Since the 1970s when it was first proposed, the Unruh effect has eluded detection, mainly because the probability of seeing the effect is infinitesimally small, requiring either enormous accelerations or vast amounts of observation time. But researchers at MIT and the University of Waterloo believe they have found a way to significantly increase the probability of observing the Unruh effect, which they detail in a study appearing in Physical Review Letters.

Rather than observe the effect spontaneously as others have attempted in the past, the team proposes stimulating the phenomenon, in a very particular way that enhances the Unruh effect while suppressing other competing effects. The researchers liken their idea to throwing an invisibility cloak over other conventional phenomena, which should then reveal the much less obvious Unruh effect.

If it can be realized in a practical experiment, this new stimulated approach, with an added layer of invisibility (or “acceleration-induced transparency,” as described in the paper) could vastly increase the probability of observing the Unruh effect. Instead of waiting longer than the age of the universe for an accelerating particle to produce a warm glow as the Unruh effect predicts, the team’s approach would shave that wait time down to a few hours.

“Now at least we know there is a chance in our lifetimes where we might actually see this effect,” says study co-author Vivishek Sudhir, assistant professor of mechanical engineering at MIT, who is designing an experiment to catch the effect based on the group’s theory. “It’s a hard experiment, and there’s no guarantee that we’d be able to do it, but this idea is our nearest hope.”

The study’s co-authors also include Barbara Šoda and Achim Kempf of the University of Waterloo.

Close connection

The Unruh effect is also known as the Fulling-Davies-Unruh effect, after the three physicists who initially proposed it. The prediction states that a body that is accelerating through a vacuum should in fact feel the presence of warm radiation purely as an effect of the body’s acceleration. This effect has to do with quantum interactions between accelerated matter and quantum fluctuations within the vacuum of empty space.

To produce a glow warm enough for detectors to measure, a body such as an atom would have to accelerate to the speed of light in less than a millionth of a second. Such an acceleration would be equivalent to a g-force of a quadrillion meters per second squared (a fighter pilot typically experiences a g-force of 10 meters per second squared).

“To see this effect in a short amount of time, you’d have to have some incredible acceleration,” Sudhir says. “If you instead had some reasonable acceleration, you’d have to wait a ginormous amount of time — longer than the age of the universe — to see a measurable effect.”

What, then, would be the point? For one, he says that observing the Unruh effect would be a validation of fundamental quantum interactions between matter and light. And for another, the detection could represent a mirror of the Hawking effect — a proposal by the physicist Stephen Hawking that predicts a similar thermal glow, or “Hawking radiation,” from light and matter interactions in an extreme gravitational field, such as around a black hole.

“There’s a close connection between the Hawking effect and the Unruh effect — they’re exactly the complementary effect of each other,” says Sudhir, who adds that if one were to observe the Unruh effect, “one would have observed a mechanism that is common to both effects.”

A transparent trajectory

The Unruh effect is predicted to occur spontaneously in a vacuum. According to quantum field theory, a vacuum is not simply empty space, but rather a field of restless quantum fluctuations, with each frequency band measuring about the size of half a photon. Unruh predicted that a body accelerating through a vacuum should amplify these fluctuations, in a way that produces a warm, thermal glow of particles.

In their study, the researchers introduced a new approach to increase the probability of the Unruh effect, by adding light to the entire scenario — an approach known as stimulation.

“When you add photons into the field, you’re adding ‘n’ times more of those fluctuations than this half a photon that’s in the vacuum,” Sudhir explains. “So, if you accelerate through this new state of the field, you’d expect to see effects that also scale ‘n’ times what you would see from just the vacuum alone.”

However, in addition to the quantum Unruh effect, the additional photons would also amplify other effects in the vacuum — a major drawback that has kept other hunters of the Unruh effect from taking the stimulation approach.

Šoda, Sudhir, and Kempf, however, found a work-around, through “acceleration-induced transparency,” a concept they introduce in the paper. They showed theoretically that if a body such as an atom could be made to accelerate with a very specific trajectory through a field of photons, the atom would interact with the field in such a way that photons of a certain frequency would essentially appear invisible to the atom.

“When we stimulate the Unruh effect, at the same time we also stimulate the conventional, or resonant, effects, but we show that by engineering the trajectory of the particle, we can essentially turn off those effects,” Šoda says.

By making all other effects transparent, the researchers could then have a better chance of measuring the photons, or the thermal radiation coming from only the Unruh effect, as the physicists predicted.

The researchers already have some ideas for how to design an experiment based on their hypothesis. They plan to build a laboratory-sized particle accelerator capable of accelerating an electron to close to the speed of light, which they would then stimulate using a laser beam at microwave wavelengths. They are looking for ways to engineer the electron’s path to suppress classical effects, while amplifying the elusive Unruh effect.

“Now we have this mechanism that seems to statistically amplify this effect via stimulation,” Sudhir says. “Given the 40-year history of this problem, we’ve now in theory fixed the biggest bottleneck.”

This research was supported, in part, by the National Science and Engineering Research Council of Canada, the Australian Research Council, and a Google Faculty Research Award.

A crucial component in automobile catalytic converters and in emerging hydrogen fuel cell technology, the demand for this rare silvery white transition metal continues to outstrip supply, driving its price per ounce far above gold and silver.

Palladium and other rare, costly precious metals like platinum, iridium, and ruthenium, are also crucial in chemical transformations, specifically transition metal catalysis, which has become an indispensable tool for putting together complex molecules in the development of pharmaceutical drugs, polymers, and other useful chemicals.

The scarcity and expense of these precious metals has created a need to develop catalysts from transition metals that are more abundant and generally cheaper, like nickel, a cousin of palladium.

As a result, the last decade has seen a dramatic expansion of new catalytic bond-forming transformations involving nickel.

“We know from the literature that nickel complexes are extremely useful in performing some transformations, maybe better than other transition metals out there,” said Liviu Mirica, William H. and Janet G. Lycan Professor of Chemistry at the University of Illinois at Urbana-Champaign. “People have gotten very good at optimizing conditions for specific transformations, so we are slowly getting to where nickel could rival palladium in these transformations.”

More recently, scientists have been focusing on developing nickel catalysts that can be directly photoinitiated by light, which Mirica said has proven to be a very successful area of research producing reactions that have not been previously possible.

However, they still require the use of an additional photocatalyst — typically based on precious metals such as iridium or ruthenium that are even more expensive than palladium.

In a paper recently published in Nature Communications, Mirica and postdoctoral researcher Hanah Na report their work on the development of a completely novel tridentate ligand that coordinates with nickel to create a catalyst that can be directly activated by light to form a carbon-oxygen bond without the use of an additional photocatalyst. C-O bonds are prevalent in many natural products, pharmaceuticals, and agrochemicals.

Mirica and Na believe their new class of tridentate pyridinophane ligands (^RN3) can lead to the development of new nickel catalysts and are a practical platform for detailed mechanical studies of other nickel-catalyzed chemical reactions.

“It is a competent catalyst and on top of it, it can actually do this photocatalysis by itself, it doesn’t require these other photocatalysts,” Mirica said. “It opens up many avenues of research that we think could be used for many additional applications.”

These tridentate pyridinophane ligands (^RN3) build on previous work by Mirica, who had already developed a novel four-pronged molecule known as a tetradentate ligand, whose structure resembles the pocket of a baseball glove. This ligand structure promoted rapid C-C bond forming reactivity while also stabilizing the higher oxidation states of nickel.

“It’s very stable. But all of those intermediates over the past decade have been way too stable. They’re not competent in catalytic applications,” Mirica said.

Then there is the bidentate ligand framework bipyridyl that most chemists are using in nickel photocatalytic processes, which provides enhanced reactivity and the ability to adjust optimization to get the desired reaction.

“It’s great for catalytic chemistry but you can’t isolate or see these special nickel species,” Mirica said.

Typically, Mirica explained, classic organic chemists have a particular chemical transformation in mind and try whatever catalysts they think will be good, and whatever conditions or additives would be useful and optimize it, focusing on a very specific transformation.

“We have a slightly different approach: a metallo-centric approach and in this case nickel is the metal of interest,” he said. “I am interested in being able to design, isolate, characterize nickel complexes with different coordination numbers, different ligand environments, and in different oxidation states, which ultimately will dictate their reactivity.”

This latest ligand structure is somewhere between the other two.

“We open up a coordination site, we open up that nickel center, by removing one of the four nitrogens, to allow other things to bind to it and eventually it allows you to do catalytic activity, but still be able to isolate and characterize intermediates,” he said.

Their novel tridentate ligand enabled them to reveal for the first time the key reaction steps and intermediate species in this catalytic cycle. An in-depth mechanistic understanding of Ni-mediated photocatalysis is essential for rational reaction design and optimization of the nickel-mediated chemical process, the researchers explain in the report.

Their mechanistic study employed techniques including Nuclear Magnetic Resonance (NMR), electron paramagnetic resonance (EPR), in situ infrared (IR) spectroscopy and electrochemical and photophysical measurements, and computational studies.

From a mechanical perspective, the photocatalytic cycle is well-understood, but the Ni-mediated redox cycle has remained a mystery. Paramagnetic Ni(I) and Ni(III) species are assumed to be part of the process, but have not been thoroughly investigated, and the key catalytic steps of oxidative addition, trans-metalation, and reductive elimination at the nickel centers have never been directly observed.

In the past several decades, Na explained, visible light-mediated photoredox catalysis has made vital contributions in the field of synthetic organic chemistry. Traditionally, developing new methodologies and reaction condition optimization are often achieved by trial and error rather than being based on a thorough understanding of the underlying reaction mechanism.

Na said this might be because understanding of the underlying chemistry requires a major contribution from the inorganic and organometallic chemistry fields (beyond the scope of the research interests in synthetic organic chemistry), including the synthesis and characterization of related metal complexes and study of their photochemistry and photophysics.

“As inorganic and organometallic chemists, we want to contribute to this emerging research field, mostly focusing on unraveling clues to understand underlying reaction mechanisms — which is not much done by organic chemists,” Na said. “We believe that our work would provide crucial insight into the reaction design and search for new chemical transformations in the burgeoning field of photoredox catalysis, and thus can impact both the organic and inorganic chemistry community.”

The goal, Mirica explained, is to unleash new reactivity that could ultimately be helpful to organic chemists, who could then employ this system and use it for very particular synthetic targets.

“They may not work now as well as the finely optimized or finely tuned systems that people use on a daily basis in an organic lab, but we hope that our new Ni catalysts will be commonly used several years down the line,” Mirica said.

A new study at the University of Missouri found a “bi-directional” relationship between gastrointestinal issues and internalized symptoms in children and adolescents with autism — meaning the symptoms seem to be impacting each other simultaneously. The findings could influence future precision medicine research aimed at developing personalized treatments to ease pain for individuals with autism experiencing gastrointestinal issues.

“Research has shown gastrointestinal issues are associated with an increased stress response as well as aggression and irritability in some children with autism,” said Brad Ferguson, an assistant research professor in the MU School of Health Professions, Thompson Center for Autism and Neurodevelopmental Disorders and Department of Radiology in the MU School of Medicine. “This likely happens because some kids with autism are unable to verbally communicate their gastrointestinal discomfort as well as how they feel in general, which can be extremely frustrating. The goal of our research is to find out what factors are associated with gastrointestinal problems in individuals with autism so we can design treatments to help these individuals feel better.”

In the study, Ferguson and his team analyzed health data from more than 620 patients with autism at the MU Thompson Center for Autism and Neurodevelopmental Disorders under the age of 18 who experience gastrointestinal issues. Then, the team examined the relationship between the gastrointestinal issues and internalized symptoms, such as stress, anxiety, depression, and social withdrawal. Ferguson explained the findings provide more evidence on the importance of the “gut-brain axis,” or connection between the brain and the digestive tract, in gastrointestinal disorders in individuals with autism.

“Stress signals from the brain can alter the release of neurotransmitters like serotonin and norepinephrine in the gut which control gastrointestinal motility, or the movement of stool through the intestines. Stress also impacts the balance of bacteria living in the gut, called the microbiota, which can alter gastrointestinal functioning,” Ferguson said. “The gut then sends signals back to the brain, and that can, in turn, lead to feelings of anxiety, depression and social withdrawal. The cycle then repeats, so novel treatments addressing signals from both the brain and the gut may provide the most benefit for some kids with gastrointestinal disorders and autism.”

Ferguson said an interdisciplinary team of specialists is needed to help solve this complex problem and develop treatments going forward.

Ferguson collaborates with David Beversdorf, a neurologist at the MU Thompson Center for Autism and Neurodevelopmental Disorders, who also studies gastrointestinal problems in individuals with autism. In a recent study, Beversdorf, who also has appointments in the MU College of Arts and Science and MU School of Medicine, helped identify specific RNA biomarkers linked with gastrointestinal issues in children with autism.

“Interestingly, the study from Beversdorf and colleagues found relationships between microRNA that are related to anxiety behavior following prolonged stress as well as depression and gastrointestinal disturbance, providing some converging evidence with our behavioral findings,” Ferguson said.

Now, Ferguson and Beversdorf are working together to determine the effects of a stress-reducing medication on gastrointestinal issues in a clinical trial.

“I have a great relationship with Beversdorf and the MU Thompson Center Autism Research Core (ARC) that allows our team to quickly go from findings in the laboratory to clinical trials,” Ferguson said.

Ferguson explained that some treatments may work for some individuals with autism but not necessarily for others.

“Our team uses a biomarker-based approach to find what markers in the body are common in those who respond favorably to certain treatments,” Ferguson said. “Our goal is to eventually develop a quick test that tells us which treatment is likely to work for which subgroups of patients based on their unique biomarker signature, including markers of stress, composition of gut bacteria, genetics, co-occurring psychological disorders, or a combination thereof. This way, we can provide the right treatments to the right patients at the right time.”

“Bidirectional relationship between internalizing symptoms and gastrointestinal problems in youth with autism spectrum disorder” was recently published in the Journal of Autism and Developmental Disorders. Ferguson also collaborated with Kristen Dovgan, an assistant professor in the Department of Psychology at Marist College, and Kyra Gynegrowski, an undergraduate student in the Department of Psychology at Marist College. Funding for the study was provided by the Autism Speaks Autism Treatment Network, which is now known as the Autism Care Network.

In a new study published in the journal Nature Microbiology, Efrem Lim and his colleagues explore the galaxy of viruses present in the gut, known as the gut virome. They find that some preterm infants undergo marked alterations in their pattern of gut viruses shortly before developing a serious and often fatal disease known as necrotizing enterocolitis (NEC).

Professor Lim is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics. He is also the principal investigator of the Center for Viral Genomics at ASU and an assistant professor at ASU’s School of Life Sciences.

The study was conducted in collaboration with ASU colleagues and researchers from the Washington University School of Medicine.

Although the bacterial component of the gut microbiome has received considerable research attention, viruses inhabiting the gut remain a largely hidden realm. The viral signature highlighted in the study, along with changes in gut bacterial communities, could provide an early warning signal that an infant is at risk of developing NEC, allowing clinicians to take emergency action.

“For many years now, there’s been some inkling that the microbiome is implicated in this rapidly developing disease,” Lim says. “Studies have shown that changes in the microbiome of the gut in these preterm infants seem to predict the progression to NEC disease.”

Yet teasing out the specific microbial changes leading to the disease has been challenging and the precise mechanism causing the affliction is still unknown. The current study is the first to comprehensively investigate changes in the viral microbiome that appear to set the stage for the development of NEC in preterm infants.

A microbial world is born

Microbes begin colonizing the infant gut during birth, when a baby encounters a variety of microorganisms from its mother’s vaginal tract. As the baby suckles, it picks up additional microbes from its mother’s skin as well as those that have infiltrated her breast milk.

The infant will acquire new microbes from other family and non-family members and even from household pets. These all become incorporated into the developing gut microbiome, composed of some 20-100 billion microbes.

This vast microbial community will go on to shape many aspects of an individual’s health, throughout the person’s life. Unsurprisingly, abnormal alterations in the gut microbiome can spell serious trouble and premature infants are particularly vulnerable to such disruptions.

Before their time

Preterm birth usually refers to infants born after less than 37 weeks of pregnancy. The condition appears to be on the rise, though the causes of this are not fully understood. In many low-income countries, factors including HIV, infections, malaria, and high adolescent pregnancy rates have all been implicated.

In 2020, preterm birth affected 1 of every 10 infants born in the United States. Babies born too early (particularly before 32 weeks), have higher rates of death and disability. Those that survive may experience lasting health issues, including feeding difficulties; breathing, vision and hearing problems; and abnormalities including developmental delays and cerebral palsy.

Babies born prematurely are also at risk of NEC. The disease often strikes suddenly. When babies are born after fewer than 32 weeks of gestation, the incidence of NEC ranged from 2-7% in high-income countries. Mortality among infants with necrotizing enterocolitis ranges from 22-38%.

A stealthy disease

While rarely occurring in full-term infants, this largely mysterious disease affects 1 in 1,000 premature babies. The condition strikes without warning and can cause an infant to go from appearing healthy to a dire state of illness within hours. The disease usually occurs two to six weeks after birth.

The disease produces severe inflammation of intestinal tissue, causing it to die. Such afflictions are known as necro-inflammatory diseases. A perforation may also form in the intestine, allowing bacteria to leak into the abdomen or bloodstream. The sequence of steps leading to NEC remain unclear, though risk factors are believed to include the prolonged use of antibiotics early in life and formula feeding (in addition to preterm birth).

Although studies have strongly implicated changes in the gut microbiome as contributors to the development of NEC, no single bacterial genus has been consistently associated with the disease.

Babies who survive the affliction often face lifelong health issues, which can include neurodevelopmental disabilities and a condition known as short bowel syndrome.

The role of viruses

In the current study, 138 stool samples were collected over the first 11 weeks of life. The samples were from 23 preterm infants in a neonatal intensive care unit in St. Louis, Missouri. Nine of these infants developed NEC, while 14, matched for weight and gestational age, did not.

The study explored the samples using metagenomics, a sequencing method that allows researchers to comprehensively sample genes from all organisms present in a sample. This allows microbiologists like Lim to evaluate bacterial diversity and detect microbial abundance in various environments. The technique also enables the detailed study of microorganisms that are difficult or impossible to culture in the laboratory. (In early 2020, Lim used metagenomic sequencing to rapidly probe the 30,000 letter code of the SARS CoV-2 virus, identifying a unique mutation.)

The study demonstrates that the NEC infants showed a convergence of viral and bacterial signatures in the gut virome. Notably, babies with NEC showed a reduced diversity in viral composition between communities in the gut, a feature known as ?-diversity. The diminishing viral ?-diversity occurred over a 10-day period preceding the onset of NEC, providing a potential biomarker, alerting clinicians to the looming danger. The findings suggest that the developing virome holds vital clues reflecting on the health of preterm infants.

Microbial horizons

The research could lead not only to faster diagnosis and better therapies for NEC but also for a broad range of diseases mediated by the microbiome. Further, existing therapies directed at modifying the gut microbiome, for example, fecal transplant therapy, could be further improved by taking stock of the viral component.

The study demonstrates that the underexplored viral constituents of the microbiome have much to teach us and almost certainly play an important role not only in the transition to NEC in preterm infants but also in other diseases. With new and rapidly evolving sequencing technologies, researchers can begin to mine the virome for valuable diagnostic signposts of disease and develop more effective therapies.

Efrem Lim is the 2022 recipient of the ASU Faculty Research Achievement Award, delivered at the university’s Founder’s Day celebration on March 17.