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Dr Alex Combes
Dr Combes received his PhD in 2009 from the University of Queensland (UQ) where he investigated the genetic and cellular interactions controlling testis organogenesis in the laboratory of Prof. Peter Koopman. After a brief postdoctoral position in Epigenetics with Prof. Emma Whitelaw he returned to Developmental Biology to work on an international, multidisciplinary effort led by Professor Melissa Little to quantitate and mathematically model kidney organogenesis.
Dr. Combes and his colleague Dr. Kieran Short (Monash), established a multiscale imaging approach to visualise and analyse kidney development, which resulted in one of the most comprehensive profiles of any mammalian organ system to date. Since then Dr Combes has applied advanced imaging and genomics to build our knowledge of kidney development, disease and regeration.
Dr. Combes is a Team Leader at the Murdoch Children's Research Institute and is jointly appointed with the Department of Anatomy and Neuroscience, University of Melbourne as a Senior Research Fellow. He continues to work closely with Professor Melissa Little on kidney development and disease at Murdoch Childrens Research Institute.
- Dyason Fellowship, 2016
- Discovery Early Career Researcher Award, Australian Research Council, 2015-2018
- David Walsh Prize, Australia and New Zealand Society for Cell and Developmental Biology, 2009
- University of Queensland Confirmation Scholarship, University of Queensland, 2007
- Institute for Molecular Bioscience PhD Scholarship, University of Queensland, 2006
Investigating kidney development to understand disease and guide renal regeneration
The adult kidney is a complex tissue with more than 25 distinct cell types with all the functional units of the organ forming during fetal life. A detailed understanding of the developmental programs that guide the specification and growth of each cell type underpins knowledge of congenital disease and can be used to direct the differentiation of human pluripotent cells into renal tissue.
My research has significantly contributed to our understanding of how the kidney forms at the genetic, cellular and tissue levels. Developing and applying a state of the art multiscale imaging approach to capture cell and tissue dynamics in fixed and live samples across time, my work has enhanced our understanding of the regulation and behaviour of key progenitor populations in the kidney and how they interact to control the functional capacity of the adult organ.
Our recent work interrogating the developing mouse kidney and human kidney organoids with high throughput single cell RNA sequencing has revealed a roadmap for the production of renal cell types, and has addressed how faithfully stem cell derived renal tissues replicate cell types in the developing human kidney. These findings provide immediate opportunities to bioengineer cell types for disease modelling and drug screening.
Despite this substantial insight, we still lack a complete understanding of renal progenitor cells and their maintenance, as well as the instructive signals required to generate mature cell types in the final organ. Advances in single cell sequencing, imaging, biosensors and genomics offer opportunities to further explore kidney development and will provide fundamental insights into mammalian tissue morphogenesis. Outcomes of these endeavours will have significant bearing on bioengineering, congenital disease, and regenerative medicine.
Identifying novel drivers of kidney growth and patterning: Analysis of targeted disruption to nephron progenitor turnover with single cell sequencing and advanced imaging will lead to new capabilities to manipulate progenitor expansion and differentiation.
Understanding the role of cell migration in nephron progenitor regulation: Employing advanced live imaging and lineage tracing to interrogate the role and function of cell movement in regulating progenitor turnover and commitment.
Functional analysis of novel genes associated with kidney development and disease: Functional analysis of genes associated with new aspects of development and novel disease-associated genes from patient sequencing cohorts to explore the molecular mechanisms of kidney development and disease.
See Google Scholar or PubMed for complete and current publication list.
Lawlor K, Zappia L, Lefevre J, Hamilton N, Oshlack O, Little M.H., Combes A.N# Nephron progenitor commitment is a stochastic process influenced by cell migration Elife 2019 # Senior and corresponding author
Combes AN#, Zappia L, Er P, Oshlack A, Little MH Single cell analysis reveals congruence between kidney organoids and human fetal kidney Genome Medicine 2019, #Co-corresponding author
Phipson B, ER P, Combes AN, Forbes T, Howden S, Zappia L, Yen D, Lawlor K, Hale L, Sun J, Wolvetang E, Takasato M, Little MH Evaluation of variability in human kidney organoids Nature Methods, 2019
O'Brien LL, Combes AN, Short KM, Lindström NO, Whitney PH, Cullen-McEwen LA, Ju A, Abdelhalim A, Michos O, Bertram JF, Smyth IM, Little MH, McMahon AP. Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment. Elife, 2018
Combes AN#, Wilson S, Phipson B, Binnie BB, Ju A, Lawlor KT, Cebrian C, Walton SL, Smyth IM, Moritz KM, Kopan R, Oshlack A, Little MH Haploinsufficiency for SIX2 increases nephron progenitor proliferation leading to elevated branching and nephron number. Kidney International. 2018 #Co-corresponding author
Little MH, Combes AN, Takasato M Understanding kidney morphogenesis to guide regeneration of kidney tissue Nature Reviews Nephrology, 2016
Combes AN#, Lefevre JG, Wilson S, Hamilton NA, Little MH Cap mesenchyme cell swarming during kidney development is influenced by attraction, repulsion, and adhesion to the ureteric tip Developmental Biology, 2016, #Co-corresponding author
Combes AN, Davies JA, Little MH Cell–Cell Interactions Driving Kidney Morphogenesis Current Topics in Developmental Biology. 2015
Combes AN*, Short KM*, Lefevre J*, Hamilton NA, Little MH, Smyth IM An integrated pipeline for the multidimensional analysis of branching morphogenesis. Nature Protocols. 2014, *Equal contribution
Short KM*, Combes AN*, Lefevre J, Ju AL, Georgas KM, Lamberton T, Cairncross O, Rumballe BA, McMahon AP, Hamilton NA, Smyth IM, Little MH Global quantification of tissue dynamics in the developing mouse kidney Developmental Cell. 2014 *Equal contribution
- Australian Research Council (DECRA 2015-2018)
- Australian Research Council (DP 2019-2021)
- Australian Research Council (LEIF 2017)
- National Health and Medical Research Council (Project 2019-2021)
- Stem Cell Medicine Pilot Projects (2016-2019)