of study can help governments and organizations make hard choices about where to prioritize conservation funding to maximize biodiversity,” Hinckley said.

This research was supported by the Smithsonian, Spain’s Ministry of Economy and Competitiveness as well as its Ministry of Universities, the European Union and Harvard University.

Researchers at the Wellcome Sanger Institute, the University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI), and collaborators developed the tool, known as CellHint. CellHint uses machine learning to unify data produced across the world, allowing it to be accessed by the wider research community, potentially driving new discoveries.

In a new study, published today (21 December) in Cell, researchers applied CellHint to reveal underexplored connections between healthy and diseased lung cell states. They looked at eight diseases, such as interstitial lung disease and chronic obstructive pulmonary lung disease, and showed the possible benefits of this tool. They also applied CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with around 3.7 million cells.

Cellhint is freely available worldwide and was created as part of the Human Cell Atlas initiative¹ which aims to map every cell type in the human body to transform understanding of health and disease.

Single-cell genomics enables the understanding of every cell in the context of the human body at high resolution. Currently, a challenge in assembling the diverse datasets produced by single-cell research is that there is no unified system for naming and organising data.

To address this, researchers from the Wellcome Sanger Institute, and collaborators developed CellHint, which can unify cell types produced by independent laboratories. CellHint then places the data into a defined graph that shows the relationships between cell subtypes, giving a full picture of all the cells identified across different datasets.

The team applied CellHint to current data and revealed underexplored relationships between healthy and diseased lung cell states in eight diseases. It also identified cell types in adult human hippocampus that could be of potential interest for future research.

The researchers also applied CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with around 3.7 million cells. Each cell was annotated, which is the process of labelling cells with particular information. They also showed how it can create various models for automatic cell annotation across human tissues.

Dr Chuan Xu, first author from the Wellcome Sanger Institute, said: “CellHint stands out from other tools because it makes full use of the often inconsistent but valuable cell annotation information from individual studies, to achieve biologically-driven data integration. We are excited that with CellHint, cells from independent laboratories can be re-annotated and researchers can utilise the resulting information to put each cell into different contexts beyond the original study. We hope that this tool will greatly facilitate the reuse of molecular and cellular data and information across laboratories, potentially driving new discoveries in biology.”

Dr Sarah Teichmann, senior author from the Wellcome Sanger Institute and co-founder of the Human Cell Atlas, said: “The Human Cell Atlas is creating detailed reference maps of all cells in the human body to transform our understanding of biology, health and disease, and single-cell technologies underpin this hugely ambitious project. Global collaboration and open data sharing are vital to achieve the aim of a representative Human Cell Atlas that will benefit humanity worldwide. CellHint enables the unification and sharing of single-cell data, which allows the global research community to contribute to and benefit from the ongoing research that is happening around the world, and help drive advances in health and healthcare.”

Now the lab is back with important results that build on that discovery. New findings published in Molecular Cell provide details about the hidden organization of the cytoplasm — the soup of liquid, organelles, proteins, and other molecules inside a cell. The research shows it makes a big difference where in that cellular broth that messenger RNA (mRNA) get translated into proteins.

“You know the old real estate saying, ‘location, location, location.’ It turns out it applies to how proteins get made inside of cells, too,” says Dr. Mayr, a molecular and cell biologist at the Sloan Kettering Institute, a hub for basic and translational research within MSK. “If it’s translated over here, you get twice as much protein as if it’s translated over there.”

This first-of-its-kind study highlights the degree to which the cytoplasm is “beautifully organized,” rather than being just a big jumble of stuff, she says.

Not only do the findings shed new light on fundamental cellular biology, but the knowledge also holds promise for increasing or altering the production of proteins in mRNA vaccines and therapies, the researchers note.

The study was led by former lab member Ellen Horste, PhD, whom Mayr tapped for the daunting but exciting project when she joined the lab several years ago. Dr. Horste received her doctorate from the Gerstner Sloan Kettering Graduate School in June and now works for a gene therapy company.

“When we started, we had a hard time getting funding for this project,” Dr. Mayr says. “Everyone thought isolating the individual components would be totally impossible. This was really Ellen’s project from her first day in the lab to her last day. It was quite challenging, and I couldn’t be more proud of her.”

Adapting an approach commonly used by immunologists, the team was able to color-code individual particles within cells using antibodies and then sort them by color. They used RNA sequencing to identify which RNAs were associated with which particles.

“And it was really striking to see that in each of these intracellular neighborhoods, very different types of mRNAs were being translated,” Dr. Mayr says.

Welcome to the Cellular Neighborhood

Most of the well-known components inside a cell have a defined shape and come wrapped in an exterior membrane: the nucleus, mitochondria, lysosomes, the Golgi apparatus.

Two of the key components at the heart of the Mayr team’s study don’t have membranes — which is what has made them so hard to find in the first place, and a challenge to isolate and study in the lab.

A quick biology review: Cells build proteins using instructions encoded in DNA. Those DNA sequences are transcribed into mRNA inside the cell nucleus. These messenger RNA then move out into the cytoplasm where they are translated into a useful protein.

The new study demonstrated that where in the cytoplasm this translation step happens isn’t random, and that there’s an underlying logic or “code” that directs mRNAs to specific neighborhoods within the cell.

“The whole cytoplasm is nicely compartmentalized,” Dr. Mayr says. “We were able to demonstrate there is a code at work that’s based on the mRNA’s biophysical features — their size and shape — and the particular RNA-binding proteins they partner with. This code directs the mRNAs to different locations for translation.”

Investigating Translation in 3 Locations Inside the Cell

Through a painstaking series of experiments, the research team was able to show that mRNAs of different lengths and shapes tend to gravitate to specific neighborhoods. And that if you intervene to redirect them to a different location, it can have a profound impact on the amount of protein that gets produced and on the protein’s function.

The researchers looked at mRNAs that locate to the surface of the endoplasmic reticulum (an organelle involved in protein synthesis and other cellular functions). It’s well established that proteins associated with cellular membranes and those that get secreted by the cell for use elsewhere are translated there. The research revealed that nearly 15% of mRNAs that encode non-membrane proteins are also translated at the ER — and they encode large and highly expressed proteins.

Meanwhile, the mRNAs that get translated in the cytosol (the liquid part of the cytoplasm) tend to be very small proteins.

And mRNAs that locate to TIS granules tend to be transcription factors (proteins that regulate the transcription of genes). TIS granules are a membrane-less cellular component Mayr’s lab discovered in 2018. They form a network of interconnected proteins and mRNAs, and are closely allied with the endoplasmic reticulum, forming a distinct space where mRNA and proteins can collect and interact.

A fluorescent microscopy image of a cell, with TIS granules shown in red and the endoplasmic reticulum is shown in green. The central black area is the cell’s nucleus.

Cracking the Code

Cracking the code for how mRNA localize to different locations revealed some surprising findings.

After discovering the TIS granule network five years ago, the lab had turned its attention to understanding which of the many thousands of mRNAs in a cell localize there, and whether they have shared characteristics.

The team homed in on one part of the mRNA that doesn’t usually get much attention — the tail. It’s separate from the middle part of the mRNA, which contains the instructions for building the protein. Scientists call the tail the three prime untranslated region (3? UTR), and it turns out to be critical for the localization process.

“The tail usually contains a longer sequence than the part of the RNA that’s actually used to make the protein,” Dr. Mayr says. “But for a long time, people didn’t pay that much attention to the tail regions since you can still make the protein without them.” (They’re also important in other ways, as Dr. Mayr outlined in a 2019 review article.)

It turns out that the tail is essential for partnering with RNA-binding proteins so that, together, the mRNA goes to the correct translation region within the cell. (RNA-binding proteins are a type of protein that attaches to RNA molecules and can modulate various aspects of their activity.)

At first the team thought it was primarily these RNA-binding proteins that directed the action — guiding the mRNAs to neighborhood one, neighborhood two, and so forth, Dr. Mayr says.

“But the really surprising finding was that the RNA-binding proteins actually play a secondary role rather than a primary role in the process,” she says.

The default sorting of mRNA to a location, the researchers found, is based on the overall size and shape of the mRNAs. But being in partnership with a binding protein can override this default and redirect them.

“Our data show that if you translate an mRNA in the TIS granules, the resulting protein will perform one function, and if you translate it outside of the TIS granules, it will perform a different function,” she says. “And this is how, in higher organisms like us, one protein can have more than one function.”

Toward Future Applications

One specific protein the team examined during the study is MYC. The MYC gene is one of the more famous oncogenes, and mutations in MYC underlie the development of many cancers.

“We observed that several MYC protein complexes were only formed when MYC mRNA was translated in the granules and not when it was translated in the cytosol,” Dr. Mayr says. “Our results show there’s an important biological relevance to these neighborhoods, even when only about 20% of mRNAs get translated in the TIS granules.”

Together, these insights suggest that mRNA could be targeted to achieve different functions, as well as to vary the amount of a protein that gets produced, she adds.

“So, we hope that in the future we can make smarter medicines by making more or less of a particular factor, and also by manipulating its function,” Dr. Mayr says. “This probably won’t happen in the next five years, but it’s something we are paving the way to do.”

But how these complex structures, known as apical extracellular matrices (aECMs) are assembled into elaborately woven architectures has remained an elusive question.

Now, following years of research and the power of a technologically advanced instrument, University of California San Diego scientists have unraveled the underpinnings of such matrices in a tiny nematode. The roundworm Caenorhabditis elegans has been studied extensively for decades due to its transparent structure that allows researchers to peer inside its body and examine its skin.

Described in the journal Nature Communications, School of Biological Sciences researchers have now deciphered the assemblage of aECM patterns in roundworms at the nanoscale. A powerful, super-resolution microscope helped reveal previously unseen patterns related to columns, known as struts, that are key to the proper development and functioning of aECMs.

“Struts are like tiny pillars that connect the different layers of the matrix and serve as a type of scaffolding,” said Andrew Chisholm, a professor in the School of Biological Sciences and the paper’s senior author.

Although roundworms serve as a model organism for laboratory studies due to their simple, transparent bodies, below the surface they feature intricate architectures. They also have nearly 20,000 genes, not unlike the number of human genes, and therefore provide lessons on structure and function of more advanced organisms.

Focusing on the roundworm exoskeleton known as the cuticle, the researchers found that defects in struts result in unnatural layer swelling, or “blistering.” Within the cuticle layer, the research study focused on collagens, which are the most abundant family of proteins in our bodies and help keep bodily materials conjoined.

“The struts hold the critical layers together,” said Chisholm. “Without them, the layers separate and cause disorders such as blistering. In blistering mutants you don’t see any struts.”

Conventional laboratory instruments had previously imaged struts without detail, often resulting in undefined blobs. But through Biological Sciences Assistant Professor Andreas Ernst’s laboratory they accessed advanced instrumentation — known as 3D-structured illumination super resolution microscopy (3D-SIM) — which put the struts into stunning focus and allowed their functions to be more easily defined. The researchers were then able to solve the nanoscale organization of struts and previously undocumented levels of patterning in the cuticle layer.

“We could see exactly where these proteins were going in the matrix,” said Chisholm. “This is potentially a paradigm for how the matrix assembles into very complex structures and very intricate patterning.”