��Ī - Wellcome-MRC ��Ī Stem Cell Institute

Lab-grown ‘mini-guts’ could change how we treat Crohn’s disease

cjb250 — Tue, 11 Jun 2024 09:31:24 +0000

��Ī scientists have grown ‘mini-guts’ in the lab to help understand Crohn’s disease, showing that ‘switches’ that modify DNA in gut cells play an important role in the disease and how it presents in patients.

‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

jg533 — Thu, 28 Mar 2024 10:03:44 +0000

Everyone has BRCA1 and BRCA2 genes, but mutations in these genes - which can be inherited - increase the risk of breast and ovarian cancer.

The study found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer.

This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such scale - normally these cells are only found in late-stage tumours.

The results raise the possibility of using existing immunotherapy drugs as early intervention to prevent breast cancer developing, in carriers of BRCA1 and BRCA2 gene mutations.

The researchers have received a ‘Biology to Prevention Award’ from Cancer Research UK to trial this preventative approach in mice. If effective, this will pave the way to a pilot clinical trial in women carrying BRCA gene mutations.

“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells - which in turn seem to be working to keep these immune cells at bay,” said Professor Walid Khaled in the ��Ī’s Department of Pharmacology and Wellcome-MRC ��Ī Stem Cell Institute, senior author of the report.

He added: “We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

“Drugs already exist that can overcome this block in immune cell function, but so far, they’ve only been approved for late-stage disease. No-one has really considered using them in a preventative way before.”

The results are published today in the journal Nature Genetics.

Risk-reducing surgery, in which the breasts are removed, is offered to those at increased risk of breast cancer. This can be a difficult decision for young women to make and can have a significant effect on body image and sexual relationships.

“The best way to prevent breast cancer is to really understand how it develops in the first place. Then we can identify these early changes and intervene,” said Khaled.

He added: “Late-stage breast cancer tends to be very unpredictable and hard to manage. As we make better and better drugs, the tumours just seem to find a way around it.”

Using samples of healthy breast tissue collected from 55 women across a range of ages, the researchers catalogued over 800,000 cells - including all the different types of breast cell.

The resulting Human Breast Cell Atlas is now available as a resource for other researchers to use and add to. It contains huge amounts of information on other risk factors for breast cancer including Body Mass Index (BMI), menopausal status, contraceptive use and alcohol consumption.

“We've found that there are multiple breast cell types that change with pregnancy, and with age, and it’s the combination of these effects - and others - that drives the overall risk of breast cancer,” said Austin Reed, a PhD student in the ��Ī’s Department of Pharmacology and joint first author of the report.

He added: “As we collect more of this type of information from samples around the world, we can learn more about how breast cancer develops and the impact of different risk factors - with the aim of improving treatment.”

One of the biggest challenges in treating breast cancer is that it is not just one disease, but many. Many different genetic variations can lead to breast cancer, and genetic risk interacts with other risk factors in complicated ways.

For example, it is known that the likelihood of breast cancer increases with age, but this risk is greatly reduced by pregnancy early in life. And age-associated risk is greatly increased in carriers of the breast cancer genes BRCA1 and BRCA2.

The new study aimed to understand how some of these risk factors interact, by characterising the different cell types in the human breast under many different physiological states.

The researchers used a technique called ‘single cell RNA-sequencing’ to characterise the many different breast cell types and states. Almost all cells in the body have the same set of genes, but only a subset of these are switched on in each cell – and these determine the cell’s identity and function. Single cell RNA-sequencing reveals which genes are switched on in individual cells.

“Breast cancer occurs around the world, but social inequalities mean not everyone has access to treatment. Prevention is the most cost-effective approach. It not only tackles inequality, which mostly affects low-income countries, but also improves disease outcome in high-income countries,” said Dr Sara Pensa, Senior Research Associate in the ��Ī’s Department of Pharmacology and joint first author of the study.

Breast tissue samples were provided by the Breast Cancer Now tissue bank.

The research was primarily funded by the Medical Research Council and Cancer Research UK.

Reference: Reed, A.D. et al: ‘A human breast cell atlas enables mapping of homeostatic cellular shifts in the adult breast.’ Nature Genetics, March 2024. DOI: 10.1038/s41588-024-01688-9

Researchers at the ��Ī have created the world’s largest catalogue of human breast cells, which has revealed early cell changes in healthy carriers of BRCA1 and BRCA2 gene mutations.

We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

Walid Khaled

Angiola Harry on Unsplash

Woman holds pink breast cancer awareness ribbon. Credit angiola-harry-unsplash

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£3 million UKRI funding to support research into better health, ageing, and wellbeing

cjb250 — Mon, 12 Feb 2024 10:20:56 +0000

UKRI funding of £3 million is awarded today to support a new research cluster, as part of the MRC National Mouse Genetics Network (MRC NMGN), focused on improving existing models of ageing with the aim of improving lifelong health and wellbeing. The cluster is led by scientists at the Universities of ��Ī and Newcastle.

The MRC NMGN focuses on age-related biological changes in model organisms, particularly the mouse, to try and improve our understanding and diagnosis of the most challenging disease area of our time - and generate therapeutic avenues.

This award brings the UKRI’s total investment in the MRC NMGN to £25 million.

The need to improve how people age has become a major requirement of modern societies. Regular increases in life expectancy result in older populations, making healthy ageing essential for a better quality of life and a reduced burden on health and social services.

Understanding the biological mechanisms underlying the ageing process is paramount for tackling the challenges brought about by our older populations.

The new tools generated as a result of this research will be made available to the scientific community to improve understanding of the ageing process, and to provide a resource for preclinical testing and intervention.

Professor Walid Khaled from ��Ī’s Wellcome-MRC ��Ī Stem Cell Institute and Department of Pharmacology, and Co-lead of the new MRC National Mouse Genetics Network Ageing Cluster, said: “I am very pleased to be co-leading this project from ��Ī and I am looking forward to working with the rest of the team from around the UK. ‘Prevention is better than cure’ and so our project will generate a reference map that we will use in the future to assess interventions that could prevent ageing related health decline.”

Professor Anne Ferguson-Smith, Pro-Vice-Chancellor (Research & International Partnerships) and Arthur Balfour Professor of Genetics at ��Ī, said: "Collaboration is central to our research activities in ��Ī. The new Ageing Cluster is a fine example of multiple institutions working together to add value and bring exciting new insight and expertise to advance the critically important field of healthy ageing. I am proud to be part of this important initiative which can deliver new routes to improved health span."

Professor David Burn, Pro Vice Chancellor, Faculty of Medical Sciences at Newcastle University, added: "I am delighted that Newcastle University is an important part of the UKRI Mouse Genetics Network Ageing Cluster. This cluster offers researchers the opportunity to develop new animal models so that we may better understand ageing. This, in turn, will allow us to translate this research into extending healthy lifespan in humans in the future.”

The University is bringing together its world leading expertise to tackle the topic of extending the healthy lifespan. Scientists in the School of Biological Sciences are addressing some of the biggest questions in human biology, including: What if we could identify those at risk of developing chronic age-related conditions before they present in the clinic? What if we could intervene before any symptoms arise and prevent disease onset?

UKRI’s strategy for 2022-2027 aims to harness the full power of the UK’s research and innovation system to tackle major national and global challenges. A total of £75m has been allocated to the theme of Securing better health, ageing and wellbeing, which aims to improve population health, tackle the health inequalities affecting people and communities, and advance interventions that keep us healthier for longer.

The ��Ī has received UKRI funding for research on age-related biological changes in model organisms as part of a national collaboration.

‘Prevention is better than cure’ and so our project will generate a reference map that we will use in the future to assess interventions that could prevent ageing related health decline

Walid Khaled

Lauren Christy Pitcher (University Biomedical Services)

White mouse

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Role of inherited genetic variants in rare blood cancer uncovered

jg533 — Wed, 17 Jan 2024 10:03:16 +0000

Large-scale genetic analysis has helped researchers uncover the interplay between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

Researchers from the ��Ī, Wellcome Sanger Institute, and collaborators, combined various comprehensive data sets to understand the impact of both cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

The study, published in the journal Nature Genetics, describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

This analysis has an impact on current clinical predictions of disease development in individuals. Further research is required to understand the biological mechanisms behind how these inherited genetic variants influence the chances of developing rare blood cancer. In the future, this knowledge could aid drug development and interventions that reduce the risk of disease.

Myeloproliferative neoplasms, MPNs, are a group of rare, chronic, blood cancers. There are around 4,000 cases of MPN in the UK each year. These occur when the bone marrow overproduces blood cells, which can result in blood clots and bleeding. MPNs can also progress into other forms of blood cancer, such as leukaemia.

In the population, there is a large amount of natural variation between individuals’ blood cells, which can affect the amount of blood cells a person has and their particular traits. This is because multiple different genes can influence blood cell features in an individual. During routine blood tests, researchers take known information about these genes and analyse the variation to give a genetic risk score, which is how likely that individual is to develop a disease over their lifetime.

MPNs have been linked to random somatic mutations in certain genes including in a gene called JAK2. However, mutated JAK2 is commonly found in the global population, and the vast majority of these individuals do not have or go on to develop MPN.

Whilst previous studies have identified over a dozen associated inherited genetic variants that increase the risk of MPN, these studies insufficiently explain why most individuals in the population do not go on to develop MPN.

This new study, from the Wellcome Sanger Institute and collaborators, combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will go on to cause MPN. They also found that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, thus, mimicking disease.

Dr Jing Guo, from the ��Ī and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk. By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

Professor Nicole Soranzo, co-senior author from the ��Ī, the Wellcome Sanger Institute, and Human Technopole, Italy, said: “There has been increasing realisation that human diseases have complex causes involving a combination of common and rare inherited genetic variants with different severity.

“We have previously shown that variation in blood cell parameters and function has complex genetic variability by highlighting thousands of genetic changes that affect different gene functions. Here, we show for the first time that common variants in these genes also affect blood cancers, independent of causative somatic mutations. This confirms a new important contribution of normal variability beyond complex disease, contributing to our understanding of myeloproliferative neoplasms and blood cancer more generally.”

Dr Jyoti Nangalia, co-senior author from the Wellcome-MRC ��Ī Stem Cell Institute at the ��Ī, and the Wellcome Sanger Institute, said: “We have a good understanding of the genetic causes of myeloproliferative neoplasms. In fact, many of these genetic mutations are routine diagnostic tests in the clinic. However, these mutations can often be found in healthy individuals without the disease.

“Our study helps us understand how inherited DNA variation from person to person can interact with cancer-causing mutations to determine whether disease occurs in the first place, and how this can alter the type of any subsequent disease that emerges. Our hope is that this information can be incorporated into future disease prediction efforts.”

This research was funded by Cancer Research UK and Wellcome.

Reference

J Guo, K Walter, P M Quiros, et al. ‘Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.’ Jan 2024, Nature Genetics. DOI: 10.1038/s41588-023-01638-x

Adapted from a press release by the Wellcome Sanger Institute

Combining three different sources of genetic information has allowed researchers to further understand why only some people with a common mutation go on to develop rare blood cancer.

Our hope is that this information can be incorporated into future disease prediction efforts

Jyoti Nangalia

Photo by Sangharsh Lohakare on Unsplash

DNA

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Developing ‘kinder’ treatments for a devastating childhood cancer

cjb250 — Wed, 20 Sep 2023 15:00:35 +0000

Neuroblastomas can be devastating to children and their families and the treatments can be harsh. But thanks to scientists, some tadpoles and a little poetry, improved treatments could soon be on their way.

Scientists develop test to identify people at risk of developing acute myeloid leukaemia and related cancers

jg533 — Thu, 24 Aug 2023 15:14:28 +0000

Researchers at the Wellcome-MRC ��Ī Stem Cell Institute (CSCI), the ��Ī’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analysed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists created 'MN–predict', a platform for predicting the risk of developing blood cancers such as acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10- to 15-year period.

The test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukaemia prevention.

Professor George Vassiliou, senior author of the study, said: “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukaemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.”

The myeloid neoplasms are a group of related cancers encompassing acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists have discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells - the cells responsible for normal blood formation. The mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukaemia.

While mutations that promote cell growth are common, leukaemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

The work is published today in the journal Nature Genetics.

Dr Muxin Gu, first author of the paper, said: “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers, and use novel treatment to prevent the cancers developing.”

Dr Pedro M Quiros, joint senior author of the study, said: “Despite some recent advances in their treatment, unfortunately these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favour of treating the full-blown disease.”

The research and development of MN-Predict was funded by Cancer Research UK and the Leukaemia and Lymphoma Society. Scientists from the Early Cancer Institute, ��Ī, University of Bristol, University of Oviedo (Spain), University of York, AstraZeneca (UK), German Cancer Research Center (DKFZ, Germany), St James's Hospital, Leeds (UK) and University of Pavia (Italy) also participated in the study.

Reference

Gu M, Cheloor-Kovilakam S, Dunn W, Marando L, Barcena C, Mohorianu I, Smith A, Kar S, Fabre M, Gerstung M, Cargo C, Malcovati L, Quiros P, Vassiliou G: 'Multiparameter prediction of myeloid neoplasia risk.' Nature Genetics. 2023. DOI: 10.1038/s41588-023-01472-1

Adapted from a press release by the Wellcome-MRC ��Ī Stem Cell Institute.

The new ‘MN-predict’ platform will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.

George Vassiliou

Nguyễn Hiệp on Unsplash

Person having a blood test

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Wellcome awards ��Ī £18 million for two Discovery Research Platforms

cjb250 — Wed, 03 May 2023 23:01:48 +0000

The Discovery Research Platforms (DRPs) will be home to transformative research environments that empower researchers to overcome specific barriers holding back progress in their fields of research. They aim to accelerate research for the benefit of the wider global research community, with researchers and teams developing new tools, knowledge and capabilities to help unlock new findings about life, health and wellbeing.

Michael Dunn, Director of Discovery Research at Wellcome, said: “Discovery research is essential to advancing our ability to understand and improve health. But in addition to researchers’ bold and imaginative ideas, we know that new tools, methods and capabilities are also needed to unlock new avenues of research that can disrupt and transform the research landscape globally.”

The two ��Ī DRPs, which will receive £9million each over seven years, are:

The Discovery Research Platform for Tissue Scale Biology – which seeks to move stem cell biology to the tissue and organ scale of research, creating a new network of local and international researchers to enable strategies that capitalise on new in vitro models to develop better treatments for human patients.

Professor Bertie Gottgens, Director of the Wellcome-MRC ��Ī Stem Cell Institute, said: "I am delighted that Wellcome will support our ambition to build a new Discovery Research Platform to provide international leadership for Tissue Scale Biology.

“Our vision for this platform resulted from extensive discussions across the wider ��Ī Stem Cell community and the formation of a highly interdisciplinary team connecting the ��Ī Stem Cell Institute with the West ��Ī Engineering/Technology community. It also incorporates exciting new training partnerships with Anglia Ruskin University and the ��Ī Academy for Science and Technology, to help us fill critical skills shortages and widen participation across ��Ī."

The Discovery Research Platform for Integrating Metabolic and Endocrine Science – which aims to address practical barriers preventing data integration across metabolic and endocrine science, investigate how hormones control metabolic processes and how these can go wrong in disorders such as obesity, diabetes and cachexia, and create tools to facilitate global access to this data. The Platform will encompass research on molecules, cells and model organisms but will have a major focus on discovery science in human participants, patients and populations.

The funding will sustain key technological platforms and the highly-trained staff needed to support these. It will also underpin partnerships with research centres across the UK as well as in Germany and Denmark, all of which will provide new opportunities for training.

The Platform will have a major focus on the broad dissemination of integrated data and the creation of tools to facilitate access by the global community. The award will also accelerate the team’s drive to make transformational changes to research culture with new initiatives in widening access and open science reinforced by a new programme of research into the culture of biomedical science, in collaboration with Dr Yeun Joon Kim, Associate Professor at the ��Ī Judge Business School.

Professor Sir Stephen O’Rahilly, Co-Director at the Wellcome-MRC Institute of Metabolic Science and Director of the MRC Metabolic Diseases Unit, said: “Wellcome’s support of our scientists’ research in metabolism and endocrinology, and of the technological platforms that underpin it, has been critically important to the discoveries we have made and the translation of that research into improvements in health. This new award will allow us to build on those achievements and deliver more ground-breaking science in a manner that emphasises openness, diversity and a spirit of collaboration.”

��Ī has been awarded two of Wellcome’s eight new Discovery Research Platforms, the global charitable foundation announced today.

Odra Noel

Acinar tissue - The flowers of diabetes

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The off-patent drug that could protect us from future COVID-19 variants

cjb250 — Mon, 05 Dec 2022 16:00:00 +0000

��Ī scientists have identified a drug that can be repurposed to prevent COVID-19 in research involving a unique mix of ‘mini-organs’, donor organs, animal studies and patients.

�������������Ī - Wellcome-MRC �������������Ī Stem Cell Institute

Lab-grown ‘mini-guts’ could change how we treat Crohn’s disease

‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

£3 million UKRI funding to support research into better health, ageing, and wellbeing

Role of inherited genetic variants in rare blood cancer uncovered

Developing ‘kinder’ treatments for a devastating childhood cancer

Scientists develop test to identify people at risk of developing acute myeloid leukaemia and related cancers

Reference

Wellcome awards �������������Ī £18 million for two Discovery Research Platforms

The off-patent drug that could protect us from future COVID-19 variants

��Ī - Wellcome-MRC ��Ī Stem Cell Institute

Wellcome awards ��Ī £18 million for two Discovery Research Platforms