Children with Diamond-Blackfan anaemia (DBA) carry a genetic fault that inflames their bone marrow, and a physician-scientist now wants to find out exactly which cells are causing that inflammation and whether blocking it could offer a gentler treatment. This matters because the only drug that works—steroids—requires doses so high that more than half of patients cannot tolerate them long-term, leaving them with no good options: either risky lifelong blood transfusions or a bone marrow transplant. Most DBA research has focused narrowly on red blood cells, ignoring the inflammatory signals that may be driving the anaemia. The researcher has already discovered high levels of a molecule called TNFalpha in DBA marrow and will now identify the culprit cells, map how steroids alter gene expression, and test whether blocking TNFalpha could work as a treatment. If successful, this work could replace steroids with a targeted anti-inflammatory therapy that helps more patients with fewer side effects. The insights may also apply to other anaemias common in inflammatory diseases. Because ribosome problems have been linked to other blood disorders, cancers, and autism, understanding why DBA selectively destroys red blood cells could reveal fundamental principles about how ribosomal diseases harm some cell types while leaving others untouched.
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Diamond-Blackfan anaemia (DBA) syndrome is a rare genetic disease affecting about 1 in 100,000 people of all ethnicities. The main problems are severe anaemia (low red blood cells), often starting in childhood, birth defects that need surgery, short height and a high risk of cancer (1-in-7 people by age 45). DBA disrupts children and families’ lives, with missed school and work, financial stress, and social isolation due to having a rare disease. Steroids are the only drug that can help DBA, but high doses are needed, causing serious side effects. Because of this, over half of DBA patients cannot tolerate steroids in the long-term and need to stop them. The only alternative treatments are lifelong red blood cell transfusions or bone marrow transplantation, which are risky and can cause major health problems. DBA is caused by a genetic change in one of several ribosomal protein genes, leading to impaired ribosomes, the structures in every cell that produce proteins. Limited treatment options for DBA is due to our poor understanding of how anaemia develops. Most DBA research focuses on red blood cells alone, but these are impacted by many other cells and signals in the bone marrow, like trees in an orchard influenced by the weather conditions. I discovered high levels of inflammation, including a molecule called tumour necrosis factor alpha (TNFalpha), in the bone marrow of patients with DBA. The aim of my proposal is to better understand the cellular and molecular basis of inflammation in DBA and use this knowledge to develop new treatment avenues. First, I will identify which cells in DBA marrow cause inflammation. Then, I will study how steroids help DBA by defining how they change gene expression and inflammatory signals in marrow. Finally, I will test if reducing inflammation, for example by blocking TNFalpha, could lead to new treatments that help more people with DBA, with fewer side effects than steroids. I am the right person to deliver this work as I am a physician-scientist, motivated to improve the care of my patients with DBA. I have a strong track-record in DBA research and have established unique resources over the last 10 years: the National UK DBA Patient Registry (a database of clinical and laboratory data from 205 patients) and the largest repository worldwide of precious bone marrow cells from children with DBA, who have donated their samples to research. I will study these cells from patients and collaborate with experts to create new "mini marrow" models of DBA (called organoids). This recent scientific advancement mimics the marrow ‘orchard’, allowing patient cells to be studied outside of the human body but in a lifelike context. Developing treatments that target the pathways causing DBA would transform DBA patient care. Unique data from patients and their precious samples will be useful for other researchers in the field. My research also has the potential to improve the treatment of other anaemias, since anaemia is a very common complication of many inflammatory diseases. Finally, other blood diseases, cancers and autism have been linked to ribosomes. Though these are essential for all cells, ribosomal disorders affect only some cell types. Understanding why DBA affects mainly red blood cells, will provide broader scientific insight into how diseases characterised by insufficient ribosomes impair some cells, but spare others.
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