Evolution of Oxygen Sensing in Animals

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The work we are proposing to do is based on insights we have obtained into the way humans sense oxygen. Regulating the delivery of oxygen to tissues is a problem for all organisms that use it as an energy source and particularly so for large animals such as humans that are composed of many billions of cells and different types of tissues. Many human diseases such as heart attacks, strokes, cancer, and anaemia involve damage to cell and hence tissue function by low oxygen levels (hypoxia). In previous work (important components of which were supported by the BBSRC) we have identified a group of oxygenases (enzymes that catalyse the incorporation of atmospheric oxygen into their substrates) that act as cellular 'oxygen sensors',by catalysing the hydroxylation (involving addition of an oxygen atom) of specific amino acid residues in a protein called HIF (hypoxia inducible factor). Hydroxylation destroys and inactivates HIF, but since it requires oxygen, this reaction is suppressed in hypoxia, allowing HIF to become activate in hypoxic cells (hence its name). HIF is a transcription factor (a regulator of gene expression) that, when switched on, regulates many genes that are involved in altering cell metabolism, growing new blood vessels, increasing blood production and other actions that help the body to survive hypoxia. These findings have opened up a new field of research on this type of protein modification, what it does, how it is regulated by hypoxia, and how it affects the cell's responses to hypoxia. The work on HIF has also raised many questions as to whether this type of modification (hydroxylation) occurs for other types of protein within cells, and what the effects might be. Recently, we have found that the HIF system also exists in the simplest living animal, Trichoplax adhaerens, which lives in the sea. Our initial data suggest that the Trichoplax oxygen sensing system is closely related to the human system, but is much simpler, largely because Trichoplax has a much smaller genome than humans. We aim to carry out a detailed comparison between the human and Trichoplax HIF systems, to investigate whether the HIF or related oxygen sensing systems exist in other organisms. Our initial data suggests that HIF is present in all animals but not in the group of organisms from which animals are though to have evolved (choanoflagellates), leading us to propose that the HIF system evolved along with the rises in oxygen levels and multicellular animals, at or just before the famous Precambrian period in the evolution of life. This aspect of evolution has been elegantly described in the recent television series 'First Life' presented by David Attenborough. However, we have also found that enzymes related to the HIF hydroxylases also exist in bacteria even though HIF doesn't. We think that these enzymes had an oxygen sensing role via an unknown mechanism in prokaryotes, and eventually evolved into the human oxygen sensing enzymes. Our work thus ultimately aims to connect molecular and genomic analyses with evolutionary studies. However, it is our experience that the cross-species analyses can lead to deeper understanding of the underlying mechanisms of how human cells work - these are often difficult to dissect because of the complexity of human cell biology. Finally, although our work will employ the use of invertebrates, aspects of their cell biology and embryonic development appear to be well conserved with human cells, raising the possibility that they may contribute to the replacement of mammals in drug development.