Research
The Centre provides a strategic focus on understanding the molecular mechanisms and cellular processes that underpin the development of human disease. Examples include developmental and age-related diseases – such as cardiovascular, cancer, and inherited diseases.
Research focus and core objectives
By uniting expertise across basic science, clinical research and enabling technologies, the Centre will address mechanisms by which diseases arise from disruptions to core mechanisms such as signalling, metabolism, cell-cell communication and tissue repair, in an integrated and scalable way.
Aligned with the UK Government’s Life Sciences Vision, the Centre will translate fundamental discovery into clinical impact, leverage advanced technologies, and foster partnerships across academia, the NHS and industry, while strengthening the UK’s global leadership in life sciences.
Highlighted research
2026
Development of a Photostable pH Biosensor Based on mStayGold
Michael Chang , Lilly Nash, Ruben Bierings, Kei Takahashi-Yamashiro , Takuya Terai, Tom Carter, Robert E. Campbell, Kelvin K. Tsao.
https://doi.org/10.1002/cbic.70512
Many important cellular processes are regulated by spatially localised changes in acidity (pH). To study localised pH changes on a subcellular scale is technically challenging. An early break through in this area was the development of genetically encoded pH sensors based on Green fluorescent protein (GFP) derived from the jelly fish Aequorea victoria. These sensors can be fused to proteins that target the sensor to highly specific locations within cell. However, the limited photostability of GFP-based pH biosensors severely restricts the time-scale over which they can be used to monitor localised pH changes.
In the study reported here, researchers at the University of Tokyo, the Erasmus Medical Centre in Rotterdam and City St George’s University, London developed and tested a significantly more photostable genetically encoded pH biosensor, termed SerapH1.0. SerapH1.0 is based on mStayGold, a green fluorescent protein derived from the jelly fish Cytaeis uchidae. The new biosensor was developed using a combination of directed evolution coupled with a novel CO2 screen to specifically identify pH sensitive variants, a step that accelerated the development process.
To test SerapH1.0 in living cells, the biosensor was fused to the propolypeptide of the glycoprotein, Von Willebrand factor (VWF), which when expressed in vascular endothelial cells targeted SerapH1.0 into the regulated secretory granules of these cells, the Weibel-Palade bodies (WPBs; Figure 1 top panel). WPBs have an acidic lumen, between pH 5-6, that maintains VWF in a highly condensed state during storage and which facilitates expulsion of VWF during WPB exocytosis. Under resting conditions the fluorescence of WPB-targeted SerapH1.0 is almost zero (Figure 1 middle & bottom panels), but following WPB exocytosis SerapH1.0 fluorescence increases rapidly (Figure 1 bottom panel) allowing direct visualisation of the fate of the secreted VWF propeptide.
The development of SerapH1.0 opens new opportunities to study pH regulated processes previously inaccessible due to the photostability limitations of GFP-based sensors.
Figure 1. Weibel Palade body (WPB)-targeted SerapH1.0 allows detection of WPB exocytosis in living endothelial cells. Top; Endothelial cell expressing VWF propeptide-SerapH1.0 (green) and immunolabelled for endogenous VWF (magenta). Scale bar is 10 µm. The rod-shaped structures are Weibel Palade bodies, the VWF storage granules. Middle; A still from a movie of a single living endothelial cell expressing VWFpp-SerapH1.0 prior to stimulation with histamine. Bottom; example of a single VWFpp-SerapH1.0-expressing WPB undergoing exocytosis. *Frame in which exocytosis occurred. Scale bar is 10 µm, video acquired at 10 frames per second.
2025
A novel cause of type 1 von Willebrand disease: impaired exocytosis of Weibel-Palade bodies due to biallelic MADD variants
Sophie Hordijk, Stijn A. Groten, Petra E. Bürgisser, Sebastiaan N.J. Laan, Georg-Christoph Korenke, Diane Beysen, Frank W.G. Leebeek, Paul A. Skehel, Maartje van den Biggelaar, Tom Carter, Ruben Bierings
https://doi.org/10.1182/blood.2024027935
Researchers at the Erasmus University Medical Center, Rotterdam and City St George’s University, London have identified the kinase activating death domain (MADD) as the first causal gene for quantitative von Willebrand Disease (VWD) in patients without pathogenic VWF variants.
The secretion of von Willebrand factor (VWF) into our circulation is vital for normal haemostasis, the physiological process by which we stop ourselves bleeding after injury. The main source of circulating VWF are endothelial cells (ECs) that line the inside of all our blood vessels. Inside ECs VWF is stored ready for secretion into the blood in a special secretory granule called the Weibel Palade body (WPB; Figure 1).
Figure 1. Weibel Palade bodies. Left; Endothelial cells immunolabelled for endogenous VWF. The bright rod-shaped structures are Weibel Palade bodies, the VWF storage granules. Right; Cryo-electron micrograph of a single WPB showing VWF tubules in yellow.
Bleeding disorders caused by a lack of or dysfunction in VWF are collectively called von Willebrand disease (VWD). The most common form of VWD (Type 1) is associated with reduced circulating levels of VWF. Most cases of Type 1 VWD are caused by mutations in the VWF gene, but in about 30% of patients no mutations are present indicating there are other factors important in determining VWF levels in the blood. In this study the authors show for the first time that loss of a single protein involved in regulation of VWF secretion, MADD, can result in Type 1 VWD.
What does MADD do? MADD controls the activation of a family of small Rab GTPases that, in the active form, are recruited specifically to the membrane of WPBs (Figure 2).
Figure 2. MADD switches WPB Rabs ON to regulate VWF secretion. Left; Active Rab27A/Rab3 (GTP bound; green) orchestrate the tethering, docking and exocytosis of WPBs through recruitment of multiple cytosolic effector molecules. Right; Loss of MADD prevents Rab activation and WPB exocytosis.
WPB Rabs include Rab27A and Rab3 isoforms, all of which behave as molecular switches cycling between an ON (GTP bound; green in Figure 2) and an OFF (GDP bound; red in Figure 2) state. MADD switches WPB Rabs into the ON state. In the ON state the Rabs localise to the WPB membrane and recruit a range of soluble proteins from the cell cytosol to the WPB membrane. These soluble effectors mediate anchoring of the WPB to the actin cytoskeleton near the plasma membrane, and, during cell activation, the docking and fusion of the organelle with the plasma membrane to release VWF into the blood. Loss of MADD locks WPB Rabs in their OFF state severely impairing the secretion of VWF into the blood.
In this study, endothelial colony forming cells (ECFCs) isolated from the blood of patients with biallelic MADD variants were found to have no detectable MADD, no Rab proteins present on WPBs, highly impaired VWF secretion and, in patients, low plasma VWF levels in the range for Type1 VWD.
Professor Tom Carter from City St George’s University commented “For many years we have speculated that circulating levels of VWF are determine not only by VWF gene expression and the VWF clearance mechanisms that operate in the circulation, but also by the machinery that makes and regulates and secretion of VWF into the blood. This study provides direct evidence to support the idea that defects in the machinery regulating VWF secretion can cause VWD”.