University of Pittsburgh School of Medicine researchers have developed an early-stage, experimental “living eye drop” that uses a naturally occurring eye bacterium to support corneal wound healing.
The proof-of-‑concept study, published in Cell Reports, demonstrates that the harmless eye-dwelling microbe Corynebacterium mastitidis can be genetically modified to secrete an anti-inflammatory therapeutic that promotes healing following corneal injury in a mouse model.
“This is the first demonstration that a microbe that lives on the ocular surface could be engineered to deliver a therapeutic that improves eye health,” said senior author Anthony St. Leger, associate professor of ophthalmology and of immunology and a faculty member of the UPMC Vision Institute. “It opens the door to the idea of ‘living medicine’ for the eye – something you apply once, and it stays, protects and helps the tissue heal.”
Because tears continually wash medications away, treating ocular surface disease often requires multiple daily applications of eye drops. This can limit the effectiveness of therapies for conditions such as corneal abrasions or dry eye disease.
To explore an alternative delivery method, the Pitt team engineered C. mastitidis, a benign bacterium that naturally resides under the eyelid, to continuously secrete cytokine interleukin10 (IL10). In mice, corneas that were gently scratched and treated with the engineered bacteria healed faster than those treated with regular bacteria or saline. When the IL10 receptor was blocked, this benefit disappeared – confirming the therapeutic effect was IL10-dependent.
The researchers also created a version of the microbe that releases human IL10, which improved wound closure in lab-grown cells that make up the outermost layer of human cornea and reduced inflammatory signaling in human immune cells. These studies offer an initial indication that the approach could eventually be adapted for use in people, though substantial development remains.
“What makes this exciting is that the system is modular,” St. Leger explained. “We built it so you can swap in different genes – different cytokines, growth factors or other proteins – to tailor the therapy to specific eye diseases.”
Though promising, the technology is still in early development. The researchers note that many steps must be completed before any clinical translation is possible, including developing built-in “off switches” to safely and reliably remove or deactivate the engineered bacteria after they are no longer needed.
The South African healthcare system is currently facing a period of intense pressure. Between staffing shortages and a rise in medical legal claims, the gap between basic nursing education and the actual demands of patient care is a major concern. To improve patient safety and support our healthcare workers, we must focus on practical, hands-on experience and constant skill building.
Why nursing challenges matter in South Africa
Nursing errors are rarely the fault of one person. In South Africa, they are usually the result of a system under strain. Nurses are dealing with overcrowded wards, long shifts, and a very high number of patients with complex conditions like HIV and TB. When staff are exhausted and overworked, the risk of making a mistake increases.
These errors have a massive impact. For patients and their families, it leads to a loss of trust. For hospitals, it leads to expensive legal battles. South Africa is currently dealing with billions of Rands in medical claims, but this is money that should be spent on better equipment and hiring more people. If we want a stronger healthcare system, we must reduce the risks that lead to these errors in the first place.
Hands-on training makes the difference
Nursing education has traditionally leaned heavily on theoretical learning, but knowing the theory of a procedure is very different from doing it in a busy hospital. Practical, skills-based training is what helps a nurse transition safely from the classroom to the ward.
Donald McMillan, MD at Allmed
One of the most effective tools for this is simulation-based training. This involves using specialised training rooms that look like real hospital wards, complete with advanced mannequins that can mimic medical emergencies. Here, nurses can practice critical skills like inserting drips, reading ECGs, or managing emergency care in a safe environment. This allows them to build confidence and “muscle memory” before they ever treat a real patient. This type of training is essential for preparing nurses for the high-pressure reality of South African clinics.
Continuous professional development builds confidence
Medicine is always changing. New treatment guidelines, technologies, and medicines are introduced all the time, changing the way care is delivered. Continuous Professional Development (CPD) helps nurses keep pace with these changes, ensuring their skills remain relevant, their knowledge up to date, and their patients receive the best possible care throughout every stage of their careers.
However, CPD is about more than just following rules; it is about building professional confidence. When nurses have the chance to learn new things and specialise in areas like intensive care or pharmacology, they feel more capable and valued. In a country where many nurses choose to work overseas, providing these opportunities for growth at home is a great way to keep our best talent in South Africa.
A systemic approach for better care
Enhancing the quality of nursing care in South Africa requires a coordinated, multi-stakeholder approach. Training institutions, hospital administrators, and regulatory bodies must collaborate to create an ecosystem that supports the nurse at every career stage. This systemic approach should focus on three specific areas:
Integrated mentorship: Establishing formal programmes where expert clinicians provide real-time bedside teaching to new graduates.
Accredited upskilling: Providing accessible pathways for nurses to specialise in critical areas such as ICU, neonatal care, and oncology.
Technological alignment: Utilising digital tools to track competency levels and identify specific areas where additional training is required.
By making practical training and ongoing learning a priority, we do more than just prevent mistakes. We empower our nurses to be the skilled professionals they want to be. When nurses are competent and confident, they provide better care, which helps rebuild public trust and makes the South African healthcare system stronger for everyone.
At 25, Kaitlin should be living independently. At 18, Lihle should be finishing school. Instead, both are fighting for their lives against aplastic anaemia (AA), a rare blood disease that leaves patients vulnerable to infections, uncontrolled bleeding, and severe anaemia. A stem cell transplant gives approximately 80% of patients a real chance at recovery, but for around 70% of those patients, that match will not come from within their family. It will come from a generous stranger.
“AA strikes hardest between 15 and 25 – the years nobody expects to spend fighting for their life,” says Palesa Mokomele, Head of Community Engagement and Communication at DKMS Africa. “We want South Africans to understand that registering as a stem cell donor is a simple act that could give someone like Kaitlin or Lihle their life back. Every person who registers increases their chances of finding a match.”
A long road to the right diagnosis: Kaitlin’s story
For years, nobody could tell Kaitlin from KwaZulu-Natal what was wrong. She experienced prolonged and excessive bleeding and severe fatigue, which was repeatedly misattributed to gynaecological issues. She kept going back to the hospital and kept being sent home. It was only in August 2025, when her condition deteriorated dramatically, and the bleeding would not stop despite ongoing treatment, that she was finally referred to a haematologist. A bone marrow biopsy told them what years of tests had missed: Kaitlin had AA.
Before this, she was working full-time and living independently. Today, she cannot work. She cannot manage basic daily tasks. She requires weekly blood transfusions simply to stay alive. Medication trials have yielded no response, and her doctors have been clear: a stem cell transplant is her only path to recovery.
Through it all, Kaitlin has held on. “I draw strength from my faith and from the people I love most – my nephews and siblings, who show up for me even on the hardest hospital days. I just want my life back, and a matching donor could make that possible.”
Sudden illness, endless resilience: Lihle’s story
Lihle was 14 years old when his life changed overnight. It started with severe nosebleeds in November 2021. Then one night, the bleeding became uncontrollable. He lost consciousness. After two months in hospital, the diagnosis came: Severe Aplastic Anaemia (SAA). That same year, his father passed away.
The eldest of four children, Lihle grew up fast. Hailing from Butterworth in the Eastern Cape and raised in Carletonville, Gauteng, he has always felt the weight of being the firstborn – the one his younger siblings look up to. Their mother cares for them all – while also carrying the emotional weight of losing her husband and watching her son fight for his life.
Lihle shares that he is determined to finish his education, set an example, and one day return to the football pitch. Like Kaitlin, all he needs is a matching donor to make that possible.”
How you can help
“No family should have to face what Kaitlin’s and Lihle’s are going through – knowing that a cure exists, but that the donor hasn’t been found yet. For patients from Black, Coloured and Indian/Asian backgrounds, that search is even harder, because the registry does not yet reflect the diversity of our population. We are calling on all South Africans to register. It costs nothing. It takes minutes. And it could mean everything,” concludes Mokomele.
Signing up could be the most important thing you ever do. If you are aged 17 – 55 and in good health, please register today at: https://www.dkms-africa.org/save-lives
Researcher demo-ing an early prototype of the robotic medical crash cart. Credit: Cornell Tech
Healthcare workers have an intense workload and often experience mental distress during resuscitation and other critical care procedures. Although researchers have studied whether robots can support human teams in other high-stakes, high-risk settings such as disaster response and military operations, the role of robots in emergency medicine has not been explored.
Enter Angelique Taylor, the Andrew H. and Ann R. Tisch Assistant Professor at Cornell Tech and the Cornell Ann S. Bowers College of Computing and Information Science. She is also an assistant professor in emergency medicine at Weill Cornell Medicine and director of the Artificial Intelligence and Robotics Lab (AIRLab) at Cornell Tech.
In a pair of articles published at the Institute of Electrical and Electronics Engineers (IEEE) conference on Robot and Human Interactive Communication (RO-MAN) in August 2025, Taylor and her collaborators at Weill Cornell Medicine, associate professor Kevin Ching and assistant professor Jonathan St. George, described research on their new robotic crash cart (RCC) — a robotic version of the mobile drawer unit that holds supplies and equipment needed for a range of medical procedures.
“Healthcare workers may not know or may forget where all the various supplies are located in the cart drawers, and often they’re kind of shuffling through the cart,” Taylor said. This can cause delays during emergency procedures that require iterative tasks with precise timing, exacerbating medical errors and putting patients at risk, she noted.
To create the RCC, Taylor and her team outfitted a standard cart with LED light strips, a speaker, and a touchscreen tablet integrated with the Robot Operating System. This middleware connects computer programs to robot hardware, enabling them to work together to provide users with verbal and nonverbal cues.
During an emergency procedure, a user can request the location of a supply on the tablet. Then the lights around the drawer with that supply blink, or a spoken instruction plays through the speaker. Users can also receive prompts to remind them about necessary medications and recommend supplies.
In their article, “Help or Hindrance: Understanding the Impact of Robot Communication in Action Teams,” Taylor’s team conducted pilot studies of the RCC. One pilot involved 84 participants, aged 21 to 79, about half of whom had a clinical background. Working in groups of 3 to 4, they conducted a series of simulated resuscitation procedures with a manikin patient using three different carts: a RCC with blinking lights for object search and spoken task reminders, a RCC with blinking lights for task reminders and spoken language for object search, or a standard cart.
The team found that participants preferred the RCC that provided verbal and nonverbal cues over no cues with the standard cart — rating it lower in terms of workload and higher in usefulness and ease of use.
“These results were exciting and achieved statistical significance, suggesting that the use of a robot is beneficial,” said Taylor. The article, by Taylor, Ph.D. student Tauhid Tanjim, and colleagues at Weill Cornell, was a Kazuo-Tanie Paper Award finalist, an honor given to the top three papers in their category at the conference.
Similar to the pilot studies, Taylor, along with colleagues at Cornell and Michigan State University, found that the RCC reduced participant workload, depending on whether the robot provided verbal or non-verbal cues. However, they evaluated robots with only one type of cue, not both, and identified room for improvement, particularly in the robot’s visual cues. They are now studying healthcare workers’ impressions of an RCC with multimodal communication.
Taylor hopes that other research teams will start exploring how robots can support healthcare teams in critical care settings. To that end, Taylor and her colleague presented an article at the February 2025 Association for Computing Machinery/IEEE International Conference that offers a toolkit for researchers to build their own RCC.
By Carina Storrs, freelance writer for Cornell Tech.
Ageing in later life is often portrayed as a steady slide toward physical and cognitive decline. But a new study by scientists at Yale University suggests an alternate narrative – that older individuals can and do improve over time and their mindset toward ageing plays a major part in their success.
Analysing more than a decade of data from a large, nationally representative study of older Americans, lead author Becca R. Levy, a professor of social and behavioural sciences at the Yale School of Public Health (YSPH), found that nearly half of adults aged 65 and older showed measurable improvement in cognitive function, physical function, or both, over time.
The improvements were not limited to a small group of exceptional individuals and, notably, were linked to a powerful but often overlooked factor: how people think about ageing itself.
“Many people equate ageing with an inevitable and continuous loss of physical and cognitive abilities,” said Levy, an international expert on psychosocial determinants of ageing health. “What we found is that improvement in later life is not rare, it’s common, and it should be included in our understanding of the ageing process.”
The findings are published in the journal Geriatrics.
For the study, the researchers followed more than 11 000 participants in the Health and Retirement Study, a federally supported longitudinal survey of older Americans. The research team tracked changes in cognition using a global performance assessment, and physical function using walking speed — often described by geriatricians as a “vital sign” because of its strong links to disability, hospitalisation, and mortality.
Over a follow-up period of up to 12 years, 45% of participants improved in at least one of the two domains, according to the study. About 32% improved cognitively, 28% improved physically, and many experienced gains that exceeded thresholds considered clinically meaningful. When participants whose cognitive scores remained stable over that period (rather than declining) were included, more than half defied the stereotype of inevitable deterioration in cognition.
“What’s striking is that these gains disappear when you only look at averages,” said Levy, author of the book “Breaking the Age Code: How Your Beliefs About Aging Determine How Long & How Well You Live.” “If you average everyone together, you see decline. But when you look at individual trajectories, you uncover a very different story. A meaningful percentage of the older participants that we studied got better.”
The authors also examined potential reasons for why some people improve and some do not. They hypothesized that an important factor could be participants’ baseline age beliefs — or, specifically, whether they had assimilated more positive or more negative views about ageing by the start of the study. In support of this hypothesis, they found that those with more positive age beliefs were significantly more likely to show improvements in both cognition and walking speed, even after accounting for factors such as age, sex, education, chronic disease, depression, and length of follow-up.
The findings build on Levy’s stereotype embodiment theory, which posits that age stereotypes absorbed from culture – through a range of domains including social media and advertisements – eventually become self-relevant and biologically consequential. Levy’s prior studies have found negative age beliefs predict poorer memory, slower walking speed, higher cardiovascular risk, and biomarkers associated with Alzheimer’s disease.
The current study shows that those who have assimilated more positive age beliefs often show improvement, Levy said.
“Our findings suggest there is often a reserve capacity for improvement in later life,” she said. “And because age beliefs are modifiable, this opens the door to interventions at both the individual and societal level.”
The improvements were not limited to people who started out with impairments. Even among participants who had normal cognitive or physical function at baseline, a substantial proportion improved over time. That challenges the assumption that later-life gains reflect only people getting better after being sick or rebounding from earlier setbacks, the authors said.
The authors hope their findings will reverse the popular perception that continuous decline is inevitable and encourage policy makers to increase their support for preventive care, rehabilitation, and other health-promoting programs for older persons that draw on their potential resilience.
Researchers at the University of Missouri may have uncovered a clue explaining why young adults with autism are roughly six times more likely to develop Parkinson’s disease later in life.
In a recent study, the researchers found that some young adults with autism show abnormalities in dopamine transporters, tiny molecules in the brain that recycle unused dopamine, on brain scans that are typically used to diagnose older adults with Parkinson’s disease.
Future research could help determine whether the health of dopamine transporters could be an early warning sign of Parkinson’s disease developing later in life.
“While the loss of these dopamine transporters can be biomarkers for Parkinson’s disease, no one had ever thought to look at them in the context of young adults with autism, so hopefully this work can help us explore if there is a potential link going forward,” David Beversdorf, a professor in the School of Medicine and College of Arts and Science, said. “There has been previous work looking into the total amount of dopamine in the brains of people with autism, but we took a new approach by looking at abnormalities in terms of how dopamine is processed in a specific part of the brain called the basal ganglia via these dopamine transporters.”
Dopamine under the spotlight
Dopamine is a neurotransmitter involved in numerous body functions, such as memory, pleasure, motivation, behaviour and attention. Of particular interest to Beversdorf, a clinician at the Thompson Center for Autism and Neurodevelopment, is that dopamine also helps control muscle movement as well as cognition.
Beversdorf, who collaborated with lead author Nanan Nuraini on the study, originally wanted to know whether certain repetitive behaviors common in some young adults with autism, such as hand-flapping or rocking back and forth, were linked with abnormalities in dopamine transporters.
While he did not notice patterns in that regard, what he found surprised him.
Beversdorf looked at Dopamine Transporter (DaT) brain scans of 12 young adults with autism.
Four different nuclear medicine specialists examined the scans. All of them agreed that two of the 12 young adults had abnormal dopamine transporters and that eight appeared normal. They disagreed on the remaining two.
“Since these DaT scans are typically used to diagnose or evaluate older adults with Parkinson’s disease, the appearance of abnormalities in some young adults with autism was very surprising, so we should look into this topic more going forward,” Beversdorf said. “While it’s too early to jump to conclusions, hopefully our work raises awareness about the importance of monitoring the brain health of young adults with autism as they age.”
Next, Beversdorf hopes to study a broader range of people with autism by conducting more DaT scans across different age groups.
“The earlier we can identify those who might be at greater risk for getting Parkinson’s disease down the road, the sooner we can discuss preventative measures, including whether certain medications could potentially slow down the progression of disease,” Beversdorf said.
Even when controlling for age and family background, COVID’s impact was evident
Photo by Kelly Sikkema on Unsplash
The COVID pandemic disrupted children’s ability to self-regulate, according to research from three UK universities just published in the journal Child Development.
The study by Lancaster University, East Anglia and Durham reveals that the pandemic hampered children’s ability to regulate their behaviour, stay focused and adapt to new situations – skills known collectively as executive functions.
The greatest impact was seen among pupils who were in reception when the first lockdowns began – a crucial stage at four or five when youngsters normally learn to socialise, follow routines and navigate the busy world of the classroom. Primary school in the UK then begins at Grade 1, starting at age five or six.
These children showed less growth in their self-regulatory and cognitive flexibility scores over time compared to a second group of children who were in preschool when the pandemic started.
The research team say these children may still be feeling the effects years later.
How the research happened
Scientists were already running a long-term study tracking youngsters from toddlerhood to early school years when the COVID pandemic hit.
They followed 139 children aged between two-and-a-half and six-and-a-half years old over several years, including 94 families who joined the study before Covid struck.
This meant that they had a rare baseline of children’s abilities before the pandemic began, which allowed them to track exactly how development changed during and after the lockdowns.
Using a standardised assessment called the Minnesota Executive Function Scale, they were able to measure the same cognitive skills at regular intervals.
Dr Eleanor Johns from Lancaster University’s Department of Psychology said: “We began this study to understand how children’s executive function develops across early childhood, and we saw clear, steady growth between 2.5 and 6.5 years of age. However, because our longitudinal study spanned the COVID-19 pandemic, we also had a unique opportunity to examine how this unprecedented disruption affected the children we were already following.
“We found that children who had just started school when the first lockdown began showed a slower rate of growth in executive function compared to those who were preschool age. Starting school is a major developmental transition, as children learn new routines, adapt to classroom rules, and develop self-regulation alongside their peers. When schools closed almost overnight, those opportunities were suddenly removed.”
The research revealed that:
Individual differences in executive function abilities were remarkably stable. Children who had stronger skills at two-and-a-half years old tended to remain ahead at six-and-a-half years.
Children from lower socio-economic households consistently scored lower, echoing long-standing research on the impact of maternal education and home environment.
Even when controlling for age and family background, COVID’s impact was evident. Children who were in reception at the start of the pandemic made more modest improvements in executive function compared to those still in preschool.
Dr Johns said: “Our findings suggest that the structured school environment and regular interaction with peers play a crucial role in supporting the development of executive function. When those experiences were disrupted, children’s executive function developed more slowly than that of younger children who were still in preschool.”
The researchers say their work highlights a generation of children who may need more support from teachers, schools and health services in coming years.
Before antibiotics and antiseptics, healers across ancient Egypt, Greece, and China reached for honey to treat wounds. Archaeological evidence shows humans have been harvesting and collecting honey for thousands of years – and for much of that time, we understood it to be more than just food.
Today, honey sits in most kitchen cupboards as a perfectly ordinary pantry staple. But honey has never entirely shed its medicinal reputation. And modern research shows us why: it possesses genuine antimicrobial properties, capable of killing or inhibiting a wide range of bacteria, including drug-resistant strains.
This matters now more than ever. Antimicrobial resistance – where bacteria evolve to survive drugs designed to kill them – is one of the defining public health crises of our time. Infections caused by these resistant microbes are becoming harder and more expensive to treat, creating an urgent need for alternative therapies.
Our new study, published in the journal MicrobiologyOpen, shows honeys from Australia’s native flora might be a big part of the solution.
What did we do?
We analysed 56 honey samples collected from more than 35 apiaries across New South Wales. Many samples came from landscapes recovering from the 2019–2020 bushfires. Most were derived from native Australian plants such as eucalyptus, leptospermum and melaleuca.
We tested the honeys against two common bacterial pathogens: Staphylococcus aureus (golden staph) and E. coli – both among the six leading causes of deaths associated with antibiotic resistance. For each sample we measured the minimum concentration needed to stop bacterial growth. The lower the concentration, the more potent the honey.
We also carried out comprehensive chemical profiling, measuring sugars, organic acids, amino acids, enzymes and a wide range of plant-derived compounds. Statistical and machine-learning analyses helped us identify which chemical features best explained antibacterial strength.
What did we find?
More than three-quarters of the honey samples stopped bacterial growth even when the honeys were diluted to 10% or less. This places Australian native flora honeys alongside some of the world’s most potent varieties.
The most striking factor was floral diversity.
Honeys from mixed floral sources – where bees foraged across multiple native plant species rather than a single species – were consistently the most antimicrobial.
This potency wasn’t due to any single compound but to a chemically rich combination.
Multiple bioactive factors – substances that have a measurable effect on living cells or tissues – worked together to inhibit bacteria. These included naturally produced hydrogen peroxide, plant-derived phenolic compounds (naturally occurring chemicals that plants produce as part of their own defence systems), and antioxidants.
When bacteria encounter honey, this combination acts on several fronts at once. The low moisture content draws water out of bacterial cells, while the acidity disrupts their metabolism. Hydrogen peroxide damages their cellular structures, and phenolic and antioxidant compounds interfere with their ability to function and reproduce.
The strength of mixed floral honeys may also reflect the health of the bees themselves.
Access to diverse forage keeps colonies well nourished. And healthier bees produce more biologically active honey as their enzymes help integrate and activate the plant compounds into a complex antimicrobial mixture.
What does this mean for antimicrobial resistance?
Honey won’t replace antibiotics for serious or systemic infections.
But for topical applications – chronic wounds, burns, or surgical site infections – it is a genuinely promising option. Because honey attacks bacteria through multiple simultaneous mechanisms, resistance is far less likely to emerge than with single-target drugs. Our team is now exploring these applications in more detail.
Australia is particularly well-placed to lead in bioactive honey production. Around 70% of Australian honey comes from native plants. These plants are found not only in forests but also across farmland, regional landscapes, and urban green spaces.
Our findings show that prioritising floral diversity over monoculture isn’t just good for ecosystems – it produces more potent honey. With the beekeeping industry under serious pressure from bushfires, floods, and now the varroa mite, protecting and restoring florally-rich landscapes is critical: for bee health, for industry resilience, and for expanding our natural antimicrobial toolkit.
In the meantime, the next jar of Australian honey you buy may just be doing more good than you realise.
Researchers have discovered new diagnostic and prognostic markers for multiple sclerosis.
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Researchers from the Max Planck Institute of Biochemistry and the Technical University of Munich (TUM) have discovered new diagnostic markers for multiple sclerosis (MS), a disease which affects 3 million people worldwide.
Using mass spectrometry, about 1500 proteins were analysed simultaneously per sample in the cerebrospinal fluid (CSF) of 5000 patients. The study uncovered a set of marker proteins that improve differentiation of MS from other inflammatory brain diseases where classical MS markers are negative. Additionally, the study identified changes in the CSF proteome that may potentially predict disease progression. This approach could also open up new avenues for the diagnosis of other diseases. The study was published in Cell.
Unspecific neurological symptoms can lead to lengthy or even inaccurate diagnoses of diseases, which is why improved protein markers are needed for swift and clear diagnosis
Using a new mass spectrometry method, approximately 1500 proteins were analyzed per cerebrospinal fluid sample across 5000 patients, and up to 2000 proteins in a further improved method
A new set of disease markers enable improved differentiation of multiple sclerosis (MS) from other inflammatory brain diseases, in particular for patients lacking the classical markers
The proteome of the cerebrospinal fluid (CSF) at diagnosis is informative for various aspects of disease evolution in a patient, such as long-term disability, risk of conversion from relapsing to progressive disease course and time to conversion
The method also has the potential to discover other proteins that could be used as markers for the diagnosis of other neurological diseases
Biomarker needs for multiple sclerosis
Imagine living with unexplained neurological symptoms: numbness, visual disturbances, fatigue, but not receiving a clear diagnosis for months or years. Non-specific neurological symptoms can make diagnosis difficult because, despite modern imaging techniques, there are no reliable molecular biomarkers for many neurological diseases.
Professor Bernhard Hemmer, head of the Department of Neurology at TUM University Hospital, explains: “The diagnosis of neurological diseases such as multiple sclerosis is based on a combination of imaging techniques using magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. While MRI reveals inflammatory changes in the brain and spinal cord, CSF shows chronic immune activity in the nervous system. In most cases, this combination enables a reliable diagnosis. In individual cases, however, differentiation can be challenging. This can lead to lengthy and less reliable diagnoses and is associated with uncertain and delayed treatment decisions. For this reason, we need new biomarkers to better diagnose the various diseases. In addition to diagnostic challenges, predicting disease progression, particularly disability accumulation, to guide optimal treatment, remains a major unmet need in MS”.
Proteomic study of cerebrospinal fluid across neurological diseases
In order to find new biomarkers, neurologists Bernhard Hemmer and Christiane Gasperi, both experts in MS research at TUM, have joined forces with Professor Matthias Mann, a world-leading expert in proteomics research. Matthias Mann, director at the MPI of Biochemistry, explains: “We have been developing the technology for measuring proteins using mass spectrometry in our laboratory together with colleagues for decades. Now we can reliably and accurately measure proteins in body fluids. However, for a long time researchers could only measure tens to hundreds of samples and only those proteins with the highest concentration in a body fluid. These proteins often turned out not to be the best markers for diseases. To go one step further, we combined the latest advances in mass spectrometry hardware, software, and sample preparation and adapted the workflow to cerebrospinal fluid.”
In this study, CSF samples from more than 5000 people with a wide range of neurological diseases were analysed. Jakob Bader, first author of the study and postdoctoral researcher in the field of proteomics research, explains: “Proteomics is a scientific discipline that aims to characterise a biological system by measuring all proteins, or at least as many as possible. For our study, it is essential to cover as many proteins as possible in order to increase the likelihood of measuring and later finding real disease markers in our analyses. The great advantage of this proteomic approach is that the identity of the markers does not have to be known beforehand. This saves years of research work in which individual candidates are examined one after the other.”
To avoid misinterpreting random differences between people as disease markers, it is essential to have a sufficient number of patients. Similarly, it is only possible to determine whether a marker is specific to a particular disease by considering the many other relevant diseases in parallel. “The breakthrough was achieving both objectives simultaneously: Analysing thousands of proteins while studying thousands of patients across many neurological diseases.” Jakob Bader adds.
A systematic analysis of disease effects and possible confounders
The 5,000 CSF samples came from a wide range of neurological disorders, including stroke, brain cancer, infections, autoimmune diseases such as MS, and others. Additionally, patient samples were analysed from individuals who had provided CSF samples for the diagnosis of severe headache disorders but in whom no neurological disease was found. This allowed the researchers to use these samples as controls. Systematic comparison of these disorders revealed shared and specific protein deviations from the controls.
For diagnostic use, an elevated protein concentration rarely points unambiguously to a single disorder. The study further revealed that disease-unspecific other effects like a person’s age, sex, and in particular degradation of the barriers insulating the brain from the CSF have a very large impact on the composition of this fluid, which complicates the quest for disease markers.
Biomarkers for a hard-to-identify form of multiple sclerosis
To showcase the potential of proteomic analysis for biomarker discovery, the researchers focused on the search for diagnostic markers for MS, a challenging task but with a direct medical need. Physician Christiane Gasperi says: “In approximately 10% of MS patients, diagnosis of the disease is particularly difficult because they lack the typical MS marker of so-called oligoclonal bands of antibodies that are specific to the CSF and not found in the blood. This complicates and potentially delays the diagnosis.”
She continues: “However, for our patients, a quick and clear diagnosis of the disease is of enormous importance. While current therapies cannot cure MS, they can slow its progression and reduce the long-term disability. That makes it crucial to start treatment early. At the same time, these therapies can have significant side effects, so treatment decisions require a high level of diagnostic certainty. When this confidence is not reached yet, therapy is often delayed. Thus, MS patients really benefit from an early intervention that depends on a clear and early diagnosis.”
To find better markers, the researchers applied an enhanced version of the proteomic method to measure about 2000 proteins in samples of MS and other inflammatory diseases of the CNS, which can mimic MS, and thus pose the greatest diagnostic challenges. This let them identify a set of 22 proteins that distinguishes MS from these inflammatory diseases with better accuracy than other parameters in the CSF that are currently measured in clinical practice. Christiane Gasperi comments: “It is particularly encouraging that we have found a combination of marker proteins that help in the diagnosis of this particularly difficult-to-identify form of MS.”
Predicting disease progression at diagnosis
Beyond improving diagnosis, the study also addressed a second major challenge: Some patients remain relatively stable for many years, while others accumulate disability more rapidly or transition from the relapsing disease course that is typical early on to a progressive course where disability accumulates persistently. At the time of diagnosis, it is very difficult to predict which trajectory a patient will follow. This uncertainty complicates treatment decisions and can be deeply unsettling for those newly diagnosed.
By analyzing hundreds of MS patient samples, the researchers showed that the CSF proteome at the time of diagnosis was associated with the level of disability years later. In addition, these patterns reflected a higher risk for patients to convert from the relapsing to the progressive disease course, as well as shorter times until such conversion occurred. Bernhard Hemmer explains: “Our findings suggest that important aspects of future disability and disease course are reflected in the proteome from the very beginning. This demonstrates that the biological information required for a prognostic test is already present at diagnosis.”
He summaries the study: “For diagnosis, we were able to define and validate a focused protein panel that improves differentiation in difficult cases. Additionally, we found that the overall protein pattern in the CSF at the time of diagnosis is linked to how the disease develops years later. Together, these findings bring us closer to more precise diagnosis and a more individualized treatment strategy from the very beginning.
An avenue for efficient biomarker discovery in neurology
Matthias Mann sees broader potential: “Proteins control almost all biological processes in the body and have long been the most important group of diagnostic markers. Nevertheless, we are probably only at the beginning here. With the methodology established here, we can now analyse the proteome in the CSF of many patients with an unprecedented number of proteins. This technological progress changes how we should search for biomarkers. Comprehensive proteome analysis of large patient collectives promise to be the most efficient path to new and better biomarkers. Beyond MS, this approach opens up prospects for many other diseases of the central nervous system – from Alzheimer’s and Parkinson’s to brain tumours and other neurological disorders.”
Research in Aging Cell indicates that blood levels of particular small non-coding RNAs, which regulate gene expression, may influence how long a person lives.
Investigators evaluated 828 small non-coding RNAs in blood samples from 1,271 community-dwelling older adults 71 years of age and older who were participating in an ongoing study. They then used machine learning to develop a model that could predict survival at 2, 5, and 10 years based on baseline small non-coding RNAs, age, and clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, lipid and metabolite levels, and medical conditions).
The test worked especially well for predicting survival over the next 2 years. “One surprising finding involved a group of small non-coding RNA molecules called piRNAs”, said co–corresponding author Virginia Byers Kraus, MD, PhD, of the Duke Molecular Physiology Institute. Scientists have long known that piRNAs help protect DNA in reproductive cells, but their role in the rest of the body is still a mystery. In this study, nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets to prolong longevity.
“These results suggest that simple blood tests measuring piRNAs might one day help doctors better understand health and aging – and possibly even guide new treatments to help people live longer, healthier lives,” said Dr Byers Kraus.
