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Sensing oxygen to develop medication
The basic chemistry behind how the human body senses oxygen was pioneered in Oxford, and it is leading towards new treatments for anaemia and cancer.
Professor Mridul Mukherji, Division of Pharmaceutical Sciences, University of Missouri, Kansas City
The results from Schofield lab are helping produce pharmaceuticals that are showing promising results in clinical trials, and, hopefully, will soon be used for the treatment of anemia, ischemic heart disease and stroke. It is a perfect example of how fundamental understanding of a key biological process leads to novel therapeutics for human diseases.
Since the isolation of penicillin, there has been a strong tradition of drug development in the University of Oxford. But a lot has changed since the pioneering work on antibiotics and, rather than culturing moulds, the Schofield Group in the Chemistry Department have more molecular ideas about what they can deliver for medicine.
Working with the Ratcliffe-Pugh group in the Nuffield Department of Clinical Medicine, they set out to understand the basic chemistry behind how humans sense, and respond, to the presence of oxygen. In the human body, oxygen-regulated proteins affect how cells respond to differing levels of the gas. When there is a shortage, the proteins activate a host of genes involved in the adaptation of cells to the lowered oxygen levels. The result is that the body produces more red blood cells and blood vessels to cope with the lower oxygen concentration.
The team discovered a family of enzymes that sense oxygen in order to regulate the activity of these proteins – and oddly enough they are actually closely related to the ones responsible for the production of penicillin. The Schofield Group have since been working hard to characterize them so that they can develop medications to artificially recreate the body’s reaction to a shortage or excess of oxygen.
Artificially boosting the production of red blood cells and growth of vessels by blocking the sensing enzymes, alleviates the symptoms of conditions like anaemia. What is more, activating the enzymes can suppress blood vessel growth, which helps in the treatment of cancer. Together with pharmaceutical companies, the University’s spin-out company ReOx is helping to develop new anaemia treatments, and several compounds are now in clinical trials.
The basic science has also inspired labs around the world, and that has led to the discovery of a whole family of enzymes that modify DNA and its associated proteins. It turns out that mutations to genes caused by some of these enzymes are linked to cancer, mental degradation and cleft pallet – a finding which the Oxford team hope to capitalise on.
Funded by: The Biotechnology and Biological Sciences Research Council, Cancer Research UK, the Engineering and Physical Sciences Research Council, Wellcome Trust, and the European Union.