̽��ֱ�� of Cambridge - animal research

Mouse study suggests a common diabetes drug may prevent leukaemia

cjb250 — Wed, 16 Apr 2025 07:59:00 +0000

Around 3,100 people are diagnosed with acute myeloid leukaemia (AML) each year in the UK. It is an aggressive form of blood cancer that is very difficult to treat. Thanks to recent advances, individuals at high risk of AML can be identified years in advance using blood tests and blood DNA analysis, but there’s no suitable treatment that can prevent them from developing the disease.

In this study, Professor George Vassiliou and colleagues at the ̽��ֱ�� of Cambridge investigated how to prevent abnormal blood stem cells with genetic changes from progressing to become AML. ̽��ֱ��work focused on the most common genetic change, which affects a gene called DNMT3A and is responsible for starting 10-15% of AML cases.

Professor Vassiliou, from the Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge and Honorary Consultant Haematologist at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH) co-led the study. He said: “Blood cancer poses unique challenges compared to solid cancers like breast or prostate, which can be surgically removed if identified early. With blood cancers, we need to identify people at risk and then use medical treatments to stop cancer progression throughout the body.”

̽��ֱ��research team examined blood stem cells from mice with the same changes in DNMT3A as seen in the pre-cancerous cells in humans. Using a genome-wide screening technique, they showed that these cells depend more on mitochondrial metabolism than healthy cells, making this a potential weak spot. ̽��ֱ��researchers went on to confirm that metformin, and other mitochondria-targeting drugs, substantially slowed the growth of mutation-bearing blood cells in mice. Further experiments also showed that metformin could have the same effect on human blood cells with the DNMT3A mutation.

Dr Malgorzata Gozdecka, Senior Research Associate at the Cambridge Stem Cell Institute and first author of the research said: “Metformin is a drug that impacts mitochondrial metabolism, and these pre-cancerous cells need this energy to keep growing. By blocking this process, we stop the cells from expanding and progressing towards AML, whilst also reversing other effects of the mutated DNMT3A gene.”

In addition, the study looked at data from over 412,000 UK Biobank volunteers and found that people taking metformin were less likely to have changes in the DNMT3A gene. This link remained even after accounting for factors that could have confounded the results such as diabetes status and BMI.

Professor Brian Huntly, Head of the Department of Haematology at the ̽��ֱ�� of Cambridge, Honorary Consultant Haematologist at CUH, and joint lead author of the research, added: “Metformin appears highly specific to this mutation rather than being a generic treatment. That specificity makes it especially compelling as a targeted prevention strategy.

“We’ve done the extensive research all the way from cell-based studies to human data, so we’re now at the point where we have a made a strong case for moving ahead with clinical trials. Importantly, metformin’s lack of toxicity will be a major advantage as it is already used by millions of people worldwide with a well-established safety profile.”

̽��ֱ��results of the study, funded by Blood Cancer UK with additional support from Cancer Research UK, the Leukemia & Lymphoma Society (USA) and the Wellcome Trust, are published in Nature.

Dr Rubina Ahmed, Director of Research at Blood Cancer UK, said: “Blood cancer is the third biggest cancer killer in the UK, with over 280,000 people currently living with the disease. Our Blood Cancer Action plan shed light on the shockingly low survival for acute myeloid leukaemia, with only around 2 in 10 surviving for 5 years, and we urgently need better strategies to save lives. Repurposing safe, widely available drugs like metformin means we could potentially get new treatments to people faster, without the need for lengthy drug development pipelines.”

̽��ֱ��next phase of this research will focus on clinical trials to test metformin’s effectiveness in people with changes in DNMT3A at increased risk of developing AML. With metformin already approved and widely used for diabetes, this repurposing strategy could dramatically reduce the time it takes to bring a new preventive therapy to patients.

Tanya Hollands, Research Information Manager at Cancer Research UK, who contributed funding for the lab-based screening in mice, said: “It's important that we work to find new ways to slow down or prevent AML in people at high risk. Therefore, it’s positive that the findings of this study suggest a possible link between a commonly-used diabetes drug and prevention of AML progression in some people. While this early-stage research is promising, clinical trials are now needed to find out if this drug could benefit people. We look forward to seeing how this work progresses.”

Reference
Gozdecka, M et al. Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis. Nature; 16 Apr 2025; DOI: 10.1038/s41586-025-08980-6

Adapted from a press release from Blood Cancer UK

Metformin, a widely used and affordable diabetes drug, could prevent a form of acute myeloid leukaemia in people at high risk of the disease, a study in mice has suggested. Further research in clinical trials will be needed to confirm this works for patients.

We’ve done the extensive research all the way from cell-based studies to human data, so we’re now at the point where we have a made a strong case for moving ahead with clinical trials

Brian Huntly

̽��ֱ�� of Cambridge

Brown lab mouse on blue gloved hand

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� 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.

Yes

Cambridge researchers developing brain implants for treating Parkinson’s disease

sc604 — Thu, 23 Jan 2025 10:33:21 +0000

As part of a £69 million funding programme supported by the Advanced Research + Invention Agency (ARIA), Professor George Malliaras from Cambridge’s Department of Engineering will co-lead a project that uses small clusters of brain cells called midbrain organoids to develop a new type of brain implant, which will be tested in animal models of Parkinson’s disease.

̽��ֱ��project led by Malliaras and Professor Roger Barker from the Department of Clinical Neurosciences, which involves colleagues from the ̽��ֱ�� of Oxford, the ̽��ֱ�� of Lund and BIOS Health, is one of 18 projects funded by ARIA as part of its Precision Neurotechnologies programme, which is supporting research teams across academia, non-profit R&D organisations, and startups dedicated to advancing brain-computer interface technologies.

̽��ֱ��programme will direct £69 million over four years to unlock new methods for interfacing with the human brain at the neural circuit level, to treat many of the most complex neurological and neuropsychiatric disorders, from Alzheimer’s to epilepsy to depression.

By addressing bottlenecks in funding and the lack of precision offered by current approaches, the outputs of this programme will pave the way for addressing a much broader range of conditions than ever before, significantly reducing the social and economic impact of brain disorders across the UK.

Parkinson’s disease occurs when the brain cells that make dopamine (a chemical that helps control movement) die off, causing movement problems and other symptoms. Current treatments, like dopamine-based drugs, work well early on, but can cause serious side effects over time.

In the UK, 130,000 people have Parkinson’s disease, and it costs affected families about £16,000 per year on average – more than £2 billion in the UK annually. As more people age, the number of cases will grow, and new treatments are urgently needed.

One idea is to replace the lost dopamine cells by transplanting new ones into the brain. But these cells need to connect properly to the brain’s network to fix the problem, and current methods don’t fully achieve that.

In the ARIA-funded project, Malliaras and his colleagues are working on a new approach using small clusters of brain cells called midbrain organoids. These will be placed in the right part of the brain in an animal model of Parkinson’s disease. They’ll also use advanced materials and electrical stimulation to help the new cells connect and rebuild the damaged pathways.

“Our ultimate goal is to create precise brain therapies that can restore normal brain function in people with Parkinson’s,” said Malliaras.

“To date, there’s been little serious investment into methodologies that interface precisely with the human brain, beyond ‘brute force’ approaches or highly invasive implants,” said ARIA Programme Director Jacques Carolan. “We’re showing that it’s possible to develop elegant means of understanding, identifying, and treating many of the most complex and devastating brain disorders. Ultimately, this could deliver transformative impact for people with lived experiences of brain disorders.”

Other teams funded by the programme include one at Imperial College London who is developing an entirely new class of biohybridised technology focused on engineering transplanted neurons with bioelectric components. A Glasgow-led team will build advanced neural robots for closed-loop neuromodulation, specifically targeting epilepsy treatment, while London-based Navira will develop a technology for delivering gene therapies across the blood-brain barrier, a crucial step towards developing safer and more effective treatments.

Adapted from an ARIA media release.

Cambridge researchers are developing implants that could help repair the brain pathways damaged by Parkinson’s disease.

Our ultimate goal is to create precise brain therapies that can restore normal brain function in people with Parkinson’s

George Malliaras

Science Photo Library via Getty Images

Substantia nigra in the human brain, illustration

Yes

Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest

cjb250 — Thu, 31 Oct 2024 10:00:09 +0000

Researchers in the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Tauopathies are neurodegenerative diseases characterised by the build-up in the brain of tau protein ‘aggregates’ within nerve cells. These include forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary disease driver, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as has been reported in football and rugby players), where tau build-up is one consequence of disease but results in degeneration of brain tissue.

There has been little progress in finding effective drugs to treat these conditions. One option is to repurpose existing drugs. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau build-up in a living organism.

To work around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish grow to maturity and are able to breed within two to three months and produce large numbers of offspring. Using genetic manipulation, it is possible to mimic human diseases as many genes responsible for human diseases often have equivalents in the zebrafish.

In a study published today in Nature Chemical Biology, Professor David Rubinsztein, Dr Angeleen Fleming and colleagues modelled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Dr Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity levels in cells – helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes – the ‘cell’s incinerators’ – to move to the surface of the cell, where they fused with the cell membrane and ‘spat out’ the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

Fellow joint author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further build-up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process.”

̽��ֱ��team hopes to test methazolamide on different disease models, including more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

̽��ֱ��research was supported by the UK Dementia Research Institute (through UK DRI Ltd, principally funded through the Medical Research Council), Tau Consortium and Wellcome.

Reference
Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer’s disease.

Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms

Ana Lopez Ramirez

Kuznetsov_Peter

Zebrafish

Yes

Licence type:

Public Domain

Monoclonal antibodies offer hope for tackling antimicrobial resistance

cjb250 — Mon, 16 Sep 2024 10:31:11 +0000

A team lead by researchers at the ̽��ֱ�� of Cambridge has developed a monoclonal antibody drug, using a technique involving genetically engineered mice, that may help prevent infection from Acinetobacter baumannii, a bacteria associated with hospital-acquired infections, which is particularly common in Asia.

A. baumannii bacteria can cause life-threatening respiratory illness and sepsis in vulnerable individuals, particularly in newborn babies whose immune systems have not fully developed. It is usually spread through contaminated surfaces, medical equipment and via contact with others. In recent years infections with strains of this bacteria that are resistant to almost every antibiotic available have become common.

Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge said “A. baumannii is good at sticking to medical equipment, and if people are vulnerable or don't have a particularly well-developed immune system, they can succumb to this infection and get aggressive pneumonia requiring ventilation – and in many cases, the patients can acquire the infection from the ventilation itself.

“ ̽��ֱ��bacteria are naturally resistant to many antimicrobials, but as they’re now found in hospitals, they’ve acquired resistance to almost everything we can use. In some hospitals in Asia, where the infections are most common, there isn't a single antibiotic that will work against them. They’ve become impossible to treat.”

In a study published today in Nature Communications, the team produced monoclonal antibodies using transgenic mice – mice that have been genetically-engineered to have a human-like immune system, producing human antibodies instead of mouse antibodies. They went on to show that these monoclonal antibodies were able prevent infection with A. baumannii derived from clinical samples.

Monoclonal antibodies are a growing area of medicine, commonly used to treat conditions including cancer (for example, Herceptin for treating some breast cancers) and autoimmune disease (for example, Humira for treating rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis).

Usually, monoclonal antibodies are developed from the antibodies of patients who have recovered from an infection, or they are designed to recognise and target a particular antigen. For example, monoclonal antibodies targeting the ‘spike protein’ of the SARS-CoV-2 coronavirus were explored as a way of treating COVID-19.

In the approach taken by the Cambridge team, however, transgenic mice were exposed to the outer membrane of A. baumannii bacteria, triggering an immune response. ̽��ֱ��researchers then isolated almost 300 different antibodies and tested which of these was the most effective at recognising live bacteria, identifying the single monoclonal antibody mAb1416 as the best.

Professor Baker said: “Using this method, we don't infect the mice with the live bacteria, but we instead immunise them using multiple different elements and let the mouse’s immune system work out which ones to develop antibodies against. Because these mice have ‘humanised’ immune systems, we wouldn’t then need to reengineer the antibodies to work in humans.”

̽��ֱ��team treated mice with mAb1416, and 24 hours later exposed them to A. baumannii isolated from a child with sepsis in an intensive care unit. They found that those mice treated with the drug saw a significant reduction in bacterial load in their lungs a further 24 hours later, compared to mice that were not treated.

All of the isolates used to produce and test the monoclonal antibodies were from patients in Ho Chi Minh City, Vietnam, but the isolate used to test mAb1416 was taken from a patient ten years later than the other isolates. This is important because it shows that mAb1416 was protective against A. baumannii bacteria that may have evolved over time.

Professor Baker said: “Using this technique, you can take any bacterial antigen or cocktail of antigens, rather than waiting for somebody that's recovered from a particular infection – who you assume has developed an appropriate antibody response – give it to the mice and extract the antibodies you think are the most important.”

More work is now needed to understand the mechanism by which mAb1416 protects against infection, as this could allow the team to develop an even more effective treatment. Any potential new drug will then need to be tested in safety trials in animals before being trialled in patients.

Professor Baker added: “We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there's no reason why this couldn’t become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.”

̽��ֱ��research was funded by the Bill & Melinda Gates Foundation, the UK Medical Research Council Newton Fund, the Viet Nam Ministry of Science and Technology, and Wellcome.

Professor Baker is a fellow at Wolfson College, Cambridge.

Reference
Baker, S, Krishna, A & Higham, S. Exploiting human immune repertoire transgenic mice to identify protective monoclonal antibodies against an extensively antimicrobial resistant nosocomial bacterial pathogen. Nat Comms; 12 Sept 2024; DOI: 10.1038/s41467-024-52357-8

Monoclonal antibodies – treatments developed by cloning a cell that makes an antibody – could help provide an answer to the growing problem of antimicrobial resistance, say scientists.

We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them

Stephen Baker

TopMicrobialStock (Getty Images)

A Petri dish with a culture of the Superbug Acinetobacter baumannii next to antibiotics

Yes

UK organisations release statistics for use of animals in research in 2023

Anonymous — Wed, 11 Sep 2024 08:00:00 +0000

̽��ֱ��statistics for the ̽��ֱ�� of Cambridge are available on our website as part of our ongoing commitment to transparency and openness around the use of animals in research.

This coincides with the publication of the Home Office’s report on the statistics of scientific procedures on living animals in Great Britain in 2023.

̽��ֱ��10 organisations carried out 1,435,009 procedures, 54% (over half) of the 2,681,686 procedures carried out on animals for scientific research in Great Britain in 2023. Of these 1,435,009 procedures, more than 99% were carried out on mice, fish and rats and 82% were classified as causing pain equivalent to, or less than, an injection.

̽��ֱ��10 organisations are listed below alongside the total number of procedures they carried out in 2023. This is the ninth consecutive year that organisations have come together to publicise their collective statistics and examples of their research.

Organisation	Number of Procedures (2023)
̽��ֱ�� of Cambridge	223,787
̽��ֱ�� of Oxford	194,913
̽��ֱ��Francis Crick Institute	192,920
UCL	176,019
̽��ֱ�� of Edinburgh	139,881
Medical Research Council	124,156
̽��ֱ�� of Manchester	110,885
King's College London	109,779
̽��ֱ�� of Glasgow	102,089
Imperial College London	60,580
TOTAL	1,435,009

In total, 69 organisations have voluntarily published their 2023 animal research statistics.

All organisations are committed to the ethical framework called the ‘3Rs’ of replacement, reduction and refinement. This means avoiding or replacing the use of animals where possible, minimising the number of animals used per experiment and optimising the experience of the animals to improve animal welfare. However, as institutions expand and conduct more research, the total number of animals used can rise even if fewer animals are used per study.

All organisations listed are signatories to the Concordat on Openness on Animal Research in the UK, which commits them to being more open about the use of animals in scientific, medical and veterinary research in the UK. More than 125 organisations have signed the Concordat, including UK universities, medical research charities, research funders, learned societies and commercial research organisations.

Wendy Jarrett, Chief Executive of Understanding Animal Research, which developed the Concordat on Openness, said:

“Animal research remains a small but vital part of the quest for new medicines, vaccines and treatments for humans and animals. Alternative methods are gradually being phased in, but, until we have sufficient reliable alternatives available, it is important that organisations that use animals in research maintain the public’s trust in them. By providing this level of information about the numbers of animals used, and the experience of those animals, as well as details of the medical breakthroughs that derive from this research, these Concordat signatories are helping the public to make up their own minds about how they feel about the use of animals in scientific research in Great Britain.”

Professor Anna Philpott, Head of the School of Biological Sciences at the ̽��ֱ�� of Cambridge, said:

“Cambridge research is changing how we understand health and ageing, and how we treat disease. Animal research continues to play a small but vital role in this work and in the development of ground-breaking new medical devices and drug treatments. We are committed to using animals only where there is no alternative as a means of making progress.”

Story adapted from a press release by Understanding Animal Research.

CASE STUDY: Egging on vital research

̽��ֱ��actin cytoskeleton is a system of long filaments, vital in embryonic development. Problems with its control have been linked to the kidney problems experienced by patients with the rare conditions called Lowe syndrome and Dent disease 2. But since the actin cytoskeleton is in all the cells of the body it has been very difficult to translate an understanding of it into a drug treatment.

Wellcome Trust Senior Research Fellow Dr Jenny Gallop at the ̽��ֱ�� of Cambridge has created a simpler version of the actin cytoskeleton that she can study in the lab. A key component is cytoplasm extracted from frog eggs.

Gallop’s lab keeps around 120 female frogs that are induced to lay eggs in a way that matches their natural cycles. This requires a hormone injection - just a mild discomfort to the frogs - every three to four months to make them ovulate. Over time, Gallop has refined her methods so that only half the original number of frogs are now needed.

This has enabled her to understand what might be going wrong in Lowe syndrome and Dent disease 2 – and realise that an existing drug might be able to help. Alpelisib has already been approved to safely treat breast cancer, and Gallop is now applying for approval to test whether it works to treat the kidney problems in patients with Dent disease 2.

Repurposing an existing drug means the long drug-development process has already been done. Conversations with people affected by the diseases inspire Gallop’s team to keep going. And the frogs have played a vital role in this decade-long journey.

Read the full story

̽��ֱ��10 organisations in Great Britain that carry out the highest number of animal procedures - those used in medical, veterinary and scientific research – have released their annual statistics today.

Jacqueline Garget

African Clawed Frogs held in water-filled tanks

Yes

Licence type:

Attribution

High cholesterol levels at a young age significant risk factor for atherosclerosis

cjb250 — Wed, 04 Sep 2024 15:00:18 +0000

̽��ֱ��research also suggests that people who are taking lipid-lowering drugs such as statins to lower their cholesterol levels should remain on them, even if their cholesterol levels have fallen, as stopping treatment could increase their risk of atherosclerosis.

Atherosclerosis is one of the major causes of heart and circulatory disease. It involves the hardening and narrowing of the vessels that carry blood to and from the heart. It is caused by the build-up of abnormal material called plaques – collections of fat, cholesterol, calcium and other substances circulating in the blood.

Atherosclerosis is largely considered a disease of the elderly and so most screening, prevention and intervention programmes primarily target those with high cholesterol levels, generally after the age of 50.

But in a study published today in Nature, a team led by scientists at the ̽��ֱ�� of Cambridge shows that high cholesterol levels at a younger age – particularly if those levels fluctuate – can be even more damaging than high cholesterol levels that only begin in later life.

To study the mechanisms that underlie atherosclerosis, scientists often use animal modes, such as mice. ̽��ֱ��mice will typically be fed a high fat diet for several weeks as adults to see how this leads to the build up of the plaques characteristic of the condition.

Professor Ziad Mallat and colleagues at the Victor Phillip Dahdaleh Heart and Lung Research Institute at the ̽��ֱ�� of Cambridge decided to explore a different approach – to see whether giving mice the same amount of high fat food but spread over their lifetime changed their atherosclerosis risk.

“When I asked my group and a number of people who are experts in atherosclerosis, no one could tell me what the result would be,” said Professor Mallat, a British Heart Foundation (BHF) Professor of Cardiovascular Medicine.

“Some people thought it would make no difference, others thought it would change the risk. In fact, what we found was that an intermittent high fat diet starting while the mice were still young – one week on, a few weeks off, another week on, and so on – was the worst option in terms of atherosclerosis risk.”

Armed with this information, his team turned to the Cardiovascular Risk in Young Finns Study, one of the largest follow-up studies into cardiovascular risk from childhood to adulthood. Participants recruited in the 1980s returned for follow-up over the subsequent decades, and more than 2,000 of them had received ultrasound scans of their carotid arteries when they were aged around 30 years and again at around 50 years.

Analysing the data, the team found that those participants who had been exposed to high cholesterol levels as children tended to have the biggest build of plaques, confirming the findings in mice.

“What this means is that we shouldn’t leave it until later in life before we start to look at our cholesterol levels,” Professor Mallat said. “Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life than we previously thought.”

̽��ֱ��mouse studies showed that fluctuating levels of cholesterol appeared to cause the most damage. Professor Mallat says this could explain why some people who are on statins but do not take them regularly remain at an increased risk of heart attack.

“If you stop and start your statin treatment, your body is being exposed to a yo-yo of cholesterol, which it doesn’t like, and it seems this interferes with your body’s ability to prevent the build-up of plaques,” he added.

̽��ֱ��reason why this is so damaging may come down to the effect that cholesterol has on specific types of immune cells known as ‘resident arterial macrophages’. These reside in your arteries, helping them to clear damaged cells and fatty molecules known as lipids, which include cholesterol, and stopping the build-up of plaques.

When the team examined these macrophages in their mouse models, they found that high cholesterol levels – and in particular, fluctuating cholesterol levels – changed them physically and altered the activity of their genes. This meant that the cells were no longer protective, but were instead detrimental, accelerating atherosclerosis.

̽��ֱ��research was funded by the British Heart Foundation.

Reference
Takaoka, M et al. Early intermittent hyperlipidaemia alters tissue macrophages to boost atherosclerosis. Nature; 4 Sept 2024; DOI: 10.1038/s41586-024-07993-x

Our risk of developing atherosclerosis – ‘furring’ of the arteries – can begin much earlier in life than was previously thought, highlighting the need to keep cholesterol levels low even when we are young, new research has discovered.

Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life

Ziad Mallat

SolStock (Getty Images)

Teenagers eating pizza by the river

Yes

Egging on vital research

jg533 — Thu, 11 Jul 2024 08:08:20 +0000

Jenny Gallop uses frog egg extract to figure out key cellular processes - which has helped understand and potentially treat two rare genetic diseases in humans.

Genetic study points to oxytocin as possible treatment for obesity and postnatal depression

cjb250 — Tue, 02 Jul 2024 15:00:18 +0000

Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.

While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the ̽��ֱ�� of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. ̽��ֱ��mothers also had obesity, but in addition had experienced postnatal depression.

To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).

Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.

Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”

TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.

Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.

Professor Sadaf Farooqi from the Institute of Metabolic Science at the ̽��ֱ�� of Cambridge said: “There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.

̽��ֱ��researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”

There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. ̽��ֱ��team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.

Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Reference
Li, Y, Cacciottolo, TM & Yin, N. Loss of Transient Receptor Potential Channel 5 Causes Obesity and Postpartum Depression. Cell; 2 July 2024; DOI: 10.1016/j.cell.2024.06.001

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. ̽��ֱ��discovery, reported on 2 July in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.

This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology. We need to be more understanding and sympathetic towards people who suffer with these conditions

Sadaf Farooqi

Olli Turho (Getty Images)

Illustration of a tired African American mother crying

Yes