Swietach Group

Current projects — Cancer

We study tumours as ecosystems whose chemistry, metabolism and structure shape how cancer grows, spreads and responds to therapy. A major strand asks how tumour cells survive and compete in acidic, nutrient‑stressed niches. Using genome‑wide CRISPR screens, we identified oxidative phosphorylation (OXPHOS) as a key survival pathway specifically under acidic conditions, and flagged NDUFS1 as a drug‑addressable node. We are now testing whether approved OXPHOS inhibitors can be repurposed and selectively delivered to acidic regions (for example, via pH‑targeting peptides) to spare normal tissue. These studies help explain why some drugs work better in hostile microenvironments and point towards condition‑dependent cancer therapies.

A second line of work maps how cancer cells keep their interior healthy despite living in acid. We showed that chronic extracellular acidity triggers lysosomal degradation of the acid‑loading transporter AE2 (SLC4A2), helping cells alkalinize their cytoplasm and tolerate stress. We are now exploring ways to block this adaptation or combine it with metabolic inhibitors, aiming to “pull the rug” from under acid‑adapted clones.

Because cancer does not act alone, we also examine tumour–stroma cooperation. Our work on gap‑junction networks shows that neighbouring cells can share small metabolites, buffering the effects of metabolic gene defects. We are extending this idea to the tumour microenvironment to learn when stromal exchange protects cancer—and how to interrupt that protection without harming normal tissue.

Across these projects, we build practical tools and frameworks: single‑cell and live‑tissue imaging to read out fitness in different niches; models that link microenvironmental chemistry to growth and drug response; and collaborations with clinical partners to test biomarkers that report on a tumour’s local conditions. We also contribute field‑level synthesis—for example, recent reviews laying out how proton chemistry shapes aggressive behaviour and where the therapeutic entry points might lie—so that findings can travel from bench to bedside.

Our team works in multi‑centre programmes on ion and pH transport in pancreatic and colorectal cancer, aligning discovery science with platforms for patient stratification and drug targeting. The aim is simple and actionable: measure what matters in the tumour niche, exploit the weaknesses it creates, and deliver the right therapy to the right place.

Current projects — Cardiac

We investigate how chemical and mechanical cues in heart tissue control contraction, rhythm and growth—and how these cues go wrong in disease. One active programme maps nuclear microenvironments in cardiomyocytes. We showed that a more alkaline nucleoplasm favours expression of contractile genes, offering a direct link from local chemistry to gene regulation. We are now developing readouts and interventions that modulate these nuclear conditions, with the goal of supporting contractile performance and limiting maladaptive remodelling.

A complementary line of work asks how myocytes auto‑regulate their own acid–base balance. We discovered sensing mechanisms that detects acidic stress and re‑balances sarcolemmal transporters, helping cells stabilise their internal environment. We are expanding this into preclinical models of ischaemia and heart failure to test when boosting or braking specific transporters restores pH homeostasis and improves function.

We also study inherited and acquired metabolic disorders that derail the heart. In models of propionate overload (relevant to propionic acidaemia), we linked altered acyl‑coenzyme A fluxes to histone acetylation/propionylation, PDE9A up‑regulation, and contractile dysfunction. Current work probes whether metabolic or epigenetic interventions can reset these programmes and protect the myocardium.

With clinical partners, we are building translation pipelines: organ‑scale preparations, imaging and omics to track early failure points; and drug‑target discovery for membrane transporters (for example, NBCn1/SLC4A7) implicated in hypertrophic growth. Alongside discovery, we pursue targeted delivery—testing whether engineered extracellular vesicles can carry protective payloads to the heart after injury. These strands are backed by programme and project grants that combine basic physiology with therapeutic development.

Methodologically, we integrate single‑cell electrophysiology, high‑resolution imaging and quantitative modelling with in vivo readouts. The unifying theme is control: identify micro‑domains that set performance limits, trace their failure in disease, and intervene precisely—whether by tuning transporters, reshaping microenvironmental chemistry, or modulating gene programmes—so the heart can maintain rhythm, power and efficiency under stress.

Current projects — Blood

We focus on the functional quality of red blood cells (RBCs): not just how much oxygen they carry, but how fast and reliably they unload it where it is needed. We built tools to time oxygen release cell‑by‑cell and found that cytoplasmic diffusion can be a key bottleneck—a property that changes with storage and cell shape. Building on this, we developed FlowScore, a simple flow‑cytometry proxy of oxygen‑unloading kinetics that can run in routine labs. Current studies with transfusion services test FlowScore as a quality marker to flag units that deliver oxygen more effectively.

A second programme asks how storage conditions alter RBC performance—and how to fix it. We showed that standard storage can slow oxygen release, that this change is trackable with practical proxies (such as side‑scatter), and that rejuvenation or hypoxic storage can restore faster unloading. We are now evaluating how these strategies extend shelf life and, crucially, whether they improve organ oxygenation in model systems that mimic clinical use.

To connect bench findings to organs, we tested whether slower oxygen release limits diffusion in perfused human kidneys. In paired experiments, rejuvenating RBCs boosted the kidney’s oxygen diffusion capacity and raised cortical pO₂, demonstrating that RBC kinetics can constrain tissue oxygenation under clinically relevant conditions. This work sharpens the case for function‑guided blood selection in surgery, trauma and perfusion medicine.

Translation is central. We collaborate with industry and NHS partners on hypoxic storage technologies and on bench‑to‑bank implementation of FlowScore‑style metrics, including automated pipelines that link cell geometry to oxygen‑handling performance. A related preclinical effort studies how donor factors, disease and storage drive unit‑to‑unit variability, and whether matching patients to high‑function units improves outcomes.

Across the portfolio, we standardise open methods, share datasets, and design scalable assays that fit blood‑bank workflows. The vision is practical: give clinicians better, faster information about what transfused blood will do—so that every unit is not only compatible, but effective at delivering oxygen to tissues when it matters most.

SCIENTIFIC PUBLICATIONS