Karen Steel is a Principal Investigator at the Wellcome Trust Sanger Institute. After her first degree from Leeds University, she received her PhD from University College London for her investigations of the inner ear in several deaf mouse mutants. She moved to Nottingham to the newly-established MRC Institute of Hearing Research for her first postdoc, and set up the mouse genetics and deafness research programme there. After a second postdoc in Munich, she returned to Nottingham to lead the mouse genetics research there.

In 2003, she moved to the Wellcome Trust Sanger Institute to establish the Mouse Genetics Project, a high-throughput phenotypic screening programme using newly-generated, targeted mouse mutants to detect signs of a broad range of diseases, including hearing impairment. She has published over 190 scientific articles.

Awards, honours and elections

  • Recipient of the Kresge-Mirmelstein prize for excellence in hearing research, New Orleans, 1998
  • Elected Fellow of the Academy of Medical Sciences, London, 2004
  • Elected Council member of Association for Research in Otolaryngology (2004-2008)
  • Elected President of International Mammalian Genome Society (2007-2012)
  • Edith Whetnall lecturer, Section of Otology of the Royal Society of Medicine, London, 2008
  • Elected Fellow of the Royal Society, London, 2009
  • Award of Merit, Association for Research in Otolaryngology, to be presented in Baltimore, Feb 2013

Service

Karen Steel has served on MRC, Wellcome Trust and ERC grants committees, acted as scientific advisor to three charities working with deaf people, and served as an expert witness to the House of Lords Select Committee on Aging. She has also served on several Scientific Advisory Boards, two editorial boards, and reviewed grants and manuscripts for a wide range of organizations. She has been on the organizing panel for the Molecular Biology of Hearing and Deafness meeting since its inception in 1992.

Research contribution

Karen Steel’s primary research interest is the genetics of deafness, using mouse mutants to gain access to the molecules involved in normal development and function. She has focussed on identifying genes underlying deafness and understanding the molecular and physiological basis for the dysfunction. Her group, together with many collaborators, has published phenotypic descriptions of over 80 different mouse mutants representing 36 loci, and they have identified 38 mutations in 22 different genes by positional cloning. For several of these, she has collaborated with human geneticists to identify mutations in the same genes in humans with deafness. Each new mutation and gene identified adds valuable information about critical processes in the auditory system, but it is likely that there will be over 500 genes required for normal hearing and identifying these is a key first step in constructing the molecular pathways and networks involved. For this reason, gene discovery remains a core goal of the research.

To identify critical genes underlying deafness, three approaches have been used. Firstly, spontaneous mutations causing hearing and balance defects in the mouse were used. Several of these genes identified by positional cloning (eg Myo7a, Cdh23, Whrn) turned out to be involved in Usher syndrome in humans. Secondly, Karen Steel co-ordinated an EC-funded programme to generate new point mutations randomly throughout the genome of mice using a powerful mutagen (n-ethyl-n-nitrosourea) followed by screening the offspring for hearing or balance problems, and then positional cloning. Nine out of the thirteen different genes carrying mutations identified in this programme were new deafness genes. Thirdly, the Mouse Genetics Project at the Sanger Institute was set up to generate mice carrying new targeted mutations, and following screening of nearly 500 lines so far, nine new genes associated with raised thresholds for auditory brainstem responses to sounds have been detected as well as several more with other abnormalities in responses.

Analysis of these new mouse mutants showed that a very wide range of mechanisms can cause deafness, including middle ear malformations, middle ear inflammation, inner ear malformation, sensory hair cell developmental defects, homeostatic failure, and stalled maturation. Despite the common assumption that hearing loss is due to sensory hair cell degeneration, analysis of this large panel of mutants shows that degeneration is an epiphenomenon, not a primary cause of deafness. One early finding was that that a lack of melanocytes in the stria vascularis on the lateral wall of the cochlear duct caused abnormal strial control of homeostasis leading to deafness, establishing a new physiological basis for one form of hearing impairment.  As a final example, after identifying the first gene involved in deafness, Myo7a, detailed ultrastructural and electrophysiological studies indicated that myosin VIIa appears to anchor the cell membrane to the actin core of the stereocilia that form the hair bundle on top of sensory hair cells, and that without functional myosin VIIa protein, the membrane-bound transduction channel complex is loosely coupled to the core and readily slips, closing the channel.

Current research focus

Progressive loss of auditory function with age is a major problem in the human population. Hearing loss is profoundly isolating, both socially and economically, and has a major impact on the quality of life of those affected. Both the genome and the environment will contribute to the pathological process, and genetics is used as a tool to identify some of the molecular mechanisms. The current research in Karen Steel’s laboratory aims to understand the reasons for this decline in function, using mouse models with progressive loss of hearing ability. It is likely that at least three sites within the cochlea can contribute to progressive deafness: the lateral wall of the cochlear duct which is responsible for maintaining the optimum homeostatic environment, the hair bundle at the top of sensory hair cells which is the site of transduction from a mechanical stimulus (sound vibration) to a voltage change within the hair cell, and the specialized ribbon synapses at the base of the sensory hair cells that respond extremely rapidly to voltage changes. These three sites are the focus of investigation in several newly-generated mouse mutants with progressive decline in measures of auditory function, and the findings are related to human hearing loss by comparing both pathophysiological findings and variations in candidate genes highlighted in human population studies.

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