New research shows just how complex and sophisticated these bacterial circadian clocks are, clearing the way for an exciting new phase of study. This work will provide diverse opportunities, from precision timing of the use of antibiotics, to bioengineering smarter gut and soil microbiomes.

An international collaboration from Ludwig Maximillian University Munich (LMU Munich), The John Innes Centre, The Technical University of Denmark, and Leiden University, made the discovery by probing gene expression as evidence of clock activity in the widespread soil bacterium Bacillus subtilis.

Lead author Dr. Francesca Sartor (LMU Munich) reports: “The circadian clock in this microbe is pervasive: we see it regulating several genes, and a range of different behaviours.”

Professor Antony Dodd from the John Innes Centre added, “It is astonishing that a unicellular organism with such a small genome has a circadian clock with some properties that evoke clocks in more complex organisms.”

Previous work by this collaborative team had demonstrated the existence of a circadian clock in a lab-derived strain of this bacteria. This was the first-time circadian clocks had been observed in the bacterium Bacillus subtilis. Researchers used a technique which inserts an enzyme called luciferase that produces light when a gene is expressed. This bioluminescence guided the team in monitoring the bacterial clock as conditions varied.

The senior author of the publication, Professor Martha Merrow at LMU Munich said: “This study shows that circadian clocks are widely found in Bacillus subtilis. We might capitalize on knowledge of the clock to improve health outcomes and increase sustainability of food production or biotechnology.”

This new study is a significant step forward for multiple reasons. It reveals that these clocks exist in strains collected from natural environments, so could be widespread in this bacteria. Furthermore, B. subtilis continues to show circadian rhythms in both constant dark and constant light, and the researchers reveal examples of nuanced responses found in the circadian clocks of many other organisms. In the field of circadian biology, these responses are known as “aftereffects” and “Aschoff’s Rule.” Taken together, this suggests that, as in more complex organisms, the bacteria can synchronize their physiology and metabolism to different times of the day as light and temperature conditions change.

The discovery offers opportunities for biotechnology, human health, and plant science. Understanding properties of bacterial circadian clocks may help us with industrial applications of microbiology; it could lead to a new understanding of how microbiomes are formed and may indicate how well antibiotics work at certain times of the day to disrupt pathogenic bacteria. The knowledge may also help us in crop protection. Bacillus subtilis is a beneficial soil bacterium used by farmers to assist nutrient exchange, plant development and defense against pathogenic microbes.

The team is developing Bacillus subtilis as a model organism for the study of circadian clocks in bacteria. One of the next steps is to work out which genes are operating to make up the clock mechanism. The team is also curious about how the B. subtilis circadian clock depends on multicellular organization for its full functionality.

Circadian clocks are internal oscillators which offer a selective advantage to organisms by adapting their physiology and metabolism to 24 h changes in the environment, such as the changes in light, temperature or predator behaviour. They give rise to the jarring effects of jet lag, when we pass into different time zones.

Professor Ákos T. Kovács, from Leiden University and Technical University of Denmark said, “The French biologist Jacques Monod once famously said, ‘What is true for E. coli is true for the elephant.’ At the time, he was referring to the universal rules of molecular biology- of DNA and proteins. Similarly, it is amazing that the circadian clock in Bacillus subtilis– a bacterium with just four thousand genes — has a complex circadian system that is reminiscent of circadian clocks in complex organisms such as flies, mammals, and plants.”

“The findings of this study are exciting, especially given much of the recent news regarding sargassum is about the negative effects of its overgrowth in Florida and the Caribbean,” said Lindsay Dubbs, a research associate professor and director of the Outer Banks Field Site at the UNC Institute for the Environment and research associate at East Carolina University’s Coastal Studies Institute. “We were able to show sargassum’s role in nitrogen fixation as meaningful in supporting marine productivity.”

Nitrogen is critical for life. Plants and animals need it for growth. More nitrogen in the ocean means greater biological productivity and growth. Sargassum mats provide an important habitat for organisms to perform nitrogen fixation, but few studies have measured it in sargassum communities.

“Only four studies have been published detailing rates of nitrogen fixation by epiphytes on pelagic sargassum and none in over 30 years,” said Claire Johnson, a Ph.D. student in the Department of Earth, Marine, and Environmental Sciences in the UNC College of Arts and Sciences and a graduate research assistant at the Coastal Studies Institute. “It’s really exciting for us to be able to contribute this long-term dataset which provides an updated view of this process and, in doing so, will hopefully bring attention to something which has been overlooked for decades.”

The team compared the nitrogen fixation rate with other marine sources, including commonly studied nitrogen fixing organisms such as planktonic diazotrophs and coastal epiphytes — plants that grow on other plants — and found the sargassum communities outpaced them — contributing significantly to the marine nitrogen cycle and potentially to sargassum blooms.

Collecting this type of data can be difficult, but the team’s proximity to the Gulf Stream from their lab at the Coastal Studies Institute on East Carolina University’s Outer Banks campus on Roanoke Island made it possible for them to make day-long trips to collect samples seasonally and process them quickly. The team was able to collect whole fronds of the seaweed and process them with minimal handling, better keeping the microorganisms intact for the study. Each piece was carefully managed in large tubs at the laboratory, where they collected data on nitrogen fixation rates. The team collected samples over a six-year period.

Sargassum is typically abundant in the Caribbean Sea, Gulf of Mexico, Gulf Stream and Sargasso Sea. The team’s work in North Carolina provides a comprehensive view of how nitrogen fixation rates vary over time, but understanding how they could vary across a wider geographic range could be a next step for further research.

“This research is even more critical now given the sargassum blooms in the South Atlantic,” said Johnson. “If nitrogen is being fixed by epiphytes on sargassum in this population on a scale anywhere near what we are seeing here, it would almost certainly have a significant impact on the Atlantic marine nitrogen budget.”

“There is so much to be learned about this plant, the other life that it supports, and the factors that contribute to it becoming a nuisance in some places. I am optimistic that our long-term dataset will continue to reveal new insights about its importance and complexity,” Dubbs added.

This organic matter, composed of decaying leaves and branches, airborne particulates and moisture, is called canopy soil or arboreal soil. Its study is relatively new, says Utah State University ecologist Jessica Murray. She’s among researchers unraveling mysteries of the dense, mossy humus that provides rich habitat for insects, birds, fungi, worms and plants, as well as a generous reservoir for carbon storage.

Murray and colleagues from Texas A&M University, the University of Toronto Scarborough and Imperial College London published new information about the enigmatic resource in the July 27, 2023, online edition of Geoderma. The team’s research was supported by USU, the U.S. Department of Agriculture National Institute of Food and Agriculture, and the Natural Sciences and Engineering Research Council of Canada.

“In this study, we sought to understand where canopy soils are found, where they are most abundant, and if their properties — and thus, soil development processes — differ as a function of climate or other small-scale factors,” says Murray, a doctoral student in USU’s Department of Biology and Ecology Center. “This is the first study to look at the distribution patterns of canopy soils across forests and one of very few studies that have sought to examine canopy soil properties.”

Murray collected much of the data for the study some 80 feet above the ground at six primary forest sites across Costa Rica’s Cordillera de Tilarán and Cordillera Volcánica Central, encompassing both Caribbean and Pacific slope mountain ranges. Her field gear includes climbing gear, ropes, a safety harness and helmet.

“I climbed about 30 trees to collect data,” she says. “And getting to one of those sites was the hardest hike of my life.”

Murray is referring to a site designated “Puesto 1070,” located along a contiguous tract of primary forest, which required a steep trek from about 1,970 feet in elevation to 3,608 — in thick mud.

“It took eight hours to complete the hike just to the study site,” she says. “We were carrying all of our climbing gear, food for eight days, sleeping bags and sampling equipment. Thank heavens we finished that site early, because, with our hard-earned appetites, we also nearly finished our food supply ahead of schedule.”

Murray says tree canopies in the tropical montane forest systems are especially dense, with thick moss, soil and an abundance of epiphytes — plants that grow on other plants — often referred to as “air plants” — that are not parasitic and have little or no attachment to other obvious nutrient sources.

“It’s like another world in the air — canopies teeming with plant, insect and animal life,” she says. “I initially conducted surveys to assess canopy soil abundance from the ground with binoculars. But it was really necessary to climb up into the trees to get an accurate picture of what was going on.”

Murray asserts forest canopies store much more carbon that generally assumed.

“It’s kind of a back-of-the-envelope calculation on my part, but one I’m ready to defend and eager to investigate further,” she says. “I think canopy soil stores 0.4 to 4 percent of total soil carbon in the forests where it is found, which is not being counted in ecosystem carbon budgets.”

Mentored by USU Biology Professor John Stark and former USU faculty member Bonnie Waring, the latter now with Imperial College London and an author on the paper, Murray says the team’s results indicate both climate and tree size play an important role in canopy soil abundance, carbon stocks and chemistry.

“Climate, particularly fog and temperature changes, appear to drive canopy soil abundance across forests, while tree size determines canopy soil abundance within a forest,” she says. “Our findings reveal canopy soil’s vulnerability to climate change, and its decline, could cause a significant decrease in carbon storage resources.”

Further, she says, those resources could take longer than expected to restore.

“When we talk about reforestation, we don’t stop to consider the time needed for forest regrowth plus canopy mat regrowth,” Murray says. “It may take decades longer for recovered forests destroyed by wildfire or development to regenerate robust canopy soil mats.”

A 2022 recipient of the Ecological Society of America’s Katherine S. McCarter Graduate Student Policy Award, Murray is among a number of Aggies presenting at the ESA’s 2023 Annual Meeting Aug. 6-11, in Portland, Oregon. She presents the talk, “The Persistence of Metabolically Protected vs. Mineral-Associated Soil Organic Carbon in the Presence of Organic Inputs,” on Thursday, Aug. 10 at the Oregon Convention Center.

“For that meeting, I’ll be presenting on research different from, but related to, the study published in Geoderma, including work about the basic mechanisms of soil carbon sequestration that uses canopy soils from my sites in Costa Rica,” she says.

n a study published today in Cell, one of the most prominent peer-reviewed scientific journals in the field of Biochemistry & Molecular Biology, scientists from the National University of Singapore (NUS) and Imperial College London have discovered a new way by which bacteria transmit their genes, enabling them to evolve much faster than previously understood. Led by Assistant Professor John Chen from the Department of Microbiology and Immunology and the Infectious Diseases Translational Research Programme at the NUS Yong Loo Lin School of Medicine (NUS Medicine), the insights could help scientists to better understand how pathogenic bacteria evolve and become increasingly virulent and resistant to antibiotics.

The ability to share genetic material is the major driver of microbial evolution because it can transform a benign bacterium into a deadly pathogen in an instant. Phages, the viruses of bacteria, can act as conduits that allow genes to transfer from one bacterium to another by a process known as genetic transduction. Currently, there are three known mechanisms of transduction: generalised, specialised, and lateral. Lateral transduction was also discovered by the same groups of researchers in 2018, and it is at least one thousand times more efficient than the next most powerful mechanism, generalised transduction.

The new process is termed lateral cotransduction, and the architects behind this new frequency and speed in bacterial evolution are the Staphylococcus aureus pathogenicity islands (SaPIs), which are selfish DNA elements that exploit and parasitise phages and are commonly found integrated into the chromosomes of S. aureus isolates. S. aureus is a type of bacteria that can cause Staph infections in humans and animals. While it primarily manifests as skin infections, it can become life-threatening if it spreads to the bloodstream and infects organs, bones, or joints.

Professor José R. Penadés from the Department of Infectious Diseases, and Director for the Centre for Bacterial Resistance Biology at Imperial College London, said, “This breakthrough sheds light on a novel pathway through which bacteria evolve. Given the alarming surge of antibiotic-resistant superbugs, comprehending the mechanisms driving bacterial evolution becomes increasingly critical.”

This newly discovered process, lateral cotransduction, rivals lateral transduction in terms of efficiency but surpasses the latter in versatility and complexity. While lateral transduction is only known to occur when dormant phages within bacterial genomes become reactivated and initiate reproduction in the lytic cycle, lateral cotransduction can occur during the reactivation process and the infection of new bacterial cells.

Additionally, unlike phages that sacrifice their genes to transmit bacterial host DNA, SaPIs can transfer themselves completely intact with bacterial DNA through lateral cotransduction. This remarkable capability enables them to perpetually repeat the process, making them significantly more potent and efficient in transmitting bacterial genes.

Asst Prof Chen said, “Through the study, we have demonstrated that bacteria can evolve much faster than we understood. While genetic transduction has always been the exclusive domain of phages, in an unexpected twist of irony, our research has shown that parasites of the most prolific parasites on the planet (the phages) are probably the most powerful and efficient transducing agents currently known.”

The rise of superbugs has called for new ways to treat antibiotic-resistant strains. One such method that has gained traction in recent years is phage therapy, which involves the use of phages to eliminate harmful bacteria in infections and diseases. However, instead of just fighting bacteria, some therapeutic phages could turn out to be the unwitting accomplices of SaPIs or other related elements capable of lateral cotransduction.

According to Prof Penadés, “This process likely occurs in various other bacterial species as well. This groundbreaking finding marks a paradigm shift in our understanding of bacterial evolution and will immensely influence the ways we combat antibiotic resistance.”

“They (phages) could be used to destroy bacteria in the short term but end up spreading harmful genes to other cells in the long term, which could prove to be disastrous. With this new way of understanding the evolutionary mechanisms of disease-causing organisms, it is important for therapeutic phages to be carefully vetted before they are used for therapy,” said Asst Prof Chen.

Understanding the ionosphere high in the Earth’s atmosphere is important due to its effects on communications systems, satellites and crucial chemical features including the ozone layer. New insights into the activity of high energy electrons have come from a simulation study led by geophysicist Yuto Katoh at Tohoku University, reported in the journal Earth, Planets and Space.

“Our results clarify the unexpected role of the geomagnetic field surrounding the Earth in protecting the atmosphere from high energy electrons,” says Katoh.

The ionosphere is a wide region between roughly 60 and more than 600 kilometers above the Earth’s surface. It contains electrically charged particles that are a mixture of ions and free electrons generated by the interaction of the atmosphere with radiation from the sun.

Polar regions of the ionosphere are subjected to a particularly steady and energetic stream of incoming electrons in a process called electron precipitation. These ‘relativistic’ electrons move at close to the speed of light, where the effects of Einstein’s relativity theory become ever more significant. They collide with gas molecules and contribute to many phenomena in the ionosphere, including colourful auroral displays. The processes are heavily influenced by the effects of the geomagnetic field on the charged particles involved.

The Tohoku team, with colleagues in Germany and other institutions in Japan, developed a sophisticated software code that focused particular attention on simulating the effects of a relatively unstudied ‘mirror force’ on the electron precipitation. This is caused by the magnetic force acting on charged particles under the influence of the geomagnetic field.

The simulations demonstrated how the mirror force causes relativistic electrons to bounce back upwards, to an extent dependent on the angles at which the electrons arrive. The predicted effects mean that electrons collide with other charged particles higher in the ionosphere than previously suspected.

Illustrating one example of the significance of this work, Katoh comments: “Precipitating electrons that manage to pass through the mirror force can reach the middle and lower atmosphere, contributing to chemical reactions related to variations in ozone levels.” Decreased ozone levels at the poles caused by atmospheric pollution reduce the protection ozone offers living organisms from ultraviolet radiation.

Katoh emphasizes the key theoretical advance of the research is in revealing the surprising significance of the geomagnetic field and the mirror force in protecting the lower atmosphere from the effects of electron precipitation activities by keeping them further away.

“We have now started a project to combine the simulation studies used in this work with real observations of the polar ionosphere to build even deeper understanding of these crucial geophysical processes,” says Katoh.

Most stars with a mass similar to the Sun form in multi-star systems together with other stars. So an understanding of multi-star system formation is important to an overall theory of star formation. However, the complexity and lack of high-resolution, high-sensitivity data left astronomers uncertain about the formation scenario. In particular, recent observations of protostars often reported structures called “streamers” of gas flows toward the protostars, but it has been unclear how these streamers form.

An international team led by Jeong-Eun Lee, a professor at Seoul National University, used the Atacama Large Millimeter/submillimeter Array (ALMA) to observe the trinary protostar system IRAS 04239+2436 located 460 light-years away in the constellation Taurus.

The team found that emissions from sulfur monoxide (SO) molecules trace three spiral arms around the three protostars forming in the system.

Comparison with simulations led by Tomoaki Matsumoto, a professor at Hosei University using the supercomputers “ATERUI” and “ATERUI II” in the Center for Computational Astrophysics at the National Astronomical Observatory of Japan (NAOJ) indicate that the three spiral arms are streamers feeding material to the three protostars. The combination of observations and simulations revealed, for the first time, how the streamers are created and contribute to the growth of the protostars at the center.

Video: https://youtu.be/_2d8p-NRuBc

Cyclopropanes are a key feature in many drugs currently approved by the U.S. Food and Drug Administration, including those used to treat COVID-19, asthma, hepatitis C, and HIV/AIDs. These structures can increase a drug’s potency, alter its ability to dissolve in the body, minimize its interactions with unintended targets, and otherwise fine-tune performance. Cyclopropanes are a ring of three connected carbon atoms, with one carbon attached to the rest of the drug molecule and the other two each attached to two hydrogen atoms.

“Cyclopropanes are an essential component of many drugs and adding them to drug candidates can be an important part of the drug discovery process,” said Ramesh Giri, professor of chemistry in the Eberly College of Science at Penn State and leader of the research team. “Previous efforts to improve the creation of cyclopropanes have focused on altering a mechanistic pathway devolved more than 60 years ago. We approached this from a different angle and identified a completely new pathway that is a simple, practical, and broadly applicable.”

The new method transforms a specific chemical structure on compounds called alkenes — used in the synthesis of many molecules — into cyclopropanes. The method takes advantage of “radical chemistry,” where intermediate steps of reactions leave some carbon atoms with unpaired electrons called free radicals that propel the reaction forward. This specific method uses visible light to initiate the reaction and uses common chemical ingredients, including oxygen.

Traditional methods to create cyclopropanes require highly reactive and difficult-to-acquire ingredients and must be conducted under controlled conditions, and the resulting compounds often have a very short shelf life. These unstable ingredients are critical to producing an intermediate compound in the process called a carbene — a highly reactive carbon atom with two unpaired electrons. The new method completely bypasses the carbene intermediate, producing the unpaired electrons one at a time as radicals.

“All of the ingredients used in this pathway are commercially available or easy to create in the lab and do not require any special safety precautions, and the end product can be stored for prolonged periods,” Giri said. “We can add all the ingredients together in one mixture while exposed to air with as little as 10% oxygen, and it proceeds in one step. The reaction is simple and safe enough that we are even planning to include it as part of an undergraduate chemistry lab.”

Another shortcoming of traditional methods is that they generally do not work with complex molecules. For this reason, cyclopropanes are typically installed early in the synthesis when the molecule is less complex, but following steps can cause the ring to open up, and later attempts to make derivatives of the molecule would require backtracking to those early steps. Using the new method, the researchers successfully transformed a variety of alkenes with a wide range of complexities into cyclopropanes, including pharmaceutically relevant compounds such as the steroid estrone, penicillin and vitamin B.

“We explored the entire range of molecule complexity that people might encounter during drug synthesis,” Giri said. “In some cases, traditional methods might be able to develop the same end product but in many more steps. In other cases, traditional methods would be unable to create these products, because the starting alkenes are too sensitive or too complex. The new method is not only safer, more efficient and more practical, but has a wider range of applications than traditional methods.”

Some of the ingredients in the reaction can also be swapped out to add additional chemical groups to the final product to achieve various therapeutic goals. One of the reaction’s ingredients is as a type of compound called a methylene. There are hundreds of different methylenes that are commercially available, each with a specific chemical group that makes it a methylene as well as other groups that differ and could theoretically be added to the alkene as a cyclopropane Is created. The researchers demonstrated the breadth of the new method using 19 different methylene compounds.

“The idea of using a visible light-based reaction and radical chemistry to transform alkenes into cyclopropanes using methylenes at first seems counterintuitive, which is why it was so important for us to thoroughly demonstrate this new catalytic method,” Giri said. “The key insight was introducing oxygen into the reaction, which helps create a radical that then interacts with the alkene. My lab has been studying other reactions that use alkenes to create a radical and wondered if the same idea could be applied to creating cyclopropanes.”

Next, Giri and his lab plan to scale up the method so that it is industrially viable.

“With future development and scaling up, this method has the potential to transform the way alkenes are cyclopropanated, which could have important implications for drug discovery, development, and creation,” he said.

In addition to Giri, the research team at Penn State includes postdoctoral researcher Dhruba Poudel, postdoctoral researcher at the time of the research Amrit Pokhrel, postdoctoral researcher at the time of the research Raj Kumar Tak, and postdoctoral research Majji Shankar. The U.S. National Institute of General Medical Sciences and Penn State supported this research.

STING is primarily on the lookout for DNA, which can indicate either a foreign invader such as a virus or damage to the host tissue or cell. When STING detects that danger signal, it can turn on at least three different pathways — one leading to interferon production, one to non-canonical autophagy (involved in recycling cell components and clearing pathogens), and a third to formation of the inflammasome, a complex of proteins that activates inflammatory responses. The mechanism by which STING stimulates interferon production is well characterized, but it has not been understood how it activates the other two processes.

Now, a team of MIT and Harvard Medical School researchers has discovered how STING activates those two pathways. They found that STING has a surprising and previously unknown function: It can act as an ion channel that allows protons to leak out of an organelle known as the Golgi body. This makes it the first human immune sensor that can translate danger signals into ion flow.

“Arriving at this new idea that STING is a proton channel required connecting prior findings by other labs that either STING or proton flux could activate the inflammasome and non-canonical autophagy, which led us to hypothesize that STING initiates or mediates proton flux to trigger both downstream processes,” says Nir Hacohen, a member of the Broad Institute of MIT and Harvard, a professor of medicine at Massachusetts General Hospital and Harvard Medical School, and a senior author of the study.

“Because of its importance to host immunity, there is a great interest in developing drugs that can activate or suppress STING activity, and the discovery of STING’s ion channel activity will provide new ways to think about designing therapeutics to modulate STING,” says Darrell Irvine, the Underwood-Prescott Professor at MIT with appointments in the departments of Biological Engineering and of Materials Science and Engineering; a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard; and a senior author of the study.

MIT biology PhD student Bingxu Liu and Rebecca Carlson PhD ’23, a recent graduate of the Medical Engineering and Medical Physics program through the Harvard-MIT Division of Health Sciences and Technology, are the lead authors of the paper, which appears today in Science. Paul Blainey, the Karl Van Tassel Associate Professor of Biological Engineering at MIT and a member of the Broad Institute and the Koch Institute, is also an author of the paper.

A surprising role

STING (short for stimulator of interferon genes) is considered one of the major factors that triggers the immune response in the context of infection, autoimmunity, and cancer. Drugs that activate STING have been developed and tested in clinical trials as cancer immunotherapy drugs that would help stimulate the immune system to destroy tumors.

STING is a protein that can span membranes, and it is usually found embedded in the membrane of an organelle called the endoplasmic reticulum (ER). Once it detects DNA, it relocates to the Golgi body, where it begins to activate proteins that turn on genes required for interferon production.

“People know pretty well how STING induces interferon, but how STING induces autophagy and inflammasome formation has been an open debate in the field for the last 10 years,” Liu says.

Previous research has shown that both autophagy and formation of inflammasomes (large protein complexes that stimulate inflammation) can be provoked by protons leaking from cell organelles, which makes the inside of the cell more acidic. Because of that, the researchers wondered if STING might somehow induce proton leakage.

To explore this possibility, the researchers labeled the Golgi with a protein that fluoresces when the pH goes up. When they treated the cells with a molecule that activates STING, the Golgi became less acidic, meaning that it was losing protons. A genetic screen minimized the possibility of another ion channel controlling this ion flow, so the researchers hypothesized that STING itself was acting as a proton channel.

“In addition to its biological significance, this study is a notable example of the maturing functional genomics field, where pooled screening data are sufficiently reliable to set the direction of focused investigation — even from negative results, as was the case here,” Blainey says.

After running the structure of the STING protein through a computer model that can predict whether a given protein structure might contain a pore, the researchers found that the STING protein is predicted to contain a region that resembles a pore. Serendipitously, last year a company that was seeking STING agonists (molecules that activate STING) found a new molecule that was later shown by an academic group to bind in this precise location.

The MIT/Harvard team hypothesized that the agonist, known as C53, blocks the putative pore. When C53 was added to cells , protons did not leak out of the Golgi, and downstream pathways activating autophagy and inflammasome formation were not turned on, even if STING was activated through other means. However, interferon activation, which goes through a different pathway, still occurred.

“For the first time, we were able to decouple these downstream processes, where we can activate interferon with C53, but inhibit those other two pathways leading to autophagy and inflammasome formation,” Carlson says. “In the context of inflammatory diseases where STING is overactivated, we can now start asking which of those molecular mechanisms is most important and contributes the most to the phenotype that we’re seeing.”

Selective control

In future studies, the researchers hope to use C53 to determine the relative importance of these three pathways and try to figure out which ones would be most useful to stimulate or to block to treat a variety of diseases.

The U.S. Food and Drug Administration has not approved any STING agonist thus far, although multiple clinical trials are currently underway. One potential reason that other STING agonists have not made it beyond clinical trials is that the treatment can result in unwanted cell death mediated by STING. Drugs that stimulate interferon production but not cell death or other inflammatory pathways could offer a way to overcome that obstacle, according to the MIT/Harvard team.

The researchers hope to explore whether STING might play a role in influencing the behavior of other cellular activities known to be controlled by ion channels. “Now that we know that STING is an ion channel, we can propose other effects that we think could occur based on this knowledge that STING does transport protons,” Carlson says.

The research was funded by the U.S. National Institutes of Health, the Howard Hughes Medical Institute, a Fannie and John Hertz Foundation Fellowship, a U.S. National Science Foundation Graduate Research Fellowship, a European Molecular Biology Organization Fellowship, and a Cancer Research Institute/Bristol Myers Squibb Fellowship.