The study, published Feb. 5 in Cell, reveals a new twist in the complex relationship between humans and their associated microbes, and points the way toward novel therapies that could help combat a rising tide of drug-resistant pathogens.

The new discovery stemmed from work on inflammatory bowel disease, which often causes patients to carry larger than normal populations of fungi in their guts. These patients often develop strong antibody responses against mannan, a molecule common to a wide range of fungal species. However, Dr. Iliyan Iliev, associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, noticed that healthy controls in these studies also had some level of anti-fungal antibodies. “There was no actual evidence for fungal infections in the healthy individuals that we examined, so we started thinking about the possible function of those antibodies,” said Dr. Iliev, who is senior author on the study and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.

The team developed a platform that allowed them to determine which gut fungi are targeted by antibodies in the blood of individual patients. They detected a strong response against the yeast Candida albicans. Turning to experiments in mice, Dr. Iliev and Itai Doron, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate in the lab and lead author on the study, found that colonizing the animals’ guts with Candida albicans caused them to develop antibodies against the fungus in their bloodstreams, even though they didn’t develop blood-borne fungal infections. Instead, the animals’ immune cells appeared to transport fungal antigens to the spleen, stimulating the production of circulating antibodies in the bloodstream. “Those fungi just educate that immune response,” Dr. Iliev said.

In patients with suppressed immune systems, such as organ transplant recipients and some cancer patients, fungi in the gut can invade the bloodstream and cause life-threatening infections. Dr. Iliev and his colleagues mimicked this process by treating mice with immunosuppressive drugs. When a Candida species colonizes the gut of these mice, the fungus moves into the bloodstream, causing a fatal infection. Treating the mice with purified anti-fungal antibodies from donor animals protected the immunosuppressed mice from these infections. The same strategy worked against infection with either Candida albicans or the emerging pathogenic yeast Candida auris, which has become a major cause of fungal disease in immunosuppressed patients and the elderly in recent years.

Collaborating with researchers at INSERM in Paris, France, the Weill Cornell Medicine team also looked at serum from patients with mutations in a gene called CARD9. This mutation affects a critical adapter protein in the immune system, leaving the affected individuals susceptible to severe fungal infections. Dr. Iliev’s team found that the serum of these patients lacked the anti-fungal antibodies normally seen in serum of patients without this mutation. Experiments in mice confirmed an essential and specific role for CARD9 in priming the production of anti-fungal antibodies.

Graphic depicting relationship between fungi in gut, antibody levels and CARD gene Relationship between gut fungi, anti-fungal antibodies, CARD9 gene, and fungal immunity. Image courtesy of the Iliev lab.

The results suggest that normal intestinal fungi such as Candida albicans may function as a kind of intestinal vaccine against fungal infection in healthy people, by inducing the production of bloodborne antibodies that can target multiple species of potentially pathogenic fungi. When those fungi do enter the bloodstream, the antibodies bind them and target them for destruction by cells of the immune system. In patients with suppressed immunity, the anti-fungal antibodies may decline, leaving them vulnerable to fungal infection. New therapies that involve either stimulating the production of anti-fungal antibodies, or injecting such purified antibodies directly into patients’ bloodstreams, could potentially help combat these increasingly common infections.

If that approach works, it would be a welcome development. “Many fungal infections in immunosuppressed patients and elderly patients are happening by translocation of pathogenic Candida species from the gastrointestinal tract, and the survival rates upon systemic spreading are alarmingly low,” said Dr. Iliev.

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In a study published Feb. 3 in Cell Host and Microbe, the investigators showed that patients with Crohn’s disease have an overabundance of a type of gut bacteria called adherent-invasive Escherichia coli (AIEC), which promotes inflammation in the intestine. Their experiments revealed that a metabolite produced by the bacteria interacts with immune system cells in the lining of the intestine, triggering inflammation. Interfering with this process, by either reducing the bacteria’s food supply or eliminating a key enzyme in the process relieved gut inflammation in a mouse model of Crohn’s disease.

“The study reveals a therapeutically targetable weak point in the bacteria,” said senior author Dr. Randy Longman, associate professor of medicine in the Division of Gastroenterology and Hepatology and the Director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.

To find this “Achilles heel,” Dr. Longman and his colleagues, including Drs. Ellen Scherl and Chun-Jun Guo at Weill Cornell Medicine and collaborators Dr. Gretchen Diehl at Memorial Sloan Kettering and Dr. Kenneth Simpson at Cornell’s Ithaca campus, targeted a process the AIEC bacteria uses to convert a byproduct of sugar fermentation in the gut to grow. Specifically, the AIEC uses 1,2-propanediol, a byproduct of the breakdown of a type of sugar called fucose that is found in the lining of the intestines. When the AIEC converts 1,2-propanediol, it produces propionate, which the study showed interacts with a type of immune system cell called mononuclear phagocytes that are also found in the lining of the gut. This sets off a cascade of inflammation.

Next, the investigators genetically engineered AIEC bacteria to lack a key enzyme in this process called propanediol dehydratase. Without propanediol dehydratase, the bacteria do not set off a cascade of inflammation in a mouse model of Crohn’s disease. Reducing the available supply of fucose in the animal’s gut also reduced inflammation.

“Changing one metabolic pathway in one type of bacteria can have a big impact on intestinal inflammation,” said the study’s co-lead author Dr. Monica Viladomiu, a post-doctoral associate in medicine in the Division of Gastroenterology and Hepatology and in the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. Maeva Metz, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate in Dr. Longman’s laboratory, is also co-lead author.

The discovery could lead to better treatments for Crohn’s disease, a type of inflammatory bowel disease that affects more than 4 million people worldwide. Currently, patients with Crohn’s disease are often treated with antibiotics, which can kill both beneficial and harmful bacteria causing unwanted side effects. But treatments that precisely target the inflammatory cascade discovered by Dr. Longman and colleagues might help reduce inflammation while preserving beneficial bacteria.

“If we can develop small molecule drugs that inhibit propanediol dehydratase or use dietary modifications to reduce the availability of fucose, we may be able to reduce intestinal inflammation in patients with Crohn’s disease with fewer side effects,” said Dr. Longman, who is also a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.

One of the next steps for the team will be testing potential treatments. They also plan to study the potential role of an enzyme called fucosyltransferase 2 in protecting the gut against this inflammatory cascade. Dr. Longman explained that many patients with Crohn’s disease have mutations in the gene that encodes this enzyme, rendering it nonfunctional.

“From a clinical perspective, that’s interesting because it may help us stratify people for whom one intervention or another maybe more useful,” Dr. Longman said.

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“The prominence and early onset of retinal degeneration in JNCL makes it likely that cellular processes that are compromised in JNCL are critical for health and function of the retina,” said Ruchira Signh, Ph.D., an associate professor in the Department of Ophthalmology and Center for Visual Science and lead author of the study which appears in the journal Communications Biology. “It is important to understand how vision loss is triggered in this disease, what is primary and what is secondary, and this will allow us to develop new therapeutic strategies.”

Batten disease is caused by a mutation in the CLN3 gene, which is found on chromosome 16. Most children suffering from JNCL have a missing part in the gene which inhibits the production of certain proteins. Rapidly progressive vision loss can start in children as young as 4 and eventually develop learning and behavior problems, slow cognitive decline, seizures, and loss of motor control. Most patients with the disease die between the ages of 15 and 30.

It has been well established that vision loss in JNCL is due to degeneration of the light-sensing tissue in the retina. The vision loss associated with JNCL can precede other neurological symptoms by many years in some instances, which often leads to patients being misdiagnosed with other more common retinal degenerations. However, one of the barriers to studying vision loss in Batten disease is that mouse models of CLN3 gene mutation do not produce the retinal degeneration or vision loss found in humans. Additionally, examination of eye tissue after death reveals extensive degeneration of retinal cells which does not allow researchers to understand the precise mechanisms that lead to vision loss.

URMC is a hub for Batten disease research. The Medical Center is home to the University of Rochester Batten Center (URBC), one of the nation’s premier centers dedicated to the study and treatment of this condition. The URBC is led by pediatric neurologist Jonathon Mink, M.D., Ph.D., who is a co-author of the study. Batten disease is also one of the key research projects that will be undertaken by the National Institute of Child Health and Human Development-supported University of Rochester Intellectual and Development Diseases Research Center.

To study Batten disease in patient’s own cells, the research team reengineered skin cells from patients and unaffected family members to create human-induced pluripotent stem cells. These cells, in turn, were used to create retinal cells which possessed the CLN3 mutation. Using this new human cell model of the disease, the new study shows for the first time that proper function of CLN3 is necessary for retinal pigment epithelium cell structure, the cell layer in the retina that nourishes light sensing photoreceptor cells in the retina and is critical for their survival and function and thereby vision.

Singh points out that understanding how RPE cell dysfunction contributes to photoreceptor cell loss in Batten disease is important first step, and it will enable researchers to target specific cell type in the eye using potential future gene therapies, cell transplantation, and drug-based interventions.

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Tail wagging the dog

Doing force microscopy by ‘vibrating the table under the finger’ may look like making the entire procedure a whole lot more complicated. In a sense it does. But mastering the complexity of this inverted approach comes with great payoff. The new method promises to push the sensitivity of force microscopy to its fundamental limit, beyond what can be expected from further improvements of the conventional ‘finger tapping’ approach.

The key to the superior sensitivity is the choice of substrate. The ‘table’ in the experiments of Eichler, Degen and their co- workers is a perforated membrane made of silicon nitride, a mere 41 nm in thickness. Collaborators of the ETH physicists, the group of Albert Schliesser at the University of Copenhagen in Denmark, have established these low- mass membranes as outstanding nanomechanical resonators with extreme ‘quality factors’. That is, that once the membrane is tipped on, it vibrates millions of times, or more, before coming to rest. Given these exquisite mechanical properties, it becomes advantageous to vibrate the ‘table’ rather than the ‘finger’. At least in principle.

New concept put to practice

Translating this theoretical promise into experimental capability is the objective of an ongoing project between the groups of Degen and Schliesser, with theory support from Dr. Ramasubramanian Chitra and Prof. Oded Zilberberg of the Institute for Theoretical Physics at ETH Zurich. As a milestone on that journey, the experimental teams have now demonstrated that the concept of membrane- based scanning force microscopy works in a real device.

In particular, they showed that neither loading the membrane with samples nor bringing the tip to within a distance of a few nanometres compromises the exceptional mechanical properties of the membrane. However, once the tip approaches the sample even closer, the frequency or amplitude of the membrane changes. To be able to measure these changes, the membrane features not only an island where tip and sample interact, but also a second one — mechanically coupled to the first — from where a laser beam can be partially reflected, to provide a sensitive optical interferometer.

Quantum is the limit

Putting this setup to work, the team successfully resolved gold nanoparticles and tobacco mosaic viruses. These images serve as a proof of principle for the novel microscopy concept, but they do not yet push the capabilities into new territory. But the destination is just there. The researchers plan to combine their novel approach with a technique known as magnetic resonance force microscopy (MRFM), to enable magnetic resonance imaging (MRI) with a resolution of single atoms, thus providing unique insight, for example, into viruses.

Atomic-scale MRI would be another breakthrough in imaging, combining ultimate spatial resolution with highly specific physical and chemical information about the atoms imaged. For the realization of that vision, a sensitivity close to the fundamental limit given by quantum mechanics is needed. The team is confident that they can realise such a ‘quantum-limited’ force sensor, through further advances in both membrane engineering and measurement methodology. With the demonstration that membrane-based scanning force microscopy is possible, the ambitious goal has now come one big step closer.

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The study, published today (5 February 2021) in Science Advances, sought to understand why neuroblastomas range in severity, with some easy to treat and others having relatively low five-year survival rates. The fact that all neuroblastomas arise from sympathoblasts makes them an attractive drug target, because these cells exist only in the tumour after the child is born.

Neuroblastoma is a rare cancer that generally affects children under five years old. It begins in the abdomen, usually in the adrenal glands — hormone-producing glands above the kidneys. Neuroblastoma is remarkable in that its severity can vary greatly between individuals. In some children the cancer will disappear without treatment, whereas in others the cancer is relentless. The five-year survival rate for neuroblastoma is one of the lowest of all childhood cancers*.

This varied outlook prompted the researchers to ask whether the range of severity could be caused by neuroblastomas arising from different cell types at different stages of the child’s development in the womb. This was made possible by the advent of single cell mRNA sequencing, a high-resolution technology that can identify different cell types present in a tissue according to the genes expressed by individual cells.

In this study, gene expression of 19,723 cancer cells was analysed and compared to a reference of 57,972 developmental adrenal cells in the hope of identifying the cell types from which neuroblastomas arise and to find novel treatment targets.

Dr Jan Molenaar, a senior author of the study from the Princess Máxima Center for Pediatric Oncology in the Netherlands, said: “What is most striking about our findings is that despite the great diversity of clinical behaviour of neuroblastoma, there is an overarching neuroblastoma cell type that is found in all patients. The identification of sympathoblasts as the root of all neuroblastoma is an important step towards understanding how the disease develops and, hopefully, how we can treat it.”

Currently, many cancer treatments cause serious side effects for the patient. But in recent years, technological advances have sped up drug development by allowing researchers to identify differences between the biological processes, such as the expression of a particular gene, within healthy human cells and those within cancerous ones. These differences can be exploited to attack cancer cells without affecting the patient’s healthy cells.

The presence of sympathoblasts, a developmental cell type not normally found in children after they are born, makes it a promising drug target for the treatment of neuroblastoma.

Dr Karin Straathof, a senior author of the study from Great Ormond Street Hospital, said: “Neuroblastoma is an unusual cancer in that some tumours resolve without intervention, yet the disease still has one of the lowest five-year survival rates of any childhood cancer. This study fills important gaps in our knowledge of what neuroblastoma cells are and revealed novel treatment targets. My hope is that new, less intrusive therapies can be developed by targeting sympathoblasts, a developmental cell type that exists only in neuroblastoma tumours after a child is born.”

As well as facilitating the discovery of sympathoblasts as the root of neuroblastoma, the single-cell reference map of the developmental adrenal gland will also contribute to the Human Cell Atlas project**. The project aims to create comprehensive reference maps of all types of human cells — the fundamental units of life — as a basis for understanding human health and diagnosing, monitoring, and treating disease.

Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute and Cambridge University Hospitals, said: “Our study shows the power of looking at individual childhood cancer cells in revealing not just one, but a plethora of novel treatment ideas. This raises the exciting prospect that a single cell atlas of all types of paediatric tumours may transform our understanding of childhood cancer.”

But until now, no optical coating had ever been developed that could simultaneously reflect and transmit the same wavelength, or color.

In a paper in Nature Nanotechnology, researchers at the University of Rochester and Case Western Reserve University describe a new class of optical coatings, so-called Fano Resonance Optical Coatings (FROCs), that can be used on filters to reflect and transmit colors of remarkable purity.

In addition, the coating can be made to fully reflect only a very narrow wavelength range.

“The narrowness of the reflected light is important because we want to have a very precise control of the wavelength,” says corresponding author Chunlei Guo, professor at Rochester’s Institute of Optics. “Before our technology, the only coating that could do this was a multilayered dielectric mirror, that is much thicker, suffers from a strong angular dependence, and is far more expensive to make. Thus, our coating can be a low-cost and high-performance alternative.”

The researchers envision a few applications for the new technology. For example, they show how FROCs could be used to separate thermal and photovoltaic bands of the solar spectrum. Such capability could improve the effectiveness of devices that use hybrid thermal-electric power generation as a solar energy option. “Directing only the useful band of the solar spectrum to a photovoltaic cell prevents its overheating,” says Guo.

The technology could also lead to a six-fold increase in the life of a photovoltaic cell. And the rest of the spectrum “is absorbed as thermal energy, which could be used in other ways, including energy storage for night-time, electricity generation, solar-driven water sanitation, or heating up a supply of water,” Guo says.

“These optical coatings can clearly do a lot of things that other coatings cannot do,” Guo adds. But as with other new discoveries, “it will take a little bit of time for us or other labs to further study this and come up with more applications.

“Even when the laser was invented, people were initially confused about what to do with it. It was a novelty looking for an application.”

Guo’s lab, the High-Intensity Femtosecond Laser Laboratory, is noted for its pioneering work in using femtosecond lasers to etch unique properties into metal surfaces.

The FROC project resulted from a desire to explore “parallel” ways to create unique surfaces that do not involve laser etching. “Some applications are easier with laser, but others are easier without them,” Guo says.

Fano resonance, named after the physicist Ugo Fano, is a widespread wave scattering phenomenon first observed as a fundamental principle of atomic physics involving electrons. Later, researchers discovered that the same phenomenon can also be observed in optical systems. “But this involved very complex designs,” Guo says.

Guo and his colleagues found a simpler way to take advantage of Fano resonance in their optical coatings.

They applied a thin, 15 nanometer-thick film of germanium to a metal surface, creating a surface capable absorbing a broad band of wavelengths. They combined that with a cavity that supports a narrowband resonance. The coupled cavities exhibit Fano resonance that is capable of reflecting a very narrow band of light.

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The study, published in Scientific Reports, used an animal model of drug addiction to show that a return to social interaction gives the same result as living in a rich, stimulating environment in reducing cravings for both sugar and nicotine rewards.

“This was an animal study, but we can probably all relate to the mental health benefits of being able to go for a coffee with our friends and having a chat,” lead author Dr Kelly Clemens from UNSW Sydney’s School of Psychology said. “Those sorts of activities can divert our attention from being at home and eating and drinking — but they can also be rewarding in and of themselves, and we come away from those interactions feeling relaxed, happy and valued in a way that means our general demeanour and mental health has improved.”

Prior to the COVID-19 pandemic, social isolation was already increasing in Australia, with almost a quarter of Australians reporting feelings of loneliness or social isolation. The researcher said social isolation could have a significant impact on both mental and physical health. It can lead to anxiety, depression, compulsive overeating, and an increased risk of cardiovascular disease and cancer. “Social isolation in particular can both lead to increased drug taking, but can also make it harder for those wanting to cut down or quit,” Dr Clemens said.

The UNSW Scientia Fellow is interested in why people relapse into drug use — in this case, nicotine — when they are socially isolated. “We know that if you’re a regular smoker and you’re trying to give up and then you see somebody else smoking on tv, smell cigarette smoke, or you see a packet of cigarettes, people experience very strong cravings,” she said. “So we wanted to know if isolation increases the likelihood of picking up on those cues, and of initiating cravings.”

Existing evidence tells us that both people and rodents who are anxious, or in a socially isolated environment, pay more attention to substance cues in their environment, she said. These cues are more likely to enter into their long-term memory. “And they can actually have a bigger influence over behaviour later on,” she said.

While many studies have focused on the effect of isolation on adolescents, Dr Clemens concentrated on adult rats in this research. The researcher examined how cues linked to nicotine intake influenced cravings in adult rats in social isolation, and if the cravings could be reversed by returning the animals to group housing. They measured cravings by recording the amount of times the rat pressed a lever to turn on the cue that had been linked to nicotine. The team found that after a brief period of abstinence, the socially isolated rats were much more likely to relapse to nicotine seeking. But their cravings were reversed once they returned to group housing, highlighting the importance of social interaction in the treatment of substance abuse disorders.

“When we put the rats back with their cage mates, they weren’t interested in the cue for the nicotine anymore, and they showed little evidence of relapse,” Dr Clemens said. “The key finding of this particular study is the reversal of susceptibility to relapse with that return to group housing.”

Dr Clemens said she was surprised that the benefit of returning to a social environment was so rapid. “The impact of social isolation took much longer to manifest, suggesting that social interaction may have a lasting protective effect against the development and relapse of addiction,” she said.

The Scientia Fellow said the research demonstrated the consequences of social isolation for drug use are not permanent. “Smokers who want to quit are often provided with a pharmacological response to their addiction. They can access many medications and replacement therapies that can have variable results,” she said. “Our findings suggest that something as simple as socialising with your friends could reduce those cravings and make you less likely to smoke.

This is consistent with other recent evidence that suggested people crave social interaction, and that isolation interacts with the brain’s reward circuitry. “But it’s important to note that this was research done in animals, and how exactly it translates to human behaviour needs to be the subject of further research.”

While the study focused on nicotine, Dr Clemens found a similar result from sugar which was used as a control measure in the study. “This tells us that our results probably extend to other high fat, high sugar food and drinks. It is possible that if we did a similar study with alcohol, and other drugs of abuse, we might find a similar pattern. But we would have to test that specifically.”

Dr Clemens said a follow up study could investigate if social isolation is leading to long term or transient changes in the brain that underlie the behavioural changes that she observed.

Researchers want to develop gels for healthcare applications by mixing in medicinal compounds, and giving patients injections so that the gel releases the active pharmaceutical ingredient over a period of months to avoid weekly or daily needle sticks.

But standing in the way is a problem that’s as easily understandable as the difference between using hair gel on a beach versus in a blizzard — heat and cold change the character of the gel.

“We can make gels with the right slow-release properties at room temperature but once we injected them, body heat would rapidly dissolve them and release the medicines too quickly,” said Eric Appel, assistant professor of materials science and engineering.

In a paper published Feb. 2 in the journal Nature Communications, Appel and his team detail their successful first step toward making temperature-resistant, injectable gels with a concoction designed to cleverly bend the laws of thermodynamics.

Appel explained the science behind this rule-breaking with an analogy to making Jello: the solid ingredients are poured into water, then heated and stirred to mix well. As the mixture cools, the Jello solidifies as the molecules bond together. But if the Jello is reheated, the solid reliquefies.

The Jello example illustrates the interplay between two thermodynamic concepts — enthalpy, which measures the energy added to or subtracted from a material, and entropy, which describes how energy changes make a material more or less orderly at the molecular level. Appel and his team had to make a medicinal Jello that didn’t melt, thus losing its time-release properties, when the cool solid was heated by the body.

To accomplish this, the Stanford team created a gel made of two solid ingredients — polymers and nanoparticles. The polymers were long, spaghetti-like strands that have a natural propensity to get entangled, and the nanoparticles, only 1/1000th the width of a human hair, encouraged that tendency. The researchers began by separately dissolving the polymers and particles in water and then stirring them together. As the commingling ingredients began to bond, the polymers wrapped tightly around the particles. “We call this our molecular Velcro,” said first author Anthony Yu, who did the work as a Stanford graduate student and is now a postdoctoral scholar at MIT.

The powerful affinity between the polymers and particles squeezed out the water molecules that had been caught between them, and as more polymers and particles congealed, the mixture began to gel at room temperature. Crucially, this gelling process was achieved without adding or subtracting energy. When the researchers exposed this gel to the body’s temperature (37.5 C) it did not liquefy like ordinary gels because the molecular Velcro effect enabled entropy and enthalpy — orderliness and temperature change, respectively — to remain roughly in balance in accord with thermodynamics.

Appel said it will take more work to make injectable, time-release gels safe for human use. While the polymers in these experiments were biocompatible, the particles were derived from polystyrene, which is commonly used to make disposable cutlery. His lab is already trying to make these thermodynamically-neutral gels with fully biocompatible components.

If they are successful, a time-release gel could prove valuable for providing anti-malarial or anti-HIV treatments in under-resourced areas where it’s difficult to administer the short-acting remedies currently available.

“We are trying to make a gel that you could inject with a pin, and then you’d have a little blob that would dissolve away very slowly for three to six months to provide continuous therapy,” Appel said. “This would be a game-changer for fighting critical diseases around the world.”

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Materials provided by Stanford University School of Engineering. Original written by Tom Abate. Note: Content may be edited for style and length.