| James Nathan is a Respiratory Physician working on cellular mechanisms of oxygen and metabolite sensing. He undertook his research training at the University of Cambridge (Wellcome Clinical Research Training Fellowship, 2004) and Harvard Medical School (MRC Clinician Scientist Award, 2009), exploring basic mechanisms of protein degradation and proteasome function. In 2014, he was awarded a Wellcome Senior Clinical Research Fellowship for his laboratory in the CIMR. Here, using a combination of forward genetic and biochemical approaches his group uncovered new insights into how cells respond to their nutrient environments through enzymes that are sensitive to both oxygen and metabolites (Cell Metabolism, 2016 & eLife, 2017).|
Summary: His current Wellcome Senior Clinical Research Fellowship will enable him to continue this work, exploring how the main pathway for sensing oxygen, the Hypoxia Inducible Factor (HIF) response, is regulated by metabolites, mitochondrial function and oxygen. This research will not only lead to an improved understanding of the mechanisms involved, but potentially open up new therapeutic avenues for treating cancers and inflammatory disease, where inappropriate HIF activation contributes to disease progression.
| Alex Taylor has interests that span molecular biology, immunology, chemical biology, molecular evolution and biotechnology, and are best summarised as fundamental synthetic biology, or xenobiology. His research at King’s College London (2007) was focused on understanding how natural evolution shapes key molecules in adaptive immunity – antibodies (immunoglobulins) and their cellular receptors – through comparative immunology, biophysics and structural biology. He later joined the MRC Laboratory of Molecular Biology in Cambridge in 2010 where he developed synthetic genetic systems based on analogues of DNA (collectively known as xeno nucleic acids, or XNAs), composed of chemical building blocks not found in nature.|
Summary: His Wellcome Trust Henry Dale Fellowship will enable him to use protein engineering and directed evolution to adapt polymerases to alternative nucleotide triphosphates. The results of this can encode sequences in a range of synthetic genetic polymers, which are called ‘XNAs’. Such systems allow us to explore functional landscapes beyond the comparatively narrow chemistry of natural DNA and RNA polymers through artificial directed evolution (‘synthetic genetics’). Recently, he used XNA systems for a series of proof-of-principle projects providing the first examples of functional molecules composed entirely of artificial scaffolds – the evolution of antibody-like ligands (‘aptamers’; Science, 2012) and catalysts (‘XNAzymes’; Nature, 2015), as well as the self-assembly of nanotechnology designs using only XNA components.
‘Synthetic genetics’ offers novel approaches to understanding the emergence of life’s hallmark processes from abiotic systems, as well as clear pathways to applications in ‘grand challenge’ areas in biomedicine. By establishing an ambitious and forward-looking program of research at CITIID, he will seek to use ‘synthetic genetics’ to develop a new generation nucleic acid biotechnologies for precision medicine – research reagents, diagnostic tools and therapeutics with the specificity and efficacy of protein biologics (such as monoclonal antibodies), but with the chemical versatility of short DNA oligonucleotides. Functional XNAs could form the basis of exciting new approaches to detecting and fighting pathogens, cancers and allergic and autoimmune diseases, as well as for directing biology for immunotherapy and tissue bioengineering.
| Stephen Baker is a molecular microbiologist working in global health. His work focusses on integrating genomics with clinical and epidemiological sciences to understand how bacterial pathogens spread, evolve and cause disease. He was been based at the Wellcome overseas unit for 12 years but is now Director of Research for global health in the Department of Medicine at the University of Cambridge. His Wellcome Trust Senior Research Fellowship will enable him to develop his work in the department to generate new insights into how organisms trigger immunological responses during natural infection and use this information to develop new control tools.|
Summary: Enteric fever is a febrile disease caused by the bacteria Salmonella Typhi and Salmonella Paratyphi A. Typhi is well studied and new conjugate vaccines will likely have a major impact on disease burden. In contrast, Paratyphi A is poorly studied and there are currently no licensed vaccines that protect against this organism. His fellowship will provide a better understanding of the population structure and biology of Paratyphi A, leading to the construction of novel conjugate vaccines. Firstly, through a network of collaborators in Asia, he will define the population structure of a contemporary Paratyphi A collection. Pivotal selective events will be identified using phylogenetics and genome mapping; the conservation of potential vaccine candidates will be investigated. O-antigen is a key structure in Paratyphi A and a component of all developmental Paratyphi A vaccines. However, O-antigen phase variation in Paratyphi A may limit vaccine efficacy. Steve will identify the mechanism of Paratyphi A O-antigen variation and assess the potential role of antigenic variation in immune escape. Lastly, he has identified a panel of immunogenic Salmonella antigens, and will investigate their function in Paratyphi A and link them to O- antigen to generate novel, bespoke conjugate vaccines.