The atlas, published on the 9th of October in Nature, was created by researchers from the Wellcome Sanger Institute, Wellcome – MRC Cambridge Stem Cell Institute, Newcastle University, University of Cambridge and their collaborators. It is a comprehensive, high-resolution resource that improves our understanding of normal development and assists medical efforts to tackle diseases, such as leukaemia and immune disorders, which can form during development.
Until now, it was unknown precisely how the blood and immune systems develop in humans – a process known as haematopoiesis. As adults, it is bone marrow that creates our blood and immune cells. But in early embryonic life, the yolk sac and liver play a major role in making blood and immune cells. These cells subsequently seed peripheral tissues such as skin, kidney and finally bone marrow.
Scientists used single cell technology to analyse 140,000 liver cells and 74,000 skin, kidney and yolk sac cells. By isolating cells from the developing liver, they could identify them by what genes they were expressing and see what the cells looked like. Haematopoietic cells in sections of developmental liver were ‘tagged’ using heavy metal markers so researchers could map each cell to its location.
Professor Muzlifah Haniffa, a senior author of the study from Newcastle University and Senior Clinical Fellow at the Wellcome Sanger Institute, said: “Until now research in this area has been a little bit like blindfolded people studying an elephant, with each describing just a small part of it. This is the first time that anyone has described the whole picture, how the blood and immune systems develop in such detail. It’s been an extraordinary, multidisciplinary effort that is now available as a tool for the whole scientific community.”
A developing foetus requires huge amounts of oxygen to fuel growth. The research discovered that during development, ‘mother’ haematopoietic stem cells stay in the liver. But as the liver alone cannot supply sufficient red blood cells, the next generation ‘daughter’ cells – known as progenitor cells – travel to other tissues. They mature in places such as the skin, where they develop into red blood cells to help meet the high demand for oxygen.
, a senior author from the Wellcome – MRC Cambridge Stem Cell Institute and the Department of Haematology at the University of Cambridge, said: “We knew that as adults age our immune system changes. This study shows how the liver’s ability to make blood and immune cells changes in a very short space of time, even between seven and 17 weeks post-conception. If we can understand what makes the stem cells in the liver so good at making red blood cells, it will have important implications for regenerative medicine.”
Researchers also mapped genes known to be involved in immune deficiencies to see which cells were expressing them. Gene mutations can lead to immune disorders such as leukaemia, and it is hoped that by understanding how the healthy developing liver functions, it will be possible to understand how immune disorders arise and even how to treat them.
Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute, University of Cambridge and co-chair of the Human Cell Atlas Organising Committee, said: “The first comprehensive cellular map of the developmental liver is another milestone for the Human Cell Atlas initiative. The data is now freely available for anyone to use and will be a great resource to better understand healthy cellular development and disease-causing genetic mutations.”
Dr Katrina Gold, Genetics and Molecular Sciences Portfolio Manager at Wellcome, said: "Our immune system is vital in helping to protect us from disease, yet we know very little about how immune cells develop and behave in the early embryo. This study is hugely important, laying a critical foundation for future research that could help improve our understanding of disorders linked to the early immune system, such as childhood leukaemias. The Human Cell Atlas has the potential to transform our understanding of health and disease and we’re excited to see these first discoveries from our Wellcome-funded multidisciplinary team of scientists.”
Publication: Dorin-Mirel Popescu, Rachel A. Botting and Emily Stephenson et al. (2019). Decoding human fetal liver haematopoiesis. Nature. DOI: 10.1038/s41586-019-1652-y
Recent months have seen increasing excitement over the new wave of cellular immunotherapies. These complex novel treatments use immune cells that are taken from a patient, genetically modified with a Chimeric Antigen Receptor (CAR) to target a specific cancer, expanded into large numbers and then re-infused. In 2018 Cambridge University Hospitals NHS Foundation Trust ran a successful first-in-NHS trial of a similar therapy for metastatic melanoma, and subsequently has been selected as one of only three UK centres for Zuma-8, a major international study of CAR T-cells in chronic lymphocytic leukaemia. Following inspections of the site by Kite, one of the two largest CAR T-cell manufacturers, the study is scheduled to open in Cambridge in October.
The success of the Cellular Immunotherapy programme in Cambridge led in April to the selection of Cambridge University Hospitals as one of three new national centres in the second wave of NHS providers of CAR T-cell therapy. NHS England tariffs have been set at a level that is designed to allow appropriate investment in staffing and infrastructure for these complex therapies.
Ben Uttenthal, Lead for Immune Effector Cell Therapies, said ‘This is fantastic news for patients in our region, who will now have access to these cutting edge treatments for cancer. We expect to have treated our first NHS patients with CAR T-cell therapy, for high grade B cell lymphoma and acute lymphoblastic leukaemia, before the end of this year. The clinical infrastructure that we are putting in place for this will give a real boost to translational research in cellular immunotherapies here in Cambridge.’
Many congratulations to programme member Professor Nicole Soranzo who has been elected as a member of the European Molecular Biology Organisation. A total of 48 new EMBO members were elected in June and will be formally welcomed as members at the organisation's annual meeting in Heidelberg in October. Professor Soranzo said: "I am delighted to be elected to EMBO. Understanding the molecular basis of health and disease, through the lens of genetics, is central to my scientific approach. To join such a distinguished group of scientists is an honour. Yet the scale of science needed to investigate the underlying genetics of complex disease requires worldwide collaboration and I would like to thank everyone in my team and all my collaborators for their dedication, creativity and support."
Read the full article on the Sanger Insititute website.
We are pleased to welcome Dr Simon Richardson to the programme. Simon has been awarded a 5-year CRUK Clinician Scientist Fellowship and will be working in Professor Brian Huntly's lab. The focus of the fellowship will be on the role CREBBP in Acute B Lymphoblastic Leukaemia (B-ALL) and, in particular, its role in relapse and chemo-resistance. During the project, Simon will work to generate new mouse models of B-ALL, in parallel with drug development using human cell lines and patient material.
Simon completed his PhD in Professor Tariq Enver’s lab at the UCL Cancer Institute using human pluripotent stem cells modelling the impact of the childhood B-ALL driver mutation ETV6-RUNX1 on human fetal lymphopoiesis. Following his PhD, Simon has been working in Dr Marc Mansour’s lab focussing on adapting next generation sequencing techniques to identify novel non-coding mutations in cytogenetically normal acute myeloid leukaemia.
In the Cambridge Biomedical Campus supplement published in the Cambridge Independent in May, Craig Brierley (Head of Research Communications at the University of Cambridge) interviewed research nurse Myrna Maquinana and Principal Investigator Dr Elisa Laurenti about their work. Myrna and her team work at the Rosie Hospital and the Cambridge Blood and Stem Cell Bank and collect cord blood donations for use in research. Dr Laurenti and her team are one of the groups using the cord blood donations, they are using the blood stem cells in donated cord blood to understand how blood production works. Elisa explains that by building our understanding of the biology of blood stem cells, it may be possible to develop new targets for treatment of blood cancers.
Many congratulations to Dr Peter Campbell who has been elected as a Fellow of the Academy of Medical Sciences. The award honours scientists whose research has advanced medical science, delivered cutting-edge research discoveries, and produced benefits for patients and wider society. This year 50 Fellows were chosen from 413 candidates. Dr Campbell said “I am delighted to become a Fellow of the Academy of Medical Sciences, it is a great honour to be recognised in this way. However, this award really belongs to my colleagues and collaborators here at the Sanger Institute and worldwide. Cancer is a massively complex interplay of genetic interactions that requires large-scale collaboration across to continents to investigate and analyse. I am grateful to everyone I have worked with over the years, and hope that our work will lay the foundations of understanding that will deliver improved treatment and prevention of this terrible disease.” Read the full article on the Sanger Institute website.
Image credit: Wellcome Sanger Institute, Genome Research Limited.
Programme members Professor Brian Huntly, Dr Elisa Laurenti and Dr Stephen Loughran (Green Lab) will present talks at the Pint of Science event 'The dark side of blood' on Wednesday 22nd of May at Novi in Cambridge. Pint of Science is a worldwide science festival that takes place 20-22 May and brings researchers to local pubs to present their scientific discoveries. The talks will focus how blood stem cells maintain blood formation in healthy people and what goes wrong during cancer development. To find out more and to book tickets, visit the Pint of Science website.
Many congratulations to Maurizio Mangolini (Ringshausen group) who was recently awarded the Terry Hamblin prize at the UK CLL Forum. The Terry Hamblin prize was established in 2008 in honour of Professor Terry Hamblin, the founder of the UK CLL Forum. The prize is awarded annually for the best CLL (Chronic Lymphocytic Leukemia) related publication from a UK-based group. Maurizio was awarded the prize for the paper 'Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia' published in Nature Communications in September 2018 and you can read the full paper on the Nature Communications website.
Many congratulations to Rebecca Caeser (Hodson lab) on winning a poster prize at the Cancer Research UK Cambridge Insititute Symposium for her poster 'Recreating the genetic events of lymphomagenesis in primary human germinal center B-cells'. The poster focusses on a novel ex vivo system developed in the lab to recreate the genetic events of lymphomagenesis in primary human germinal center B-cells. This allows the group to test defined genetic alterations on a genetically normal background and identify potent tumour suppressor pathways using CRISPR. The group have also used this system to create "synthetic" lymphoma models that recapitulate human DLBCL (Diffuse Large B-Cell Lymphoma).
Many congratulations to Dr Paolo Gallipoli who has been awarded a 5 year Cancer Research UK Advanced Clinician Scientist Fellowship. This award will allow Paolo to start his independent research programme studying metabolic adaptive responses as a mechanism of resistance to novel therapies across multiple subtypes of acute myeloid leukaemia (AML) at the level of leukaemic stem cell. Paolo's research will use several different techniques including forward genetic screening, proteomic/metabolomic analysis by mass spectrometry, ChIP/RNA sequencing and standard functional in vitro and in vivo assays to understand how changes in cell metabolism provide escape routes to current therapeutics in AML and their link to the establishment of leukaemic transcriptional programme. The main aim is to identify novel therapeutic vulnerabilities that can be targeted therapeutically to prevent the establishment of resistance to therapies in AML.
Professor Alan Warren was interviewed by the BBC about his research into about his research in the leukaemia predisposition disorder Shwachman-Diamond syndrome (SDS) and use of Cryogenic Electron Microscopy. The interview was featured on BBC Look East, BBC News and BBC Breakfast and is available to watch online.
Programme member Dr Elisa Laurenti took part in a short film project promoting collaborations between Israeli and British researchers working together on BIRAX funded projects. BIRAX (the Britain Israel Research and Academic Exchange Partnership) is a £10 million initiative of the British Council and British Embassy in Israel in collaboration with the Pears Foundation and the UJIA. You can watch the film here.
A number of programme researchers will be relocating to the new Capella Building on the Cambridge Biomedical Campus later this year. The building was recently featured on BBC Look East as part of a piece looking at the development of the Biomedical Campus and you can watch the video and find out more about the new building here.
The new building is sited at the Cambridge Biomedical Campus adjacent to Addenbrookes Hospital and is due for completion in Spring 2019. Built by Kier Construction and designed by architects from The Fairhurst Design Group, the six-storey centre will be located directly next to the Cancer Research UK Cambridge Institute. Capella will be home to three institutes – the Wellcome-MRC Cambridge Stem Cell Institute, the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), and the Milner Therapeutics Institute. The building will contain state-of-the-art research facilities along with a café, seminar room and exhibition space for events and will bring together 650 members of staff who are currently located across a number of university sites.
An active ingredient in eye drops that were being developed for the treatment of a form of eye disease has shown promise for treating an aggressive form of blood cancer. Scientists at the Wellcome Sanger Institute, University of Cambridge, University of Nottingham and their collaborators have found that this compound, which targets an essential cancer gene, could kill leukaemia cells without harming non-leukemic blood cells. The results, published in Nature Communications reveal a potential new treatment approach for Acute Myeloid Leukaemia (AML), an aggressive blood cancer with a poor prognosis.
Joint leader of the project, programme member Dr George Vassiliou said:
“We have discovered that inhibiting a key gene with a compound being developed for an eye condition can stop the growth of an aggressive form of acute myeloid leukaemia without harming healthy cells. This shows promise as a potential approach for treating this aggressive leukaemia in humans.”
Read the full press release on the Sanger Insititute's website.
Many congratulations to programme members Professor Bertie Gottgens and Dr Elisa Laurenti who have been awarded a grant from the MRC as part of the the global Human Cell Atlas initiative. Professor Gottgens is the Principal Investigator on the award from the MRC and will work with Co-Investigators programme member Dr Elisa Laurenti, Professor Muzlifah Haniffa (Newcastle University) and Professor Irene Roberts (University of Oxford) on the project, 'A protein-transcriptome atlas of haematopoiesis across the human life span'.
Recent technological innovations have made it possible to map very comprehensively the activity of all genes within single cells, at a scale of thousands of cells at the same time. The team propose to utilize one of the latest protocols in this field to map both messenger RNA as well as protein levels, and thus obtain especially detailed insights into the molecular make up of over 550,000 individual blood and immune cells across the human lifespan. Through integration with the wider Human Cell Atlas Initiative, the team's datasets will deliver an important reference, that will serve as a platform for future studies aiming to reveal the molecular alterations that cause the misbehaviour of blood cells in a broad range of disorders including blood cancers and immune diseases.
Many congratulations to programme member Dr George Vassiliou who has been awarded an ERC Consolidator Grant. The ERC award (of €2 million) will fund a project to study how mutations in genes involved in RNA splicing can start a process that leads to the development of lethal blood cancers such as the myelodysplastic syndromes and acute myeloid leukaemia. At present we do not understand how these mutated genes drive abnormal growth of cells and why they particularly do so in old, but not in young people. Working this out will help us device new ways to treat and potentially also to prevent the development of these cancers.
BIA-ALCL is a rare type of Non-Hodgkin Lymphoma, a cancer of the lymphoid system, with cases found in women who have had breast implants for multiple reasons, including breast augmentation and breast reconstruction following mastectomy for breast cancer.
Concerns about BIA-ALCL have been discussed on the recent Panorama programme focussed on implants. Speaking to the BBC about incidences of BIA-ALCL, Dr Turner said: "It is a concern, absolutely, particularly now that we're seeing breast implant associated lymphoma developing in these ladies.”
In a study published last year in the European Journal of Surgical Oncology, Dr Turner and collaborators looked at incidences of BIA-ALCL in the UK, and, between 2012-2016 found 23 instances of the disease in 15 regional centres. Speaking to the BBC, Dr Turner notes “the risk is small but it's a risk that we should know about and be informed of."
Dr Turner’s research into BIA-ALCL looks into the causes of the disease and with a focus on the hypothesis that toxins induce hyper-proliferation of T cells surrounding the implant as she published in the journal Mutation Research in 2014.
By investigating the mechanisms causing the disease, Dr Turner and her colleagues aim to prevent BIA-ALCL occurring in the future.
On the 19th of November, the UK – Israel and the Dotan Center International Symposium ‘Advances in Research of Haematological Malignancies’ was held at the Felsenstein Medical Research Center on the Rabin-Schneider Medical Campus in Israel. There were four sessions throughout the day focussing on the latest research in the field and presentations were given by Haematological Malignancies programme member Professor Bertie Gottgens and co-programme lead Professor Brian Huntly with the Plenary Lecture delivered by co-programme lead Professor Tony Green. Cellular and Molecular Biology programme member Dr KJ Patel from the MRC Laboratory of Molecular Biology also presented at the symposium.
The symposium attendees are pictured, with Mr David Quarrey, British Ambassador to Israel (centre).
International experts from multiple disciplines gathered at Homerton College in Cambridge, UK from September 12-14, 2018 to consider recent advances and emerging opportunities in the clonal tracking of hematopoiesis in one of a series of StemCellMathLab workshops. The group included thirty-five participants with experience in the fields of theoretical and experimental aspects of clonal tracking, and ranged from PhD students to senior professors. Data from a variety of model systems as well as from clinical gene therapy trials were discussed alongside strategies for data analysis and sharing, as well as challenges arising due to underlying assumptions in data interpretation and communication. Recognizing the power of this technology underpinned a group consensus of a need for improved mechanisms for sharing data and analytical protocols to maintain reproducibility and rigor in its application to complex tissues.
The workshop was co-organised by Programme members Dr David Kent and Dr Elisa Laurenti and collaborators Dr Ingmar Glauche (TU Dresden), Dr Anne-Marie Lyne (Institute Curie), and Dr Leila Perié (Institute Curie). This workshop summary is an extract from the full workshop report published in Experimental Haematology.
Scientists have developed a successful method to make truly personalised predictions of future disease outcomes for patients with certain types of chronic blood cancers. Researchers including co-programme lead Professor Tony Green and members from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and their collaborators, combined extensive genetic and clinical information to predict the prognosis for patients with myeloproliferative neoplasms. The research also identified eight different genetic subgroups of the disease that link with patterns of clinical disease and patient prognosis. Published in the New England Journal of Medicine, this work could lead to personalised medicine for patients with these blood cancers. It will help doctors identify those patients who are likely to have a very good future outlook, and which patients may benefit from specific treatments or clinical trials.
Throughout Blood Cancer Awareness Month in September we posted updates from our programme on our Twitter account @CRUKCamHaem including latest research and publications, and a chance to find out more about some of our programme members. Visit our meet our researchers page to find out more about the work of Professor Bertie Gottgens and PhD students Rebecca Caeser and Antonella Santoro.
Blood stem cells produce all blood cell types throughout life, including red blood cells that transport oxygen throughout our body and white blood cells called lymphocytes that help us fight infections. New research using cutting-edge single cell technologies reveals that the regulation of the balance between red and white blood cell production, already occurs within the blood stem cell compartment and not later on as originally thought. In a study published in Nature Communications, the Laurenti Lab identified a novel subtype of long-lived blood stem cells that cannot produce red blood cells, but only produce lymphocytes. This cell type is likely play a role during ageing and in the development of blood cancers, where the production of all mature blood cell types is highly imbalanced.
The 6th Cambridge International Stem Cell Symposium took place from the 19th - 21st September and brought together biological, clinical and physical stem cell scientists, working across multiple tissues and at different scales, to share data, discuss ideas and address the biggest fundamental and translational questions in stem cell biology. Nearly 500 delegates came together at the event which included talks in the field of Haematological Malignancies from international speakers and from programme members Dr Elisa Laurenti, Dr David Kent and Dr Cedric Ghevaert.
Research published in Nature has revealed that adult humans have many more blood-creating stem cells in their bone marrow than previously thought, ranging between 50,000 and 200,000 stem cells. Haematological Malignancies Programme researchers based at the Wellcome Sanger Institute and Wellcome – MRC Cambridge Stem Cell Institute developed a new approach for studying stem cells, based on methods used in ecology. Programme member and joint senior author Dr David Kent said: “This new approach is hugely flexible. Not only can we measure how many stem cells exist, we can also see how related they are to each other and what types of blood cells they produce. Applying this technique to samples from patients with blood cancers, we should now be able to learn how single cells outcompete normal cells to expand their numbers and drive a cancer. As the cost of genomic sequencing comes down, it is transforming scientific research such that studies previously thought to be impossibly large, are now becoming routine. It is a very exciting time to be working in this space.”
The Cambridge Lymphoma Biology International Symposium took place from the 17th – 18th July in the historic setting of St John’s College, co-chaired by Programme members Dr Dan Hodson and Dr Ingo Ringshausen. The symposium brought together the European Lymphoma community at the biggest research focussed lymphoma conference in Europe with 130 researchers, clinicians, staff and students attending from 28 countries. Talks focused on work from leading labs working on Lymphoma and Chronic Lymphocytic Leukaemia (CLL) with the plenary talk given by Klaus Rejewsky from the Max Delbrück Center in Berlin. The Dennis-Cook poster prize was awarded jointly to Rebecca Caeser (University of Cambridge) and Rita Barbosa (Francis Crick Institute). The event also incorporated the Third Cancer Core Europe Lymphoma Meeting. The symposium was supported by CRUK, the British Society for Haematology, Lonza, Miltenyi and Pan Biotech.
An international team of researchers have found that patients with Acute Myeloid Leukaemia (AML) had genetic changes in their blood years before they suddenly developed the disease. The study, published in the journal Nature, found that blood tests looking for changes in the DNA code can reveal the roots of AML in healthy people. Haematological Malignancies Programme Member Dr George Vassiliou, one of the joint leaders on the study said: “Our study provides for the first time evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease. We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that one day AML prevention would provide a compelling alternative to treatment.”
Scientists have discovered the first leukaemia protective gene that is specific to the male-only Y chromosome. In a study led by Haematological Malignancies Programme Lead Professor Brian Huntly and Haematological Malignancies Programme Member Dr George Vassiliou, researchers found that this Y-chromosome gene protects against the development of Acute Myeloid Leukaemia (AML) and other cancers.