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Showing posts with label Biology & Health. Show all posts
Showing posts with label Biology & Health. Show all posts

Thursday, 2 December 2021

How T Cells recognise infection or disease

Monash University researchers have expanded their knowledge of how T cells might recognise infections or disease, providing key insight into how an often-overlooked T cell lineage becomes activated when encountering pathogens such as viruses, bacteria, and cancers.

T cells communicate with other cells in the body in search of infections or diseases. This crosstalk relies on specialised receptors known as T cell receptors that recognise foreign molecular fragments from an infection or cancer that are presented for detection by particular molecules called major histocompatibility complex (MHC) or MHC-like.

In this study, Monash Biomedicine Discovery Institute scientists have expanded the understanding of how a poorly defined class of gamma delta T cells recognises an MHC-like molecule known as MR1. MR1 is a protein sensor that takes cellular products generated during infections or disease and presents them for T cells to detect, thereby alerting the immune system.

These gamma delta T cells play an understudied role within specific tissues around the body including the intestinal tract and may be an important factor in diseases that impact these tissues.

The findings are published today in the Proceedings of the National Academy of Sciences.

The study was co-led by Dr Benjamin S. Gully and Dr Martin Davey with first author Mr Michael Rice from the Monash Biomedicine Discovery Institute.

Mr Rice, a PhD student in the Rossjohn lab, says the more we understand how such cells recognise, interact with and even kill infected, diseased or cancerous cells, the greater informed we are when developing therapies and treatments for a range of conditions.

“Gamma delta T cells are key players in the immune response to infected and cancerous cells, yet we know very little about how they mediate these important functions,” said Mr Rice.

By using a high-intensity X-ray beam at the Australian Synchrotron, the scientists were able to obtain a detailed 3D atomic model of how the gamma delta T cell receptor recognises MR1. What sets these cells apart from others seems to be the unusual ways in which they interact with MR1. This work further recasts our understanding of how T cell receptors can interact with specialised MHC-like molecules and represents a notable development for our understanding of T cell biology.

Mr Rice stated: “By using high-resolution protein imaging and biochemical assays, we were able to identify key mechanisms that govern gamma delta T cell receptor recognition of MR1, a key sensor of bacterial infection.”

Co-lead author Dr Gully said: “These cells have evaded characterisation for a long time, leading to many assumptions on how they become activated. Here we have shown that these gamma delta T cells can recognise MHC-like molecules in their own unique ways and in ways we could not have predicted.

“These results will now inform our attempts to understand the roles of these gamma delta T cells within the tissues in which they are found, and in deciphering their roles within disease.”

Dr Davey said: “These are important T cells that form a major component of the immune system within human tissues such as the lungs and gastrointestinal tract. With a greater understanding of how our immune system operates within these tissues, we can reveal crucial insight into disease.

“A better understanding of these tissue-specific T cells could reveal their power as a new line of immunotherapies for infection and cancer immunotherapy.”


Rice MT, Borstel A von, Chevour P, et al. Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor. PNAS. 2021;118(49). DOI: 10.1073/pnas.2110288118

Sunday, 28 November 2021

Researchers Use Nanoparticles To Kill Dangerous Bacteria That Hide Inside Human Cells

Researchers from the University of Southampton, working with colleagues at the Defence Science and Technology Laboratory (Dstl), have developed a new technology based on nanoparticles to kill dangerous bacteria that hide inside human cells.

Burkholderia is a genus of bacterium that causes a deadly disease called melioidosis. This disease kills tens of thousands of people each year, particularly in southeast Asia. Antibiotics administered orally or intravenously often don’t work very well against it as the bacteria hide away and grow in white blood cells called macrophages. 

New research, led by Dr. Nick Evans and Dr. Tracey Newman, has shown that tiny capsules called polymersomes – which are about 1000th the diameter of a human hair – could be used to carry bug-killing antibiotics right to the site where the bacteria grow inside the cells. Their findings have been published in the journal ACS Nano.

Macrophages are cells of the immune system that have evolved to take up particles from the blood which is crucial to their role in preventing infection, but it also means that they can be exploited by some bacteria which infect and grow inside them.

In this study, the research team added polymersomes to macrophages that were infected with bacteria. Their results showed that the polymersomes were readily taken up by the macrophages and associated with the bacteria inside the cells. This means they could be an effective way to get a high concentration of antibiotics to the site of infection. The team hope this could eventually lead to patients being treated by injection or inhalation of antibiotic-laden capsules, saving many lives each year.

Eleanor Porges, a PhD student in the University of Southampton’s Faculty of Medicine and first author on the study said: “What is so attractive about this technology is that the antibiotics are only released when they get to the place they are needed. We hope by doing this we may be able to use less antibiotic and to even repurpose antibiotics that wouldn’t normally be considered effective.”

Dr. Nick Evans, Associate Professor in Bioengineering at the University of Southampton added: “What was interesting is that previous research has involved complicated chemistry to engineer the polymersomes in order to release the drug at the right time and place by changes to heat or the pH scale. Our research has shown that this is not necessary, which makes their use much less complex and perhaps easier to produce for clinical use.

“The results of our study were a real team effort, with people all pulling together from backgrounds in microbiology, imaging and nanotechnology working between Dstl and Southampton. This is what made the data so compelling.”

The team are now in the early stages of developing this for clinical application with Dstl, the science inside UK defense and security.


Antibiotic-Loaded Polymersomes for Clearance of Intracellular Burkholderia thailandensis by Eleanor Porges, Dominic Jenner, Adam W. Taylor, James S. P. Harrison, Antonio De Grazia, Alethia R. Hailes, Kimberley M. Wright, Adam O. Whelan, Isobel H. Norville, Joann L. Prior, Sumeet Mahajan, Caroline A. Rowland, Tracey A. Newman and Nicholas D. Evans, 5 November 2021, ACS Nano.

Friday, 26 November 2021

Scientists uncover how cells control “the final cut” during cell division

Cell division is one of the most critical periods of organ growth and homeostasis. Cells in the body proliferate at different rates. Some divide constantly and throughout life, like the ones that line the gut, whereas others divide only rarely. Cell division is central to biology, but also to disease.

Cell division is a high-fidelity physical process that ends with the separation into two daughter cells, a process known as cytokinesis.

Cytokinesis, the separation of a cell into two daughter cells, initiates with the strangling of the mother cell around the equator by the filaments that form the cell’s skeleton. Next, cell shrinking at the equator as well as centrifugal movement of the daughter cells induce the thinning of the connection between the daughter cells. “It is like pulling apart two pieces of a chewing gum that form a long, thin stretch of gum that eventually breaks apart”, says Dr Miguel A. Valverde, head of the Molecular Physiology Laboratory at UPF and leader of the project. The long, thin stretch of plasma membrane and cytoplasm connecting the two daughter cells is called the intercellular bridge and the final cut that results in two separate cells is called abscission.

However, there is a major difference between the passive rupture of the gum due to the mechanical force applied ­–pulling apart­– and the fascinating precision machinery of abscission. In the case of abscission, the thinning of the intercellular bridge forms a tube of less than one micrometre (10-6 metres) in diameter with the objective of adapting its form and size to the anchoring of the spring-like proteins ­–and their regulators­– that strangle the plasma membrane to generate two independent cells. “This final cut is a critical step in cell division. It cannot occur too soon because the daughter cells may not receive all the required information, nor too late because the separating daughter cells may fuse again into a single cell but with two nuclei, thereby acquiring an incorrect number of chromosomes, which is known as aneuploidy ­–a significant characteristic of numerous kinds of cancer”, affirms Dr. Cristina Pujades, principal investigator of the Developmental Biology group at UPF.

Cancer is often the result of DNA mutations or problems with how cells divide.

Since the discovery in the 19th century that cells divide, scientists have tried to unravel the mechanisms operating in this high-precision process. “We reasoned that during the formation of the intercellular bridge between daughter cells there is tensioning of the plasma membrane that may activate mechanosensitive ion channels”, says Dr. Julia Carrillo, first author of the scientific publication.

Calcium entering the cell following the activation of Piezo1 promotes the recruitment of the proteins forming the conical spring that strangles the intercellular connection between daughter cells.

The UPF team found that during cytokinesis, the mechanosensitive Piezo1 ion channel is almost uniquely activated at the intercellular bridge where it generates a diffusible calcium signal. Moreover, they found that Piezo1 is necessary for successful cytokinesis in different cell types, including the endothelial cells that line the interior of the blood vessels, cells that cure our wounds, breast cancer cells or in whole organisms such as zebrafish embryos in which the activity of Piezo1 was reduced using genetic silencing or a toxin obtained from a scorpion that specifically binds to the Piezo1 channel inhibiting its function.

Piezo ion channel proteins were identified in 2010 as fast sensors of mechanical forces by this year Nobel Prize awardee, Ardem Patapoutian, and soon after they were recognized as the molecules that our nervous system use to sense touch. “Since their discovery, we and others have proposed that Piezo channels are not only relevant to sense the world we live in but are also used by cells to sense and react to their physical environment as they are stretched, compressed, or move around within our body” affirms Dr. Valverde.

Piezo1 is necessary for successful cytokinesis across different cell types and species.

These findings lay the foundations for understanding this brief, dynamic cell life stage that is critical for the growth and renewal of our organs and pave the way for tackling the uncontrolled proliferation of cancer cells in tumors by means of genetic or pharmacological regulation of the Piezo1 channel.


Carrillo-Garcia J, Herrera-Fernández V, Serra SA, et al. The mechanosensitive Piezo1 channel controls endosome trafficking for an efficient cytokinetic abscission. Sci Adv. 7(44):eabi7785. DOI: 10.1126/sciadv.abi7785

Monday, 15 November 2021

Regenerative Medicine Breakthrough: “Dancing Molecules” Successfully Repair Severe Spinal Cord Injuries

Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal cord injuries. 

In a new study, researchers administered a single injection to tissues surrounding the spinal cords of paralyzed mice. Just four weeks later, the animals regained the ability to walk.

The research will be published in the Nov. 12 issue of the journal Science.

By sending bioactive signals to trigger cells to repair and regenerate, the breakthrough therapy dramatically improved severely injured spinal cords in five key ways: (1) The severed extensions of neurons, called axons, regenerated; (2) scar tissue, which can create a physical barrier to regeneration and repair, significantly diminished; (3) myelin, the insulating layer of axons that is important in transmitting electrical signals efficiently, reformed around cells; (4) functional blood vessels formed to deliver nutrients to cells at the injury site; and (5) more motor neurons survived.

After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects. This is the first study in which researchers controlled the collective motion of molecules through changes in chemical structure to increase a therapeutic’s efficacy.

“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said Northwestern’s Samuel I. Stupp, who led the study. “For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”

Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology (SQI) and its affiliated research center, the Center for Regenerative Nanomedicine. He has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine.

Life expectancy has not improved since the 1980s

According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with a spinal cord injury in the United States. Life for these patients can be extraordinarily difficult. Less than 3% of people with complete injury ever recover basic physical functions. And approximately 30% are re-hospitalized at least once during any given year after the initial injury, costing millions of dollars in average lifetime health care costs per patient. Life expectancy for people with spinal cord injuries is significantly lower than people without spinal cord injuries and has not improved since the 1980s.

“Currently, there are no therapeutics that trigger spinal cord regeneration,” said Stupp, an expert in regenerative medicine. “I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients. Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.”

‘Dancing molecules’ hit moving targets

The secret behind Stupp’s new breakthrough therapeutic is tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors. Injected as a liquid, the therapy immediately gels into a complex network of nanofibers that mimic the extracellular matrix of the spinal cord. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.

“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”

Stupp and his team found that fine-tuning the molecules’ motion within the nanofiber network to make them more agile resulted in greater therapeutic efficacy in paralyzed mice. They also confirmed that formulations of their therapy with enhanced molecular motion performed better during in vitro tests with human cells, indicating increased bioactivity and cellular signaling.

“Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often,” Stupp said. “If the molecules are sluggish and not as ‘social,’ they may never come into contact with the cells.”

One injection, two signals

Once connected to the receptors, the moving molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal prompts the long tails of neurons in the spinal cord, called axons, to regenerate. Similar to electrical cables, axons send signals between the brain and the rest of the body. Severing or damaging axons can result in the loss of feeling in the body or even paralysis. Repairing axons, on the other hand, increases communication between the body and brain.

The second signal helps neurons survive after injury because it causes other cell types to proliferate, promoting the regrowth of lost blood vessels that feed neurons and critical cells for tissue repair. The therapy also induces myelin to rebuild around axons and reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing. 

“The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce,” said Zaida Álvarez, the study’s first author and former research assistant professor in Stupp’s laboratory. “Our synthetic signals are short, modified peptides that — when bonded together by the thousands — will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.”

Universal application

While the new therapy could be used to prevent paralysis after major trauma (automobile accidents, falls, sports accidents and gunshot wounds) as well as from diseases, Stupp believes the underlying discovery — that “supramolecular motion” is a key factor in bioactivity — can be applied to other therapies and targets.

“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease and Alzheimer’s disease,” Stupp said. “Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.”


Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury by Z. Álvarez, A. N. Kolberg-Edelbrock, I. R. Sasselli, J. A. Ortega, R. Qiu, Z. Syrgiannis, P. A. Mirau, F. Chen, S. M. Chin, S. Weigand, E. Kiskinis and S. I. Stupp, 11 November 2021, Science. DOI: 10.1126/science.abh3602

Sunday, 14 November 2021

Deep Brain Discovery Reveals Effects of Salt Intake

A first-of-its-kind study led by researchers at Georgia State reveals surprising new information about the relationship between neuron activity and blood flow deep in the brain, as well as how the brain is affected by salt consumption.

When neurons are activated, it typically produces a rapid increase of blood flow to the area. This relationship is known as neurovascular coupling, or functional hyperemia, and it occurs via dilation of blood vessels in the brain called arterioles. Functional magnetic resource imaging (fMRI) is based on the concept of neurovascular coupling: experts look for areas of weak blood flow to diagnose brain disorders.

However, previous studies of neurovascular coupling have been limited to superficial areas of the brain (such as the cerebral cortex) and scientists have mostly examined how blood flow changes in response to sensory stimuli coming from the environment (such as visual or auditory stimuli). Little is known about whether the same principles apply to deeper brain regions attuned to stimuli produced by the body itself, known as interoceptive signals.

To study this relationship in deep brain regions, an interdisciplinary team of scientists led by Dr. Javier Stern, professor of neuroscience at Georgia State and director of the university’s Center for Neuroinflammation and Cardiometabolic Diseases, developed a novel approach that combines surgical techniques and state-of-the-art neuroimaging. The team focused on the hypothalamus, a deep brain region involved in critical body functions including drinking, eating, body temperature regulation and reproduction. The study, published in the journal Cell Reports, examined how blood flow to the hypothalamus changed in response to salt intake.

“We chose salt because the body needs to control sodium levels very precisely. We even have specific cells that detect how much salt is in your blood,” said Stern. “When you ingest salty food, the brain senses it and activates a series of compensatory mechanisms to bring sodium levels back down.”

The body does this in part by activating neurons that trigger the release of vasopressin, an antidiuretic hormone that plays a key role in maintaining the proper concentration of salt. In contrast to previous studies that have observed a positive link between neuron activity and increased blood flow, the researchers found a decrease in blood flow as the neurons became activated in the hypothalamus.

“The findings took us by surprise because we saw vasoconstriction, which is the opposite of what most people described in the cortex in response to a sensory stimulus,” said Stern. “Reduced blood flow is normally observed in the cortex in the case of diseases like Alzheimer’s or after a stroke or ischemia.”

The team dubbed the phenomenon “inverse neurovascular coupling,” or a decrease in blood flow that produces hypoxia. They also observed other differences: In the cortex, vascular responses to stimuli are very localized and the dilation occurs rapidly. In the hypothalamus, the response was diffuse and took place slowly, over a long period of time.

“When we eat a lot of salt, our sodium levels stay elevated for a long time,” said Stern. “We believe the hypoxia is a mechanism that strengthens the neurons’ ability to respond to the sustained salt stimulation, allowing them to remain active for a prolonged period.”

The findings raise interesting questions about how hypertension may affect the brain. Between 50 and 60 percent of hypertension is believed to be salt-dependent — triggered by excess salt consumption. The research team plans to study this inverse neurovascular coupling mechanism in animal models to determine whether it contributes to the pathology of salt-dependent hypertension. In addition, they hope to use their approach to study other brain regions and diseases, including depression, obesity and neurodegenerative conditions.

“If you chronically ingest a lot of salt, you’ll have hyperactivation of vasopressin neurons. This mechanism can then induce excessive hypoxia, which could lead to tissue damage in the brain,” said Stern. “If we can better understand this process, we can devise novel targets to stop this hypoxia-dependent activation and perhaps improve the outcomes of people with salt-dependent high blood pressure.”


Newberg AB, Wintering NA, Hriso C, Vedaei F, Stoner M, Ross R. Alterations in Functional Connectivity Measured by Functional Magnetic Resonance Imaging and the Relationship With Heart Rate Variability in Subjects After Performing Orgasmic Meditation: An Exploratory Study. Frontiers in Psychology. 2021;12:5148. DOI: 10.3389/fpsyg.2021.708973

Friday, 12 November 2021

Scientists Identify the Gene That Doubles COVID-19 Risk

A major challenge throughout the COVID-19 pandemic has been effectively treating patients with SARS-CoV-2 due to the high clinical variability observed. Why have some patients presented as completely asymptomatic, while others have ultimately lost their lives to the virus? Across the globe, researchers have been conducting genomic studies in large numbers of COVID-19 patient and non-patient samples to see if the answer lies in our DNA.   

By reading and analyzing human genomes, we can search for differences, or variants, in the DNA code (genotype) across populations that may contribute to observed phenotypes. An example of a phenotype is an individual's susceptibility to specific diseases, i.e., COVID-19.

In 2020, two separate genome-wide association studies (GWAS) by Ellinghaus et al and Pairo-Castineira et al identified a particular region of DNA on chromosome three that appeared to be associated with severe forms of COVID-19. However, the mechanisms by which this region of DNA conferred the increased risk were unclear from these initial studies. New research from Professors James Davies and Jim Hughes  at the University of Oxford’s MRC – published in Nature Genetics – has used artificial intelligence (AI) to shed some light.

What is a GWAS?

A GWAS study is a method used in genomics to scan for markers in DNA or entire genomes that are associated with particular traits, such as disease.

The researchers say that the genetic signal on chromosome three has proven difficult to analyze thus far because it impacts a part of the genome often referred to as "dark matter" or "junk" DNA. This part of our DNA make-up earned such names due to the fact it contains introns, genes that do not encode proteins. For many years, the purpose of this non-coding region remained elusive, however growing research is demonstrating its importance in gene regulation, i.e., turning specific genes "on" and "off". Variants in this region therefore lead to differences in the genes that are expressed in specific cells.

Studying gene expression with spatial context

Davies and colleagues trained an AI system to analyze large amounts of genetic data from hundreds of different cell types in the body, which revealed that the signal is most likely impacting lung cells

    "We found that the increased risk is not because of a difference in gene coding for a protein, but because of a difference in the DNA that makes a switch to turn a gene on. It’s much harder to detect the gene which is affected by this kind of indirect switch effect," Hughes said in a news release.

The gene being upregulated by the sequence on chromosome three is leucine zipper transcription factor like 1 – or LZTFL1 – which was "surprising" to the research team as it has not been largely studied in the past. They conducted spatial transcriptomic analysis, which is a novel method that measures gene activity in a specific tissue sample (in this case, lung biopsies from patients with COVID-19). The analysis detected signals that are associated with an infective response known as epithelial-mesenchymal transition (EMT) that is upregulated by LZTFL1. This finding could explain the link between the genetic signals on chromosome three and increased risk of severe disease in carriers of the variant.

"Higher levels of LZTFL1 may delay the positive effects of an acute EMT response, blocking a reduction in ACE2 and TMPRSS2 levels and/or through slowing EMT-driven tissue repair. Further investigation of the potential role of LZTFL1 and EMT in pulmonary pathogenesis is needed. Our findings suggest that a gain-of-function variant in an inducible enhancer, causing increased expression of LZTFL1, may be associated with a worse outcome," the authors write in the paper.

In an official news release from the University of Cambridge, the researchers said that they do not anticipate the variant causing any issues in vaccine response, as it affects the cells lining the airways and the lungs, and not the immune system.

Prioritizing individuals for vaccination

The findings of this study could have important implications for developing novel treatments for COVID-19. "The genetic factor we have found explains why some people get very seriously ill after coronavirus infection. It shows that the way in which the lung responds to the infection is critical. This is important because most treatments have focussed on changing the way in which the immune system reacts to the virus," Davies said.

It also could help to predict those that are at an increased risk across the globe. Fifteen percent of individuals with European ancestry carry the high-risk version of the gene, vs. 60% of people with South Asian ancestry. Frances Filter, professor emeritus at King's College London said, "This is a very interesting publication. The discrepancy between the risk of serious disease and death in different ethnic groups has previously been attributed in part to socio-economic differences, but it was clear that this was not a complete explanation."

She added, "Evidence that a relatively unstudied gene, LZTFL1, has emerged as a candidate causal gene, which is potentially responsible for some of the twofold increased risk of respiratory failure from COVID-19 in some populations, provides a big step forward in our understanding of the variable susceptibility of some individuals to serious disease and death."

This work might also be used to direct vaccination efforts. While we cannot directly change our genetic code, we could potentially priorotize immunizing those that carry the genetic signal to ensure that their increased risk is counteracted by the vaccine. “Vaccine uptake has been high in South Asian groups but this study reinforces the importance of taking the booster doses now to maximise their protection and reduce their risk as immunity is now waning," Dr. Raghib Ali, senior clinical research associate at the MRC Epidemiology Unit at the University of Cambridge, said.


Downes DJ, Cross AR, Hua P, et al. Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus. Nat Gen. 2021;53(11):1606-1615. DOI: 10.1038/s41588-021-00955-3.

Thursday, 11 November 2021

Critical Link Discovered Between Dietary Fat and the Spread of Cancer

The study, published in the journal Nature and part-funded by the UK charity Worldwide Cancer Research, uncovers how palmitic acid alters the cancer genome, increasing the likelihood the cancer will spread. The researchers have started developing therapies that interrupt this process and say a clinical trial could start in the next couple of years.

Metastasis – or the spread – of cancer remains the main cause of death in cancer patients and the vast majority of people with metastatic cancer can only be treated, but not cured. Fatty acids are the building blocks of fat in our body and the food we eat. Metastasis is promoted by fatty acids in our diet, but it has been unclear how this works and whether all fatty acids contribute to metastasis.

Newly published findings, led by researchers at IRB Barcelona, Spain, reveal that one such fatty acid commonly found in palm oil, called palmitic acid, promotes metastasis in oral carcinomas and melanoma skin cancer in mice. Other fatty acids called oleic acid and linoleic acid – omega-9 and omega-6 fats found in foods such as olive oil and flaxseeds – did not show the same effect. Neither of the fatty acids tested increased the risk of developing cancer in the first place.

The research found that when palmitic acid was supplemented into the diet of mice, it not only contributed to metastasis, but also exerts long-term effects on the genome. Cancer cells that had only been exposed to palmitic acid in the diet for a short period of time remained highly metastatic even when the palmitic acid had been removed from the diet.

The researchers discovered that this “memory” is caused by epigenetic changes – changes to how our genes function. The epigenetic changes alter the function of metastatic cancer cells and allow them to form a neural network around the tumor to communicate with cells in their immediate environment and to spread more easily. By understanding the nature of this communication, the researchers uncovered a way to block it and are now in the process of planning a clinical trial to stop metastasis in different types of cancer.

The drugs that are in development for the clinical trial are antibodies being developed by ONA Therapeutics, a start-up co-founded by senior author of the study Professor Salvador Aznar-Benitah, ICREA researcher and head of the Stem Cells and Cancer lab at the Institute for Research in Biomedicine (IRB Barcelona). The company recently secured 30million Euro from private investors to develop this first-in-class treatment of metastatic cancer.  The researchers hope the trial is on track to start in the next couple of years to test their new antibody in several different types of cancer.

Professor Salvador Aznar-Benitah, Senior Group Leader at IRB Barcelona and ICREA research professor, and senior author of the paper, said: “I think it is too early to determine which type of diet could be consumed by patients with metastatic cancer that would slow down the metastatic process. That said, based on our results one would think that a diet poor in palmitic acid could be effective in slowing down the metastatic process, but much more work is needed to determine this.

“We are not concentrating on this direction of research; instead, we are focusing on new potential therapeutic targets that we could inhibit and that could have a real therapeutic benefit for the patient irrespective of their diet.

“If things keep on going as planned, we could start the first clinical trial in a couple of years. I am very excited about this and we are investing a lot of effort to generate the best possible therapy that cancer patients will hopefully be able to benefit from in the nearby future.” 

Dr. Helen Rippon, Chief Executive at Worldwide Cancer Research said: “This discovery is a huge breakthrough in our understanding of how diet and cancer are linked and, perhaps more importantly, how we can use this knowledge to start new cures for cancer.

“Metastasis is estimated to be responsible for 90% of all cancer deaths – that’s around 9 million deaths per year globally. Learning more about what makes cancer spread and – importantly – how to stop it is the way forward to reduce these numbers.

“Discovery research like this is incredibly exciting because it marks the beginning of a journey that will ultimately lead to more lives saved and more time spent with loved ones. We are all very excited to see the results from this clinical trial and the future impact these findings might have on people with metastatic cancer.”


Pascual, G., Domínguez, D., Elosúa-Bayes, M. et al. Dietary palmitic acid promotes a prometastatic memory via Schwann cells. Nature (2021). DOI: 10.1038/s41586-021-04075-0

Friday, 5 November 2021

Scientists discover how mitochondria import antioxidants

Many of the processes that keep us alive also put us at risk. The energy-producing chemical reactions in our cells, for example, also produce free radicals—unstable molecules that steal electrons from other molecules. When generated in surplus, free radicals can cause collateral damage, potentially triggering malfunctions such as cancer, neurodegeneration, or cardiovascular disease.

Cells solve this problem by synthesizing antioxidants, compounds that neutralize free radicals. In a new study, Rockefeller scientists identify a key molecule that ferries glutathione, the body's major antioxidant, into the cell's mitochondria, where free radicals are produced en masse. The discovery, published in Nature, opens new possibilities for investigating oxidative stress and its damaging effects.

"With the potential transporter identified, we can now control the amount of glutathione that enters mitochondria and study oxidative stress specifically at its source," says Kivanç Birsoy, Chapman Perelman Assistant Professor at The Rockefeller University.

The shuttle into the mitochondria

To avoid oxidative stress, cells need to properly balance the levels of free radicals and antioxidants within their mitochondria, where energy production happens. Because glutathione is produced outside of mitochondria, in the cell's cytosol, the scientists wanted to know how it gets transported into these tiny powerhouses in the first place.

To shed light on this process, Birsoy's team monitored protein expression in cells in response to glutathione's levels. "We hypothesized that glutathione is shuttled by a transporter protein whose production is regulated by glutathione," Birsoy says. "So if we lower the levels of glutathione, the cell should compensate by upregulating the transporter protein."

The analysis pointed to SLC25A39, a protein in the mitochondrial membrane whose function was hitherto unknown. The researchers found that blocking SLC25A39 reduced glutathione inside the mitochondrion, without affecting its levels elsewhere in the cell. Other experiments showed that mice cannot survive without SLC25A39. In animals engineered to lack this protein, red blood cells quickly die by oxidative stress due to their failure to bring glutathione into mitochondria.

The identification of the transporter may lead to a better understanding of a variety of disease pathways linked to oxidative stress, including those involved in aging and neurodegeneration. "These conditions could potentially be treated or prevented by stimulating antioxidant transport into mitochondria," Birsoy says.

Moreover, the team is now exploring whether SLC25A39 might hold promise as a drug target for cancer, by helping to induce fatal oxidative stress in tumor cells. "In cancer, we would want to prevent antioxidants from getting into mitochondria, and the transporter protein may be our way to do that," Birsoy says.


Ying Wang et al, SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells, Nature (2021). DOI: 10.1038/s41586-021-04025-w

Friday, 22 October 2021

How a Tangled Protein Kills Brain Cells, Promotes Alzheimer’s Disease

Look deep inside the brain of someone with Alzheimer’s disease, most forms of dementia or the concussion-related syndrome known as chronic traumatic encephalopathy (CTE) and you’ll find a common suspected culprit: stringy, hairball-like tangles of a protein called tau.

Such conditions, collectively known as “tauopathies” strike scores of people across the globe, with Alzheimer’s alone affecting six million people in the United States.

But more than a century after German psychiatrist Alois Alzheimer discovered tau tangles, scientists still have much to learn about them.

A University of Colorado Boulder study, published in the journal Neuron, shows for the first time that tau aggregates gobble up RNA, or ribonucleic acid, inside cells and interfere with an integral mechanism called splicing, by which cells ultimately produce needed proteins.

“Understanding how tau leads to neurodegeneration is the crux of not just understanding Alzheimer’s disease but also multiple other neurological diseases,” said senior author Roy Parker, a professor of biochemistry and director of the BioFrontiers Institute at CU Boulder. “If we can understand what it does and how it goes bad in disease we can develop new therapies for conditions that now are largely untreatable.”

The study was led by Evan Lester, an M.D./PhD candidate in the Medical Scientist Training Program, which enables students to simultaneously work toward a medical degree from the University of Colorado Anschutz Medical Campus and a PhD from CU Boulder.

For part of his medical training, Lester worked alongside doctors and patients at the CU Alzheimer’s and Cognition Center in Aurora, seeing up close how critically more research is needed.

“There is nothing we can do for these patients right now – no disease modifying-treatments for Alzheimer’s or most of the other tauopathies,” Lester said, noting that 70% of neurodegenerative diseases are believed to be at least partially related to tau aggregates.

For the study, the researchers isolated tau aggregates from cell lines and from the brains of mice with an Alzheimer’s-like condition. Then they used genetic sequencing techniques to determine what was inside.

They confirmed for the first time that tau aggregates contain RNA, or ribonucleic acid, a single-stranded molecule key for synthesizing proteins in cells. They identified what kind of RNA it is, specifically snRNA, or small nuclear RNA, and snoRNA, or small nucleolar RNA.

They also discovered that tau interacts with pieces of cellular machinery known as nuclear speckles, sequestering and displacing proteins inside them and disrupting a process called RNA splicing in which the cell weeds out unneeded material to generate new, healthy RNA.

“The tau aggregates appear to be sequestering splicing-related RNA and proteins, disrupting their normal function and impairing the cell’s ability to make proteins,” said Lester.

Notably, scientists examining the brains of Alzheimer’s patients after death have discovered evidence of splicing-related defects in cells.

Already, several companies have clinical trials underway testing drugs that would do away with tau entirely in patients with neurodegenerative diseases. But that could potentially have unintended consequences, said Lester.

“A big problem in the field is that no one really knows what tau does in healthy people and It likely has important functions when not in tangles,” he said.

By better understanding precisely what it does to harm and kill cells, Parker and Lester hope to bring a different approach to the table.

“The idea would be to intervene in the abnormal functions while preserving the normal functions of tau,” Lester said.

While it’s unlikely his current patients will benefit from his discovery, someday his future patients just might.


Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components by Evan Lester, Felicia K. Ooi, Nadine Bakkar, Jacob Ayers, Amanda L. Woerman, Joshua Wheeler, Robert Bowser, George A. Carlson, Stanley B. Prusiner and Roy Parker, 12 April 2021, Neuron. DOI: 10.1016/j.neuron.2021.03.026

Thursday, 14 October 2021

Neuroscientists roll out first comprehensive atlas of brain cells

When you clicked to read this story, a band of cells across the top of your brain sent signals down your spine and out to your hand to tell the muscles in your index finger to press down with just the right amount of pressure to activate your mouse or track pad.

A slew of new studies now shows that the area of the brain responsible for initiating this action -- the primary motor cortex, which controls movement -- has as many as 116 different types of cells that work together to make this happen.

The 17 studies, appearing online Oct. 6 in the journal Nature, are the result of five years of work by a huge consortium of researchers supported by the National Institutes of Health's Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative to identify the myriad of different cell types in one portion of the brain. It is the first step in a long-term project to generate an atlas of the entire brain to help understand how the neural networks in our head control our body and mind and how they are disrupted in cases of mental and physical problems.

"If you think of the brain as an extremely complex machine, how could we understand it without first breaking it down and knowing the parts?" asked cellular neuroscientist Helen Bateup, a University of California, Berkeley, associate professor of molecular and cell biology and co-author of the flagship paper that synthesizes the results of the other papers. "The first page of any manual of how the brain works should read: Here are all the cellular components, this is how many of them there are, here is where they are located and who they connect to."

Individual researchers have previously identified dozens of cell types based on their shape, size, electrical properties and which genes are expressed in them. The new studies identify about five times more cell types, though many are subtypes of well-known cell types. For example, cells that release specific neurotransmitters, like gamma-aminobutyric acid (GABA) or glutamate, each have more than a dozen subtypes distinguishable from one another by their gene expression and electrical firing patterns.

While the current papers address only the motor cortex, the BRAIN Initiative Cell Census Network (BICCN) -- created in 2017 -- endeavors to map all the different cell types throughout the brain, which consists of more than 160 billion individual cells, both neurons and support cells called glia. The BRAIN Initiative was launched in 2013 by then-President Barack Obama.

"Once we have all those parts defined, we can then go up a level and start to understand how those parts work together, how they form a functional circuit, how that ultimately gives rise to perceptions and behavior and much more complex things," Bateup said.

Together with former UC Berkeley professor John Ngai, Bateup and UC Berkeley colleague Dirk Hockemeyer have already used CRISPR-Cas9 to create mice in which a specific cell type is labeled with a fluorescent marker, allowing them to track the connections these cells make throughout the brain. For the flagship journal paper, the Berkeley team created two strains of "knock-in" reporter mice that provided novel tools for illuminating the connections of the newly identified cell types, she said.

"One of our many limitations in developing effective therapies for human brain disorders is that we just don't know enough about which cells and connections are being affected by a particular disease and therefore can't pinpoint with precision what and where we need to target," said Ngai, who led UC Berkeley's Brain Initiative efforts before being tapped last year to direct the entire national initiative. "Detailed information about the types of cells that make up the brain and their properties will ultimately enable the development of new therapies for neurologic and neuropsychiatric diseases."

Ngai is one of 13 corresponding authors of the flagship paper, which has more than 250 co-authors in all.

Bateup, Hockemeyer and Ngai collaborated on an earlier study to profile all the active genes in single dopamine-producing cells in the mouse's midbrain, which has structures similar to human brains. This same profiling technique, which involves identifying all the specific messenger RNA molecules and their levels in each cell, was employed by other BICCN researchers to profile cells in the motor cortex. This type of analysis, using a technique called single-cell RNA sequencing, or scRNA-seq, is referred to as transcriptomics.

The scRNA-seq technique was one of nearly a dozen separate experimental methods used by the BICCN team to characterize the different cell types in three different mammals: mice, marmosets and humans. Four of these involved different ways of identifying gene expression levels and determining the genome's chromatin architecture and DNA methylation status, which is called the epigenome. Other techniques included classical electrophysiological patch clamp recordings to distinguish cells by how they fire action potentials, categorizing cells by shape, determining their connectivity, and looking at where the cells are spatially located within the brain. Several of these used machine learning or artificial intelligence to distinguish cell types.

"This was the most comprehensive description of these cell types, and with high resolution and different methodologies," Hockemeyer said. "The conclusion of the paper is that there's remarkable overlap and consistency in determining cell types with these different methods."

A team of statisticians combined data from all these experimental methods to determine how best to classify or cluster cells into different types and, presumably, different functions based on the observed differences in expression and epigenetic profiles among these cells. While there are many statistical algorithms for analyzing such data and identifying clusters, the challenge was to determine which clusters were truly different from one another -- truly different cell types -- said Sandrine Dudoit, a UC Berkeley professor and chair of the Department of Statistics. She and biostatistician Elizabeth Purdom, UC Berkeley associate professor of statistics, were key members of the statistical team and co-authors of the flagship paper.

"The idea is not to create yet another new clustering method, but to find ways of leveraging the strengths of different methods and combining methods and to assess the stability of the results, the reproducibility of the clusters you get," Dudoit said. "That's really a key message about all these studies that look for novel cell types or novel categories of cells: No matter what algorithm you try, you'll get clusters, so it is key to really have confidence in your results."

Bateup noted that the number of individual cell types identified in the new study depended on the technique used and ranged from dozens to 116. One finding, for example, was that humans have about twice as many different types of inhibitory neurons as excitatory neurons in this region of the brain, while mice have five times as many.

"Before, we had something like 10 or 20 different cell types that had been defined, but we had no idea if the cells we were defining by their patterns of gene expression were the same ones as those defined based on their electrophysiological properties, or the same as the neuron types defined by their morphology," Bateup said.

"The big advance by the BICCN is that we combined many different ways of defining a cell type and integrated them to come up with a consensus taxonomy that's not just based on gene expression or on physiology or morphology, but takes all of those properties into account," Hockemeyer said. "So, now we can say this particular cell type expresses these genes, has this morphology, has these physiological properties, and is located in this particular region of the cortex. So, you have a much deeper, granular understanding of what that cell type is and its basic properties."

Dudoit cautioned that future studies could show that the number of cell types identified in the motor cortex is an overestimate, but the current studies are a good start in assembling a cell atlas of the whole brain.

"Even among biologists, there are vastly different opinions as to how much resolution you should have for these systems, whether there is this very, very fine clustering structure or whether you really have higher level cell types that are more stable," she said. "Nevertheless, these results show the power of collaboration and pulling together efforts across different groups. We're starting with a biological question, but a biologist alone could not have solved that problem. To address a big challenging problem like that, you want a team of experts in a bunch of different disciplines that are able to communicate well and work well with each other."

Other members of the UC Berkeley team included postdoctoral scientists Rebecca Chance and David Stafford, graduate student Daniel Kramer, research technician Shona Allen of the Department of Molecular and Cell Biology, doctoral student Hector Roux de Bézieux of the School of Public Health and postdoctoral fellow Koen Van den Berge of the Department of Statistics. Bateup is a member of the Helen Wills Neuroscience Institute, Hockemeyer is a member of the Innovative Genomics Institute, and both are investigators funded by the Chan Zuckerberg Biohub.


BRAIN Initiative Cell Census Network (BICCN). A multimodal cell census and atlas of the mammalian primary motor cortex. Nature, 2021; 598 (7879): 86 DOI: 10.1038/s41586-021-03950-0

Sunday, 3 October 2021

Researchers Discover 17 New Genes that Promote or Prevent Obesity

Promising news in the effort to develop drugs to treat obesity: University of Virginia scientists have identified 14 genes that can cause and three that can prevent weight gain. The findings pave the way for treatments to combat a health problem that affects more than 40% of American adults.

“We know of hundreds of gene variants that are more likely to show up in individuals suffering obesity and other diseases. But ‘more likely to show up’ does not mean causing the disease. This uncertainty is a major barrier to exploit the power of population genomics to identify targets to treat or cure obesity. To overcome this barrier, we developed an automated pipeline to simultaneously test hundreds of genes for a causal role in obesity. Our first round of experiments uncovered more than a dozen genes that cause and three genes that prevent obesity,” said Eyleen O’Rourke of UVA’s College of Arts & Sciences, the School of Medicine’s Department of Cell Biology and the Robert M. Berne Cardiovascular Research Center. “We anticipate that our approach and the new genes we uncovered will accelerate the development of treatments to reduce the burden of obesity.”

O’Rourke’s new research helps shed light on the complex intersections of obesity, diet and our DNA. Obesity has become an epidemic, driven in large part by high-calorie diets laden with sugar and high-fructose corn syrup. Increasingly sedentary lifestyles play a big part as well. But our genes play an important role too, regulating fat storage and affecting how well our bodies burn food as fuel. So if we can identify the genes that convert excessive food into fat, we could seek to inactivate them with drugs and uncouple excessive eating from obesity.

Genomicists have identified hundreds of genes associated with obesity – meaning the genes are more or less prevalent in people who are obese than in people with healthy weight. The challenge is determining which genes play causal roles by directly promoting or helping prevent weight gain. To sort wheat from chaff, O’Rourke and her team turned to humble worms known as C. elegans. These tiny worms like to live in rotting vegetation and enjoy feasting on microbes. However, they share more than 70% of our genes, and, like people, they become obese if they are fed excessive amounts of sugar.

The worms have produced great benefits for science. They’ve been used to decipher how common drugs, including the antidepressant Prozac and the glucose-stabilizing metformin, work. Even more impressively, in the last 20 years three Nobel prizes were awarded for the discovery of cellular processes first observed in worms but then found to be critical to diseases such as cancer and neurodegeneration. They’ve also been fundamental to the development of therapeutics based on RNA technology.

In new work just published in the scientific journal PLOS Genetics, O’Rourke and her collaborators used the worms to screen 293 genes associated with obesity in people, with the goal of defining which of the genes were actually causing or preventing obesity. They did this by developing a worm model of obesity, feeding some a regular diet and some a high-fructose diet.

This obesity model, coupled to automation and supervised machine learning-assisted testing, allowed them to identify 14 genes that cause obesity and three that help prevent it. Enticingly, they found that blocking the action of the three genes that prevented the worms from becoming obese also led to them living longer and having better neuro-locomotory function. Those are exactly the type of benefits drug developers would hope to obtain from anti-obesity medicines.

More work needs to be done, of course. But the researchers say the indicators are encouraging. For example, blocking the effect of one of the genes in lab mice prevented weight gain, improved insulin sensitivity and lowered blood sugar levels. These results (plus the fact that the genes under study were chosen because they were associated with obesity in humans) bode well that the results will hold true in people as well, the researchers say.

“Anti-obesity therapies are urgently needed to reduce the burden of obesity in patients and the healthcare system,” O’Rourke said. “Our combination of human genomics with causality tests in model animals promises yielding anti-obesity targets more likely to succeed in clinical trials because of their anticipated increased efficacy and reduced side effects.”


W. Ke et al. 2021. Genes in human obesity loci are causal obesity genes in C. elegans. PLoS Genet 17 (9): e1009736; DOI: 10.1371/journal.pgen.1009736

Saturday, 2 October 2021

Staying Young: Scientists Discover New Enzymatic Complex That Can Stop Cells From Aging

Scientists in Montreal discover a new enzymatic complex that can stop cells from aging, opening the way to possible new cancer therapies.

Researchers at Université de Montréal and McGill University have discovered a new multi-enzyme complex that reprograms metabolism and overcomes “cellular senescence,” when aging cells stop dividing.

In their study published on September 16, 2021, in Molecular Cell, the researchers show that an enzyme complex named HTC (hydride transfer complex) can inhibit cells from aging. 

“HTC protects cells from hypoxia, a lack of oxygen that normally leads to their death,” said senior author Gerardo Ferbeyre, an UdeM biochemistry professor and principal scientist at the CRCHUM, the university’s affiliated teaching hospital research center.

“Importantly, HTC can be hijacked by certain cancer cells to improve their metabolism, resist to a hypoxic environment and proliferate,” said Ferbeyre, who made the discovery with Sebastian Igelmann, a PhD student in his lab and first author of the study.

HTC is made up of three enzymes: pyruvate carboxylase, malate dehydrogenase 1, and malic enzyme 1. They were all highly expressed in samples from a prostate cancer mouse model generated at the University of Veterinary Medicine Vienna, in Austria, and in tissue samples from prostate cancer patients.

“Most interestingly, inhibition of these enzymes stopped the growth of prostate cancer cells, suggesting that HTC could be a key target to develop new therapeutics for a variety of cancers, including prostate cancer,” said Ferbeyre.

Most key metabolic cycles were identified more than 50 years ago, but HTC remained hidden to researchers. “We found it by performing state-of-the art metabolomic analysis, the study of chemical processes of cell metabolism,” said co-author Ivan Topisirovic, a McGill researcher and medical professor.

The scientists were able to assemble the enzyme complex from purified proteins and obtain biophysical data about its composition. Their next step will be to generate a detailed high-resolution structure of the enzyme complex in order to design drugs able to modulate its functions.


A hydride transfer complex reprograms NAD metabolism and bypasses senescence by Sebastian Igelmann, Frédéric Lessard, Oro Uchenunu, Jacob Bouchard, Ana Fernandez-Ruiz, Marie-Camille Rowell, Stéphane Lopes-Paciencia, David Papadopoli, Aurélien Fouillen, Katia Julissa Ponce, Geneviève Huot, Lian Mignacca, Mehdi Benfdil, Paloma Kalegari, Haytham M. Wahba, Jan Pencik, Nhung Vuong, Jordan Quenneville, Jordan Guillon, Véronique Bourdeau, Laura Hulea, Etienne Gagnon, Lukas Kenner, Richard Moriggl, Antonio Nanci, Michael N. Pollak, James G. Omichinski, Ivan Topisirovic and Gerardo Ferbeyre, 16 September 2021, Molecular Cell. DOI: 10.1016/j.molcel.2021.08.028

Monday, 20 September 2021

New Research Shows Regular Exercise May Lower Risk of Developing Anxiety by Almost 60%

The findings of a study published with Frontiers suggests that those who engage in regular exercise may lower their risk of developing anxiety by almost 60%. Using data on almost 400,000 people spanning more than two decades, the authors from Lund University in Sweden were also able to identify a noticeable difference in exercise performance level and the risk of developing anxiety between males and females.

A quick online search for ways to improve our mental health will often come up with a myriad of different results. However, one of the most common suggestions put forward as a step to achieving wellness – and preventing future issues – is doing some physical exercise, whether it be a walk or playing a team sport.

Anxiety disorders – which typically develop early in a person’s life – are estimated to affect approximately 10% of the world’s population and have been found to be twice as common in women compared to men.

And while exercise is put forward as a promising strategy for the treatment of anxiety, little is known about the impact of exercise dose, intensity or physical fitness level on the risk of developing anxiety disorders.

To help answer this question, researchers in Sweden recently published a study in Frontiers in Psychiatry to show that those who took part in the world’s largest long-distance cross-country ski race (Vasaloppet) between 1989 and 2010 had a “significantly lower risk” of developing anxiety compared to non-skiers during the same period.

The study is based on data from almost 400,000 people in one of the largest ever population-wide epidemiology studies across both sexes.

Surprising finding among female skiers

“We found that the group with a more physically active lifestyle had an almost 60% lower risk of developing anxiety disorders over a follow-up period of up to 21 years,” said first author of the paper, Martine Svensson, and her colleague and principal investigator, Tomas Deierborg, of the Department of Experimental Medical Science at Lund University, Sweden.

“This association between a physically active lifestyle and a lower risk of anxiety was seen in both men and women.”

However, the authors found a noticeable difference in exercise performance level and the risk of developing anxiety between male and female skiers.

While a male skier’s physical performance did not appear to affect the risk of developing anxiety, the highest performing group of female skiers had almost the double risk of developing anxiety disorders compared to the group which was physically active at a lower performance level.

“Importantly,” they said, “the total risk of getting anxiety among high-performing women was still lower compared to the more physically inactive women in the general population”.

These findings cover relatively uncharted territory for scientific research, according to the researchers, as most previous studies focused on depression or mental illness as opposed to specifically diagnosed anxiety disorders.

Furthermore, some of the largest studies looking at this topic only included men, were much smaller in sample size, and had either limited or no follow-up data to track the long-term effects of physical activity on mental health.

Next steps for research

The surprising discovery of an association between physical performance and the risk for anxiety disorders in women also emphasized the scientific importance of these findings for follow-up research.

“Our results suggest that the relation between symptoms of anxiety and exercise behavior may not be linear,” Svensson said.

“Exercise behaviors and anxiety symptoms are likely to be affected by genetics, psychological factors, and personality traits, confounders that were not possible to investigate in our cohort. Studies investigating the driving factors behind these differences between men and women when it comes to extreme exercise behaviors and how it affects the development of anxiety are needed.”

They added that randomized intervention trials, as well as long-term objective measurements of physical activity in prospective studies, are also needed to assess the validity and causality of the association they reported.

But does this mean that skiing in particular can play an important role in keeping anxiety at bay, as opposed to any other form of exercise? Not so, Svensson and Deierborg said, given that previous studies have also shown the benefits of keeping fit on our mental health.

“We think this cohort of cross-country skiers is a good proxy for an active lifestyle, but there could also be a component of being more outdoors among skiers,” they said.

“Studies focusing on specific sports may find slightly different results and magnitudes of the associations, but this is most likely due to other important factors that affect mental health and which you cannot easily control in research analysis.”


Physical Activity Is Associated With Lower Long-Term Incidence of Anxiety in a Population-Based, Large-Scale Study by Martina Svensson, Lena Brundin, Sophie Erhardt, Ulf Hållmarker, Stefan James and Tomas Deierborg, 10 September 2021, Frontiers in Psychiatry. DOI: 10.3389/fpsyt.2021.714014