Obesity accelerates loss of COVID-19 vaccination immunity, study finds

A new study led by scientists at the Universities of Cambridge and Edinburgh has found the protection offered by COVID-19 vaccination declines more rapidly in people with severe obesity than in those with normal weight. It suggests that people with obesity are likely to need more frequent booster doses to maintain their immunity.

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear.

The study supported by NIHR’s Cambridge BRC, BioResource and Cambridge CRF, shows that the ability of antibodies to neutralise the virus declines faster in vaccinated people who have obesity. The findings have important implications for vaccine prioritisation policies around the world.

During the pandemic, people with obesity were more likely to be hospitalised, require ventilators and to die from COVID-19. In this study, the researchers set out to investigate how far two of the most extensively used vaccines protect people with obesity compared to those with a normal weight, over time.

A team from the University of Edinburgh, led by Professor Sir Aziz Sheikh, looked at real-time data tracking the health of 3.5 million people in the Scottish population as part of the EAVE II study. They looked at hospitalisation and mortality from COVID-19 in adults who received two doses of Covid-19 vaccine (either Pfizer-BioNTech BNT162b2 mRNA or AstraZeneca ChAdOx1).

They found that people with severe obesity (a BMI greater than 40 kg/m²) had a 76% higher risk of severe COVID-19 outcomes, compared to those with a normal BMI. A modest increase in risk was also seen in people with obesity (30-39.9kg/m²), which affects a quarter of the UK population, and those who were underweight. ‘Break-through infections’ after the second vaccine dose also led to hospitalisation and death sooner (from 10 weeks) among people with severe obesity, and among people with obesity (after 15 weeks), than among individuals with normal weight (after 20 weeks).

Professor Sir Aziz Sheikh said: “Our findings demonstrate that protection gained through COVID-19 vaccination drops off faster for people with severe obesity than those with a normal body mass index. Using large-scale data assets such as the EAVE II Platform in Scotland have enabled us to generate important and timely insights that enable improvements to the delivery of COVID-19 vaccine schedules in a post-pandemic UK.”

The University of Cambridge team – jointly led by Dr James Thaventhiran, from the MRC Toxicology Unit and Professor Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge BRC theme lead for Nutrition, Obesity, Metabolism and Endocrinology – studied people with severe obesity attending Addenbrooke’s Hospital in Cambridge, and compared the number and function of immune cells in their blood to those of people of normal weight.

They studied people six months after their second vaccine dose and then looked at the response to a third “booster” vaccine dose over time. The Cambridge researchers found that six months after a second vaccine dose, people with severe obesity had similar levels of antibodies to the COVID-19 virus as those with a normal weight.

But the ability of those antibodies to work efficiently to fight against the virus (known as ‘neutralisation capacity’) was reduced in people with obesity. 55% of individuals with severe obesity were found to have unquantifiable or undetectable ‘neutralising capacity’ compared to 12% of people with normal BMI.

“This study further emphasises that obesity alters the vaccine response and also impacts on the risk of infection,” said Dr Agatha van der Klaauw from the Wellcome-MRC Institute of Metabolic Science and first author of the paper. “We urgently need to understand how to restore immune function and minimise these health risks.”

The researchers found that antibodies produced by people with severe obesity were less effective at neutralising the SARS-CoV-2 virus, potentially because the antibodies were not able to bind to the virus with the same strength.

When given a third (booster) dose of a COVID-19 vaccine, the ability of the antibodies to neutralise the virus was restored in both the normal weight and severely obese groups. But the researchers found that immunity again declined more rapidly in people with severe obesity, putting them at greater risk of infection with time.

Dr James Thaventhiran, a Group Leader from the MRC Toxicology Unit in Cambridge and co-lead author of the SCORPIO study said: “It is promising to see that booster vaccines restore the effectiveness of antibodies for people with severe obesity, but it is concerning that their levels decrease more quickly, after just 15 weeks. This shows that the vaccines work as well in people with obesity, but the protection doesn’t last as long.”

Professor Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science and co-lead author of the SCORPIO study said: “More frequent booster doses are likely to be needed to maintain protection against COVID-19 in people with obesity. Because of the high prevalence of obesity across the globe, this poses a major challenge for health services”.

Reference

A.A. van der Klaauw et al., ‘Accelerated waning of the humoral response to COVID-19 vaccines in obesity’, Nature Medicine (2023). DOI: 10.1038/s41591-023-02343-2

Adapted from University of Cambridge press release

New study recommends replacing skull section after brain bleed treatment

A new trial supported by NIHR Cambridge BRC has found – where possible – surgeons should replace the removed section of the skull following surgery to treat a form of brain bleed. Researchers say the approach will save patients undergoing skull reconstruction further down the line.

NIHR funded and supported the RESCUE-ASDH study. The international randomised trial involved 40 centres in 11 countries and 450 patients took part. The results published at the annual meeting of the American Association of Neurological Surgeons and in the New England Journal of Medicine.

One of the life-threatening results of head injury is acute subdural haematoma – a bleed occurring between the brain and skull. It can lead to the build-up of pressure. These bleeds need surgery to stem the blood flow, remove the blood clot and relieve the pressure.

There are two approaches to such surgery. The first is a decompressive craniectomy – involving leaving a section of the skull out – which can be as large as 13cm in length. This protects the patient from brain swelling, often seen with this injury. Typically the missing skull needs reconstruction. Some treatment centres replace the patient’s own bone several months after surgery. In others, they use a manufactured plate.

The second approach is a craniotomy. The skull section is replaced after the bleed is stemmed and the blood clot removed. This approach prevents the need for a skull reconstruction further down the line.

To date there was little conclusive evidence and no accepted criteria for which approach to use. Researchers at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust launched RESCUE-ASDH to answer this question. Patients were randomly assigned to undergo craniotomy or decompressive craniectomy.

A total of 228 patients underwent craniotomy and 222 decompressive craniectomy. Researchers assessed the outcomes for these patients and their quality of life up to a year after surgery.

Patients in both groups had similar disability-related and quality-of-life outcomes at 12 months post-surgery. There was a trend towards better outcomes with craniotomy.

Around one in four patients (25.6%) in the craniotomy group and one in five (19.9%) in the craniectomy group had a good recovery.

Around one in three patients in both groups (30.2% craniotomy group and 32.2% craniectomy group died within the first 12 months following surgery. 

14.6% of the craniotomy group and 6.9% of the craniectomy group required additional cranial surgery within two weeks after randomisation. However, this was balanced due to fewer people in the first group experienced wound complications (3.9% compared to 12.2%).

The trial’s Chief Investigator Peter Hutchinson, Professor of Neurosurgery at Cambridge, said: “RESCUE-ASDH is the first multicentre study to address a very common clinical question: which technique is optimal for removing an acute subdural haematoma – a craniotomy or a decompressive craniectomy?

 “This was a large trial and the results convincingly show that there is no statistical difference in the 12 month disability-related and quality of life outcomes between the two techniques.”

Co-chief investigator Professor Angelos Kolias, Consultant Neurosurgeon at Cambridge, said: “Based on the trial findings, we recommend that after removing the blood clot, if the bone flap can be replaced without compression of the brain, surgeons should do so, rather than performing a pre-emptive decompressive craniectomy.

 “This approach will save patients from having to undergo a skull reconstruction, which carries the risk of complications and additional healthcare costs, further down the line.”

Professor Andrew Farmer, Director of NIHR’s Health Technology Assessment (HTA) Programme, which funded the study, said: “The findings of this world-leading trial provide important evidence which will improve the way patients with head injuries are treated. 

“High quality, independently funded research like this is vital in providing evidence to improve health and social care practice and treatments. Research is crucial in informing those who plan and provide care.” 

The NIHR Global Health Research Group on Acquired Brain and Spine Injury and the NIHR Clinical Research Network (CRN) supported the study.

The CENTER-TBI project of the European Brain Injury Consortium, and the Royal College of Surgeons of England Clinical Research Initiative supported it too.

Adapted from NIHR release.

Volunteers needed for new needle-free coronavirus vaccine at CRF

Recruitment is underway in Cambridge for volunteers to take part in clinical trials of a revolutionary new needle-free vaccine to protect against COVID-19.

The vaccine – known as DIOS-CoVax – has been developed by Professor Jonathan Heeney at the University of Cambridge and spin-out company DIOSynVax. It is envisaged as a booster targeting COVID-19 virus variants and relatives that threaten future coronavirus pandemics.

This next generation vaccine is administered through a needle-free ‘injection’ – a blast of air that delivers it into the skin. It has already been part of safety trials conducted at the NIHR Southampton Clinical Research Facility, but now recruitment is being expanded and will take place at the NIHR Cambridge Clinical Research Facility.

Professor Heeney said: “We’re excited to be bringing our vaccine ‘home’ and are looking to recruit healthy volunteers to help in this crucial stage of development of what we hope will become a universal coronavirus vaccine.

“Our vaccine is innovative, both in terms of how it aims to protect against the SARS-CoV-2 virus responsible for our current pandemic and future coronaviruses, but also in how it is delivered. If you’re someone who hates needles, our vaccine could be the answer as it’s delivered by a jet of air, not a needle.”

If the clinical trials are successful, the vaccine could be scaled up and manufactured as a powder to boost global vaccination efforts, particularly in low- and middle-income countries.

The clinical trials team at Cambridge University Hospitals NHS Foundation Trust is looking for healthy volunteers aged 18-50 to take part in the study. Volunteers will receive payment for their time, and participation on the trial will last around 12 months with volunteers attending 11 visits. To find out more contact the Project Management Team at cuh.dioscovaxtrial@nhs.net.

Adapted from University of Cambridge press release. Image credit: Lloyd Mann.

Cambridge researchers honoured at Microbiology Society Annual Awards

Congratulations to Professors Sharon Peacock and Ravindra Gupta who received top awards at the Microbiology Society Annual Awards.

The Microbiology Society awards recognise excellence and are made to those making significant contributions in the field of microbiology, based on nominations received from its membership.

Winners are selected for their work to advance understanding of microbiology and champion the contribution made by microbiology and their work in addressing global challenges. 

Professor Sharon Peacock – Marjory Stephenson Prize 2023

Professor Sharon Peacock, Professor of Public Health and Microbiology at the University of Cambridge and researcher at NIHR Cambridge BRC, is an academic clinical microbiologist who has built her scientific expertise around pathogen genomics, antimicrobial resistance and a range of tropical diseases.

She was the founding director of COG-UK (the COVID-19 Genomics UK Consortium), formed in April 2020 to provide SARS-CoV-2 genomes to UK public health agencies, the National Health Service and researchers. Generating information on variants proved vital for their detection and tracking, and for studies of viral transmissibility, immune evasion, and disease severity.  

Professor Peacock has dedicated more than a decade of her career to the translation of pathogen sequencing into clinical and public health microbiology. She has also used sequencing to examine the extent to which antibiotic-resistant organisms can spread between humans, livestock and the environment. Over her career, Professor Peacock has raised more than £60M in science funding, published more than 500 peer-reviewed papers, and trained a generation of scientists in the UK and elsewhere.

She said of the award: “I am honoured to be the 2023 recipient of the Microbiology Society’s Marjory Stephenson Prize. The prize reflects the work of a large number of dedicated people in the COVID-19 Genomics UK Consortium and beyond, who worked voluntarily and tirelessly across the UK to generate SARS-CoV-2 genomes for public health agencies and researchers worldwide during the pandemic. 

“Microbiology has always been a vitally important discipline, but perhaps never more so than in this era of pandemics, antimicrobial resistance and the exploration of our microbiome and how this influences health and disease. I consider the scientific community fortunate in having the benefit of the ongoing contributions made by the Microbiology Society.” 

Professor Ravindra Gupta – Translational Microbiology Prize 2023

Professor Ravindra Gupta, Infectious Disease Threats theme lead at NIHR Cambridge BRC, has been a Professor of Clinical Microbiology at the Cambridge Institute for Therapeutic Immunology and Infectious Diseases since 2019.  

The Gupta lab based there has worked extensively in HIV drug resistance, both at molecular and population levels, and contributed to the appreciation of the scale of drug resistance globally. The group’s work extends to studies on HIV reservoirs in cells, particularly macrophages.

In 2020 Professor Gupta’s team validated and introduced the SAMBA II point of care test into clinical practice at Addenbrooke’s for rapid diagnosis of COVID-19. During the latter half of 2020 the lab started to study the evolution of the virus within patients in response to antibody-based therapies, as a paradigm of how new variants with multiple mutations have arisen.

The team is also characterising the virology of key spike protein mutations in new variants and their impact on natural and vaccine induced immunity. Professor Gupta is a co-opted member of the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG). NERVTAG advises the government on the threat posed by new and emerging respiratory viruses. 

In 2020 Professor Gupta was named as one of the 100 Most influential people by TIME. In 2021 he was elected to Fellowship of the Academy of Medical Sciences and in November 2022 featured in the Clarivate list of the world’s most highly cited scientists. 

He said of the award:  “I am thrilled and honoured to receive the Translational Microbiology Prize from the Microbiology Society. For me, it represents a recognition of the work of my team and our collaborators over the years in applying scientific knowledge to combat viruses such as HIV-1 and SARS-CoV-2. This award from an internationally reputed organisation in infectious diseases also provides impetus to continue our endeavours with ever greater passion and commitment.” 

A big congratulations also to Dr Tanmay Bharat, Programme Leader at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) in Cambridge, who received the Fleming Prize 2023.

This article is adapted from Microbiology.org

Underactive immune response may explain obesity link to COVID-19 severity

Individuals who are obese may be more susceptible to severe COVID-19 because of a poorer inflammatory immune response, say Cambridge scientists.

Scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) and Wellcome Sanger Institute showed that following SARS-CoV-2 infection, cells in the lining of the lungs, nasal cells, and immune cells in the blood show a blunted inflammatory response in obese patients, producing suboptimal levels of molecules needed to fight the infection.

Since the start of the pandemic, there have been almost 760 million confirmed cases of SARS-CoV-2 infection, with almost 6.9 million deaths. While some people have very mild – or even no – symptoms, others have much more severe symptoms, including acute respiratory distress syndrome requiring ventilator support.

One of the major risk factors for severe COVID-19 is obesity, which is defined as a body mass index (BMI) of over 30. More than 40% of US adults and 28% of adults in England are classed as obese.

While this link has been shown in numerous epidemiological studies, until now, it has not been clear why obesity should increase an individual’s risk of severe COVID-19. One possible explanation was thought to be that obesity is linked to inflammation: studies have shown that people who are obese already have higher levels of key molecules associated with inflammation in their blood. Could an overactive inflammatory response explain the connection?

Professor Menna Clatworthy, pictured right, is the Immunity, Inflammation and Transplantation theme lead at NIHR Cambridge BRC and a clinician scientist at the University of Cambridge, studying tissue immune cells at CITIID alongside caring for patients at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust. She said: “During the pandemic, the majority of younger patients I saw on the COVID wards were obese. Given what we know about obesity, if you’d asked me why this was the case, I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite.”

The team analysed blood and lung samples taken from 13 obese patients with severe COVID-19 requiring mechanical ventilation and intensive care treatment, and 20 controls (non-obese COVID-19 patients and ventilated non-COVID-19 patients). These included patients admitted to the Intensive Care Unit at Addenbrooke’s Hospital.

Her team used a technique known as transcriptomics, which looks at RNA molecules produced by our DNA, to study activity of cells in these key tissues. Their results are published in the American Journal of Respiratory and Critical Care Medicine.

Contrary to expectations, the researchers found that the obese patients had underactive immune and inflammatory responses in their lungs.  In particular, when compared to non-obese patients, cells in the lining of their lungs and some of their immune cells had lower levels of activity among genes responsible for the production of two molecules known as interferons (INF) – interferon-alpha and interferon-gamma – which help control the response of the immune system, and of tumour necrosis factor (TNF), which causes inflammation.

When they looked at immune cells in the blood of 42 adults from an independent cohort, they found a similar, but less marked, reduction in the activity of interferon-producing genes as well as lower levels of IFN-alpha in the blood.

Professor Clatworthy said: “This was really surprising and unexpected. Across every cell type we looked at, we found that that the genes responsible for the classical antiviral response were less active. They were completely muted.”

The team was able to replicate its findings in nasal immune cells taken from obese children with COVID-19, where they again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma. This is important because the nose is one of the entry points for the virus – a robust immune response there could prevent the infection spreading further into the body, while a poorer response would be less effective.

One possible explanation for the finding involves leptin, a hormone produced in fat cells that controls appetite. Leptin also plays a role in the immune response: in individuals who are normal weight, levels of the hormone increase in response to infection and it directly stimulates immune cells. But obese people already have chronically higher levels of leptin, and Clatworthy says it is possible that they no longer produce sufficient additional leptin in response to infection, or are insensitive to it, leading to inadequate stimulation of their immune cells.

The findings could have important implications both for the treatment of COVID-19 and in the design of clinical trials to test new treatments.

Because an overactive immune and inflammatory response can be associated with severe COVID-19 in some patients, doctors have turned to anti-inflammatory drugs to dampen this response. But anti-inflammatory drugs may not be appropriate for obese patients.

Co-author Dr Andrew Conway Morris from the Department of Medicine at the University of Cambridge and Honorary Consultant on the intensive care unit at Addenbrooke’s Hospital said: “What we’ve shown is that not all patients are the same, so we might need to tailor treatments. Obese subjects might need less anti-inflammatory treatments and potentially more help for their immune system.”

Clinical trials for potential new treatments would need to involve stratifying patients rather than including both severe and normal weight patients, whose immune responses differ.

The research was largely supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research (NIHR), including via the NIHR Cambridge Biomedical Research Centre.

Paper Reference

Guo, SA, Bowyer, GS, Ferdinand, JR, Maes, M & Tuong, ZK et al. Obesity associated with attenuated tissue immune cell responses in COVID-19. Am J Resp Critical Care Med; 1 Mar 2023; DOI: 10.1164/rccm.202204-0751OC 

Celebrating International Women’s Day 2023

Today marks International Women’s Day, celebrated globally on the 8th March it focuses on highlighting women, calling for equal opportunities and removing discrimination.

The NIHR Cambridge BRC is focusing on three women who make substantial contributions to health research. Click on their profiles below to find out more about their roles and why they believe more women are needed in research.​

”Research is not your average desk job, and the fulfilment the job brings is far greater. So speak to people working in research, and don’t be afraid to ask to shadow in the area, research is fulfilling, motivating and exciting. Never be afraid to try new things!”

Cherry May Sanchez, Team lead and Cancer Research UK Senior Research Nurse.

“If you’re passionate about learning and discovery, then you have what is needed in research. Listen to your heart to choose the subject that captivates and motivates you, since research will present many challenges. And consciously develop a critical thinking and problem-solving approach.”

Ana Toribio, Stratified Medicine Core Laboratory Next Generation Sequencing (SMCL NGS) Hub Manager

“This day is so important because we need to recognise the hard work that women from all over the world, and from all backgrounds, do and achieve in all aspects of their lives, not just in their career.”

Sabine Hein, Senior Study Coordinator, NIHR BioResource

Cambridge Festival 2023

We have two exciting events lined up for this year’s Cambridge Festival – an in-person event at the Cambridge Academy for Science and Technology on 18 March, and five days later, a webinar for 16+ audiences on using health data in research. Find out more on this page!

Discovering research with NIHR Cambridge BRC!

Did you know that medical research is happening all over the Cambridge Biomedical Campus, though you probably won’t ever see it going on!

But behind the scenes, researchers, scientists, doctors, nurses, midwives and other health professionals are working on important research to help sick people get better.

To help you visualise the stages involved, visit us during the Cambridge Festival and take part in our giant board puzzle with places to visit and clues to solve. Prizes for all puzzle-solvers!

This is a free event suitable for all ages, taking place from 11am-4pm on Saturday, 18 March at the Cambridge Academy for Science and Technology in Cambridge. There’s no need to book – just turn up on the day.

Can health data really save lives?

Health data has the potential to drive research that can improve the treatment and diagnosis of illness – but that data ultimately comes from patients, who may have questions and concerns about its use.

So how can researchers work with patients and the public to co-create boundaries and priorities that allow the use of patient data to save and improve lives in a socially acceptable way?

Join NIHR Cambridge BRC Director Prof Miles Parkes, academic consultant neuro-oncologist Dr Raj Jena and Prof Barbara Pierscionek, Deputy Dean (Research & Innovation) at Anglia Ruskin University, as they look at the benefits of using health data for research – and its possible risks.

Joining them for the panel discussion are lay members Caroline Brocklehurst and Helen Street. Caroline is part of the co-creation group providing the patient perspective for the NIHR Cambridge BRC-funded CYNAPSE​ project, which aims to build a secure infrastructure allowing Cambridge-based researchers to accountably and efficiently use health data to support critical studies. Helen has a background in health data governance and an ongoing interest in patient and public engagement with health data research.

Who’s speaking

About this event

This free event is suitable for anyone who wants to find out more about how our health data is being used to advance health research. You could be a member of the public, a student at college or university, a carer, researcher or healthcare professional – come along and join us online.

No scientific or medical background needed – just a curiosity to delve deeper into the topic!

The talks will be followed by a chance to ask the speakers your questions about health data in research.

Can’t make the date? It’s being recorded and will be on the NIHR Cambridge BRC YouTube channel from early April 2023!

Join us on Thursday 23 March 2023 from 7.00pm to 8.30pm – book your free ticket on Eventbrite

Other NIHR events taking place on the campus

Why not explore other events on the Cambridge Biomedical Campus that our partner NIHR organisations are running throughout the Cambridge Festival?

• NIHR BioResource
• NIHR Cambridge Clinical Research Facility
• NIHR Eastern Clinical Research Network
• NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation
• NIHR Blood and Transplant Research Unit in Donor Health and Genomics

The National Institute for Health and Care Research (NIHR) is the UK’s largest funder of health and care research. Its mission – to improve the health and the wealth of the nation through research – is shared across all its constituent programmes, units and centres.

The NIHR Cambridge Biomedical Research Centre (BRC) is based on the Cambridge Biomedical Campus and combines scientific research in world-class institutes, patient care in NHS hospitals, and drug discovery in pharmaceutical companies including AstraZeneca and GlaxoSmithKline.

We reach out to scientists on the Biomedical Campus and beyond to ensure that their discoveries are pulled into the NHS, where clinical researchers can use them, in partnership with the life sciences industry, to improve health.

If you’d like to find out more about how the NIHR works, visit www.nihr.ac.uk. To find out how YOU can be a part of it, go to bepartofresearch.uk.

Major funding for Cambridge will help find new cancer treatments

Clinicians and scientists in Cambridge have today (23 January 2023) welcomed news that the search for new cancer treatments in the city is to receive a major funding investment of around £3 million, providing future hope for people diagnosed with the disease.

Cambridge’s Experimental Cancer Medicine Centre (ECMC) will receive the cash injection over the next five years to help doctors and scientists find the cancer interventions of the future for both adults and children.

The funding has been made possible by a partnership between Cancer Research UK, the National Institute for Health and Care Research (NIHR) and the Little Princess Trust specifically for children’s cancers.

Cambridge is part of a network of 17 ECMCs across the UK, funded by Cancer Research UK, that deliver clinical trials of promising new treatments and work in conjunction with local NHS facilities to provide access to cutting-edge cancer treatments. Testing these treatments helps to establish new ways of detecting and monitoring the disease, and to evaluate how it responds to the treatment.

Since 2012, Cambridge’s ECMC has contributed to the diagnosis and treatment of thousands of people with cancer or at risk of developing cancer in over 230 clinical trials conducted at Cambridge University Hospitals NHS Foundation Trust and supported by the NIHR Cambridge BRC.

The funding will allow new, experimental treatments – including immunotherapies – for a wide variety of cancers to be developed as well as improve existing treatments.

Cambridge ECMC lead Dr Bristi Basu said: “We are delighted that Cambridge has secured this funding.

“It clearly demonstrates recognition of our research excellence in experimental cancer medicine and is a credit to all our research teams working in alliance with our patient and public involvement group, and our academic and industrial partners.

“Clinical trials are crucial to new and improved treatments becoming adopted as standard treatments by the NHS, and this funding will allow us to advance how we can diagnose and treat cancer effectively.

“Over the next five years, we’ll continue to champion experimental medicine studies for patient benefit, across the spectrum of early to advanced disease, supporting translation of basic research to patient-facing trials, so impacting people with cancer in Cambridge and beyond.

“The new Cambridge Cancer Research Hospital opening in 2026/27 will enable even greater ambition in our plans.”

One in two people in the UK will be diagnosed with cancer within our lifetimes*, so finding new effective treatments is vital.

Cancer Research UK has been integral in aiding the discovery of many new cancer treatments such as the drug tamoxifen, for which Cancer Research UK funded phase four clinical trials to validate it as an effective treatment for breast cancer.

Tamoxifen is now a mainstay treatment for people with oestrogen receptor positive breast cancer and appears on the World Health Organisation’s list of essential drugs for the disease.

As a result of tamoxifen, nearly two thirds of people diagnosed with breast cancer this decade are predicted to survive their disease for 20 years or more.

Executive Director of Research and Innovation for Cancer Research UK, Dr Iain Foulkes, said: “We are proud to be supporting an expansion of our successful ECMC network, bringing together vast medical and scientific expertise to translate the latest scientific discoveries from the lab into the clinic.

“The ECMC network is delivering the cancer treatments of the future, bringing new hope to people affected by cancer. The trials taking place today will give the next generation the best possible chance of beating cancer.

“The adult and paediatric ECMC networks will offer clinical trials for many different types of cancer. Researchers will be working to find new treatments and tackle the unique challenges presented by cancers in children and young people. Working with our partners, this new funding will bring hope for more effective, personalised therapies for everyone affected by cancer.”

Chief Executive of the NIHR, Professor Lucy Chappell, said: “The ECMC network is a vital strategic investment in the UK’s cancer research community, bringing together top scientists and clinicians to tackle some of the biggest scientific challenges in cancer and improve outcomes for patients.

“Through this route, we enable more people to join trials that could help them. The ECMC network will give access to brand new experimental treatments for patients, including children and young people, paving the way for these treatments to be used in the clinic one day. This is a crucial part of NIHR’s work and enables more people to join trials that might help them. We are proud to be partnering with Cancer Research UK and the Little Princess Trust in funding this network.

“The UK has considerable strengths in cancer research. We will continue to back life-saving research for the thousands of adult and children patients affected by cancer every year.”

Minister of State for Health, Helen Whately, said: “A cancer diagnosis can be devastating, but the earlier the diagnosis, the better the chance to treat it and beat it. We are already picking up more cancers early by screening, but we can do even better.

“This partnership between Cancer Research UK, the National Institute for Health and Care Research and the Little Princess Trust will fund innovative trials that could lead to new life-saving treatments.

“Every life lost to cancer is devastating and I’m pleased that across the country people will be given renewed hope – especially children and young people – that we can beat this awful disease.”

Artificial pancreas successfully trialled for use by type 2 diabetes patients

Cambridge scientists have successfully trialled an artificial pancreas for use by patients living with type 2 diabetes. The device – powered by an algorithm developed at the University of Cambridge – doubled the amount of time patients were in the target range for glucose and halved the time spent experiencing high glucose levels.

Around 415 million people worldwide are estimated to be living with type 2 diabetes, which costs around $760 billion in annual global health expenditure. According to Diabetes UK, in the UK alone, more than 4.9million people have diabetes, of whom 90% have type 2 diabetes, and this is estimated to cost the NHS £10bn per year.

Type 2 diabetes causes levels of glucose – blood sugar – to become too high. Ordinarily, blood sugar levels are controlled by the release of insulin, but in type 2 diabetes insulin production is disrupted. Over time, this can cause serious problems including eye, kidney and nerve damage and heart disease.

The disease is usually managed through a combination of lifestyle changes – improved diet and more exercise, for example – and medication, with the aim of keeping glucose levels low.

Researchers from the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge and supported by the NIHR Cambridge BRC, have developed an artificial pancreas that can help maintain healthy glucose levels. The device combines an off-the-shelf glucose monitor and insulin pump with an app developed by the team, known as CamAPS HX. This app is run by an algorithm that predicts how much insulin is required to maintain glucose levels in the target range.

The researchers have previously shown that an artificial pancreas run by a similar algorithm is effective for patients living with type 1 diabetes, from adults through to very young children. They have also successfully trialled the device in patients with type 2 diabetes who require kidney dialysis.

Today, in Nature Medicine, the team report the first trial of the device in a wider population living with type 2 diabetes (not requiring kidney dialysis). Unlike the artificial pancreas used for type 1 diabetes, this new version is a fully closed loop system – whereas patients with type 1 diabetes need to tell their artificial pancreas that they are about to eat to allow adjustment of insulin, for example, with this version they can leave the device to function entirely automatically.

The researchers recruited 26 patients from the Wolfson Diabetes and Endocrine Clinic at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust, and a local group of GP surgeries. Patients were randomly allocated to one of two groups – the first group would trial the artificial pancreas for eight weeks and then switch to the standard therapy of multiple daily insulin injections; the second group would take this control therapy first and then switch to the artificial pancreas after eight weeks.

The team used several measures to assess how effectively the artificial pancreas worked. The first was the proportion of time that patients spent with their glucose levels within a target range of between 3.9 and 10.0mmol/L. On average, patients using the artificial pancreas spent two-thirds (66%) of their time within the target range – double that while on the control (32%).

A second measure was the proportion of time spent with glucose levels above 10.0mmol/L. Over time, high glucose levels raise the risk of potentially serious complications. Patients taking the control therapy spent two-thirds (67%) of their time with high glucose levels – this was halved to 33% when using the artificial pancreas.

Average glucose levels fell – from 12.6mmol/L when taking the control therapy to 9.2mmol/L while using the artificial pancreas.

The app also reduced levels of a molecule known as glycated haemoglobin, or HbA1c. Glycated haemoglobin develops when haemoglobin, a protein within red blood cells that carries oxygen throughout the body, joins with glucose in the blood, becoming ‘glycated’. By measuring HbA1c, clinicians are able to get an overall picture of what a person’s average blood sugar levels have been over a period of weeks or months. For people with diabetes, the higher the HbA1c, the greater the risk of developing diabetes-related complications. After the control therapy, average HbA1c levels were 8.7%, while after using the artificial pancreas they were 7.3%. 

No patients experienced dangerously-low blood sugar levels (hypoglycaemia) during the study. One patient was admitted to hospital while using the artificial pancreas, due to an abscess at the site of the pump cannula.

Dr Charlotte Boughton from the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge, pictured right, who co-led the study, said: “Many people with type 2 diabetes struggle to manage their blood sugar levels using the currently available treatments, such as insulin injections. The artificial pancreas can provide a safe and effective approach to help them, and the technology is simple to use and can be implemented safely at home.”

Dr Aideen Daly, also from the Wellcome-MRC Institute of Metabolic Science, said: “One of the barriers to widespread use of insulin therapy has been concern over the risk of severe ‘hypos’ – dangerously low blood sugar levels. But we found that no patients on our trial experienced these and patients spent very little time with blood sugar levels lower than the target levels.”

Feedback from participants suggested that participants were happy to have their glucose levels controlled automatically by the system, and nine out of ten (89%) reported spending less time managing their diabetes overall. Users highlighted the elimination of the need for injections or fingerprick testing, and increased confidence in managing blood glucose as key benefits. Downsides included increased anxiety about the risk of hypoglycaemia, which the researchers say may reflect increased awareness and monitoring of glucose levels, and practical annoyances with wearing of devices.

The team now plan to carry out a much larger multicentre study to build on their findings and have submitted the device for regulatory approval with a view to making it commercially available for outpatients with type 2 diabetes.

Paper Reference

Daly, AB, Boughton, CK, et al. Fully automated closed-loop insulin delivery in adults with type 2 diabetes: an open-label, single-centre randomised crossover trial. Nat Med; 11 Jan 2023; DOI: 10.1038/s41591-022-02144-z

Professor Krishna Chatterjee awarded a CBE

Congratulations to Professor Krishna Chatterjee, consultant endocrinologist at Cambridge University Hospitals and director of NIHR Cambridge Clinical Research Facility who has been awarded a CBE in the King’s New Year Honours for his ground-breaking work on endocrine disorders.

Professor Chatterjee is also a professor of endocrinology at the University of Cambridge and led the COVBOOST vaccine trial locally during the pandemic. His research group focuses on genetic and molecular endocrinology, exploring disorders including resistance to thyroid hormone (RTH) and PPARgamma gene defects associated with lipodystrophic insulin resistance. He was awarded a CBE for his services to people with endocrine disorders.

He said: “I am delighted that our work has been recognised in this way. This also represents the efforts of many clinical and scientist colleagues in the University, CUH and our NIHR Clinical Research Facility, with whom I have worked over many years.

“Together with the patients participating in our research, we strive to continue advancing knowledge and health outcomes in endocrine disorders.”

Blood thinning drug to treat recovery from severe Covid is not effective

A UK-wide trial, led by Addenbrooke’s Hospital and the University of Cambridge, has found that a drug used to reduce the risk of blood clots does not help patients recovering from moderate and severe Covid – despite this approach being offered to patients.

The HEAL-COVID trial (Helping to Alleviate the Longer-term consequences of Covid-19) is funded by the NIHR and the NIHR Cambridge Biomedical Research Centre. To date, more than a thousand NHS patients hospitalised with Covid have taken part in HEAL-COVID, a platform trial that is aiming to find treatments to reduce the number who die or are readmitted following their time in hospital.

In these first results from HEAL-COVID, it’s been shown that prescribing the oral anticoagulant Apixaban does not stop Covid patients from later dying or being readmitted to hospital over the following year (Apixaban 29.1%, versus standard care 30.8%).

As well as not being beneficial, anticoagulant therapy has known serious side effects, and these were experienced by participants in the trial with a small number of the 402 participants receiving Apixaban having major bleeding that required them to discontinue the treatment.

There was also no benefit from Apixaban in terms of the number of days alive and out of hospital at day 60 after randomisation (Apixaban 59 days, versus standard care 59 days).

Following these results, the trial will continue to test another drug called Atorvastatin, a widely used lipid lowering drug (‘a statin’) that acts on other mechanisms of disease that are thought to be important in Covid.

Chief Investigator for the trial Professor Charlotte Summers, is an intensive care specialist at Addenbrooke’s Hospital and the University of Cambridge, pictured right, said: “Having survived the ordeal of being hospitalised with Covid-19, far too many patients find themselves back in hospital, often developing longer-term complications as a result of the virus. There is an urgent need for us to find treatments that prevent this significant burden of illness and improve the lives of so many still being affected by Covid.”

“These first findings from HEAL-COVID show us that a blood thinning drug, commonly thought to be a useful intervention in the post-hospital phase is actually ineffective at stopping people dying or being readmitted to hospital.  This finding is important because it will prevent unnecessary harm occurring to people for no benefit.   It also means we must continue our search for therapies that improve longer term recovery for this devastating disease.”

Dr Mark Toshner, joint Chief Investigator for HEAL-COVID, pictured left, said: “Up until now it’s been assumed that Apixaban helps patients recover after severe Covid-19 and that thinning their blood to prevent clots is beneficial.  This trial is the first robust evidence that longer anticoagulation after acute Covid-19 puts patients at risk for no clear benefit.

“Our hope is that these results will stop this drug being needlessly prescribed to patients with Covid-19 and we can change medical practise.  Finding out that a treatment doesn’t work is really important.  It’s not the solution many hoped it would be, with our results highlighting once again why testing treatments in randomised trials is important.”

“At present, the world’s research efforts have focussed on acute Covid-19. We now urgently need evidence about how to best treat patients beyond their initial infection.”

Professor Nick Lemoine, NIHR Clinical Research Network Medical Director, said: “Research into Covid-19 recovery remains vital as we move out of the pandemic. Results such as these from the HEAL-COVID study, help to strengthen our knowledge of how patients can be treated following their stay in hospital and how recovery rates can be improved upon.

“Findings from clinical trials, whether they identify new treatments or rule out methods of care, are vital and rigorous evidence when it comes to changing best medical practice.”

The trial is being led by Cambridge University Hospitals NHS Foundation Trust (CUH) and University of Cambridge, in collaboration with Liverpool Clinical Trials Centre (University of Liverpool) and Aparito Limited. 

HEAL-COVID enrols patients when they are discharged from hospital, following their first admission for Covid-19.  They are randomised to a treatment and their progress tracked.

Cambridge researchers listed among world’s most influential researchers

Congratulations to our NIHR Cambridge BRC theme leads who have been named in the Clarivate listings of the ‘world’s most influential researchers’.

The researchers were selected on their exceptional research influence and highly cited research papers that rank in the top 1% by citations on the global database, Web of Science, over the last decade.  

The full list of Cambridge researchers can be found on the Clarivate website.

Name	Title	Associated theme
Professor Ed Bullmore	Honorary Consultant Psychiatrist and Head of the Department of Psychiatry	Mental Health
Professor John Danesh	Professor of Epidemiology	Population and quantitative sciences
Professor Ravindra K. Gupta	Professor of Clinical Microbiology	Antimicrobial resistance
Professor David Rowitch	Developmental neuroscientist and Head of Department of Paediatrics	Women’s health and paediatrics

High blood pressure is directly linked to severe COVID-19

A study led by Addenbrooke’s Hospital and the University of Cambridge has shown that people with high blood pressure are more likely to be admitted to hospital or die from COVID-19, regardless of other factors such as age, sex, ethnicity or BMI.

The research, published this week in the Journal PLOS ONE, is the first study to show the extent to which high blood pressure, known as hypertension, can be directly linked to patients developing severe COVID-19. 

It also showed that the type of medication people were receiving to treat hypertension did not appear to modify this risk.  In addition, those patients who had poorly controlled blood pressure i.e. above treatment targets, were at the highest risk of dying or being hospitalised.

The study findings may help explain why ethnic minority and low-income groups were disproportionately affected by COVID-19, as hypertension is more common in these individuals, and rates of blood pressure control poorer (see notes).

The research has important implications for public health priorities, given that hypertension is already the leading risk factor for death in the UK. 

It also comes as rates of blood pressure control have worsened in the UK, due to the pandemic, with the number or people being screened and identified with the condition dropping as well (see notes).

Holly Pavey is lead author of the study and a British Heart Foundation (BHF) funded PhD student at the University of Cambridge.  She said:

“Before this research, it wasn’t clear to what extent high blood pressure was putting patients at greater risk of hospitalisation or dying from COVID-19.  Other factors such as age, socio-economic status, sex, ethnicity and BMI were all in the frame too as increasing the risk of severe COVID-19.  

“By using data from many thousands of UK volunteers, we found that in individuals who tested positive for COVID-19, those with high blood pressure had a 22% higher risk of being hospitalised of dying from the virus, compared to those without high blood pressure.   This risk was almost doubled for those with poorly controlled blood pressure.”

The research was supported by the NIHR Cambridge Biomedical Research Centre and use data from the UK Biobank, a research database, containing in-depth genetic and health information from half a million UK volunteers. The study included over 16,000 of these individuals who had tested positive for COVID-19 and who had linked GP records, death records and COVID-19 lab results. 

Researchers analysed data up until early 2021, which helped to reduce any bias from new variants of the virus, which were much more transmissible, as well as reducing any bias from the effects of widespread vaccinations.

However, the UK Biobank volunteer population is generally healthier than the general UK population and has relatively few participants from ethnic minority groups, so generalisations to the wider UK population need to be undertaken with caution.

Even though the death and hospitalisation rate due to COVID-19 has been hugely reduced over the last year due to virus mutations, the NHS vaccination program and availability of effective treatments, this research highlights the importance of having well-controlled blood pressure, in case of new, more severe strains of COVID-19 or other viruses in the future.

Ian Wilkinson, a cardiology consultant at Cambridge University Hospitals NHS Foundation Trust (CUH) and Professor of Therapeutics at the University of Cambridge, is the study’s senior author.  He said: “Hypertension remains the leading risk factor for death in the UK and worldwide, despite effective treatments, and disproportionately affects low income groups and individuals from ethnic minority backgrounds.

“Our findings further emphasise the importance of adequate blood pressure control. Unfortunately, post-pandemic, the rates of blood pressure control have worsened, as have the number of people being screened and identified as having high blood pressure. This is now a major public health problem in the UK and needs to be addressed as part of the levelling-up agenda”.

A national trial is currently underway to improve treatments for hypertension, specifically for people from black, Asian and minority ethnic communities.  At the moment most treatments have been tested mainly on white people and it’s not known if these are as effective on other ethnic groups.  

The AIM HY trial is led by Professor Ian Wilkinson and Phil Chowienczyk, Professor of Clinical Cardiovascular Pharmacology, Kings College London and Chief Investigator for the trial. 

Professor Chowienczyk said: “These findings highlight the importance of good blood pressure control, especially in individuals disproportionately affected by high blood pressure and COVID-19, such as those in ethnic minority groups in the UK. The AIM HY_INFORM trial is a major study, funded by the BHF and Medical Research Council, that will determine which drugs are most effective at lowering blood pressure in ethnic minority groups in the UK. This should report at the end of 2023 and will be instrumental in shaping new guidelines for the treatment of hypertension in the UK.”

World-first trial to transfuse lab-grown red blood cells is underway in Cambridge

Red blood cells that have been grown in a laboratory have now been transfused into another person at the NIHR Cambridge Clinical Research Facility in a world first clinical trial.

The manufactured blood cells were grown from stem cells from donors. The red cells were then transfused into volunteers in the RESTORE randomised controlled clinical trial.

This is the first time in the world that red blood cells that have been grown in a laboratory have been given to another person as part of a trial into blood transfusion.

If proved safe and effective, manufactured blood cells could in time revolutionise treatments for people with blood disorders such as sickle cell and rare blood types. It can be difficult to find enough well-matched donated blood for some people with these disorders.

The RESTORE trial is a joint research initiative by NHS Blood and Transplant and the University of Bristol, working with the University of Cambridge, Guy’s and St Thomas’ NHS Foundation Trust, NIHR Cambridge Clinical Research Facility, and Cambridge University Hospitals NHS Foundation Trust. It is part-funded by a NIHRH grant and supported by NIHR Cambridge BRC.

The trial is studying the lifespan of the lab grown cells compared with infusions of standard red blood cells from the same donor. The lab-grown blood cells are all fresh, so the trial team expect them to perform better than a similar transfusion of standard donated red cells, which contains cells of varying ages.

Additionally, if manufactured cells last longer in the body, patients who regularly need blood may not need transfusions as often. That would reduce iron overload from frequent blood transfusions, which can lead to serious complications.

The trial is the first step towards making lab grown red blood cells available as a future clinical product. For the foreseeable future, manufactured cells could only be used for a very small number of patients with very complex transfusions needs. NHSBT continues to rely on the generosity of donors.

Two people have so far been transfused with the lab grown red cells in Cambridge. They were closely monitored and no untoward side effects were reported. They are well and healthy. The identities of participants infused so far are not currently being released, to help keep the trial ‘blinded’.

The amount of lab grown cells being infused varies but is around 5-10mls – about one to two teaspoons.

Donors were recruited from NHSBT’s blood donor base. They donated blood to the trial and stem cells were separated out from their blood. These stem cells were then grown to produce red blood cells in a laboratory at NHS Blood and Transplant’s Advanced Therapies Unit in Bristol. The recipients of the blood were recruited from healthy members of the NIHR BioResource.

A minimum of 10 participants will receive two mini transfusions at least four months apart, one of standard donated red cells and one of lab grown red cells, to find out if the young red blood cells made in the laboratory last longer than cells made in the body.

Further trials are needed before clinical use, but this research marks a significant step in using lab grown red blood cells to improve treatment for patients with rare blood types or people with complex transfusion needs.

Chief Investigator Professor Cedric Ghevaert, Professor in Transfusion Medicine and Consultant Haematologist the University of Cambridge and NHS Blood and Transplant, pictured right, said: “We hope our lab grown red blood cells will last longer than those that come from blood donors. If our trial, the first such in the world, is successful, it will mean that patients who currently require regular long-term blood transfusions will need fewer transfusions in future, helping transform their care.”

Co-Chief Investigator Dr Rebecca Cardigan, Head of Component Development NHS Blood and Transplant and Affiliated Lecturer at the University of Cambridge said: “It’s really fantastic that we are now able to grow enough red cells to medical grade to allow this trial to commence, we are really looking forward to seeing the results and whether they perform better than standard red cells.”

Cambridge BRC receives £86.2 million to translate research discoveries into new treatments for patients

The National Institute for Health and Care Research (NIHR) has awarded £86.2 million to NIHR Cambridge Biomedical Research Centre (BRC) investigators to continue their ground-breaking research, translating new scientific insights into state-of-the-art diagnostics and treatments to transform healthcare. The Cambridge funding is one of 20 such awards granted to leading NHS and University partnerships across the country.

NIHR Biomedical Research Centres bring together the expertise of academic research and healthcare professionals. The Cambridge centre is a partnership between Cambridge University Hospitals and the University of Cambridge, taking advantage of the respective strengths and expertise of both organisations to create the ideal environment for cutting-edge ‘translational’ research – where scientific discoveries from the laboratory are turned into experimental and clinical trials to show their benefit, and ultimately improve care. 

This is the fourth round of Biomedical Research Centre funding and builds on the outstanding research contributions of the past 15 years. Since its creation in 2007, the NIHR Cambridge BRC is recognised globally as a leading centre for translational research and is now one of the largest BRCs in England. It hosts world-leading experts in numerous specialties and state-of-the art infrastructure to conduct translational research.

The centre has already delivered medical breakthroughs including a new screening device to detect Barrett’s oesophagus, a condition that can lead to oesophageal cancer, the artificial pancreas to help patients with Type 1 Diabetes better manage their condition and the use of whole genome sequencing for rapid diagnosis of critically ill babies and children. NIHR Cambridge BRC also played a key role in responding to the COVID-19 pandemic through the ability to rapidly mobilise expertise and equipment to diagnose COVID-19, making major contributions to our understanding of the evolution of SARS-CoV2 variants, how the virus spreads through hospitals and other settings and leading on crucial trials to investigate new treatments to prevent long-term complications in survivors of COVID.

Realising the potential of cutting-edge research

The Cambridge Biomedical Campus hosts many world-leading experts and research institutes, together with the renowned hospitals of Addenbrooke’s, the Rosie and the Royal Papworth. The NIHR Cambridge BRC brings together these researchers and institutions to focus on translating their discoveries into new diagnostics and treatments.

Over the next five years, Cambridge will continue research in areas such as cancer, dementia and cardiovascular and respiratory diseases, as well as focusing on developing areas of technology that will likely revolutionise NHS care in the coming years, such as artificial intelligence (AI), genomic medicine and new state of the art imaging techniques.

The funding also provides opportunities for a diverse range of professionals to undertake research, building a new generation of leading researchers – including expanding research expertise in allied health professionals, such as physiotherapists, radiologists and dietitians.

Professor Miles Parkes, Director of NIHR Cambridge BRC said: “The NIHR Cambridge BRC has been instrumental in delivering many exciting advances over the past 15 years, building on Cambridge’s historic strengths in discovery science and translating these into improved diagnostics and treatments.

“Together with our clinical partners, our diverse pool of world-leading scientists and first-class research facilities make the Cambridge Biomedical Campus an ideal place to conduct ground-breaking translational research.

“This new funding reflects confidence in the continued innovation, strength and dedication of our research teams. Over the next five years we will be particularly focusing on early detection and the changes that lead to disease, so we can aim to prevent and reverse serious health conditions before irreversible damage occurs. We will leverage our strengths in genomic medicine and data science to support this research and work with patients and investigators regionally and nationally, to deliver world-class translational research and improve health outcomes.’’

Professor Lucy Chappell, Chief Executive of the NIHR, said: “Research by NIHR Biomedical Research Centres has led to a number of ground-breaking new treatments, such as new gene therapies for haemophilia and motor neurone disease, the world-first treatment for Creutzfeldt–Jakob disease, a nose-drop vaccine for whooping cough, and the first UK-wide study into the long-term impact of COVID-19.

“This latest round of funding recognises the strength of expertise underpinning health and care research across the country and gives our nation’s best researchers more opportunities to develop innovative new treatments for patients.”

NIHR Cambridge BRC themes

Watch this short video to find out what our research themes are and the work we will be doing over the next five years.

Read the full press release from the Department of Health.

Dementia signs detected as early as nine years ahead of diagnosis

Cambridge scientists have shown that it is possible to spot signs of brain impairment in patients as early as nine years before they receive a diagnosis for one of a number of dementia-related diseases.

In research published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the team analysed data from the UK Biobank and found impairment in several areas, such as problem solving and number recall, across a range of conditions.

The findings raise the possibility that in the future, at-risk patients could be screened to help select those who would benefit from interventions to reduce their risk of developing one of the conditions, or to help identify patients suitable for recruitment to clinical trials for new treatments.

There are currently very few effective treatments for dementia or other neurodegenerative diseases such as Parkinson’s disease. In part, this is because these conditions are often only diagnosed once symptoms appear, whereas the underlying neurodegeneration may have begun years – even decades – earlier. This means that by the time patients take part in clinical trials, it may already be too late in the disease process to alter its course.

Until now, it has been unclear whether it might be possible to detect changes in brain function before the onset of symptoms. To help answer this question, researchers at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust turned to UK Biobank, a biomedical database and research resource containing anonymised genetic, lifestyle and health information from half a million UK participants aged 40-69.

As well as collecting information on participants’ health and disease diagnoses, UK Biobank collected data from a battery of tests including problem solving, memory, reaction times and grip strength, as well as data on weight loss and gain and on the number of falls. This allowed them to look back to see whether any signs were present at baseline – that is, when measurements were first collected from participants (between five and nine years prior to diagnosis).

People who went on to develop Alzheimer’s disease scored more poorly compared to healthy individuals when it came to problem solving tasks, reaction times, remembering lists of numbers, prospective memory (our ability to remember to do something later on) and pair matching. This was also the case for people who developed a rarer form of dementia known as frontotemporal dementia.

People who went on to develop Alzheimer’s were more likely than healthy adults to have had a fall in the previous 12 months. Those patients who went on to develop a rare neurological condition known as progressive supranuclear palsy (PSP), which affects balance, were more than twice as likely as healthy individuals to have had a fall.

For every condition studied – including Parkinson’s disease and dementia with Lewy bodies – patients reported poorer overall health at baseline.

First author Nol Swaddiwudhipong, a junior doctor at the University of Cambridge, said: “When we looked back at patients’ histories, it became clear that they were showing some cognitive impairment several years before their symptoms became obvious enough to prompt a diagnosis. The impairments were often subtle, but across a number of aspects of cognition.

“This is a step towards us being able to screen people who are at greatest risk – for example, people over 50 or those who have high blood pressure or do not do enough exercise – and intervene at an earlier stage to help them reduce their risk.”

Senior author Dr Tim Rittman from the Department of Clinical Neurosciences at the University of Cambridge added: “People should not be unduly worried if, for example, they are not good at recalling numbers. Even some healthy individuals will naturally score better or worse than their peers. But we would encourage anyone who has any concerns or notices that their memory or recall is getting worse to speak to their GP.”

Dr Rittman said the findings could also help identify people who can participate in clinical trials for potential new treatments. “The problem with clinical trials is that by necessity they often recruit patients with a diagnosis, but we know that by this point they are already some way down the road and their condition cannot be stopped. If we can find these individuals early enough, we’ll have a better chance of seeing if the drugs are effective.”

The research was funded by the Medical Research Council with support from the NIHR Cambridge Biomedical Research Centre.

Paper Reference

Swaddiwudhipong, N, et al. Pre-Diagnostic Cognitive and Functional Impairment in Multiple Sporadic Neurodegenerative Diseases. Alzheimer’s & Dementia; 13 Oct 2022; DOI: 10.1002/alz.12802

Referrals to long COVID clinic fell by 79% following roll-out of the vaccine

Referrals to Cambridge’s long COVID clinic fell dramatically in the period August 2021 to June 2022, which researchers say is likely due to the successful rollout of the vaccine.

According to the Office of National Statistics, in July this year an estimated 2 million people in the UK were living with self-reported long COVID – that is, symptoms continuing for more than four weeks after their first suspected coronavirus (COVID-19) infection. Patients report symptoms including fatigue, muscle aches, memory problems and shortness of breath more than six months post-acute COVID-19, and a significant number of patients have not fully recovered two years since the initial infection.

Two recent studies have suggested that vaccination strongly reduced long COVID symptoms one-to-three months after infection, but another study using a cohort of US Army Veterans suggested a more modest, 15% reduction at six months.

In May 2020, Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust (CUH), set up a long COVID clinic, with patients referred to the clinic based on a number of criteria, one of which is symptoms duration of at least five months. These patients tend to be those on the severe end of the symptom spectrum, having been referred following assessment by a team that includes a GP, mental health practitioners, physio and occupational therapists amongst other specialists.

Researchers at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) at the University of Cambridge and CUH, analysed data from the clinic and found a 79% drop in the number of patients being referred to the clinic from August 2021 to June 2022, compared to August 2020 to July 2021. The decrease began five months after people started receiving second doses of COVID-19 vaccines.

Six-month moving averages fell from around 10 referrals per month to just one or two referrals per month. This effect has so far been sustained until at least June 2022, despite four times more cases per month of acute COVID-19 in England across the same time periods.

Dr Ben Krishna from the University of Cambridge said: “Long COVID can have a significant impact on an individual’s life, and the large number of patients still experiencing symptoms many months after infection is placing additional strain on our healthcare services.

“We know that rollout of the vaccines has had a major impact on the number and severity of COVID infections, and evidence from our clinic suggests that it has also played an important role in reducing the rates of the most severe long COVID cases.”

The researchers say that it is possible – but unlikely – that the emergence of the Delta variant may also have affected long COVID rates. However, the observed reduction in long COVID rates in August 2021 was from patients experiencing symptoms for five months, which they say would suggest a change beginning in March 2021. This correlates well with the second doses of vaccination in the UK, but the Delta wave did not begin until April 2021.

The team say they also cannot rule out prior infections providing immunity that protects against long COVID from reinfections; however, primary infections were more common than reinfections around March-April 2021.

The team observed no changes in symptoms between those referred for long COVID before or after vaccination for any of the major symptoms such as fatigue (73% pre-vaccination vs 76% post vaccination) and shortness of breath (18% pre-vaccination vs 23% post-vaccination).

It is not yet clear what level of immunity is required to protect against long COVID, say the researchers. As immunity wanes over time, booster shots – including variant-specific booster shots – may be necessary to minimise long COVID risk.

Dr Nyaradzai Sithole from CUH said: “As the virus continues to circulate and infect – and in many cases, re-infect – people, it’s important that everyone is up-to-date with their vaccinations. This will not only help prevent, or at least lessen, their primary COVID infection, but should reduce their risk of long COVID. But whether with the emergence of new variants we will begin to see an uptick in the number of cases of long COVID remains to be seen.”

The study is published in Clinical Infectious Diseases.

The research as funded by the Addenbrooke’s Charitable Trust and the National Institute for Health and Care Research (NIHR), with support from the NIHR Cambridge Biomedical Research Centre.

Paper Reference
Krishna, B et al. Reduced incidence of Long COVID referrals to the Cambridge University Teaching Hospital Long COVID clinic. Clinical Infectious Diseases; 1 Aug 2022; DOI: 10.1093/cid/ciac630

Celebrating the role of patients in improving radiotherapy services

A new display in Addenbrooke’s Hospital highlights how patients have helped shape radiotherapy treatment.

The multimedia installation in the entrance to the Radiotherapy Department has been produced in partnership with a group of patients, some of whom have shared their experience of radiotherapy treatment.

In 2019 Cambridge was named by Cancer Research UK as one of seven centres of excellence in radiation research. When Rachael Webster, former Senior Radiographer at Addenbrooke’s, heard the good news, her mission was to include patients’ experience and views in the new RadNet Cambridge Centre’s plans to improve radiotherapy for future patients.

She said: “After a chat with one of our patient representatives we thought the best way to get more people involved in radiotherapy research is to celebrate the amazing work from patients and the public over many, many years that has helped shape the radiotherapy services we see today.”

The idea to develop a display about patient involvement in radiotherapy research began a year ago when Rachael put out adverts – at local events, online and via Facebook – inviting people who had experience of radiotherapy to be involved in a creative project.

Rachael soon assembled a group of nine patients and members of the public who were keen to be involved.

“Involving patients was the goal from the very beginning, we need to hear the patients’ voices to celebrate the patients’ voices,” she explained.

“There are a lot of misconceptions and fears about radiotherapy, especially from the past. We know radiotherapy is a safe, accurate and effective treatment for many cancers and around 50% of patients will received radiotherapy as a part of their treatment.”

Over the course of the year, the patient and public involvement group met with researchers, radiographers and designers to share the questions and concerns they had before they started their treatment, and to reflect on their honest experiences of undergoing radiotherapy.

People joined the group for different reasons. Neil said: “I wanted to be involved in the project so that I could help to promote the modern science of radiotherapy and how it can benefit patients.”

Beverly wanted to help others facing treatment, adding: “I feel more knowledgeable, more comfortable and I feel quite an advocate for helping people to feel the same. It was a way of giving something back that felt really important to me.”

And Caroline valued the opportunity to get involved, explaining: “Knowing that there was a way to make your voice heard and a way you can make a difference for other people was very empowering for me.”

The resulting display is based around a timeline illustrating how key advances in radiation research, patient participation in radiotherapy clinical trials and patient campaign groups have shaped the service today. Along the wall are QR codes for people to download podcasts and videos to hear more about radiotherapy techniques and the patients’ experiences.

The display also highlights pioneering radiotherapy research in Cambridge to target treatment more accurately and reduce long-term side effects that affect patients’ quality of life. A clinical trial in Cambridge of over a thousand patients proved the benefits of using a more targeted radiotherapy technique, called Intensity Modulated Radiotherapy (IMRT), for early-stage breast cancer and provided evidence to help IMRT become a standard of care.

Professor Charlotte Coles, RadNet Cambridge Lead and NIHR Cambridge BRC researcher, said: “I am thrilled to see this display showcasing the invaluable and essential contribution patients make by actively shaping as well as participating in radiotherapy research. I hope that conveying the incredible advances in radiotherapy research in such an accessible and relatable way will give patients and families added confidence in their radiotherapy and inspire them to get involved in research.”

The RadNet Cambridge team are keen to involve more patients, particularly those in under-represented groups, to share their experiences and to guide future research projects and clinical trials. Amy, one of the patients in the group, said: “My message to those who are approached to participate in a project like this, or to participate in some of these research projects, is that we need to be in it to influence it.”

The project has been funded by Addenbrooke’s Charitable Trust with additional funding and support from RadNet Cambridge and the Cancer Research UK Cambridge Centre.

Welcome to our new Patient and Public Involvement coordinator

Gail will be working with Dr Amanda Stranks, Patient and Public Involvement (PPI) Strategy Lead, to help researchers design PPI plans for their studies and run training sessions.

Gail will also be the first point of contact for our 70+ PPI panel members and will be welcoming new volunteers when they join.

Welcome Gail, tell us about yourself, what was your previous role and what do you like to do in your spare time?

I previously worked for the Ophthalmology department, as a theatre coordinator.

Prior to this, I was responsible for rebuilding both the paediatric Sleep Study and Long-Term Ventilation services for children with respiratory disorders.

I am currently studying a BA (hons) degree in English Literature and Creative Writing in my spare time.

What made you want to work in research?

The word research is derived from the Middle French ‘recherché’ which means ‘to go about seeking’. I have always been curious and I believe my fondness of research was built on this foundation.

What are you looking forward to in this role?

Learning, facilitating and possibly making a small contribution to the vast world of research.

If you need help with your Patient and Public Involvement contact the team at: cuh.ppi@nhs.net

Large number of stem cell lines carry significant DNA damage, say researchers

Cambridge researchers say detailed genetic characterisation including whole genome sequencing can help ensure safety of cell-based therapies

DNA damage caused by factors such as ultraviolet radiation affect nearly three-quarters of all stem cell lines derived from human skin cells, say Cambridge researchers, who argue that whole genome sequencing is essential for confirming if cell lines are usable.

Stem cells are a special type of cell that can be programmed to become almost any type of cell within the body. They are currently used for studies on the development of organs and even the early stages of the embryo.

Increasingly, researchers are turning to stem cells as ways of developing new treatments, known as cell-based therapies. Other potential applications include programming stem cells to grow into nerve cells to replace those lost to neurodegeneration in diseases such as Parkinson’s.

Originally, stem cells were derived from embryos, but it is now possible to derive stem cells from adult skin cells. These so-called induced pluripotent stem cells (iPSCs) have now been generated from a range of tissues, including blood, which is increasing in popularity due to its ease of derivation.

However, researchers at the University of Cambridge and Wellcome Sanger Institute have discovered a problem with stem cell lines derived from both skin cells and blood. When they examined the genomes of the stem cell lines in detail, they found that nearly three quarters carried substantial damage to their DNA that could compromise their use both in research and, crucially, in cell-based therapies. Their findings represent the largest genetic study to date of iPSCs and are published today in Nature Genetics.

DNA is made up of three billions pairs of nucleotides, molecules represented by the letters A, C, G and T. Over time, damage to our DNA, for example from ultraviolet radiation, can lead to mutations – a letter C might change to a letter T, for example. ‘Fingerprints’ left on our DNA can reveal what is responsible for this damage. As these mutations accumulate, they can have a profound effect on the function of cells and in some cases lead to tumours.

Dr Foad Rouhani from the Department of Surgery at the University of Cambridge and the Wellcome Sanger Institute said: “We noticed that some of the iPS cells that we were generating looked really different from each other, even when they were derived from the same patient and derived in the same experiment. The most striking thing was that pairs of iPS cells would have a vastly different genetic landscape – one line would have minimal damage and the other would have a level of mutations more commonly seen in tumours. One possible reason for this could be that a cell on the surface of the skin is likely to have greater exposure to sunlight than a cell below the surface and therefore eventually may lead to iPS cells with greater levels of genomic damage.”

The researchers used a common technique known as whole genome sequencing to inspect the entire DNA of stem cell lines in different cohorts, including the HipSci cohort at the Wellcome Sanger Institute and discovered that as many as 72% of the lines showed signs of major UV damage.

Professor Serena Nik-Zainal from the Department of Medical Genetics at the University of Cambridge, pictured right, said: “Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations – sometimes more than we find in tumours.  We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people.”

They decided to turn their attention to cell lines not derived from skin and focused on blood derived iPSCs as these are becoming increasingly popular due to the ease of obtaining blood samples. They found that while these blood-derived iPSCs, too, carried mutations, they had lower levels of mutations than skin-derived iPS cells and no UV damage. However, around a quarter carried mutations in a gene called BCOR, an important gene in blood cancers.

To investigate whether these BCOR mutations had any functional impact, they differentiated the iPSCs and turned them into neurons, tracking their progress along the way.

Dr Rouhani said: “What we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations – they had a tendency to favour other cell types instead. This is a significant finding, particularly if one is intending to use those lines for neurological research.”

When they examined the blood samples, they discovered that the BCOR mutations were not present within the patient: instead, the process of culturing cells appears to increase the frequency of these mutations, which may have implications for other researchers working with cells in culture.

Scientists typically screen their cell lines for problems at the chromosomal level – for example by checking to see that the requisite 23 pairs of chromosomes are present. However, this would not be sufficiently detailed to pick up the potentially major problems that this new study has identified. Importantly, without looking in detail at the genomes of these stem cells, researchers and clinicians would be unaware of the underlying damage that is present with the cell lines they are working with.

“The DNA damage that we saw was at a nucleotide level,” says Professor Nik-Zainal. “If you think of the human genome as like a book, most researchers would check the number of chapters and be satisfied that there were none missing. But what we saw was that even with the correct number of chapters in place, lots of the words were garbled.”

Fortunately, says Professor Nik-Zainal, there is a way round the problem: using whole genome sequencing to look in detail for the errors at the outset.

“The cost of whole genome sequencing has dropped dramatically in recent years to around £500 per sample, though it’s the analysis and interpretation that’s the hardest bit. If a research question involves cell lines and cellular models, and particularly if we’re going to introduce these lines back into patients, we may have to consider sequencing the genomes of these lines to understand what we are dealing with and get a sense of whether they are suitable for use.”

Dr Rouhani adds: “In recent years we have been finding out more and more about how even our healthy cells carry many mutations and therefore it is not a realistic aim to produce stem cell lines with zero mutations. The goal should be to know as much as possible about the nature and extent of the DNA damage to make informed choices about the ultimate use of these stem cell lines.

“If a line is to be used for cell based therapies in patients for example, then we need to understand more about the implications of these mutations so that both clinicians and patients are better informed of the risks involved in the treatment.”

The research was funded by Cancer Research UK, the Medical Research Council and Wellcome, and supported by NIHR Cambridge Biomedical Research Centre and the UK Regenerative Medicine Platform.

Paper Reference

Rouhani, FJ, Zou, X, Danecek, P, et al. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells; Nat Gen; 11 Aug 2022; DOI: 10.1038/s41588-022-01147-3