MRC Molecular Haematology Unit
Unit profile from the MRC Network publication issued Autumn 2006.
Haematological diseases present numerous challenges to researchers and clinicians who are trying to understand how mutations in blood cell development can cause such devastation to the human body. The MRC Molecular Haematology Unit is a key player in this quest for understanding.
In the next year, over 100,000 children around the world will be born with thalassaemia, an inherited blood disorder that affects haemoglobin, the oxygen-carrying protein in the blood. Over the same 12 months, some seven thousand people in the UK will be diagnosed with leukaemia and the parents of a thousand UK children will be told that their child has sickle-cell anaemia.
Blood disorders are widespread throughout all ethnic groups and their treatments are often high-maintenance. An important approach to understanding them is by studying haemopoietic (blood) stem cells. The process by which these undeveloped cells divide, replicate and form mature red and white blood cells and platelets, called haemopoiesis, is the focus of research at the MRC Molecular Haematology Unit (MHU) in Oxford. By studying how haemopoietic stem cells develop and differentiate, scientists at the unit hope to learn more about the causes and evolution of common blood diseases. Ultimately, their goal is to improve treatment options for patients who have acquired or inherited such diseases.
Most cells in the body have a particular purpose which cannot be changed. For instance, a liver cell has developed to perform specific liver functions and cannot suddenly take on the role of a heart cell. But stem cells, which are still at an early stage of development, retain the potential to turn into many different types of cell. When a stem cell divides, each new cell can either remain a stem cell or become another type of cell with a more specialised function. When a haemopoietic (blood) stem cell divides it creates two daughter cells: one is a replica of the original stem cell while the other develops and differentiates into a mature blood cell, such as a red or white blood cell or a platelet.
The MHU is housed within the Weatherall Institute of Molecular Medicine in the grounds of the John Radcliffe Hospital in Oxford. It was established in 1980 under the directorship of Sir David Weatherall. At that time the unit focused on understanding the molecular basis of the globin gene disorders, which involve the group of proteins called globins that help transport oxygen in the blood.
This work had been largely completed by the time Professor Doug Higgs was appointed MHU director in 2001.
Professor Doug Higgs
Under Doug’s directorship and following on from the unit’s previous success, the MHU began a new scientific programme based on the continued study of the globin genes and the broader study of the process of haemopoiesis. He drew together a team of international experts in the field: the unit now comprises nine research programmes that, says Doug, “Bring together a multidisciplinary, interactive team of scientists and clinicians dedicated to understanding the normal process of haemopoiesis and the diseases that occur when this process is disrupted.”
Gene regulation
Doug and his colleague Professor Bill Wood are carrying out research into gene regulation, the process by which genes are switched on and off. They are also interested in the diseases that occur when gene regulation goes awry.
Doug explains: “Within the region of one of our chromosomes, called chromosome 16, lie the alpha globin genes – the genes that direct the production of part of the haemoglobin molecule. When something affects the regulation of the alpha globin genes, patients develop alpha thalassaemia, which is one of the world’s most common genetic diseases. As well as suffering from alpha thalassaemia, rare patients are also born with mental retardation and other developmental problems. Some of these patients have a piece of chromosome 16 missing from the region we are looking at. With the information from our studies, we are identifying precisely which genes are missing in these patients and how that loss contributes to their mental and developmental difficulties.”
From pre-leukaemic disorders to leukaemia
Anaemia is usually due to a deficiency of the red blood cells that are needed to carry oxygen around the body. It causes symptoms ranging from tiredness and breathlessness to an irregular heartbeat and dizziness. Severe anaemia can be caused by myleodysplasia, a condition in which haemopoietic stem cells fail to mature properly and therefore do not function correctly. A diagnosis of myleodysplasia can then lead to other problems. Imagine all these malfunctioning cells being transported around the body through the blood stream as faulty buttons in a button factory. While correctly-manufactured buttons pass through the factory machinery, get sorted into boxes and go on to distribution, the faulty buttons go nowhere. They accumulate on the ‘rejects’ pile and unless disposed of, can block the factory machinery. When this happens in the human body, the build-up of immature, malfunctioning blood cells can eventually lead to leukaemia. In around 40 per cent of patients, myelodysplasia is a preleukaemic disorder that eventually leads to leukaemia.
Understanding myleodysplasia depends on knowing how blood cells are normally made and mature in the bone marrow, and this is the role of Dr Paresh Vyas’s group. He says: “Over the last few years we have found a common cellular defect at the first stages of haemopoietic differentiation in adult patients diagnosed with early myelodysplasia. In addition, our group has focused on one critical factor that is required in blood production: GATA1. GATA1 coordinates many aspects of the normal maturation programme of blood cells and we are studying various aspects of its biology.”
The group now knows that mutations in GATA1 help to cause a preleukaemic disorder in newborn infants with Down syndrome called Transient Myeloproliferative Disorder. In approximately 20 per cent of cases, this condition will progress to acute megakaryoblastic leukaemia (AMKL). Overall, AMKL occurs in about one per cent of children born with Down syndrome. Paresh says: “Our overall aim is to improve the diagnostic, prognostic and therapeutic aspects of the management of AMKL in Down syndrome children and myelodysplasia in adults.”
Clinical links
Paresh is one of a number of scientists within the MHU who also has clinical responsibilities. He’s a consultant haematologist at the John Radcliffe Hospital, as are several of his research colleagues. He explains: “Haematology lends itself to science as much of our clinical work is lab-based anyway; haematologists are always looking down microscopes. Furthermore, if you want to carry out research into abnormal cells, blood cells and bone marrow samples are easy to get hold of.”
Integrating the MHU scientific programme with clinical departments of haematology in Oxford and across the UK is a high priority for Doug Higgs. The unit now has monthly scientific/clinical meetings and works closely with haematologists nationwide. “We are working towards making the MHU an internationally recognised centre of excellence in haemopoiesis and haematology,” he says. Part of the unit’s ongoing work to meet this aim is the establishment of an academic department of haematology in Oxford, and the future appointment of a chair of haematology.
T-ALL order
The haemopoietic system works hard to keep up with the body’s demands. It has to keep the number of blood cells in our body constant and so must run efficiently and be highly regulated. Dr Catherine Porcher’s group studies the role of one regulator of this system, a protein called SCL. It is crucial for the formation of the first haemopoietic stem cells during embryonic development and for the production of red blood cells and platelets. If SCL is not regulated, the blood cells do not mature properly. Through a process called leukaemogenesis, this can then lead to the development of a type of leukaemia called T-cell acute lymphoblastic leukaemia (T-ALL).
Catherine and her colleagues are trying to understand how SCL works in normal haemopoiesis. She says: “This will then give us insight into how deregulation of SCL might promote leukaemogenesis, with the aim of developing new therapeutic approaches in T-ALL.”
Exploring stem cells
Often, the only treatment for leukaemia and aggressive cancers is a stem cell transplant. Around 45,000 of these procedures are carried out worldwide every year. It is already known that stem cells have the ability to self-renew, and it is now suspected that this may also be the case for cancer cells. Professor Roger Patient’s group is trying to understand better how and where stem cells are made and controlled, with a view to learning more about how other types of cells, such as cancer cells, are controlled.
Zebra fish stem cells
Roger explains: “We are working out the genetic programming of stem cells which takes place during embryonic development. We study amphibian and fish embryos because, firstly, they develop externally in large numbers rendering them ideal for study and, secondly, because the processes involved have been highly conserved during evolution and therefore what we discover in these model organisms has direct relevance to humans.”
Haemopoietic stem cells come from the same population of cells in the embryo that gives rise to the cardiovascular system. So anything that the group discovers about blood programming may also have direct relevance to heart tissues and the diseases that affect these tissues.
It’s fascinating stuff and the potential of Roger’s work is reflected in the research programme of Dr Marella De Bruijn. Her group is studying one element of the stem cell generation process – Runx1. Runx1 is a transcription factor, meaning it controls the expression of genes and so can determine whether a cell will become a blood cell and, if so, what type. Marella says: “Mutations of Runx1 are found in approximately 25 per cent of acute leukaemias. Studying how Runx1 works in normal blood stem cell formation and how it relates to other transcription factors will hopefully help the group to contribute to a better understanding of leukemogenesis and ultimately to the development of new therapies.”
Transcription factors and gene expression
To learn more about how transcription factors work and how they affect gene expression, it’s necessary to get right back to basics and study what is going on inside the nucleus of the cell. Dr Veronica Buckle and Dr Francisco Iborra are doing just that. They are looking at how the organisation of DNA within a cell nucleus and the presence of transcription factors can influence how a gene is expressed. Veronica says: “We use the development of blood cells as a model system because this is a well-characterised process. We can easily link changes in nuclear structure and transcription factor levels with gene expression.”
Despite the revolution in genetics in the last decade and in particular the sequencing of the human genome, the regulation of gene expression remains largely a mystery. Although every cell of the body contains a full complement of genes, each cell only expresses a small range that are required for its specific function, such as the oxygen-carrying protein haemoglobin in red blood cells.
Dr Richard Gibbon’s group aims to determine the role of proteins in the regulation of gene expression and their involvement in human disease. Richard is a clinical geneticist who specialises in inherited syndromes that affect intelligence. Many diseases have now been identified which are caused by disruption to proteins involved in regulating gene expression.
In one such condition, ATR-X syndrome, affected children have profound learning difficulties, a characteristic facial appearance, physical abnormalities and thalassaemia. Richard explains: “It arises because of mutations in a protein involved in the regulation of gene expression. The diverse problems suffered by children with ATR-X probably reflect the many different genes whose expression is disrupted.”
Since geneticists became aware of ATR-X, some 150 affected people from 120 families around the world have been identified as carriers. Of these, approximately 40–50 are British. As there’s no provision for ATR-X testing within the National Health Service (NHS), the MHU provides a valuable diagnostic service and reference centre for the country’s geneticists and paediatricians. Pregnant women at risk are offered in utero testing for the syndrome and families can obtain information and advice via a bespoke website or by contacting the research group directly. Richard says: “We have built up good relationships with many families and our research has benefited greatly through their goodwill and participation.”
Working decisions
Professor Tariq Enver is internationally recognised as an expert in haemopoiesis and his group is researching how and why stem cells decide whether to self-renew or to differentiate into mature blood cells. They’re also looking at how a blood stem cell becomes a specific type of cell, such as a red blood cell or a platelet. Tariq says: “These ‘working decisions’ that stem cells make are ultimately effected at the level of differential gene activity or usage, and understanding how this process works is an important challenge in developmental biology, transplantation medicine, stem cell-based gene therapy and blood cancers.” He adds: “We anticipate that our research will illuminate how normal cell fate decisions are instigated. This in turn should inform our approach for manipulating stem cells and their fate for therapeutic purposes.”
Steps towards a centre of excellence
The MHU’s work is providing invaluable insights into haemopoiesis and the development of best practice in scientific and clinical collaborations. With multiple potential therapeutic outcomes of the unit’s research, its scientists are driven in their desire to identify the fundamental processes involved in the development and mutation of blood cells. Doug Higgs sums up: “Over the past five years the very fruitful collaboration between the MRC-funded MHU and our NHS colleagues has made the first important steps towards creating a centre of excellence in haemopoiesis and blood disorders. Over the next five years we hope to develop this further and increase the low of our basic science into the clinic.”