Updated: 29 min 53 sec ago
Training AI models to answer ‘what if?’ questions could improve medical treatments
Artificial intelligence techniques can be helpful for multiple medical applications, such as radiology or oncology, where the ability to recognise patterns in large volumes of data is vital. For these types of applications, the AI compares information against learned examples, draws conclusions, and makes extrapolations.
Now, an international team led by researchers from Ludwig-Maximilians-Universität München (LMU) and including researchers from the University of Cambridge, is exploring the potential of a comparatively new branch of AI for diagnostics and therapy.
The researchers found that causal machine learning (ML) can estimate treatment outcomes – and do so better than the machine learning methods generally used to date. Causal machine learning makes it easier for clinicians to personalise treatment strategies, which individually improves the health of patients.
The results, reported in the journal Nature Medicine, suggest how causal machine learning could improve the effectiveness and safety of a variety of medical treatments.
Classical machine learning recognises patterns and discovers correlations. However, the principle of cause and effect remains closed to machines as a rule; they cannot address the question of why. When making therapy decisions for a patient, the ‘why’ is vital to achieve the best outcomes.
“Developing machine learning tools to address why and what if questions is empowering for clinicians, because it can strengthen their decision-making processes,” said senior author Professor Michaela van der Schaar, Director of the Cambridge Centre for AI in Medicine. “But this sort of machine learning is far more complex than assessing personalised risk.”
For example, when attempting to determine therapy decisions for someone at risk of developing diabetes, classical ML would aim to predict how probable it is for a given patient with a range of risk factors to develop the disease. With causal ML, it would be possible to answer how the risk changes if the patient receives an anti-diabetes drug; that is, gauge the effect of a cause. It would also be possible to estimate whether metformin, the commonly-prescribed medication, would be the best treatment, or whether another treatment plan would be better.
To be able to estimate the effect of a hypothetical treatment, the AI models must learn to answer ‘what if?’ questions. “We give the machine rules for recognising the causal structure and correctly formalising the problem,” said Professor Stefan Feuerriegel from LMU, who led the research. “Then the machine has to learn to recognise the effects of interventions and understand, so to speak, how real-life consequences are mirrored in the data that has been fed into the computers.”
Even in situations for which reliable treatment standards do not yet exist or where randomised studies are not possible for ethical reasons because they always contain a placebo group, machines could still gauge potential treatment outcomes from the available patient data and form hypotheses for possible treatment plans, so the researchers hope.
With such real-world data, it should generally be possible to describe the patient cohorts with ever greater precision in the estimates, bringing individualised therapy decisions that much closer. Naturally, there would still be the challenge of ensuring the reliability and robustness of the methods.
“The software we need for causal ML methods in medicine doesn’t exist out of the box,” says Feuerriegel. “Rather, complex modelling of the respective problem is required, involving close collaboration between AI experts and doctors.”
In other fields, such as marketing, explains Feuerriegel, the work with causal ML has already been in the testing phase for some years now. “Our goal is to bring the methods a step closer to practice,” he said. The paper describes the direction in which things could move over the coming years.”
“I have worked in this area for almost 10 years, working relentlessly in our lab with generations of students to crack this problem,” said van der Schaar, who is affiliated with the Departments of Applied Mathematics and Theoretical Physics, Engineering and Medicine. “It’s an extremely challenging area of machine learning, and seeing it come closer to clinical use, where it will empower clinicians and patients alike, is very satisfying.”
Van der Schaar is continuing to work closely with clinicians to validate these tools in diverse clinical settings, including transplantation, cancer and cardiovascular disease.
Reference:
Stefan Feuerriegel et al. ‘Causal machine learning for predicting treatments.’ Nature Medicine (2024). DOI: 10.1038/s41591-024-02902-1
Adapted from an LMU media release.
Machines can learn not only to make predictions, but to handle causal relationships. An international research team shows how this could make medical treatments safer, more efficient, and more personalised.
Artificial intelligencemedicinemachine learninghealthEngineeringMihaela van der SchaarLudwig-Maximilians-UniversitätCambridge Centre for AI in MedicineDepartment of Applied Mathematics and Theoretical PhysicsDepartment of EngineeringDepartment of MedicineSchool of the Physical SciencesSchool of TechnologySchool of Clinical MedicineYuichiro Chino via Getty ImagesComputer-generated image of human brain
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Artificial Intelligence beats doctors in accurately assessing eye problems
The clinical knowledge and reasoning skills of GPT-4 are approaching the level of specialist eye doctors, a study led by the University of Cambridge has found.
GPT-4 - a ‘large language model’ - was tested against doctors at different stages in their careers, including unspecialised junior doctors, and trainee and expert eye doctors. Each was presented with a series of 87 patient scenarios involving a specific eye problem, and asked to give a diagnosis or advise on treatment by selecting from four options.
GPT-4 scored significantly better in the test than unspecialised junior doctors, who are comparable to general practitioners in their level of specialist eye knowledge.
GPT-4 gained similar scores to trainee and expert eye doctors - although the top performing doctors scored higher.
The researchers say that large language models aren’t likely to replace healthcare professionals, but have the potential to improve healthcare as part of the clinical workflow.
They say state-of-the-art large language models like GPT-4 could be useful for providing eye-related advice, diagnosis, and management suggestions in well-controlled contexts, like triaging patients, or where access to specialist healthcare professionals is limited.
“We could realistically deploy AI in triaging patients with eye issues to decide which cases are emergencies that need to be seen by a specialist immediately, which can be seen by a GP, and which don’t need treatment,” said Dr Arun Thirunavukarasu, lead author of the study, which he carried out while a student at the University of Cambridge’s School of Clinical Medicine.
He added: “The models could follow clear algorithms already in use, and we’ve found that GPT-4 is as good as expert clinicians at processing eye symptoms and signs to answer more complicated questions.
“With further development, large language models could also advise GPs who are struggling to get prompt advice from eye doctors. People in the UK are waiting longer than ever for eye care.
Large volumes of clinical text are needed to help fine-tune and develop these models, and work is ongoing around the world to facilitate this.
The researchers say that their study is superior to similar, previous studies because they compared the abilities of AI to practicing doctors, rather than to sets of examination results.
“Doctors aren't revising for exams for their whole career. We wanted to see how AI fared when pitted against to the on-the-spot knowledge and abilities of practicing doctors, to provide a fair comparison,” said Thirunavukarasu, who is now an Academic Foundation Doctor at Oxford University Hospitals NHS Foundation Trust.
He added: “We also need to characterise the capabilities and limitations of commercially available models, as patients may already be using them - rather than the internet - for advice.”
The test included questions about a huge range of eye problems, including extreme light sensitivity, decreased vision, lesions, itchy and painful eyes, taken from a textbook used to test trainee eye doctors. This textbook is not freely available on the internet, making it unlikely that its content was included in GPT-4’s training datasets.
The results are published today in the journal PLOS Digital Health.
“Even taking the future use of AI into account, I think doctors will continue to be in charge of patient care. The most important thing is to empower patients to decide whether they want computer systems to be involved or not. That will be an individual decision for each patient to make,” said Thirunavukarasu.
GPT-4 and GPT-3.5 – or ‘Generative Pre-trained Transformers’ - are trained on datasets containing hundreds of billions of words from articles, books, and other internet sources. These are two examples of large language models; others in wide use include Pathways Language Model 2 (PaLM 2) and Large Language Model Meta AI 2 (LLaMA 2).
The study also tested GPT-3.5, PaLM2, and LLaMA with the same set of questions. GPT-4 gave more accurate responses than all of them.
GPT-4 powers the online chatbot ChatGPT to provide bespoke responses to human queries. In recent months, ChatGPT has attracted significant attention in medicine for attaining passing level performance in medical school examinations, and providing more accurate and empathetic messages than human doctors in response to patient queries.
The field of artificially intelligent large language models is moving very rapidly. Since the study was conducted, more advanced models have been released - which may be even closer to the level of expert eye doctors.
Reference: Thirunavukarasu, A.J. et al: ‘Large language models approach expert-level clinical knowledge and reasoning in ophthalmology: A head-to-head cross-sectional study.’ PLOS Digital Health, April 2024. DOI: 10.1371/journal.pdig.0000341
A study has found that the AI model GPT-4 significantly exceeds the ability of non-specialist doctors to assess eye problems and provide advice.
Artificial intelligenceArun ThirunavukarasuOxford University Hospitals NHS Foundation TrustUniversity of OxfordSchool of Clinical MedicineCorpus Christi CollegeWe could realistically deploy AI in triaging patients with eye issues to decide which cases are emergencies.Arun ThirunavukarasuMavocado on Getty
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Report highlights inequalities and hidden suffering among people living with breast cancer
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Report highlights inequalities and hidden suffering among people living with breast cancer
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Report highlights inequalities and hidden suffering among people living with breast cancer
Many people with breast cancer ‘systematically left behind’, say researchers
Experts predict 3 million new cases a year of breast cancer worldwide by 2040 and a million deaths, with people living in low- and middle-income countries disproportionately affected. Despite major advances in the diagnosis and treatment, inequalities mean that many women worldwide still experience significant suffering related to physical symptoms, emotional despair, and financial burden.
These are among the conclusions of the new Lancet Commission, led by Professor Charlotte Coles from the University of Cambridge, which sets out recommendations to tackle these urgent challenges in breast cancer. The Commission builds on previous evidence, presents new data, and integrates patient voices to shed light on a large unseen burden.
"Recent improvements in breast cancer survival represent a great success of modern medicine. However, we can’t ignore how many patients are being systematically left behind."Professor Charlotte Coles, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust
Professor Coles added: "We hope that, by highlighting these inequities and hidden costs and suffering in breast cancer, they can be better recognised and addressed by health care professionals and policymakers in partnership with patients and the public around the world."
At the end of 2020, 7.8 million women were alive having been diagnosed with breast cancer in the previous five years. Progress in research and cancer management has led to a decrease of over 40% in breast cancer mortality in most high-income countries. Estimates suggest that global breast cancer incidence will rise from 2.3 million new cases in 2020 to over 3 million by 2040.
Although breast cancer is the most common cancer, gaps in knowledge continue to prevent effective action.
Professor Charlotte Coles
Professor Charlotte Coles
Lack of information on number of people with metastatic breast cancerEven though 20-30% of patients with early breast cancer experience relapse, relapse is not typically recorded by most national cancer registries. Therefore, the number of patients living with metastatic breast cancer is not known. Meeting the needs of an under-measured patient population is difficult, and as a result, feelings of abandonment and isolation are common among those living with the condition.
"Metastatic breast cancer remains poorly understood by the public, policymakers, and even health care professionals. Some patients have told me that they feel ‘written off’. This sense of being ignored and left behind can mean they are less likely to seek help or engage with research that could help them."Lesley Stephen, collaborator and patient advocate
Lesley added: "Patients with metastatic disease need more support and information in order to feel valued."
In the last decade, metastatic breast cancer outcomes have improved considerably. The median overall survival for the two major subtypes, which include approximately 85% of metastatic breast cancer patients, has reached five years where recommended therapies are made available. In a Commission survey of 382 healthcare professionals, more than half (55%) agreed that specific subtypes of metastatic breast cancer may become curable, and three-quarters agreed that it will become a chronic disease.
The authors make a case for a minimum of 70% of registries worldwide to record cancer stage and relapse. These data could drive significant improvements in metastatic breast cancer care, outcomes, and emotional wellbeing among patients. Initiatives that promote societal inclusion of people living with metastatic breast cancer are also paramount; for example, changes to labour market laws that empower more flexible working arrangements. With a shift in perception, it may be possible to treat most, alleviate suffering for all, and forget no-one living with the disease, the Commission argues.
The hidden costs of breast cancerThe associated costs of breast cancer – including physical, psychological, social, and financial costs – are immense but under-recognised. Many of these costs are not captured by current global health metrics.
In response, the Commission established a UK-based pilot study that provides a snapshot of the economic burden and supportive care needs for people affected by breast cancer. Nearly all of the 606 people living with breast cancer and carers surveyed by the Commission stated physical or well-being issues related to breast cancer. One participant described losing their job as as result of being unable to cope during chemotherapy, while another experienced sexual dysfunction but found it difficult to ask for help.
Additionally, a fifth of participants with early breast cancer and a quarter of those with metastatic breast cancer reported difficulty in covering the costs of travel for treatment. 27% with early breast cancer and 35% with metastatic breast cancer said they had financial problems.
This pilot research suggests that, even in countries with a health care system free at the point of care, people with breast cancer can incur hidden costs.
Building on previous work, the Commission report also discusses serious health-related suffering, an indicator of the need for palliative care, with estimates provided by a small expert group. In 2020, an estimated 120 million days were spent with serious health-related suffering per year for people who died of their cancer. A further 520 million days were estimated for patients living with the disease. Behind these numbers are individuals experiencing pain, shortness of breath, fatigue, and other, often resolvable, distressing symptoms.
"Even in countries with well-developed health care systems, patients with breast cancer experience inadequate support and care. In countries lacking affordable health care facilities, patients experience these costs more commonly and intensely, too often leading to catastrophic spending and impoverishment."Dr Carlos Barrios, Oncology Research Center, Hospital São Lucas, Brazil
The Commission advocates the development of new tools and metrics that capture the many costs associated with the disease. This measurement should guide policymakers to invest in breast cancer prevention, early detection, cost-effective therapy, optimal management, financial protection, and other interventions that relieve suffering.
Better communication for better patient outcomesMany patients describe breast cancer as robbing them of power. Therefore, healthcare professional-patient communication that empowers is highlighted by the authors as an important intervention. A review of research by the Commission suggests better communication with patients can improve quality of life, decision-making, body image, and even adherence to therapy – with positive impacts on survival.
"Improving the quality of communication between patients and health professionals, though seemingly simple, could have profound positive impacts that extend far beyond the specific setting of breast cancer management."Professor Reshma Jagsi, Emory University School of Medicine, USA
Professor Jagsi added: "Patients should be encouraged to exercise their voices, choosing their level of involvement in care decisions."
The Commission calls for every healthcare professional in every country to receive communication skills training and for patient involvement in all stages of clinical research on breast cancer – from concept to translation into clinical practice. To support these transitions, the report outlines a framework based on strategies to build rapport and empathy, share information, check understanding, and jointly agree next steps with patients.
Collaborate to improve prevention and early detectionUp to a quarter of breast cancer in high income countries could be prevented by modifying risk factors for breast cancer. While education and awareness-raising efforts are important in this respect, bold policy changes that minimise population exposure to modifiable risk factors (including alcohol consumption, being overweight, and physical inactivity) are vital to reduce cancer incidence, suggests the Commission.
In addition, systematic approaches that identify those at increased risk of the disease are essential to enable equitable access to personalised prevention strategies, including cheap and effective medications that can avert breast cancer for many women.
The authors also argue for improved early detection programmes, beginning with efforts to promote stage shifting in diagnosis so that at least 60% of confirmed invasive cancers are early disease (stages one or two).
"Access to evidence-based prevention and care that isn’t dependent on where an individual lives or their ability to pay would reap wide-ranging benefits for patients, families, and health care systems striving to achieve universal health coverage."Professor Benjamin Anderson, Departments of Surgery and Global Health, University of Washington, USA
Published 16 April 2024
Adapted from a press release by The Lancet.
Reference
Coles, CE et al. The Lancet Breast Cancer Commission. Lancet; 15 Apr 2024; DOI: 10.1016/S0140-6736(24)00747-5
Images
- Woman in white bath towel holding her hair (National Cancer Institute/Unsplash)
- Professor Charlotte Coles (Patrick Harrison/Cancer Research UK)
- Young breast cancer patient (Rebekah Voz/Unsplash)
- Oncology Portrait - stock photo (FatCamera/Getty Images)
- Asian woman with cancer meeting with female physician - stock photo (FatCamera/Getty Images)
- Nurse with young women having a mammography - stock photo (choja/Getty Images)
Many people with breast cancer ‘systematically left behind’, say researchers in Lancet Commission led by Professor Charlotte Coles.
Image: Affiliation (schools and institutions): School of Clinical MedicineDepartment of OncologyCambridge Cancer CentreExternal Affiliations: National Institute for Health Research (NIHR)LancetPeople (our academics and staff): Charlotte ColesSubject (including Spotlight on ... where applicable): Cancerbreast cancerinequalitySection: ResearchSuper Tags: Health and medicineShorthand Story Description/Subtitle: New report highlights inaction on inequities and hidden sufferingShorthand Story Thumbnail: https://www.cam.ac.uk/sites/www.cam.ac.uk/files/shorthand/245641/Fc5mFrzPLZ/assets/W4fAsv8Woo/national-cancer-institute-icm-ceifk4i-unsplash-land-bw-0.6-thumbnail.jpgStudy unpicks why childhood maltreatment continues to impact on mental and physical health into adulthood
Individuals who experienced maltreatment in childhood – such as emotional, physical and sexual abuse, or emotional and physical neglect – are more likely to develop mental illness throughout their entire life, but it is not yet well understood why this risk persists many decades after maltreatment first took place.
In a study published in Proceedings of the National Academy of Sciences, scientists from the University of Cambridge and Leiden University found that adult brains continue to be affected by childhood maltreatment in adulthood because these experiences make individuals more likely to experience obesity, inflammation and traumatic events, all of which are risk factors for poor health and wellbeing, which in turn also affect brain structure and therefore brain health.
The researchers examined MRI brain scans from approximately 21,000 adult participants aged 40 to 70 years in UK Biobank, as well as information on body mass index (an indicator of metabolic health), CRP (a blood marker of inflammation) and experiences of childhood maltreatment and adult trauma.
Sofia Orellana, a PhD student at the Department of Psychiatry and Darwin College, University of Cambridge, said: “We’ve known for some time that people who experience abuse or neglect as a child can continue to experience mental health problems long into adulthood and that their experiences can also cause long term problems for the brain, the immune system and the metabolic system, which ultimately controls the health of your heart or your propensity to diabetes for instance. What hasn’t been clear is how all these effects interact or reinforce each other.”
Using a type of statistical modelling that allowed them to determine how these interactions work, the researchers confirmed that experiencing childhood maltreatment made individuals more likely to have an increased body mass index (or obesity) and experience greater rates of trauma in adulthood. Individuals with a history of maltreatment tended to show signs of dysfunction in their immune systems, and the researchers showed that this dysfunction is the product of obesity and repeated exposure to traumatic events.
Next, the researchers expanded their models to include MRI measures of the adult’s brains and were able to show that widespread increases and decreases in brain thickness and volume associated with greater body mass index, inflammation and trauma were attributable to childhood maltreatment having made these factors more likely in the first place. These changes in brain structure likely mean that some form of physical damage is occurring to brain cells, affecting how they work and function.
Although there is more to do to understand how these effects operate at a cellular level in the brain, the researchers believe that their findings advance our understanding of how adverse events in childhood can contribute to life-long increased risk of brain and mind health disorders.
Professor Ed Bullmore from the Department of Psychiatry and an Honorary Fellow at Downing College, Cambridge, said: “Now that we have a better understanding of why childhood maltreatment has long term effects, we can potentially look for biomarkers – biological red flags – that indicate whether an individual is at increased risk of continuing problems. This could help us target early on those who most need help, and hopefully aid them in breaking this chain of ill health.”
The research was supported by MQ: Transforming Mental Health, the Royal Society, Medical Research Council, National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, the NIHR Applied Research Collaboration East of England, Girton College and Darwin College.
Reference
Orellana, SC et al. Childhood maltreatment influences adult brain structure through its effects on immune, metabolic and psychosocial factors. PNAS; 9 Apr 2024 ; DOI: 10.1073/pnas.230470412
Childhood maltreatment can continue to have an impact long into adulthood because of how it effects an individual’s risk of poor physical health and traumatic experiences many years later, a new study has found.
Spotlight on neuroscienceMental healthChildrenSofia OrellanaEd BullmoreMQRoyal SocietyMedical Research CouncilNIHR Cambridge Biomedical Research CentreNIHR CLAHRC for Cambridgeshire and Peterborough NHS Foundation TrustSchool of Clinical MedicineDepartment of PsychiatryGirton CollegeDowning CollegeWe’ve known for some time that people who experience abuse or neglect as a child can continue to experience mental health problems long into adulthoodSofia Orellanamali desha (Unsplash)Black and white image of boy curled up on the floor
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Four Cambridge researchers awarded prestigious European Research Council Advanced Grants
The European Research Council (ERC) has announced today the award of 255 Advanced Grants to outstanding research leaders across Europe, as part of the EU’s Horizon Europe programme. Four University of Cambridge researchers are amongst those to receive this prestigious and competitive funding.
The University of Cambridge’s grant awardees are:
Dr Albert Guillén i Fàbregas in the Department of Engineering for his project Scaling and Concentration Laws in Information Theory.
Fàbregas, who has previously received ERC Starting, Consolidator and Proof of Concept Grants, said: “I am truly delighted with the news that the ERC will continue to fund my research in information theory, which studies the mathematical aspects of data transmission and data compression.
“This project will broaden the theory to study arbitrary scaling laws of the number of messages to transmit or compress."
Professor Beverley Glover in the Department of Plant Sciences and Director of Cambridge University Botanic Garden, for her project Convergent evolution of floral patterning through alternative optimisation of mechanical parameter space.
Glover said: “This funding will enable us to explore how iridescent colour evolved repeatedly in different flowers. We think it will shed new light on evolution itself, as we think about the development of iridescence structure from a mechanical perspective, focusing on the forces acting as a petal grows and the mechanical properties of the petal tissue.
“It's only possible for me to do this work because of the amazing living collection at Cambridge University Botanic Garden, and I'm thrilled that the ERC is keen to support it."
Professor Ian Henderson in the Department of Plant Sciences for his project Evolution of the Arabidopsis Pancentromere.
Henderson said: “This project seeks to investigate enigmatic regions of the genome called the centromeres, using the model plant Arabidopsis. These regions play a deeply conserved role in cell division yet paradoxically are fast evolving.
“I am highly honoured and excited to be awarded an ERC Advanced grant. The advent of long-read sequencing technology makes addressing these questions timely. The ERC’s long-term support will allow us to capitalise on these advances, build new collaborations, and train postdoctoral researchers.”
Professor Paul Lane in the Department of Archaeology, for his project Landscape Historical Ecology and Archaeology of Ancient Pastoral Societies in Kenya.
Lane said: “Pastoralism has been an extraordinarily resilient livelihood strategy across Africa. This project provides an excellent opportunity to reconstruct how East Africa’s pastoralists responded to significant climate change in the past, and to draw lessons from these adaptations for responding to contemporary climate crises in a region that is witnessing heightened water scarcity and loss of access to critically important grazing lands.”
“This project will allow us to utilise the department’s world-leading archaeological science laboratories and expertise to answer crucial questions about past patterns of mobility, dietary diversity, climatic regimes and food security among East African pastoralists over the last fifteen hundred years. This has never been attempted before for this time period.”
Professor Anne Ferguson-Smith, Pro-Vice Chancellor for Research at the University of Cambridge said: “Many congratulations to Albert, Beverley, Ian and Paul on receiving these prestigious and highly competitive awards. It is fantastic that their ambitious, cutting-edge research will be supported by the European Research Council, marking them as outstanding European research leaders.
“Now that the UK is an associated country to Horizon Europe I encourage other Cambridge researchers to also consider applying to the ERC and other Horizon Europe programmes.”
President of the European Research Council Professor Maria Leptin said: “Congratulations to the 255 researchers who will receive grants to follow their scientific instinct in this new funding round. I am particularly happy to see more mid-career scientists amongst the Advanced Grant winners this time. I hope that it will encourage more researchers at this career stage to apply for these grants.”
The ERC is the premier European funding organisation for excellent frontier research. The 255 ERC Advanced Grants, totalling €652 million, support cutting-edge research in a wide range of fields from medicine and physics to social sciences and humanities.
The European Commission and the UK Government have reached an agreement on the association of the UK to Horizon Europe, which applies for calls for proposals implementing the 2024 budget and onwards.
The ERC Advanced Grants target established, leading researchers with a proven track-record of significant achievements. In recent years, there has been a steady rise in mid-career researchers (12-17 years post-PhD), who have been successful in the Advanced Grants competitions, with 18% securing grants in this latest round.
The funding provides leading senior researchers with the opportunity to pursue ambitious, curiosity-driven projects that could lead to major scientific breakthroughs.
Engineeringplant sciencesArchaeologyAlbert Guillén i FàbregasBeverley GloverIan HendersonPaul LaneEuropean Research CouncilDepartment of EngineeringSchool of TechnologyDepartment of Plant SciencesCambridge University Botanic GardenSchool of the Biological SciencesDepartment of ArchaeologySchool of the Humanities and Social SciencesMagdalene CollegeQueens' CollegeGonville and Caius CollegeMany congratulations to Albert, Beverley, Ian and Paul... It is fantastic that their ambitious, cutting-edge research will be supported by the European Research Council, marking them as outstanding European research leaders.Anne Ferguson-Smith
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Pork labelling schemes ‘not helpful’ in making informed buying choices, say researchers
Researchers have evaluated different types of pig farming – including woodland, organic, free range, RSPCA assured, and Red Tractor certified, to assess each systems’ impact across four areas: land use (representing biodiversity loss), greenhouse gas emissions, antibiotics use and animal welfare. Their study concludes that none of the farm types performed consistently well across all four areas – a finding that has important implications for increasingly climate conscious consumers, as well as farmers themselves.
However, there were individual farms that did perform well in all domains, including an indoor Red Tractor farm, an outdoor bred, indoor finished RSPCA assured farm and fully outdoor woodland farm. “Outliers like these show that trade-offs are not inevitable,” said lead author Dr Harriet Bartlett, Research Associate at the University of Oxford's Smith School of Enterprise and the Environment, who was formerly at the University of Cambridge.
“Somewhat unexpectedly we found that a handful of farms perform far better than average across all four of our environmental and welfare measures,” added senior author Andrew Balmford, Professor of Conservation Science at the University of Cambridge. However, none of the current label or assurance schemes predicted which farms these would be.
“The way we classify farm types and label pork isn’t helpful for making informed decisions when it comes to buying more sustainable meat. Even more importantly, we aren’t rewarding and incentivising the best-performing farmers. Instead of focusing on farm types or practices, we need to focus on meaningful outcomes for people, the planet and the pigs – and assess, and reward farms based on these,” said Bartlett.
The findings also show that common assumptions around food labelling can be misplaced. For instance, Organic farming systems, which consumers might see as climate and environmentally friendly, have on average three times the CO2 output per kg of meat of more intensive Red Tractor or RSPCA assured systems and four times the land use. However, these same systems use on average almost 90% fewer antibiotic medicines, and result in improved animal welfare compared with production from Red tractor or RSPCA assured systems.
The way we classify livestock farms must be improved, Bartlett says, because livestock production is growing rapidly, especially pork production, which has quadrupled in the past 50 years and already accounts for 9% of greenhouse gas emissions from livestock. Pig farming also uses more antibiotics than any other livestock sector, and 8.5% of all arable land.
“Our findings show that mitigating the environmental impacts of livestock farming isn’t a case of saying which farm type is the best,” said Bartlett. “There is substantial scope for improvement within types, and our current means of classification is not identifying the best farms for the planet and animals overall. Instead, we need to identify farms that successfully limit their impacts across all areas of societal concern, and understand, promote and incentivise their practises.”
The study reached its conclusions using data from 74 UK and 17 Brazilian breed-to-finish systems, each made up of 1-3 farms and representing the annual production of over 1.2 million pigs. It is published today in the journal Nature Food.
“To the best of our knowledge, our dataset covers by far the largest and most diverse sample of pig production systems examined in any single study,” said Bartlett.
James Wood, Professor of Equine and Farm Animal Science at the University of Cambridge, commented: “This important study identifies a key need to clarify what different farm labels should indicate to consumers; there is a pressing need to extend this work into other farming sectors. It also clearly demonstrates the critical importance that individual farmers play in promoting best practice across all farming systems.”
Trade-offs in the externalities of pig production are not inevitable was authored by academics at the University of Oxford, University of Cambridge and the University of São Paulo.
The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
Reference: Bartlett, H.,‘Trade-offs in the externalities of pig production are not inevitable.’ Nature Food, April 2024. DOI: 10.1038/s43016-024-00921-2
Adapted from a press release by the University of Oxford.
Farmers don’t have to choose between lowering environmental impact and improving welfare for their pigs, a new study has found: it is possible to do both. But this is not reflected in the current food labelling schemes relied on by consumers.
food systemGlobal food securityEnvironmentHarriet BartlettJames WoodMark HolmesAndrew BalmfordUniversity of OxfordUniversidade de Sao PauloDepartment of Veterinary MedicineDepartment of ZoologySchool of the Biological SciencesCambridge Global Food Security Interdisciplinary Research CentreChurchill CollegeThe way we classify farm types and label pork isn’t helpful for making informed decisions when it comes to buying more sustainable meat.Harriet BartlettCharity Burggraaf/ GettyTwo pigs on a farm
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Scientists identify rare gene variants which confer up to 6-fold increase in risk of obesity
The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood.
The study, published in Nature Genetics, was led by researchers at the Medical Research Council (MRC) Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.
The researchers used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals.
They found that genetic variants in the gene BSN, also known as Bassoon, can raise the risk of obesity as much as six times and was also associated with an increased risk of non-alcoholic fatty liver disease and of type 2 diabetes.
The Bassoon gene variants were found to affect 1 in 6,500 adults, so could affect about 10,000 people in the UK.
The brain’s role in obesityObesity is a major public health concern as it is a significant risk factor for other serious diseases, including cardiovascular disease and type 2 diabetes, yet the genetic reasons why some people are more prone to weight gain are incompletely understood.
Previous research has identified several obesity-associated gene variants conferring large effects from childhood, acting through the leptin-melanocortin pathway in the brain, which plays a key role in appetite regulation.
However, while both BSN and APBA1 encode proteins found in the brain, they are not currently known to be involved in the leptin-melanocortin pathway. In addition, unlike the obesity genes previously identified, variants in BSN and APBA1 are not associated with childhood obesity.
This has led the researchers to believe that they may have uncovered a new biological mechanism for obesity, different to those we already know for previously identified obesity gene variants.
Based on published research and laboratory studies they report in this paper, which indicate that BSN and APBA1 play a role in the transmission of signals between brain cells, the researchers suggest that age-related neurodegeneration could be affecting appetite control.
Professor John Perry, study author and an MRC Investigator at the University of Cambridge, said: “These findings represent another example of the power of large-scale human population genetic studies to enhance our understanding of the biological basis of disease. The genetic variants we identify in BSN confer some of the largest effects on obesity, type 2 diabetes and fatty liver disease observed to date and highlight a new biological mechanism regulating appetite control.”
The use of global dataThe accessibility of large-scale databases such as UK Biobank has enabled researchers to search for rare gene variants that may be responsible for conditions including obesity.
For this study, the researchers worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico. This is important as the researchers can now apply their findings beyond individuals of European ancestry.
If the researchers can better understand the neural biology of obesity, it could present more potential drug targets to treat obesity in the future.
Dr Slavé Petrovski, VP of the Centre for Genomics Research at AstraZeneca, said: “Rigorous large-scale studies such as this are accelerating the pace at which we uncover new insights into human disease biology. By collaborating across academia and industry, leveraging global datasets for validation, and embedding a genomic approach to medicine more widely, we will continue to improve our understanding of disease – for the benefit of patients.”
Next steps for researchProfessor Giles Yeo, study author based at the MRC Metabolic Diseases Unit, added: “We have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seen, but perhaps more importantly, that the variation in Bassoon is linked to adult-onset and not childhood obesity. Thus these findings give us a new appreciation of the relationship between genetics, neurodevelopment and obesity.”
Reference
Zhao, T et al. Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease. Nat Gen; 4 Apr 2024; DOI: 10.1038/s41588-024-01694-x
Adapted from a press release from the Medical Research Council
Cambridge researchers have identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date.
ObesitygeneticsJohn PerryGiles YeoMedical Research CouncilSchool of Clinical MedicineMedical Research Council (MRC) Epidemiology UnitMRC Metabolic Diseases UnitWellcome-MRC Institute of Metabolic ScienceWe have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seenGiles YeoWorld Obesity FederationWoman with obesity washing food
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UK-wide trials to begin on blood tests for diagnosing dementia
Professor James Rowe from the Department of Clinical Neurosciences at Cambridge will co-lead a team that will test multiple existing and novel blood tests, looking at a range of types of dementia.
The trials will capitalise on recent breakthroughs in potential dementia blood tests, and generate the evidence needed for them to be validated for use in the NHS within the next five years.
The teams from Dementias Platform UK (which includes the Universities of Cambridge and Oxford) and UCL make up the Blood Biomarker Challenge - a multi-million pound award given by Alzheimer’s Society, Alzheimer’s Research UK and the National Institute for Health and Care Research and Gates Ventures including £5m raised by players of People’s Postcode Lottery. The project aims to revolutionise dementia diagnosis.
Both teams will recruit participants from sites spread across the country, to ensure their findings are applicable to the whole of the UK’s diverse population.
Timely and accurate diagnosis of the diseases that cause dementia, such as Alzheimer’s disease, is crucial as it means people can access vital care and support and take part in medical research. This will be even more imperative if new treatments are approved for use in the NHS, as these work best for people in the earliest stage of their disease.
Currently, people are usually diagnosed using memory tests and brain scans. These are less accurate than ‘gold standard’ tests like PET scans or lumbar punctures, which can confirm what type of dementia they have. However, only 2% of people can access these specialist tests.
In recent years, a number of different blood tests that can diagnose Alzheimer’s disease and other causes of dementia have shown very promising results in research settings. But they have yet to be tested widely in clinical settings in the UK.
The READ-OUT team (REAl World Dementia OUTcomes) will be led by Professor James Rowe from Cambridge and Drs Vanessa Raymont and Ivan Koychev from Oxford, who are part of Dementias Platform UK. They will test multiple existing and novel blood tests, looking at a range of types of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. The researchers will also look at whether the blood tests can help detect these diseases at various stages.
Professor Rowe said: “This is a ground-breaking study, to discover the best blood tests for dementia, not just Alzheimer’s but any type of dementia and for anyone, whatever their background age and other health problems. An early accurate diagnosis opens the way to better treatment, support and care. Cambridge researchers will lead the analysis pipeline, and the vital input from patients and families throughout the study.”
For the first three years, READ-OUT will run a fact finding study that will take blood tests in around 20 Dementias Platform UK sites across the UK, involving 3000 people from diverse populations. In the final 2 years, they will run a clinical trial with 880 people to explore how having a blood test for dementia affects diagnosis and quality of life, patients and carers, impact on care and how the results should be communicated to patients.
Dr Raymont said: “Since I first stepped into a memory clinic 30 years ago there has thankfully been a shift in the way society thinks about dementia. There was previously a feeling that this was just another part of aging, but now we’re seeing that people want to know more about their condition and they want a diagnosis as it helps them access the support they need. Both my parents lived with dementia so I know firsthand the devastation this disease causes, and how a timely and accurate diagnosis can benefit people and their families.”
A second team, ADAPT, will be led by Professor Jonathan Schott and Dr Ashvini Keshavan at UCL and will focus on the most promising biomarker for Alzheimer’s disease, called p-tau217. This reflects levels of two hallmark proteins found inside the brain in Alzheimer’s disease – amyloid and tau. The researchers will carry out a clinical trial to see whether measuring p-tau217 in the blood increases the rate of diagnosis for Alzheimer’s disease both in people with early dementia, but also in those with mild, progressive problems with memory.
These complementary research approaches will maximise the chances of providing the evidence needed to prove that blood tests are ready for use in the NHS. They will pave the way for them to be made available to all who might benefit within the next 5 years.
Fiona Carragher, Director of Research and Influencing at Alzheimer’s Society, said: “At the moment only 2% of people with dementia can access the specialised tests needed to demonstrate eligibility for new treatments, leading to unnecessary delays, worry and uncertainty. Blood tests are part of the answer to this problem – they’re quick, easy to administer and cheaper than current, more complex tests. I’ve spent decades working in research and the NHS and, after years of slow progress, it feels like we’re on the cusp of a new chapter on how we treat dementia in this country.”
Dr Sheona Scales, Director of Research at Alzheimer’s Research UK, said: “It’s fantastic that through collaborating with the leading experts in the dementia community, we can look to bring cutting-edge blood tests for diagnosing dementia within the NHS. And this will be key to widening access to groundbreaking new treatments that are on the horizon.”
For more information about the Blood Biomarker Challenge and how to take part, please visit the Dementia Platforms UK website.
Adapted from a press release from Alzheimer’s Research UK
Cambridge researchers are helping lead countrywide trials to identify accurate and quick blood tests that can diagnose dementia, in a bid to improve the UK’s shocking diagnosis rate.
Spotlight on neurosciencedementiaAlzheimer's diseaseJames RoweAlzheimer's Research UKAlzheimer's SocietySchool of Clinical MedicineDepartment of Clinical NeurosciencesThis is a ground-breaking study, to discover the best blood tests for dementia, not just Alzheimer’s but any type of dementia and for anyone, whatever their background age and other health problems. An early accurate diagnosis opens the way to better treatment, support and careJames Rowemicheile hendersonElderly couple taking a walk through the park
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UK's only research institute dedicated to understanding early cancer receives £11 million donation
Located on the Cambridge Biomedical Campus – the largest bioscience ecosystem in Europe – the Institute brings together world-leading expertise from across diverse fields including biology, physics, mathematics, epidemiology, medicine, and computer science under one roof with one goal: to predict and prevent cancer.
The donation will support the redevelopment of the Hutchison building, home to the Early Cancer Institute. This will enable the Institute to scale up its work, creating the cutting-edge laboratory space needed for its research teams to advance their early detection efforts and expand the Institute's research capabilities, attracting more world-class scientists and clinicians to join its teams.
The building will be renamed the Li Ka Shing Early Cancer Institute in honour of Hong Kong-based philanthropist Sir Ka-shing Li and the enduring partnership between the Li Ka Shing Foundation and the University of Cambridge in progressing the fight against cancer. Sir Ka-shing Li generously donated to the original Hutchison building in 2002, and then – in 2007 – to the Li Ka Shing Centre, which houses the CRUK Cambridge Institute.
Commenting on the renaming of the building in his honour, Sir Ka-shing Li said: "I am greatly encouraged that much advancement has been made towards cancer diagnosis, treatment and prevention. It is also evident now that early detection of cancer will yield the best chance of successful treatment and quality of life for the patient.
"It is a great privilege, therefore, to support the transformation of the Hutchison building to become a centre of excellence and a fitting home for the national Early Cancer Research Institute and a first of its kind in the UK. This inspirational journey with Cambridge University spanning over two decades fulfils my lifetime commitment to build the good of science, and I am truly gratified by this partnership."
Researchers at the Institute are focusing on cancers that are hard to treat, such as lung, oesophageal and liver cancers, and acute myeloid leukaemia. Detection and treatment methods have changed very little for these types of cancer over the past few years, and outcomes are often poor. Detecting and treating cancer earlier will dramatically increase survival rates and reduce healthcare costs across all tumour types.
By working across disciplines to understand the fundamental biology of how cancer develops and evolves, researchers at the Institute are making pioneering early detection research advances and translating these into clinical practice. They have used the power of theoretical physics methods to identify blood cancer years before the patient has symptoms, while biology and chemical engineering experts have collaborated to develop a method to detect and destroy early lung cancer.
The Institute’s director, Professor Rebecca Fitzgerald, pioneered the capsule sponge – a new test that can identify ten times more heartburn patients with Barrett’s oesophagus, a pre-cursor to oesophageal cancer. The device which aims to catch the disease when it is easier to treat, thus helping more people survive.
Fitzgerald, also Professor of Cancer Prevention, remarked on the gift’s far-reaching impact, highlighting the importance of the redevelopment in helping researchers make life-saving scientific advances: "This extraordinary gift will provide the cutting-edge research facilities necessary to help our researchers develop pioneering early cancer detection innovations and take these from bench to bedside with even greater speed and focus, resulting in fewer cancer-related deaths worldwide."
Professor Richard Gilbertson, the Li Ka Shing Chair of Oncology said: "It is fitting that the home of this exceptional centre for research into the early detection of cancer should be renamed the Li Ka Shing Early Cancer Institute. From his inaugural gift to establish the Li Ka Shing Centre to house the Cancer Research UK Cambridge Institute, to the endowment of a new Professorship of Oncology, Sir Ka-shing Li has been a generous and constant partner in the University’s pioneering work to help create a world free of the fear of cancer."
The Vice-Chancellor, Professor Deborah Prentice, said: "New technologies are ensuring that ideas developed here in Cambridge can be used to benefit patients around the world, and we must ensure that as many people as possible are able to benefit from our cancer research. We are very grateful for Sir Ka-shing Li’s longstanding generosity, which has allowed us to make extraordinary progress in understanding this terrible disease. As our work continues, we look forward to developing novel ways of diagnosing cancer earlier and treating it more precisely and effectively."
The University of Cambridge’s Early Cancer Institute – the UK's only research facility dedicated to understanding early cancer – has received a landmark £11 million donation to support its vital work in the fight against cancer.
CancerPhilanthropyRebecca FitzgeraldLi Ka Shing FoundationEarly Cancer InstituteCRUK Cancer CentreSchool of Clinical MedicineThis extraordinary gift will provide the cutting-edge research facilities necessary to help our researchers develop pioneering early cancer detection innovations... resulting in fewer cancer-related deaths worldwide.Rebecca FitzgeraldCredit: Li Ka Shing FoundationSir Ka-shing Li at the opening of the MRC Cancer Centre in the Hutchinson Building, 18 May 2022
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New approach to monitoring freshwater quality can identify sources of pollution, and predict their effects
The source of pollutants in rivers and freshwater lakes can now be identified using a comprehensive new water quality analysis, according to scientists at the University of Cambridge and Trent University, Canada.
Microparticles from car tyres, pesticides from farmers’ fields, and toxins from harmful algal blooms are just some of the organic chemicals that can be detected using the new approach, which also indicates the impact these chemicals are likely to have in a particular river or lake.
Importantly, the approach can also point to the origin of specific organic matter dissolved in the water, because it has a distinct composition depending on its source.
The approach uses a technique called high-resolution mass spectrometry to analyse water samples: within an hour this provides a comprehensive overview of all the organic molecules present.
Water quality is strongly determined by the diversity of organic matter dissolved in it – termed ‘chemodiversity.’ The scientists say that the thousands of different dissolved organic compounds can keep freshwater ecosystems healthy, or contribute to their decline, depending on the mixture present.
The paper is published today in the journal Science.
“Traditional approaches to monitoring water quality involve taking lots of different measurements with many devices, which takes a lot of time. Our technique is a very simple way to get a comprehensive overview of what’s going on in a particular river or lake,” said Jérémy Fonvielle, a researcher in the University of Cambridge’s Departments of Plant Sciences and Biochemistry, and co-author of the paper.
To understand what drives this chemodiversity, the team reviewed studies of dissolved organic matter in freshwater samples from rivers and lakes across Europe and northern Canada.
For example, water analysis of Lake Erie in Canada revealed high levels of phosphorus pollution. By looking at the composition of individual molecules in the water sample, researchers identified agricultural activities as the source of this pollution, rather than wastewater effluent.
“Whereas before, we could measure the amount of organic nitrogen or phosphorus pollution in a river, we couldn't really identify where pollution was coming from. With our new approach we can use the unique molecular fingerprint of different sources of pollution in freshwater to identify their source,” said Dr Andrew Tanentzap at Trent University School of the Environment, co-author of the report.
Traditional approaches involve separately measuring many indicators of ecosystem health, such as the level of organic nutrients or particular pollutants like nitrogen. These can indicate the condition of the water, but not why this state has arisen.
Dissolved organic matter is one of the most complex mixtures on Earth. It consists of thousands of individual molecules, each with their own unique properties. This matter influences many processes in rivers and lakes, including nutrient cycling, carbon storage, light absorption, and food web interactions - which together determine ecosystem function.
Sources of dissolved organic matter in freshwater include urban runoff, agricultural runoff, aerosols and wildfires.
“It's possible to monitor the health of freshwater through the diversity of compounds that are present. Our approach can, and is, being rolled out across the UK,” said Tanentzap.
Fonvielle will now apply this technique to analysing water samples from farmland drainage ditches in the Fens, as part of a project run by the University of Cambridge’s Centre for Landscape Regeneration to understand freshwater health in this agricultural landscape.
The research was funded primarily by the Natural Sciences and Engineering Research Council and the European Research Council.
Reference: Tanentzap, A.J. and Fonvielle, J.A: ‘Chemodiversity in freshwater health.’ Science, March 2024. DOI: 10.1126/science.adg8658
Analysing the diversity of organic compounds dissolved in freshwater provides a reliable measure of ecosystem health, say scientists.
EnvironmentfreshwaterJérémy FonvielleTrent UniversityCentre for Landscape RegenerationSchool of the Biological SciencesDepartment of Plant SciencesDepartment of BiochemistryOur technique is a very simple way to get a comprehensive overview of what’s going on in a particular river or lake.Jérémy FonvielleSam WoodmanStudy lake in Norway
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TB vaccine may enable elimination of the disease in cattle by reducing its spread
The research, led by the University of Cambridge and Penn State University, improves prospects for the elimination and control of bovine tuberculosis (TB), an infectious disease of cattle that results in large economic costs and health impacts across the world.
This is the first study to show that BCG-vaccinated cattle infected with TB are substantially less infectious to other cattle. This remarkable indirect effect of the vaccine beyond its direct protective effect has not been measured before.
The spillover of infection from livestock has been estimated to account for about 10% of human tuberculosis cases. While such zoonotic TB (zTB) infections are most commonly associated with gastro-intestinal infections related to drinking contaminated milk, zTB can also cause chronic lung infections in humans. Lung disease caused by zTB can be indistinguishable from regular tuberculosis, but is more difficult to treat due to natural antibiotic resistance in the cattle bacteria.
TB remains endemic in many countries around the world, including in Europe and the Americas, where its control costs farmers and taxpayers hundreds of millions of dollars each year.
The study is published today in the journal Science.
In the study, carried out in Ethiopia, researchers examined the ability of the vaccine, Bacillus Calmette-Guérin (BCG), to directly protect cattle that receive it, as well as to indirectly protect both vaccinated and unvaccinated cattle by reducing TB transmission. Vaccinated and unvaccinated animals were put into enclosures with naturally infected animals, in a novel crossover design performed over two years.
“Our study found that BCG vaccination reduces TB transmission in cattle by almost 90%. Vaccinated cows also developed significantly fewer visible signs of TB than unvaccinated ones. This suggests that the vaccination not only reduces the progression of the disease, but that if vaccinated animals become infected, they are substantially less infectious to others,” said Andrew Conlan, Associate Professor of Epidemiology at the University of Cambridge’s Department of Veterinary Medicine and a corresponding author of the study.
Using livestock census and movement data from Ethiopia, the team developed a transmission model to explore the potential for routine vaccination to control bovine tuberculosis.
“Results of the model suggest that vaccinating calves within the dairy sector of Ethiopia could reduce the reproduction number of the bacterium — the R0 — to below 1, arresting the projected increase in the burden of disease and putting herds on a pathway towards elimination of TB,” Conlan said.
The team focused their studies in Ethiopia, a country with the largest cattle herd in Africa and a rapidly growing dairy sector that has a growing burden of bovine tuberculosis and no current control program, as a representative of similarly situated transitional economies.
“Bovine tuberculosis is largely uncontrolled in low- and middle-income countries, including Ethiopia,” said Abebe Fromsa, associate professor of agriculture and veterinary medicine at Addis Ababa University in Ethiopia and the study’s co-lead author. “Vaccination of cattle has the potential to provide significant benefits in these regions.”
“For over a hundred years, programs to eliminate bovine tuberculosis have relied on intensive testing and slaughtering of infected animals,” said Vivek Kapur, professor of microbiology and infectious diseases and Huck Distinguished Chair in Global Health at Penn State and a corresponding author of the study.
He added: “This approach is unimplementable in many parts of the world for economic and social reasons, resulting in considerable animal suffering and economic losses from lost productivity, alongside an increased risk of spillover of infection to humans. By vaccinating cattle, we hope to be able to protect both cattle and humans from the consequences of this devastating disease.”
Professor James Wood, Alborada Professor of Equine and Farm Animal Science in the University of Cambridge’s Department of Veterinary Medicine, noted that despite TB being more prevalent in lower-income countries, the United Kingdom, Ireland and New Zealand also experience considerable economic pressures from the disease which continues to persist despite intensive and costly control programs.
Wood said: “For over twenty-years the UK government has pinned hopes on cattle vaccination for bovine tuberculosis as a solution to reduce the disease and the consequent costs of the controls. These results provide important support for the epidemiological benefit that cattle vaccination could have to reduce rates of transmission to and within herds.”
This research was supported by The Bill & Melinda Gates Foundation, as well as the Biotechnology and Biological Sciences Research Council; Foreign, Commonwealth and Development Office; Economic & Social Research Council; Medical Research Council; Natural Environment Research Council; and Defence Science & Technology.
Reference: Fromsa, A. et al: ‘BCG vaccination of cattle reduces transmission of bovine tuberculosis, improving the prospects for elimination.’ Science, March 2024. DOI: 10.1126/science.adl3962
Vaccination not only reduces the severity of TB in infected cattle, but reduces its spread in dairy herds by 89%, research finds.
Infectious diseasesAndrew ConlanJames WoodPenn State UniversityDepartment of Veterinary MedicineCambridge Infectious DiseasesWolfson CollegeSchool of the Biological SciencesOur study suggests that vaccination not only reduces the progression of the disease, but that if vaccinated animals become infected, they are substantially less infectious to others.Andrew ConlanGetty/ kamisokaHerd of cows in a grassy field
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‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention
Everyone has BRCA1 and BRCA2 genes, but mutations in these genes - which can be inherited - increase the risk of breast and ovarian cancer.
The study found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer.
This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such scale - normally these cells are only found in late-stage tumours.
The results raise the possibility of using existing immunotherapy drugs as early intervention to prevent breast cancer developing, in carriers of BRCA1 and BRCA2 gene mutations.
The researchers have received a ‘Biology to Prevention Award’ from Cancer Research UK to trial this preventative approach in mice. If effective, this will pave the way to a pilot clinical trial in women carrying BRCA gene mutations.
“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells - which in turn seem to be working to keep these immune cells at bay,” said Professor Walid Khaled in the University of Cambridge’s Department of Pharmacology and Wellcome-MRC Cambridge Stem Cell Institute, senior author of the report.
He added: “We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.
“Drugs already exist that can overcome this block in immune cell function, but so far, they’ve only been approved for late-stage disease. No-one has really considered using them in a preventative way before.”
The results are published today in the journal Nature Genetics.
Risk-reducing surgery, in which the breasts are removed, is offered to those at increased risk of breast cancer. This can be a difficult decision for young women to make and can have a significant effect on body image and sexual relationships.
“The best way to prevent breast cancer is to really understand how it develops in the first place. Then we can identify these early changes and intervene,” said Khaled.
He added: “Late-stage breast cancer tends to be very unpredictable and hard to manage. As we make better and better drugs, the tumours just seem to find a way around it.”
Using samples of healthy breast tissue collected from 55 women across a range of ages, the researchers catalogued over 800,000 cells - including all the different types of breast cell.
The resulting Human Breast Cell Atlas is now available as a resource for other researchers to use and add to. It contains huge amounts of information on other risk factors for breast cancer including Body Mass Index (BMI), menopausal status, contraceptive use and alcohol consumption.
“We've found that there are multiple breast cell types that change with pregnancy, and with age, and it’s the combination of these effects - and others - that drives the overall risk of breast cancer,” said Austin Reed, a PhD student in the University of Cambridge’s Department of Pharmacology and joint first author of the report.
He added: “As we collect more of this type of information from samples around the world, we can learn more about how breast cancer develops and the impact of different risk factors - with the aim of improving treatment.”
One of the biggest challenges in treating breast cancer is that it is not just one disease, but many. Many different genetic variations can lead to breast cancer, and genetic risk interacts with other risk factors in complicated ways.
For example, it is known that the likelihood of breast cancer increases with age, but this risk is greatly reduced by pregnancy early in life. And age-associated risk is greatly increased in carriers of the breast cancer genes BRCA1 and BRCA2.
The new study aimed to understand how some of these risk factors interact, by characterising the different cell types in the human breast under many different physiological states.
The researchers used a technique called ‘single cell RNA-sequencing’ to characterise the many different breast cell types and states. Almost all cells in the body have the same set of genes, but only a subset of these are switched on in each cell – and these determine the cell’s identity and function. Single cell RNA-sequencing reveals which genes are switched on in individual cells.
“Breast cancer occurs around the world, but social inequalities mean not everyone has access to treatment. Prevention is the most cost-effective approach. It not only tackles inequality, which mostly affects low-income countries, but also improves disease outcome in high-income countries,” said Dr Sara Pensa, Senior Research Associate in the University of Cambridge’s Department of Pharmacology and joint first author of the study.
Breast tissue samples were provided by the Breast Cancer Now tissue bank.
The research was primarily funded by the Medical Research Council and Cancer Research UK.
Reference: Reed, A.D. et al: ‘A human breast cell atlas enables mapping of homeostatic cellular shifts in the adult breast.’ Nature Genetics, March 2024. DOI: 10.1038/s41588-024-01688-9
Researchers at the University of Cambridge have created the world’s largest catalogue of human breast cells, which has revealed early cell changes in healthy carriers of BRCA1 and BRCA2 gene mutations.
breast cancerCancerWalid KhaledSara PensaAustin ReedBreast Cancer NowDepartment of PharmacologyWellcome-MRC Cambridge Stem Cell InstituteCRUK Cambridge InstituteMagdalene CollegeSchool of the Biological SciencesWe’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.Walid KhaledAngiola Harry on UnsplashWoman holds pink breast cancer awareness ribbon. Credit angiola-harry-unsplash
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Clinical trial underway to treat ultra-rare genetic disease with possible link to leader of mutiny on the Bounty
A clinical trial to look at repurposing the UK-licensed medicine deferiprone for patients with the ultra-rare genetic disease neuroferritinopathy has launched today at the University of Cambridge.
Neuroferritinopathy is a progressive and incurable brain disorder caused by changes in a gene that produces a specific protein - ferritin light chain protein. This change leads to the build-up of iron in the brain. The disease usually appears in middle-aged adults and causes severe symptoms that impact on day-to-day life, eventually resulting in the loss of speech and swallowing. There are currently no effective treatments.
Funded by LifeArc, the new randomised placebo-controlled trial - DefINe - will be led by Professor Patrick Chinnery from the Department of Clinical Neurosciences. It aims to stop the progression of the disease by reducing the iron accumulation in the brain with an existing drug called deferiprone. Deferiprone is an affordable oral tablet that is already licensed for use in the UK to reduce iron levels in blood conditions like thalassemia. If successful, the trial could also open the possibility of deferiprone being used for other neurodegenerative conditions linked with build-up of iron the brain.
Professor Chinnery said: “Neuroferritinopathy leads to severe disability and currently has no cure. The DefINe trial will show whether we can stop the disease in its tracks by pulling iron out of the brain using a well-known medicine called deferiprone.
“By funding this study, LifeArc has given the first hope of a treatment for affected families. If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.”
Neuroferritinopathy affects approximately 100 patients worldwide. Initial discovery of the condition came when a surprising number of individuals diagnosed found to live in the Lake District in Cumbria experienced similar symptoms with a series of incorrect diagnoses. Research into the ancestry of these families by Professor John Burn, a clinical geneticist at Newcastle Hospitals NHS Foundation Trust, discovered the genetic commonality and also found an interesting potential link to the past.
Professor Burn found that a rare mutation caused the progression of the condition and almost all the known cases were likely to be descended from the same ancestor. He traced it back to the 18th Century in Cockermouth in Cumbria and families with the surname Fletcher. Professor Burn suggested they could have shared common ancestry with Fletcher Christian (Fletcher being his surname), known for leading the mutiny on the Bounty in April 1789, given he was also from the region.
The DefINe trial will involve 40 patients taking the drug for a year, who will undergo state-of-the-art 7T magnetic resonance imaging (MRI) scanning to monitor the iron levels in the brain throughout. The evidence collected will form the basis of an application for licensing in the UK under ‘Exceptional Circumstances’, which is often used for rare conditions where the number of people affected is low. This means, if the trial is successful the drug could go on to benefit all people with the condition more quickly.
Samantha Denison, a patient hoping to participate in the trial, said: “It came as such a surprise to be informed of the trial and to learn that we have not been forgotten about. To have the chance to be involved in the trial gives me such hope. If it can help to slow or stop the condition progressing, that would be a huge relief. Just to know that by taking part we could also be helping future generations, is amazing.”
LifeArc has contributed £750,000 to the project and Lipomed, a Swiss life sciences company, has offered to provide both a cost-effective generic form of deferiprone, Deferiprone Lipomed, and a placebo to the trial – a Gift in Kind worth £250,000.
Dr Catriona Crombie, Head of LifeArc’s Rare Disease Translational Challenge, said: “Drug repurposing trials like this are an increasingly effective way of taking treatments that have already been approved and applying them to new conditions and diseases. This will help unlock new treatments for conditions that currently have few, if any, available."
Dr Chantal Manz, Chief Scientific Officer Lipomed AG, Switzerland, said: “Lipomed is very excited to support this promising study concept in patients with neuroferritinopathy, by providing deferiprone 500 mg film-coated tablets and matching placebo tablets. We recognise the unmet clinical need and the potentially significant benefit of this orally active iron chelator. Deferiprone is able to penetrate the blood-brain barrier and may reduce cerebral iron accumulation in patients with this extremely rare, but devastating genetic neurodegenerative disorder, for which no alternative treatments are available.”
Adapted from a press release by LifeArc.
neurodegenerationPatrick ChinneryNewcastle Hospitals NHS Foundation TrustLifeArcLipomed AGDepartment of Clinical NeurosciencesSchool of Clinical MedicineCambridge NeuroscienceIf successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.Patrick Chinnery Patrick Chinnery looks at brain scans
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Fish fed to farmed salmon should be part of our diet, too, study suggests
Scientists found that farmed salmon production leads to an overall loss of essential dietary nutrients. They say that eating more wild ‘feed’ species directly could benefit our health while reducing aquaculture demand for finite marine resources.
Researchers analysed the flow of nutrients from the edible species of wild fish used as feed, to the farmed salmon they were fed to. They found a decrease in six out of nine nutrients in the salmon fillet – calcium, iodine, iron, omega-3, vitamin B12 and vitamin A, but increased levels of selenium and zinc.
Most wild ‘feed’ fish met dietary nutrient recommendations at smaller portion sizes than farmed Atlantic salmon, including omega-3 fatty acids which are known to reduce the risk of cardiovascular disease and stroke.
“What we’re seeing is that most species of wild fish used as feed have a similar or greater density and range of micronutrients than farmed salmon fillets,” said lead author, Dr David Willer, Zoology Department, University of Cambridge.
“Whilst still enjoying eating salmon and supporting sustainable growth in the sector, people should consider eating a greater and wider variety of wild fish species like sardines, mackerel and anchovies, to get more essential nutrients straight to their plate.”
In the UK, 71% of adults have insufficient vitamin D in winter, and teenage girls and women often have deficiencies of iodine, selenium and iron. Yet while, 24% of adults ate salmon weekly, only 5.4% ate mackerel, 1% anchovies and just 0.4% herring.
“Making a few small changes to our diet around the type of fish that we eat can go a long way to changing some of these deficiencies and increasing the health of both our population and planet,” said Willer.
The researchers found consuming one-third of current food-grade wild feed fish directly would be the most efficient way of maximising nutrients from the sea.
“Marine fisheries are important local and global food systems, but large catches are being diverted towards farm feeds. Prioritising nutritious seafood for people can help improve both diets and ocean sustainability,” said senior author Dr James Robinson, Lancaster University.
This approach could help address global nutrient deficiencies say the team of scientists from the University of Cambridge, Lancaster University, University of Stirling and the University of Aberdeen.
The study was published today in the journal, Nature Food.
The scientists calculated the balance of nutrients in edible portions of whole wild fish, used within pelleted salmon feed in Norway, compared to the farmed salmon fillets.
They focused on nine nutrients that are essential in human diets and concentrated in seafood – iodine, calcium, iron, vitamin B12, vitamin A, omega-3 (EPA + DHA), vitamin D, zinc and selenium.
The wild fish studied included Pacific and Peruvian anchoveta, and Atlantic herring, mackerel, sprat and blue whiting – which are all marketed and consumed as seafood.
They found that these six feed species contained a greater, or similar, concentration of nutrients as the farmed salmon fillets. Quantities of calcium were over five times higher in wild feed fish fillets than salmon fillets, iodine was four times higher, and iron, omega-3, vitamin B12, and vitamin A were over 1.5 times higher.
Wild feed species and salmon had comparable quantities of vitamin D.
Zinc and selenium were found to be higher in salmon than the wild feed species – the researchers say these extra quantities are due to other salmon feed ingredients and are a real mark of progress in the salmon sector.
“Farmed salmon is an excellent source of nutrition, and is one of the best converters of feed of any farmed animal, but for the industry to grow it needs to become better at retaining key nutrients that it is fed. This can be done through more strategic use of feed ingredients, including from fishery by-products and sustainably-sourced, industrial-grade fish such as sand eels”, said Dr Richard Newton of the Institute of Aquaculture, University of Stirling, whose team also included Professor Dave Little, Dr Wesley Malcorps and Björn Kok.
“It was interesting to see that we’re effectively wasting around 80% of the calcium and iodine from the feed fish – especially when we consider that women and teenage girls are often not getting enough of these nutrients”.
Willer said “These numbers have been underacknowledged by the aquaculture industry’s standard model of quoting Fish In Fish Out (FIFO) ratios rather than looking at nutrients.
The researchers would like to see a nutrient retention metric adopted by the fishing and aquaculture industries. They believe that if combined with the current FIFO ratio, the industry could become more efficient, and reduce the burden on fish stocks that also provide seafood. The team are building a standardised and robust vehicle for integrating the nutrient retention metric into industry practice.
“We’d like to see the industry expand but not at a cost to our oceans,” said Willer.
“We’d also like to see a greater variety of affordable, convenient and appealing products made of wild ‘feed’ fish and fish and salmon by-products for direct human consumption.”
The research was funded by the Scottish Government’s Rural and Environmental Science and Analytical Services Division (RESAS), a Royal Society University Research Fellowship, a Leverhulme Trust Early Career Fellowship a Henslow Fellowship at Murray Edwards College and the University of Cambridge.
Reference: D. Willer et al. Wild fish consumption can balance nutrient retention in farmed fish Nature Food DOI: 10.1038/s43016-024-00932-z
The public are being encouraged to eat more wild fish, such as mackerel, anchovies and herring, which are often used within farmed salmon feeds. These oily fish contain essential nutrients including calcium, B12 and omega-3 but some are lost from our diets when we just eat the salmon fillet.
sustainabilityfishingGlobal food securityDavid WillerZoology DepartmentSchool of the Biological SciencesMaking a few small changes to our diet around the type of fish that we eat can go a long way to changing some of these deficiencies and increasing the health of both our population and planet Dr David Willer, Zoology DepartmentJoff Lee / The Image Bank / Getty Mackerel with potato salad
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AI predicts healthiness of food menus
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AI predicts healthiness of food menus
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AI predicts healthiness of food menus
Study highlights ‘double burden’ of unhealthy food environment in deprived areas
By Craig Brierley
Published 8 March 2024
Cambridge researchers have used artificial intelligence to predict the healthiness of café, takeaway and restaurant menus at outlets across Britain and used this information to map which of its local authorities have the most and least healthy food environments.The findings, published in Health & Place, highlight the double burden faced by people living in the most deprived areas, where there tend to be more food outlets per capita – more than double the number in the least deprived areas – and these outlets tend to be less healthy.
‘Out-of-home’ food – whether that’s food eaten in a pub, café or restaurant or takeaway food – is an increasing part of how many people eat. But this food tends to be higher in calories, saturated fat and salt and less nutritious than food prepared at home.
Studies have shown consistently that the more an individual eats food out of home – especially fast food – the poorer the quality of their diet and the higher their body weight. In the UK, there also tend to be more fast food outlets in more deprived neighbourhoods.
Not all menus are equal, however – some will be healthier than others – but little is known about whether there are differences between neighbourhoods in the healthiness of out-of-home food outlets.
“Given the link between the food environment and diet, it’s important to understand how healthy this environment is at a local level. This will empower local authorities to take action to try and improve the consumer food environment.”Yuru Huang, a Gates Cambridge Scholar at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge
To explore this, Huang and colleagues examined menus from almost 55,000 food outlets on Just Eat, an online food ordering and delivery platform. Each outlet’s menu was given a healthiness score of 0-12 (with 12 being the healthiest) based on a number of factors including: the number of special offers (such as meal deals or family meals), desserts, salads, chips, milk, water, and the diversity of vegetables.
As not every food outlet is on Just Eat, the team turned to an artificially-intelligent ‘deep learning’ model, trained on a subset of Just Eat data, to predict menu healthiness of every out-of-home food outlet in Britain – a total of almost 180,000 outlets. These outlets were classified into four categories:
- cafés, snack bars, and tea rooms
- fast food and takeaways
- pubs, bars, and inns
- restaurants
The only information available for all out-of-home food outlets were the outlets’ names and hygiene ratings. When the team tested their model, they found that the outlet’s name was the best at predicting the healthiness of its menu.
While the complexities of menu healthiness cannot be accurately captured by name only, the researchers validated their results against a different set of test data from Just Eat to that used in the model training, and against real menus from outlets in Cambridge and Peterborough to demonstrate that the model works.
Restaurants were found, on average, to have the healthiest menus, followed by: cafes, snack bars, and tea rooms; pubs, bars, and inns; and lastly fast food and takeaways.
The team used geographical data to map the food outlets, summarising the average menu healthiness of all out-of-home food outlets at the local authority level. Local authority districts with the highest menu healthiness scores included City of London, Kensington and Chelsea, and Westminster. The local authority districts with the lowest menu healthiness scores were Northeast Lincolnshire, Luton, and Kingston upon Hull.
The researchers found that, in general, the higher the level of deprivation in an area, the lower the average menu healthiness across its out-of-home food outlets – and all four categories of food outlets tended to be less healthy in more deprived areas.
Not only that, but out-of-home food outlets also tended to cluster in more deprived areas. In the most deprived areas, there were 8.39 food outlets per 1,000-3,000 people, compared to just 3.85 in the least deprived areas.
“There’s a clear pattern between the healthiness of menus at out-of-home food outlets in an area and its level of deprivation. This can create a ‘double burden’ for people living in deprived neighbourhoods, where there are more outlets and these tend to be less healthy, compared to less deprived neighbourhoods."Yuru Huang
“On top of this, there are studies that show, for example, that people with the lowest income were more likely to be obese when living in areas with a high proportion of fast-food outlets. This could even create a ‘triple burden’ for people living in these areas.”
The researchers acknowledge that the menu healthiness score does not capture the intricate nuances of the menu, such as portion size, cooking methods, and levels of food processing. This could be important, as interventions such as healthy catering awards introduced by local government focus on aspects like smaller portion sizes, reducing salt, and switching cooking oils.
This work was supported by the Medical Research Council and Gates Cambridge.
Reference
Huang, Y et al. Assessing the healthiness of menus of all out-of-home food outlets and its socioeconomic patterns in Great Britain. Health & Place; 5 Dec 2023 ; DOI: 10.1016/j.healthplace.2023.103146
Images
- Woman using a food delivery app on her mobile phone (David Espejo/Getty Images)
- Woman serving a customer in a takeaway outlet (SolStock/Getty Image)
- Person eating sushi (Betsai Ekmeiro)
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TopBuilt with Shorthand { setTimeout(() => { document.querySelectorAll('#main a').forEach(link => link.classList.remove('campl-external')); }, 2050); }); //--> Summary:Cambridge researchers have used artificial intelligence to predict the healthiness of café, takeaway and restaurant menus at outlets across Britain and used this information to map which of its local authorities have the most and least healthy food environments.
Image: Affiliation (schools and institutions): School of Clinical MedicineMedical Research Council (MRC) Epidemiology UnitCambridge Public HealthExternal Affiliations: Medical Research CouncilGates Cambridge TrustPeople (our academics and staff): Jean AdamsYuru HuangSection: ResearchSuper Tags: Health and medicineShorthand Story Description/Subtitle: Study highlights ‘double burden’ of unhealthy food environment in deprived areasShorthand Story Thumbnail: https://www.cam.ac.uk/sites/www.cam.ac.uk/files/shorthand/244861/UFAfrQs7nX/assets/ha6yCgV8pC/gettyimages-2005442904-land-thumbnail.jpgGenetic mutation in a quarter of all Labradors hard-wires them for obesity
This obesity-driving combination means that dog owners must be particularly strict with feeding and exercising their Labradors to keep them slim.
The mutation is in a gene called POMC, which plays a critical role in hunger and energy use.
Around 25% of Labradors and 66% of flatcoated retriever dogs have the POMC mutation, which researchers previously showed causes increased interest in food and risk of obesity.
The new study reveals how the mutation profoundly changes the way Labradors and flatcoated retrievers behave around food. It found that although they don’t need to eat more to feel full, they are hungrier in between meals.
In addition, dogs with the POMC mutation were found to use around 25% less energy at rest than dogs without it, meaning they don’t need to consume as many calories to maintain a healthy body weight.
“We found that a mutation in the POMC gene seems to make dogs hungrier. Affected dogs tend to overeat because they get hungry between meals more quickly than dogs without the mutation,” said Dr Eleanor Raffan, a researcher in the University of Cambridge’s Department of Physiology, Development and Neuroscience who led the study.
She added: “All owners of Labradors and flatcoated retrievers need to watch what they’re feeding these highly food-motivated dogs, to keep them a healthy weight. But dogs with this genetic mutation face a double whammy: they not only want to eat more, but also need fewer calories because they’re not burning them off as fast.”
The POMC mutation was found to alter a pathway in the dogs’ brains associated with body weight regulation. The mutation triggers a starvation signal that tells their body to increase food intake and conserve energy, despite this being unnecessary.
The results are published today in the journal Science Advances.
Raffan said: “People are often rude about the owners of fat dogs, blaming them for not properly managing their dogs’ diet and exercise. But we’ve shown that Labradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.”
The researchers say owners can keep their retrievers distracted from this constant hunger by spreading out each daily food ration, for example by using puzzle feeders or scattering the food around the garden so it takes longer to eat.
In the study, 87 adult pet Labrador dogs - all a healthy weight or moderately overweight - took part in several tests including the ‘sausage in a box’ test.
First, the dogs were given a can of dogfood every 20 minutes until they chose not to eat any more. All ate huge amounts of food, but the dogs with the POMC mutation didn’t eat more than those without it. This showed that they all feel full with a similar amount of food.
Next, on a different day, the dogs were fed a standard amount of breakfast. Exactly three hours later they were offered a sausage in a box and their behaviour was recorded. The box was made of clear plastic with a perforated lid, so the dogs could see and smell the sausage, but couldn’t eat it.
The researchers found that dogs with the POMC mutation tried significantly harder to get the sausage from the box than dogs without it, indicating greater hunger.
The dogs were then allowed to sleep in a special chamber that measured the gases they breathed out. This revealed that dogs with the POMC mutation burn around 25% fewer calories than dogs without it.
The POMC gene and the brain pathway it affects are similar in dogs and humans. The new findings are consistent with reports of extreme hunger in humans with POMC mutations, who tend to become obese at an early age and develop a host of clinical problems as a result.
Drugs currently in development for human obesity, underactive sexual desire and certain skin conditions target this brain pathway, so understanding it fully is important.
A mutation in the POMC gene in dogs prevents production of two chemical messengers in the dog brain, beta-melanocyte stimulating hormone (β-MSH) and beta-endorphin, but does not affect production of a third, alpha-melanocyte stimulating hormone (α-MSH).
Further laboratory studies by the team suggest that β-MSH and beta-endorphin are important in determining hunger and moderating energy use, and their role is independent of the presence of α-MSH. This challenges the previous belief, based on research in rats, that early onset human obesity due to POMC mutations is caused only by a lack of α-MSH. Rats don’t produce beta-melanocyte stimulating hormone, but humans and dogs produce both α- and β-MSH.
The research was funded by The Dogs Trust and Wellcome.
Reference: Dittmann, M.T. et al: ‘Low resting metabolic rate and increased hunger due to β-MSH and β-endorphin deletion in a canine model.’ Science Advances, March 2024. DOI: 10.1126/sciadv.adj3823
New research finds around a quarter of Labrador retriever dogs face a double-whammy of feeling hungry all the time and burning fewer calories due to a genetic mutation.
Obesityanimal behaviouranimal healthEleanor RaffanDepartment of Physiology, Development and Neuroscience (PDN)MRC Metabolic Diseases UnitMetabolic Research LaboratoriesWellcome-MRC Institute of Metabolic ScienceNIHR Cambridge Biomedical Research CentreSchool of the Biological SciencesSchool of the Physical SciencesLabradors with this genetic mutation are looking for food all the time, trying to increase their energy intake. It’s very difficult to keep these dogs slim, but it can be done.Eleanor RaffanJane GoodallLabrador retriever dog
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Low iron levels resulting from infection could be key trigger of long COVID
The discovery not only points to possible ways to prevent or treat the condition, but could help explain why symptoms similar to those of long COVID are also commonly seen in a number of post-viral conditions and chronic inflammation.
Although estimates are highly variable, as many as three in 10 people infected with SARS-CoV-2 could go on to develop long COVID, with symptoms including fatigue, shortness of breath, muscle aches and problems with memory and concentration (‘brain fog’). An estimated 1.9 million people in the UK alone were experiencing self-reported long COVID as of March 2023, according to the Office of National Statistics.
Shortly after the start of the COVID-19 pandemic, researchers at the University of Cambridge began recruiting people who had tested positive for the virus to the COVID-19 cohort of the National Institute for Health and Care Research (NIHR) BioResource. These included asymptomatic healthcare staff identified via routine screening through to patients admitted to Cambridge University Hospitals NHS Foundation Trust, some to its intensive care unit.
Over the course of a year, participants provided blood samples, allowing researchers to monitor changes in the blood post-infection. As it became clear that a significant number of patients would go on to have symptoms that persisted – long COVID – researchers were able to track back through these samples to see whether any changes in the blood correlated with their later condition.
In findings published in Nature Immunology, researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, together with colleagues at Oxford, analysed blood samples from 214 individuals. Approximately 45% of those questioned about their recovery reported symptoms of long COVID between three and ten months later.
Professor Ken Smith, who was Director of CITIID at the time of the study and will take up a position as Director of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, in April, said: “Having recruited a group of people with SARS-CoV-2 early in the pandemic, analysis of several blood samples and clinical information collected over a 12 month period after infection has proved invaluable in giving us important and unexpected insights into why, for some unlucky individuals, initial SARS-CoV-2 infection is followed by months of persistent symptoms.”
The team discovered that ongoing inflammation – a natural part of the immune response to infection – and low iron levels in blood, contributing to anaemia and disrupting healthy red blood cell production, could be seen as early as two weeks post COVID-19 in those individuals reporting long COVID many months later.
Early iron dysregulation was detectable in the long COVID group independent of age, sex, or initial COVID-19 severity, suggesting a possible impact on recovery even in those who were at low risk for severe COVID-19, or who did not require hospitalisation or oxygen therapy when sick.
Dr Aimee Hanson, who worked on the study while at the University of Cambridge, and is now at the University of Bristol, said: “Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later.
“Although we saw evidence that the body was trying to rectify low iron availability and the resulting anaemia by producing more red blood cells, it was not doing a particularly good job of it in the face of ongoing inflammation.”
Interestingly, although iron dysregulation was more profound during and following severe COVID-19, those who went on to develop long COVID after a milder course of acute COVID-19 showed similar patterns in the blood. The most pronounced association with long COVID was how quickly inflammation, iron levels and regulation returned to normal following SARS-CoV-2 infection – though symptoms tended to continue long after iron levels had recovered.
Co-author Professor Hal Drakesmith, from the MRC Weatherall Institute of Molecular Medicine at the University of Oxford, said iron dysregulation is a common consequence of inflammation and is a natural response to infection.
“When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It’s an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert.
“However, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. The protective mechanism ends up becoming a problem.”
The findings may help explain why symptoms such as fatigue and exercise intolerance are common in long COVID, as well as in several other post-viral syndromes with lasting symptoms.
The researchers say the study points to potential ways of preventing or reducing the impact of long COVID by rectifying iron dysregulation in early COVID-19 to prevent adverse long-term health outcomes.
One approach might be controlling the extreme inflammation as early as possible, before it impacts on iron regulation. Another approach might involve iron supplementation; however as Dr Hanson pointed out, this may not be straightforward.
“It isn't necessarily the case that individuals don't have enough iron in their body, it's just that it’s trapped in the wrong place,” she said. “What we need is a way to remobilise the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.”
The research also supports ‘accidental’ findings from other studies, including the IRONMAN study, which was looking at whether iron supplements benefited patients with heart failure – the study was disrupted due to the COVID-19 pandemic, but preliminary findings suggest that trial participants were less likely to develop severe adverse effects from COVID-19. Similar effects have been observed among people living with the blood disorder beta-thalassemia, which can cause individuals to produce too much iron in their blood.
The research was funded by Wellcome, the Medical Research Council, NIHR and European Union Horizon 2020 Programme.
Reference
Hanson, AL et al. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Imm; 1 March 2024; DOI: 10.1038/s41590-024-01754-8
Problems with iron levels in the blood and the body’s ability to regulate this important nutrient as a result of SARS-CoV-2 infection could be a key trigger for long COVID, new research has discovered.
COVID-19Ken SmithAimee HansonNIHR BioresourceUniversity of OxfordSchool of Clinical MedicineCambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID)Department of MedicineCambridge University Hospitals NHS Foundation TrustIron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months laterAimee HansonMalachi CowieA man sitting on a couch holding his head in his hands
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NHS trial of sponge-on-a-string test replaces need for endoscopy for thousands of patients
The NHS pilot, which has tested over 8,500 patients with the ‘capsule sponge test’, showed almost eight out of 10 patients who completed a test were discharged without the need for further testing, freeing up endoscopy capacity for higher risk patients and those referred for urgent tests for oesophageal cancer.
The test involves patients swallowing a small capsule-shaped device that contains a tiny sponge that collects cell samples for analysis before being extracted via a string thread attached to the sponge. It has been developed by Professor Rebecca Fitzgerald, Director of the Early Cancer Institute at the University of Cambridge.
Professor Fitzgerald said: “It is very exciting to see the positive results of the NHS England real-world pilot for our capsule-sponge test. This is a major step forward to making this simple test more routinely available outside of clinical trials. Timely diagnosis is vital for improving outcomes for patients.”
Barrett’s oesophagus – a condition affecting the food pipe which can go on to cause oesophageal cancer in some patients – is usually diagnosed or ruled out via endoscopy (a camera test of the food pipe) following a GP referral to a gastroenterologist or other specialist practitioner who can carry out the procedure.
The sponge-on-a-string test being trialled by the NHS can instead be carried out quickly in a short appointment, without the need for sedation.
Amanda Pritchard, NHS chief executive, said: “Thousands of people have now benefitted from this incredibly efficient test on the NHS – while the sponge on a string is small in size, it can make a big difference for patients – they can conveniently fit the test into their day and it can often replace the need for an endoscopy while also helping to reduce waiting lists by freeing up staff and resources.
“The NHS is always striving to adopt the latest innovations and new ways of working that help improve patient experience and increase efficiency simple sponge on a string test is just one example of many pioneering tools we’ve trialled in recent years to help diagnose and treat people sooner.”
In a survey of over 250 patients who had the capsule sponge test, patients often said they would recommend the test to a friend or family member, and 94% of patients reported experiencing only mild or no pain at all.
The NHS began piloting the test during the pandemic when there was increased pressure on services and a growing backlog for endoscopy.
Gastro-oesophageal reflux, also known as acid reflux, is a relatively common condition, affecting around one to two in every ten people to some degree, and some of these people may already have or will develop Barrett’s oesophagus, which is a precursor to oesophageal cancer.
There are around 9,300 new oesophageal cancer cases in the UK every year. The key to saving lives is to detect it an earlier stage of Barrett's oesophagus before it becomes cancerous.
The NHS pilot was launched at 30 hospital sites across 17 areas in England including Manchester, Plymouth, London, Kent and Cumbria. Evaluation of the pilot showed that using capsule sponge was highly cost effective compared to using endoscopy-only for diagnosing patients – saving around £400 per patient.
Patients with positive results from the capsule sponge test who were referred on for an endoscopy had the highest prevalence of Barrett’s oesophagus at 27.2%, compared to zero patients with negative results who completed an endoscopy.
One of the first pilot sites at East and North Hertfordshire NHS Trust has now performed around 1,400 capsule sponge tests – offering to both patients with reflux symptoms via a new consultant led, nurse run early diagnosis service, as well as to patients on an existing Barrett’s surveillance programme.
In the first 1000 patients, the capsule test identified Barrett’s in 6% patients with reflux and found two new cancers and three patients with dysplasia who may have had a longer time to diagnosis otherwise. While 72% reflux patients were discharged back to their GP without the need for an endoscopy.
As of January, 368 patients have had a positive test result of whom about half have confirmed Barrett's oesophagus.
Dr Danielle Morris, a consultant gastroenterologist at East and North Hertfordshire NHS Trust, said: “Using the capsule sponge test as a diagnosis triage tool has had huge benefits for patients, avoiding the need for unnecessary gastroscopy in almost seven out of 10 patients, and helping to reduce endoscopy waiting lists enabling us to prioritise those who really need endoscopy to have it done quickly.
“The test is performed by a single trained practitioner in an outpatient setting, so it is very resource light compared to gastroscopy, and our patients are very supportive of the service – with almost nine in 10 patients preferring the capsule sponge to a gastroscopy.”
Adapted from a press release from NHS England.
A new test to help diagnose a condition that can lead to oesophageal cancer – developed by Cambridge researchers and trialled by the NHS – has reduced the need for invasive endoscopy in thousands of low-risk patients.
Canceroesophageal cancerRebecca FitzgeraldSchool of Clinical MedicineEarly Cancer InstituteCambridge Cancer CentreIt is very exciting to see the positive results of the NHS England real-world pilot for our capsule-sponge testRebecca FitzgeraldCytedCapsule and sponge
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Treating newly-diagnosed Crohn's patients with advanced therapy leads to dramatic improvements in outcomes
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Improving outcomes for Crohn's patients
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Improving outcomes for Crohn's patients
Treating newly-diagnosed patients with advanced therapy leads to dramatic improvements in outcomes
22 February 2024
A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold.The PROFILE trial, led by researchers at the University of Cambridge, involved 386 patients with newly-diagnosed active Crohn’s disease. It sought to test whether a biomarker – a genetic signature – could predict which patients were at greatest risk of relapses of their condition, and to test two different approaches to treating the disease.
Crohn’s disease is a life-long condition characterised by inflammation of the digestive tract. It affects around one in 350 people in the UK. Even at its mildest, it can cause symptoms that have a major impact on quality of life including: stomach pain, diarrhoea, weight loss and fatigue. Typically patients experience ‘flares’ of inflammation, where their condition worsens for a time, producing more symptoms and progressive bowel damage. As many as one in 10 patients will require urgent abdominal surgery to treat their condition within their first year of diagnosis.
Medical illustration of Crohn's Disease (BruceBlaus)
Medical illustration of Crohn's Disease (BruceBlaus)
The PROFILE trial was sponsored by Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge. It recruited from 40 hospitals across the UK and was supported by the National Institute for Health and Care Research (NIHR) Clinical Research Network. The results are published today in The Lancet Gastroenterology and Hepatology.
While the biomarker did not prove useful in selecting treatments for individual patients, a ‘top-down’ treatment strategy involving use of the drug infliximab straight after diagnosis, showed dramatic results.
Infliximab works by blocking a protein found in the body’s immune system, TNF (tumour necrosis factor)-alpha, which plays an important role in inflammation. The drug is administered through regular intravenous infusions directly into the bloodstream or injections under the skin. However, due to historical concerns about cost and side-effects – including an increased risk of infection related to immunosuppression – it is currently only offered when patients experience regular flare-ups that do not respond to less potent treatments.
In the PROFILE trial, patients were assigned at random to one of two treatment groups. Each group was given a different treatment strategy and patients were followed up over the course of a year.
The first group was treated using an ‘accelerated step-up’ approach, which is the conventional treatment strategy used in the UK and across most countries around the world. In this group, patients only started on infliximab if their disease was progressing and not responding to other simpler treatments.
The second group, however, was treated using ‘top-down’ therapy – that is, they were provided with infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.
The results were dramatic: 80% of people receiving the top-down therapy had both symptoms and inflammatory markers controlled throughout the course of the entire year compared to only 15% of people receiving the accelerated step-up therapy.
Two-thirds (67%) of patients in the ‘top-down’ group had no ulcers seen on their endoscopy camera test at the end of the trial – something known as endoscopic remission. Endoscopic remission is considered very important as this has been consistently associated with decreased risk of later complications in Crohn’s disease. Most previous clinical trials of therapies have been considered highly successful based on getting 20 to 30% of patients into endoscopic remission.
As well as these findings, patients in the top-down arm also had higher quality of life scores, less use of steroid medication and lower number of hospitalisations.
Strikingly, while around one in 20 patients (5%) in the conventional treatment arm of the trial required urgent abdominal surgery for their Crohn's disease, only one in 193 (0.5%) receiving the ‘top-down’ therapy required such surgery.
Dr Nuru Noor from the Department of Medicine at the University of Cambridge, one of the study’s lead researchers and first author of the trial, said: “Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore ‘good enough’. But our findings redefine what should be considered early treatment.
“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has likely been ticking for some time – in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible."
Dr Nuru Noor
"We’ve shown that by treating earlier, we can achieve better outcomes for patients than have previously been reported.”
In fact, say the researchers, the improvements seen among the trial patients receiving ‘top-down’ therapy might be even more stark compared to usual clinical care. Few patients with Crohn’s disease in standard clinical care receive the rapid, ‘accelerated step-up’ approach provided by the trial protocol, and so the benefits of implementing a ‘top-down’ approach in standard clinical care might be even more pronounced.
Crucially, the team found no difference in risk of serious infection between treatment strategies, suggesting that infliximab straight after diagnosis was well tolerated, contrary to previous concerns about its safety. In addition, the cost of the drug, which is now an off-patent, generic and ‘biosimilar' medicine, has fallen considerably from around £15,000 to around £3,000 per patient per year.
Chief Investigator of the PROFILE trial Professor Miles Parkes, Director of the NIHR Cambridge Biomedical Research Centre, said: “Up until now, the view has been ‘Why would you use a more expensive treatment strategy and potentially over-treat people if there's a chance they might do fine anyway?’
“As we’ve shown, and as previous studies have demonstrated, there’s actually a pretty high risk that an individual with Crohn’s disease will experience disease flares and complications even in the first year after diagnosis.
“We now know we can prevent the majority of adverse outcomes, including need for urgent surgery, by providing a treatment strategy that is safe and becoming increasingly affordable."
"If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer ‘top-down’ therapy straight after diagnosis rather than having to wait and use ‘step-up’ treatment.”
Professor Miles Parkes
The PROFILE team are now actively working on an analysis of the health economics to see whether the benefits of the therapy outweigh its cost.
Professor Parkes added: “It's not just those five per cent of people requiring surgery that we need to think about. In the ‘step-up’ arm lots of people experienced disease flares without necessarily needing surgery. And every time somebody flares, they require several consultations with specialist doctors and nurses, clinical investigations such as scans and colonoscopies, time off work, time out of education and so on – all leading to major impacts on quality of life for individuals.”
While there are other anti-TNF drugs, such as adalimumab, that work in a similar manner to infliximab and are significantly cheaper, more research is required to understand if it would be as clinically effective.
Ruth Wakeman, Director of Services, Advocacy & Evidence at Crohn’s & Colitis UK said: “Crohn’s Disease affects over 200,000 people in the UK and we know that many of them have symptoms for a long time before they are diagnosed. But diagnosis is not the end of their journey, and the trial and error involved in finding the right treatment can be challenging and distressing.
“This study shows what a dramatic difference early treatment with advanced therapy can make to newly-diagnosed patients. People with Crohn’s don’t want to be stuck in hospital or having surgery, they want to be out in the world, living their lives. Anything that speeds up the path to remission can only be a good thing.”
“If the drug had been offered in the first place, things could have been very different.”Toby Moore (Credit: Mark Danson)
Toby Moore (Credit: Mark Danson)
Toby Moore, 28, was just ten years old when it became clear there was something wrong.“I was at primary school at the time and was getting lots of abdominal pain, lots of going to the toilet and vomiting, low energy levels – I was effectively unable to consume any food or drink without some kind of problem. It was just terrible.”
He visited the GP repeatedly over six months, where among other things he was told it was due to the stress of Year Six exams. He says that for his mother and father, it was probably the most challenging time of their lives as parents.
“I was eventually referred to a paediatric gastroenterologist specialist who within 30 seconds of looking at me said, ‘Right. I think you have Crohn's disease. I'd like to do these tests,’ and off we went.”
The specialist was correct. He put Toby on an ‘elemental diet’ to manage his condition, which meant that for six weeks he could eat no food or drinks (other than water), only prescription shakes aimed at allowing his digestive system to heal. Toby then had to reintroduce different foods into his diet to see if they could identify what triggered his condition.
Not long afterwards, he had a ‘flare up’, with his symptoms worsening significantly. His local Peterborough hospital was unable to help and so he was referred to the Royal Free Hospital in London. There, his parents had to make the difficult decision of whether he should receive abdominal surgery or go onto biologic medication. They chose the latter, and Toby was put on infliximab.
“If you asked my parents now, they'd call it a light switch drug. I was infused with it on a Thursday and by the Sunday I was a different person. I was eating, drinking, my symptoms had stopped. It was unbelievable. Arguably, if that had been offered in the first place instead of the lighter approach, things could have been very different.”
Toby was on infliximab for several years, but was taken off the drug in late secondary school when he became unwell – “not in a Crohn's disease way, something else was going on”. He was taken into hospital, where the doctors immediately stopped the treatment, concerned it was a trigger.
Toby was transferred to Addenbrooke’s Hospital, where Dr Miles Parkes took over his treatment. It turned out that Toby also had large vessel vasculitis, another autoimmune condition. Whereas Crohn’s affects your digestive system, this affects blood vessels. It causes the aorta, the main blood vessel in your body, to become narrowed, which causes symptoms including weight loss, unexplained lower back pain and fatigue.
Since then, Toby has been on a number of different biologic treatments, each working for a while before their effects wear off, he experiences another flare up, and is prescribed a different drug. Were it not for the drugs, he says his life would be very different.
“It can be quite debilitating, especially when it's flaring up, as I'm sure you can imagine, when you have minimal control over certain bodily functions. It's not the most pleasant.”
His current medication, upadacitinib, involves taking a daily pill. It has helped him manage his condition – flare ups aside – allowing him to live a relatively normal life, hold down a steady job as a chef in a local hospice , close to where he lives, and start a family. But he still has to be very careful.
“Where possible I try to avoid stressful situations that life throws at you. When you live at your mum and dad's life's a bit more simple, you've got a few less responsibilities, so stress is slightly less, but when you go out into the big wide world – and I've got a two-and-a-half year old daughter now – that obviously adds a new dynamic to your life!”
Toby has nothing but praise for the NHS. “They’ve been just phenomenal. Miles is very good at nipping things in the bud straight away. He always actions things, he doesn't just say, ‘Well, we'll see how you are in a month’. So it never gets too out of control.
"My opinion of the NHS is really, really high. They've been a lifeline for me.”
Toby Moore
The research was funded by Wellcome and PredictImmune Ltd and supported by the NIHR Cambridge Biomedical Research Centre.
Reference
Noor NM, Lee JC, Bond S, et al. PROFILE: a multi-centre, randomised, open-label, biomarker-stratified clinical trial of treatment strategies for patients with newly-diagnosed Crohn’s disease. Lancet Gastroenterol Hepatol; 22 Feb 2024; DOI: 10.1016/S2468-1253(24)00034-7
Main image: Crohn's disease illustration (SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY)
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold.
Image: Affiliation (schools and institutions): School of Clinical MedicineDepartment of MedicineNIHR Cambridge Biomedical Research CentreExternal Affiliations: NIHR Cambridge Biomedical Research CentreWellcomePredictImmunePeople (our academics and staff): Nuru NoorMiles ParkesSubject (including Spotlight on ... where applicable): Crohn's diseaseStoriesSection: ResearchSuper Tags: Health and medicineShorthand Story Description/Subtitle: Treating newly-diagnosed patients with advanced therapy leads to dramatic improvements in outcomesShorthand Story Thumbnail: https://www.cam.ac.uk/sites/www.cam.ac.uk/files/shorthand/244621/MATQxWmsAi/assets/19k40RASYR/gettyimages-1683230459-land-thumbnail.jpgLong COVID linked to persistently high levels of inflammatory protein: a potential biomarker and target for treatments
A University of Cambridge-led study identifies the protein interferon gamma (IFN-γ) as a potential biomarker for Long COVID fatigue and highlights an immunological mechanism underlying the disease, which could pave the way for the development of much needed therapies, and provide a head start in the event of a future coronavirus pandemic.
The study, published today in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.
Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still waiting for an effective treatment.
The study shows that initial infection with SARS-CoV-2 triggers production of the antiviral protein IFN-γ, which is a normal reaction from the immune system. For most people, when their infection clears, COVID-19 symptoms cease and production of this protein stops, but the researchers found that high levels of IFN-γ persisted in some Long COVID patients for up to 31 months.
“We have found a potential mechanism underlying Long COVID which could represent a biomarker – that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis,” said co-author, Dr Benjamin Krishna, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).
The research began in 2020 when Dr Nyarie Sithole set up a Long COVID clinic in Cambridge’s Addenbrooke’s Hospital, where he started collecting blood samples from patients and set about studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the University of Cambridge’s Dept. of Medicine.
“When the clinic started, a lot of people didn't even believe Long COVID was real,” Dr Sithole said. “We are indebted to all the patients who volunteered for this study, without whose support and participation we would obviously not have accomplished this study”.
The team studied 111 COVID-confirmed patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days following symptom onset. Between August 2020 and July 2021, they recruited 55 Long COVID patients – all experiencing severe symptoms at least 5 months after acute COVID-19 – attending the Long COVID clinic at Addenbrooke’s.
The researchers analysed blood samples for signs of cytokines, small proteins crucial to the functioning of immune system cells and blood cells. They found that the white blood cells of individuals infected with SARS-CoV-2 produced IFN-γ, a pro inflammatory molecule, and that this persisted in Long COVID patients.
Dr Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C but it causes symptoms including fatigue, fever, headache, aching muscles and depression. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.”
By conducting ‘cell depletion assays’, the team managed to identify the precise cell types responsible for producing IFN-γ. They pinpointed immune cells known as CD8+ T cells but found that they required contact with another immune cell type: CD14+ monocytes.
Previous studies have identified IFN-γ signatures using different approaches and cohorts, but this study’s focus on fatigue revealed a much stronger influence. Also, while previous studies have noticed IFN-y levels rising, they have not followed patients long enough to observe when they might drop back down.
The Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN-γ.
Vaccination helping Long COVID patients
The team measured IFN-γ release in Long COVID patients before and after vaccination and found a significant decrease in IFN-γ post vaccination in patients whose symptoms resolved.
“If SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-γ response, then vaccination may be helping to clear this. But we still need to find effective therapies,” Dr Krishna said.
“The number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that. But new cases are still cropping up, and then there is the big question of what happens when the next coronavirus pandemic comes along. We could face another wave of Long COVID. Understanding what causes Long COVID now could give us a crucial head start.”
Microclotting
Some well-publicised previous studies have proposed microclotting as a principle cause of Long COVID. While not ruling out a role of some kind, these new findings suggest that microclotting cannot be the only or the most significant cause.
Classifying long COVID
This study argues that the presence of IFN-γ could be used to classify Long COVID into subtypes which could be used to personalise treatment.
“It’s unlikely that all the different Long COVID symptoms are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to know why,” Dr Krishna said.
Reference
B. A. Krishna et al., ‘Spontaneous, persistent, T-cell dependent IFN-γ release in patients who progress to long COVID’, Science Advances (2024). DOI: 10.1126/sciadv.adi9379
SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle ache and depression. New research shows that in Long COVID patients, IFN-y production persists until symptoms improve, highlighting a potential biomarker and a target for therapies.
COVID-19Nyarie SitholeBenjamin KrishnaRoyal Papworth Hospital NHS Foundation TrustCambridge and Peterborough NHS Foundation TrustSchool of Clinical MedicineCambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID)Addenbrooke's HospitalSidney Sussex CollegeWe hope that this could help to pave the way to develop therapies and give some patients a firm diagnosisBenjamin KrishnaAnnie Spratt via Unsplashwoman sat on sofa in the dark placing a hand to her forehead
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