̽��ֱ�� of Cambridge - blood

First ever clinical trial of lab-grown red blood cell transfusion

cjb250 — Mon, 07 Nov 2022 00:05:46 +0000

̽��ֱ��manufactured blood cells were grown from stem cells from donors. ̽��ֱ��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.

Chief Investigator Professor Cedric Ghevaert, Professor in Transfusion Medicine and Consultant Haematologist at the ̽��ֱ�� of Cambridge and NHS Blood and Transplant, 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.”

̽��ֱ��RESTORE trial is a joint research initiative by NHS Blood and Transplant and the ̽��ֱ�� of Bristol, working with the ̽��ֱ�� of Cambridge, Guy’s and St Thomas’ NHS Foundation Trust, NIHR Cambridge Clinical Research Facility, and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust. It is part-funded by a National Institute for Health and Care Research (NIHR) grant.

Professor Ashley Toye, Professor of Cell Biology at the ̽��ֱ�� of Bristol and Director of the NIHR Blood and Transplant Unit in red cell products, said: “This challenging and exciting trial is a huge stepping stone for manufacturing blood from stem cells. This is the first-time lab grown blood from an allogeneic donor has been transfused and we are excited to see how well the cells perform at the end of the clinical trial.”

̽��ֱ��trial is studying the lifespan of the lab grown cells compared with infusions of standard red blood cells from the same donor. ̽��ֱ��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.

̽��ֱ��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.

Co-Chief Investigator Dr Rebecca Cardigan, Head of Component Development NHS Blood and Transplant and Affiliated Lecturer at the ̽��ֱ�� 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.”

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

̽��ֱ��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. ̽��ֱ��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.

John James OBE, Chief Executive of the Sickle Cell Society, said: “This research offers real hope for those difficult to transfuse sickle cell patients who have developed antibodies against most donor blood types. However, we should remember that the NHS still needs 250 blood donations every day to treat people with sickle cell and the figure is rising. ̽��ֱ��need for normal blood donations to provide the vast majority of blood transfusions will remain. We strongly encourage people with African and Caribbean heritage to keep registering as blood donors and start giving blood regularly.”

Dr Farrukh Shah, Medical Director of Transfusion for NHS Blood and Transplant, said: “Patients who need regular or intermittent blood transfusions may result develop antibodies against minor blood groups which makes it harder to find donor blood which can be transfused without the risk of a potentially life-threatening reaction. This world leading research lays the groundwork for the manufacture of red blood cells that can safely be used to transfuse people with disorders like sickle cell. ̽��ֱ��need for normal blood donations to provide the vast majority of blood will remain. But the potential for this work to benefit hard to transfuse patients is very significant.”

Adapted from a press release from NHS Blood and Transplant

Cambridge researchers are taking part in the world’s first clinical trial of red blood cells that have been grown in a laboratory for transfusion into another person.

If our trial 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

Cedric Ghevaert

First ever clinical trial of lab-grown red blood cell transfusion

NHS Blood and Transplant

Cell culture flasks in the incubator during manufacture of red blood cells

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 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 – as here, 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.

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Cambridge researchers change donor kidney blood type

fpjl2 — Mon, 15 Aug 2022 10:18:07 +0000

Researchers have been able to alter the blood type of deceased donor kidneys using “molecular scissors”.

Blood test to monitor cancer up to ten times more sensitive than current methods

Anonymous — Wed, 17 Jun 2020 18:00:00 +0000

In the coming years, this method and others based on this approach could lead to tests that more accurately determine if a patient is likely to relapse after treatment and could pave the way for the development of pinprick home blood tests to monitor patients. ̽��ֱ��research, funded by Cancer Research UK, is published in the journal Science Translational Medicine

̽��ֱ��technique uses personalised genetic testing of a patient’s tumour to search blood samples for hundreds of different genetic mutations in circulating tumour DNA (ctDNA); DNA released by cancer cells into the bloodstream.

Combined with new methods to analyse this data to remove background noise and enhance the signal, the team was able to reach a level of sensitivity that in some cases could find one mutant DNA molecule among a million pieces of DNA – approximately ten times more sensitive than previous methods.

Dr Nitzan Rosenfeld, senior group leader at the Cancer Research UK Cambridge Institute who led the team that conducted this research, said: “Personalised tests that can detect if cancer is still present, or find it early if it is returning, are now being tested in clinical trials.

While this may be several years away from clinical use, our research shows what is possible when we push such approaches to an extreme. It demonstrates that the levels of sensitivity we’ve come to accept in recent years in relation to testing for ctDNA can be dramatically improved. At present this is still experimental, but technology is advancing rapidly, and in the near future tests with such sensitivity could make a real difference to patients.”

Detecting ctDNA in blood samples is what is known as a ‘liquid biopsy’. It allows doctors to find out more about a patient’s cancer without the need for invasive surgery. ̽��ֱ��technique is important for monitoring cancer patients, particularly after they’ve received treatment, as it can be an indicator of whether the treatment was successful and if the patient might relapse. In some situations, other types of tests can be used to detect some cancers before they display any symptoms or show up on a scan.

Currently, the sensitivity of the methods depends on having a high enough number of mutant pieces of DNA, either relative to background DNA or in absolute numbers. When the amount of ctDNA is low, a test can produce a negative result even if a patient has residual cancer in their body that could lead to relapse.

A single tumour will contain many different mutations that caused the cancer to form. While some of them are commonly known across certain cancer types, such as EGFR in lung cancer, the overall set of mutations for a tumour varies from person to person. By analysing the genetic makeup of an individual’s tumour and targeting a set of mutations in a personalised way, liquid biopsies to monitor cancer can become much more sensitive.

Until recently, these personalised liquid biopsies have searched for around 10-20 mutations in the blood and up to around 100 at most. In the material from a tube of blood, these would be able to detect ctDNA to levels on the range of one mutant molecule among 30,000 pieces of DNA.

This new technique looks for hundreds and sometimes thousands of mutations in each blood sample, routinely achieving a sensitivity of one mutant molecule per 100,000, and under optimal conditions can reach a level measured in parts per million.

̽��ֱ��researchers describe traditional liquid biopsies as like looking for a needle in a haystack. This new approach of using personalised genetic profiles to search for many different mutations rather than just one, increases the number of ‘needles’ that can be found, making chances of success more likely.

They also say the ‘haystack’ itself could be made smaller; as the methods developed for this research could mean that smaller and smaller amounts of blood could be required for the test to still work. Eventually, this could lead to tests that would require only a pinprick of blood – a procedure that patients could perform at home – that would then be sent to a lab for analysis. This would not only mean fewer visits to the hospital, but would also allow the patient to be more frequently monitored.

̽��ֱ��researchers and their collaborators studied samples from 105 cancer patients, testing the method on small sets of patients with five different cancer types, with both early and late stage disease.

̽��ֱ��method showed promising results and was able to detect ctDNA at high sensitivity in patients with advanced breast and melanoma cancer, and in patients with glioblastoma, which is notoriously difficult to detect in blood. ̽��ֱ��test was also able to detect ctDNA in patients with earlier-stage disease, where the level of ctDNA in the blood is much lower and difficult to find. This included patients with lung or breast cancer, as well as patients with early-stage melanoma who had already had surgery, which makes detection even more difficult.

In ongoing studies funded by Cancer Research UK, the team and their collaborators plan to use this method to measure ctDNA levels in individuals who are at high risk of developing cancer to help refine future tests for cancer early detection.

Michelle Mitchell, chief executive of Cancer Research UK, said: “Liquid biopsies have the potential to revolutionise all aspects of cancer care, from early detection to personalised treatment and monitoring. As a field that relies heavily on technology, this kind of proof-of-concept research is incredibly important for us to invest in as a charity, as it’s what makes potential future leaps in the use of liquid biopsies possible, and ultimately save more lives.”

Reference:
Jonathan C. M. Wan et al. ‘ctDNA monitoring using patient-specific sequencing and integration of variant reads.’ Science Translational Medicine (2020). DOI: 10.1126/scitranslmed.aaz8084

Adapted from a Cancer Research UK press release.

A new method of analysing cancer patients’ blood for evidence of the disease could be up to ten times more sensitive than previous methods according to new research led by the ̽��ֱ�� of Cambridge.

While this may be several years away from clinical use, our research shows what is possible when we push such approaches to an extreme

Nitzan Rosenfeld

NCI Center for Cancer Research

Human Colon Cancer Cells

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Scientists create ‘genetic atlas’ of proteins in human blood

cjb250 — Wed, 06 Jun 2018 17:00:44 +0000

̽��ֱ��study, published today in the journal Nature, characterised the genetic underpinnings of the human plasma ‘proteome’, identifying nearly 2,000 genetic associations with almost 1,500 proteins. Previously, there was only a small fraction of this knowledge, mainly because researchers could measure only a few blood proteins simultaneously in a robust manner.

̽��ֱ��researchers used a new technology (“SOMAscan”) developed by a company, SomaLogic, to measure 3,600 proteins in the blood of 3,300 people. They then analysed the DNA of these individuals to see which regions of their genomes were associated with protein levels, yielding a four-fold increase on previous knowledge.

“Compared to genes, proteins have been relatively understudied in human blood, even though they are the ‘effectors’ of human biology, are disrupted in many diseases, and are the targets of most medicines,” says Dr Adam Butterworth from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, a senior author of the study. “Novel technologies are now allowing us to start addressing this gap in our knowledge.”

One of the uses for this genetic map is to identify particular biological pathways that cause disease, exemplified in the paper by pinpointing specific pathways that lead to Crohn’s disease and eczema.

“Thanks to the genomics revolution over the past decade, we’ve been good at finding statistical associations between the genome and disease, but the difficulty has been then identifying the disease-causing genes and pathways,” says Dr James Peters, one of the study’s principal authors. “Now, by combining our database with what we know about associations between genetic variants and disease, we are able to say a lot more about the biology of disease.”

In some cases, the researchers identified multiple genetic variants influencing levels of a protein. By combining these variants into a ‘score’ for that protein, they were able to identify new associations between proteins and disease. For example, MMP12, a protein previously associated with lung disease was found to be also related to heart disease – however, whereas higher levels of MMP12 are associated with lower risk of lung disease, the opposite is true in heart disease and stroke; this could be important as drugs developed to target this protein for treating lung disease patients could inadvertently increase the risk of heart disease.

MSD scientists were instrumental in highlighting how the proteomic genetic data could be used for drug discovery. For example, in addition to highlighting potential side-effects, findings of the study can further aid drug development through novel insights on protein targets of new and existing drugs. By linking drugs, proteins, genetic variation and diseases, the team has suggested existing drugs that could potentially also be used to treat a different disease, and increased confidence that certain drugs currently in development might be successful in clinical trials.

̽��ֱ��researchers are making all of their results openly available for the global community to use.

“Our database is really just a starting point,” says first author Benjamin Sun, also from the Department of Public Health and Primary Care. “We’ve given some examples in this study of how it might be used, but now it’s over to the research community to begin using it and finding new applications.”

Caroline Fox MD, Vice President and Head of Genetics and Pharmacogenomics at MSD, adds: “We are so pleased to participate in this collaboration, as it is a great example of how a public private partnership can be leveraged for research use in the broader scientific community.”

̽��ֱ��research was funded by MSD*, National Institute for Health Research, NHS Blood and Transplant, British Heart Foundation, Medical Research Council, UK Research and Innovation, and SomaLogic.

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Although our DNA provides our individual blueprint, it is the variations in the structure, function and amount of the proteins encoded by our genes which determine our susceptibility to disease and our response to medicines. This study provides exciting new insight into how proteins in the blood are controlled by our genetic make-up and opens up opportunities for developing new treatments for heart and circulatory disease.”

* MSD (trademark of Merck & Co., Inc., Kenilworth, NJ USA)

Reference
Sun, BB et al. Genomic atlas of the human plasma proteome. Nature; 7 June 2018; DOI: 10.1038/s41586-018-0175-2

An international team of researchers led by scientists at the ̽��ֱ�� of Cambridge and MSD has created the first detailed genetic map of human proteins, the key building blocks of biology. These discoveries promise to enhance our understanding of a wide range of diseases and aid development of new drugs.

Compared to genes, proteins have been relatively understudied in human blood, even though they are the ‘effectors’ of human biology, are disrupted in many diseases, and are the targets of most medicines

Adam Butterworth

qimono

Red blood cells

Researcher Profile: Benjamin Sun

“My work involves analysing big 'omic' data,” says Benjamin Sun, a clinical medical student on the MB-PhD programme at Cambridge. By this, he means data from genomic and proteomic studies, for example – terabytes of ‘big data’ that require the use of supercomputer clusters to analyse.

“My aim is to understand how variation in the human genome affects protein levels in blood, which I hope will allow us to better understand processes behind diseases and help inform drug targeting.”

Benjamin did pre-clinical training at Cambridge before intercalating – taking time out of his medical training to study a PhD, funded by an MRC-Sackler Scholarship, at the Department of Public Health and Primary Care.

“Having completed my PhD, I am currently spending the final two years of my programme at the Clinical School to complete my medical degree. My aim is to become an academic clinician like many of the inspiring figures here at the Cambridge. Balancing clinical work with research can sometimes be tough but definitely highly rewarding.”

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Blood and bodies: the messy meanings of a life-giving substance

amb206 — Thu, 03 May 2018 12:00:00 +0000

What is blood? Today we understand this precious fluid as essential to life. In medieval and early modern Europe, definitions of blood were almost too numerous to locate. Blood was simultaneously the red fluid in human veins, a humour governing temperament, a waste product, a cause of corruption, a source of life and a medical cure.

In 1628, William Harvey, physician to James I and alumnus of Gonville & Caius College, made a discovery that changed the course of medicine and science. As the result of careful observation, he deduced that blood circulated around the body. Harvey’s discovery not only changed the way blood was thought to relate to the heart but revolutionised early science by demanding that human physiology be examined through empirical observation rather than philosophical discourse.

This turning point, and its profound repercussions for ideas about blood, is one of many strands explored in Blood Matters: Studies of European Literature and Thought,. A collection of essays, edited by Bonnie Lander Johnson (English Faculty, Cambridge ̽��ֱ��) and Eleanor Decamp, it examines blood from a variety of literary, historical and philosophical perspectives.

“ ̽��ֱ��strength of the collection is that, in a series of themed headings, it brings together scholarship on blood to bridge the conventional boundaries between disciplines,” says Lander Johnson. “ ̽��ֱ��volume includes historical perspectives on practical uses of blood such as phlebotomy, butchery, alchemy and birth. Through literary approaches, it also examines metaphoric understandings of blood as wine, social class, sexual identity, family, and the self.”

Contributors include several Cambridge academics. Hester Lees-Jeffries (English Faculty) writes about bloodstains in Shakespeare (most notable, of course, in Macbeth) and early modern textile culture. Heather Webb (Modern and Medieval Languages) looks at medieval understandings of blood as a spirit that existed outside the body, binding people and communities together. Joe Moshenska (English Faculty) examines the classical literary trope of trees that bleed when their branches are broken.

“ ̽��ֱ��idea for the book came from my previous work on chastity. I was struck that early modern writing about the body is all about fluids, especially blood. Blood was perceived as the vehicle for humours, the essence of being and the spirit – and something that could flow between people,” says Lander Johnson.

“I became fascinated by the fact that we use this word all the time but we have no real sense of what we mean. Our predecessors used it even more frequently and yet there was no scholarship that could help me to begin to understand how many things blood meant for them. A conference at Oxford in 2014 brought together a group of people working in related fields. ̽��ֱ��book reflects the excitement of those three days.”

Definitions of blood in Western European medical writing during the period covered by the book are changeable and conflicting. “ ̽��ֱ��period’s many figurative uses of ‘blood’ are even more difficult to pin down. ̽��ֱ��term appeared in almost every sphere of life and thought and ran through discourses as significant as divine right theory, doctrinal and liturgical controversy, political reform, and family and institutional organisation,” says Lander Johnson.

“Blood, of course, was at the centre of the religious schism that split 16th-century society. ̽��ֱ��doctrinal dispute over transubstantiation caused ongoing disagreements over the degree to which the bread and wine taken during Mass were materially altered into the body and blood of Christ or merely symbolic.”

̽��ֱ��role of blood in sex and reproduction meant that it was routinely described as a force capable of both generation and corruption. Menstrual blood is a case in point. Menstruation was seen as a vital and purifying process, part of a natural cycle essential to human life. But menstrual blood and menstruating women were also thought to be corrupting.

In Shakespeare’s plays, blood makes many appearances, both spoken and staged, from bleeding wounds to the rebellious ‘high’ blood of youth. Lander Johnson examines Romeo and Juliet’s love affair in the light of early modern beliefs about weaning and sexual appetites.

“Writing about birth and infancy reveals that early moderns were as anxious about their children’s health as we are but for them the pressing questions were: should I breastfeed my baby myself or give it to a wet nurse? How and when should I wean it to food? What sort of food?” she says.

“ ̽��ֱ��wrong decision at this early stage of life could have a fatal outcome and was thought to not only form the child’s blood in either a healthy or corrupted state but also to shape the child’s moral appetites for the rest of their lives.”

Blood is synonymous with family and, in elite circles, with dynasty. Contributor Katharine Craik (Oxford Brookes ̽��ֱ��) explores character and social class through references to blood in Shakespeare’s Henry IV and Henry V. In these plays about warfare and the relationships between royalty and common men, blood is often a substance that eliminates the differences between soldiers who die together in arms, their blood mingling in the dirt of the battlefield.

“Frequently these same descriptions turn into assertions of an essential difference between aristocratic and vulgar bloods,” says Lander Johnson. “Shakespeare is particularly inventive at building character through distinctions of this kind.”

In contrast, Ben Parsons (Leicester ̽��ֱ��) looks at blood and adolescence in the context of the medieval classroom where ‘too much blood’ was understood to cause wild and unruly behaviour. Medieval pedagogues were concerned about how the ‘full blood’ of students ought to be managed through the kind of material they were asked to read and when, the sort of food they ate while learning, and the style of punishment administered to those who were inattentive.

Blood Matters makes a valuable contribution to the history of the body and its place in literature and popular thought. It draws together scholarship that offers insight into both theory and practice during a period that saw the beginnings of empiricism and an overturning of the folklore that governed early medicine.

Today's scientists understand blood as a liquid comprising components essential to good health. But English remains a language peppered with references to blood that hint at our conflicted relationship with a liquid vital to human life.

A collection of essays explores understandings of a vital bodily fluid in the period 1400-1700. Its contributors offer insight into both theory and practice during a period that saw the start of empiricism and an overturning of the folklore that governed early medicine.

̽��ֱ��book brings together scholarship on blood to bridge the conventional boundaries between disciplines.

Bonnie Lander Johnson

'Reproduced by kind permission of the Syndics of Cambridge ̽��ֱ�� Library (Keynes.D.2.7)

Detail from William Harvey's De motu cordis (experiment confirming direction of blood flow)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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A BLUEPRINT for blood cells: Cambridge researchers play leading role in major release of epigenetic studies

cjb250 — Thu, 17 Nov 2016 17:00:15 +0000

̽��ֱ��studies are part of BLUEPRINT, a large-scale research project bringing together 42 leading European universities, research institutes and industry entrepreneurs, with close to €30 million of funding from the EU. BLUEPRINT scientists have this week released a collection of 26 publications, part of a package of 41 publications being released by the International Human Epigenome Consortium.

One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single stem cell and how information encoded in different parts of our genome are made available to be used by different cell types. Scientists have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. ̽��ֱ��identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome – the epigenome – which acts as a blueprint unique to each cell type and developmental stage.

Unlike the genome, the epigenome changes as cells develop and in response to changes in the environment. Defects in the proteins that read, write and erase the epigenetic information are involved in many diseases. ̽��ֱ��comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes.

“This huge release of research papers will help transform our understanding of blood-related and autoimmune diseases,” says Professor Willem H Ouwehand from the Department of Haematology at the ̽��ֱ�� of Cambridge, one of the Principal Investigators of BLUEPRINT. “BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health.”

Among the papers led by Cambridge researchers, Professor Nicole Soranzo and Dr Adam Butterworth have co-led a study analysing the effect of genetic variants in our DNA sequence on our blood cells. Using a genome-wide association analysis, the team identified more than 2,700 variants that affect blood cells, including hundreds of rare genetic variants that have far larger effects on the formation of blood cells than the common ones. Interestingly, they found genetic links between the effects of these variants and autoimmune diseases, schizophrenia and coronary heart disease, thereby providing new insights into the causes of these diseases.

A second study led by Professor Soranzo looked at the contribution of genetic and epigenetic factors to different immune cell characteristics in the largest cohort of this kind created with blood donors from the NHS Blood and Transplant centre in Cambridge.

Dr Mattia Frontini and Dr Chris Wallace, together with scientists at the Babraham Institute, have jointly led a third study mapping the regions of the genome that interact with genes in 17 different blood cell types. By creating an atlas of links between genes and the remote regions that regulate them in each cell type, they have been able to uncover thousands of genes affected by DNA modifications, pointing to their roles in diseases such as rheumatoid arthritis and other types of autoimmune disease.

Dr Frontini has also co-led a study with BLUEPRINT colleagues from the ̽��ֱ�� of Vienna that has developed a reference map of how epigenetic changes to DNA can program haematopoietic stem cells – a particular type of ‘master cell’ – to develop into the different types of blood and immune cells.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which helped fund the research, said: “Our genes are critical to our health and there’s still a wealth of information hidden in our genetic code. By taking advantage of a large scale international collaboration, involving the combined expertise of dozens of research groups, these unprecedented studies have uncovered potentially crucial knowledge for the development of new life saving treatments for heart disease and many other deadly conditions.

“Collaborations like this, which rely on funding from the public through charities and governments across the globe, are vital for analysing and understanding the secrets of our genetics. Research of this kind is helping us to beat disease and improve millions of lives.”

Departmental Affiliations

Professor Nicole Soranzo – Department of Haematology
Dr Adam Butterworth – Medical Research Council (MRC)/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit
Dr Mattia Frontini – Department of Haematology, and Senior Research Fellow for the BHF Cambridge Centre for Research Excellence
Dr Chris Wallace – Department of Medicine and MRC Biostatistics Unit

References

Astle, WJ et al. ̽��ֱ��allelic landscape of human blood cell trait variation. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.10.042
Chen, L et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell; 17 Nov 2016; DOI: 10.1371/journal.pbio.0000051
Javierre et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell; 17 Nov 2016; DOI: 10.1016/j.cell.2016.09.037
Farlik et al. Cell Stem Cell; 17 Nov 2016; DOI: 10.1016/j.stem.2016.10.019

Cambridge researchers have played a leading role in several studies released today looking at how variation in and potentially heritable changes to our DNA, known as epigenetic modifications, affect blood and immune cells, and how this can lead to disease.

BLUEPRINT shows the power of collaboration among scientists across Europe in making a difference to our knowledge of how epigenetic changes impact on our health

Willem Ouwehand

haha_works

Detail of Epigenome

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Potential new treatment for haemophilia developed by Cambridge researchers

cjb250 — Thu, 27 Oct 2016 15:00:19 +0000

Around 400,000 individuals around the world are affected by haemophilia, a genetic disorder that causes uncontrolled bleeding. Haemophilia is the result of a deficiency in proteins required for normal blood clotting – factor VIII for haemophilia A and factor IX for haemophilia B. Currently, the standard treatment is administration of the missing clotting factor. However, this requires regular intravenous injections, is not fully effective, and in about a third of patients results in the development of inhibitory antibodies. Nearly three-quarters of haemophilia sufferers have no access to treatment and have a life-expectancy of only 10 years.

In a study published online today in Blood, the Journal of the American Society of Hematology, researchers report on a novel approach that gives the clotting process more time to produce thrombin, the enzyme that forms blood clots. They suggest this treatment could one day help all patients with haemophilia, including those who develop antibodies against standard therapy. ̽��ֱ��therapy is based on observations relating to a disorder associated with excessive clotting, known as factor V Leiden.

“We know that patients who have haemophilia and also have mutations that increase clotting, such as factor V Leiden, experience less-severe bleeding,” says study co-author Dr Trevor Baglin, Consultant Haematologist at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals.

Dr Baglin and colleagues therefore pursued a strategy of reducing the activity of an anticoagulant enzyme, known as activated protein C (APC). ̽��ֱ��principal function of APC is to breakdown the complex that makes thrombin, and the factor V Leiden mutation slows this process. ̽��ֱ��team, led by Professor Jim Huntington, exploited this insight by developing a specific inhibitor of APC based on a particular type of molecule known as a serpin.

“We hypothesized that if we targeted the protein C pathway we could prolong thrombin production and thereby induce clotting in people with clotting defects, such as haemophilia sufferers,” says Professor Huntington, from the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge. “So, we engineered a serpin that could selectively prevent APC from shutting down thrombin production before the formation of a stable clot.”

To test their theory, the team administered the serpin to mice with haemophilia B and clipped their tails. ̽��ֱ��researchers found that the amount of blood loss decreased as the dose increased, with the highest dose reducing bleeding to the level found in normal mice. Further studies confirmed that the serpin helped haemophilia mice form stable clots, with higher doses resulting in faster clot formation. ̽��ֱ��serpin was also able to increase thrombin production and accelerate clot formation when added to blood samples from haemophilia A patients.

“It’s our understanding that because we are targeting a general anti-clotting process, our serpin could effectively treat patients with either haemophilia A or B, including those who develop resistance to more traditional therapy,” adds Professor Huntington. “Additionally, we have focused on engineering the serpin to be long-acting and to be delivered by injection under the skin instead of directly into veins. This will free patients from the inconvenience of having to receive infusions three times a week, as is the case with current treatments.”

̽��ֱ��research team hopes that the discovery can be rapidly developed into an approved medicine to provide improved care to haemophilia sufferers around the world.

“Within three years, we hope to be conducting our first-in-man trials of a subcutaneously-administered form of our serpin,” says Dr Baglin. “It is important to remember that the majority of people in the world with haemophilia have no access to therapy. A stable, easily-administered, long-acting, effective drug could bring treatment to a great deal many more haemophilia sufferers.”

This study forms part of a patent application, filed in the name of Cambridge Enterprise, and the modified serpin is being developed by a start-up company, ApcinteX, with funding from Medicxi.

Adapted from a press release by American Society of Hematology.

Reference
Polderdijk, SGI et al. Design and characterization of an APC-specific serpin for the treatment of haemophilia. Blood; 27 Oct 2016; DOI: 10.1182/blood-2016-05-718635

A new treatment that might one day help all patients with haemophilia, including those that become resistant to existing therapies, has been developed by researchers at the ̽��ֱ�� of Cambridge.

Within three years, we hope to be conducting our first-in-man trials

Trevor Baglin

Ginny

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Anatomy of a decision: mapping early development

cjb250 — Wed, 06 Jul 2016 17:00:34 +0000

̽��ֱ��point in our development when the whole body plan is set, just before individual organs start to develop, is known as gastrulation. Understanding this point in very early development is vital to understanding how humans and animals develop and how things go wrong. One of the biggest challenges in studying gastrulation is the very small number of cells that make up an embryo at this stage.

“If we want to better understand the natural world around us, one of the fundamental questions is, how do animals develop?” says Professor Bertie Gottgens from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge. “How do you turn from an egg into an animal, with all sorts of tissues? Many of the things that go wrong, like birth defects, are caused by problems in early development. We need to have an atlas of normal development for comparison when things go wrong.”

Today, thanks to advances in single-cell sequencing, the team was able to analyse over 1000 individual cells of gastrulating mouse embryos. ̽��ֱ��result is an atlas of gene expression during very early, healthy mammalian development.

“Single-cell technologies are a major change over what we’ve used before – we can now make direct observations to see what’s going on during the earliest stages of development,” says Dr John Marioni, Research Group Leader at EMBL-EBI, the Wellcome Trust Sanger Institute and the ̽��ֱ�� of Cambridge. “We can look at individual cells and see the whole set of genes that are active at stages of development, which until now have been very difficult to access.

“Once we have that, we can take cells from embryos in which some genetic factors are not working properly at a specific developmental stage, and map them to the healthy atlas to better understand what might be happening.”

To illustrate the usefulness of the atlas, the team studied what happened when a genetic factor essential for the formation of blood cells was removed.

“It wasn’t what we expected at all. We found that cells which in healthy embryos would commit to becoming blood cells would actually become confused in the embryos lacking the key gene, effectively getting stuck,” says Dr Marioni. “What is so exciting about this is that it demonstrates how we can now look at the very small number of cells that are actually making the decision at the precise time point when the decision is being made. It gives us a completely different perspective on development.”

“What is really exciting for me is that we can look at things that we know are important but were never able to see before – perhaps like people felt when they got hold of a microscope for the first time, suddenly seeing worlds they’d never thought of,” says Professor Gottgens. “This is just the beginning of how single cell genomics will transform our understanding of early development.”

̽��ֱ��study was made possible by a Wellcome Trust Strategic Award to study Gastrulation and by the Sanger/EBI Single Cell Genomics Centre.

Reference
Scialdone A, et al. Resolving early mesoderm diversification through single-cell expression profiling. Nature; 6 July 2016; DOI: 10.1038/nature18633

Adapted from a press release from the European Bioinformatics Institute.

In the first genome-scale experiment of its kind, researchers have gained new insights into how a mouse embryo first begins to transform from a ball of unfocussed cells into a small, structured entity. Published in Nature, the single-cell genomics study was led by the European Bioinformatics Institute (EMBL-EBI) and the ̽��ֱ�� of Cambridge.

We can look at individual cells and see the whole set of genes that are active at stages of development, which until now have been very difficult to access

John Marioni

Hector Lazo

abstract blood cells

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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