7 June 2022

Surprisingly, understanding of organ assembly is extremely limited. Professor Melissa Little and team received an Human Frontier Science Program (HFSP) grant and established the most comprehensive quantitative image-based analysis of any organ ever described. The challenges of bringing together researchers from different fields is one of vocabulary, but the benefit is considerable.


How to build a kidney: quantitative modeling of kidney morphogenesis across time and space

2011 - HFSP Grant Awardees - Program Grants

  • Professor Melissa Little (Australia)
    Murdoch Children's Research Institute - Royal Children's Hospital - Melbourne 
  • Professor Andrew McMahon (US)
    Dept. of Regenerative Medicine and Stem Cell Biology - The Broad-CIRM Center - Los Angeles
  • Professor Ian Smyth (Australia)
    Dept. of Anatomy and Developmental Biology - Monash Biomedicine Discovery Institute - Melbourne 
  • Professor Helen Byrne (UK)
    Mathematical Institute - Oxford Centre for Collaborative Applied Mathematics - Oxford

Read more in the abstract.

Photo of Professor Melissa Little

Please describe the research project that you undertook with the funding offered by HFSP? 

The research proposal funded by the HFSP was entitled ‘How to build a kidney: quantitative modeling of kidney morphogenesis across time and space.’

This was a collaboration with Harvard University (Professor Andrew McMahon), Oxford University (Professor Helen Byrne), Monash University (Professor Ian Smyth) and my group at the time when I was at University of Queensland. 

The appropriate function of any organ relies on an organotypic spatial organization and differentiation of each component cell type during embryonic development. Surprisingly, our understanding of the spatio-temporo cellular dynamics and biophysical processes underpinning organ assembly is extremely limited. 

Adopting the mammalian kidney as our system, we aimed to create an integrated model of kidney organogenesis by coupling high-resolution biological observations with mathematical modeling. Such measurements will include analysis of individual cell population sizes, cell turnover and cell migration, genetic pathway activity, 3D spatial and lineage relationships of individual compartments over time. These parameters will be analysed in the context of tomographic and mathematical models of the whole organ ex vivo. The resulting models will be refined iteratively with data from developing kidneys challenged by environmental stress or genetic disruption. The anticipated comprehensive model of kidney organogenesis will serve as a valuable framework for developing better therapies and novel approaches to tissue regeneration.

How did this funding program enable you to undertake your research?

The proposal was cutting edge, fundamental research into kidney morphogenesis that applied novel high-resolution imaging across time and space together with mathematical modeling. This aligned completely with the HFSP aspirations for innovation, interdisciplinarity and international collaboration. 

As a result of this funding, we established the most comprehensive quantitative image-based analysis of any organ ever described. We also applied this approach to a variety of mutant lines to illustrate the presence of previously undetectable subtle morphogenetic effects. The funding itself has generated numerous publications and launched subsequent NHMRC funding for my own group and those of the other Principal Investigators. 

How has collaborating with international researchers supported your research effort and your research career?

The prominence of the data generated with this funding has significantly improved my international reputation in the area of kidney development. The technology is now being applied to stem cell-derived organoid models and we have developed some of our own internal and national collaborations around mathematical modeling. Dr Alex Combes, the postdoc driving the work within my team, has launched his own career as a result of his outputs from HFSP funding, including being a recipient of an ARC DECRA (2015) and now as a faculty member at Monash University. 

What are the advantages of collaborating internationally, both scientifically and for developing professional relationships/networks? Are there any challenges?
HFSP funding provides support for high risk, high reward, fundamental science, specifically supporting those projects where the combination of varied skillsets can contribute to a paradigm shift. Prior to this funding, we had done no mathematical modeling of morphogenesis. Without this funding we would not have commenced. 

The challenges of international science are obvious, particularly around communication across three time zones. However, we are accustomed to needing to travel to build and maintain networks and this grant also allowed us to do this. The challenge of bringing together fields is one of vocabulary as much as anything else, but the benefit is considerable. 

What have been the outcomes of the research?

Modeling cell turnover in a complex tissue during development. Lefevre J, Marshall DJ, Combes AN, Ju AL, Little MH, Hamilton NA. Journal of Theoretical Biology (2013) 338:66-79.

Global quantification of tissue dynamics in the developing mouse kidney Short KM, Combes AC, Lefevre J, Ju AL, Georgas KM, Lamberton T, Cairncross O, Rumballe BA, McMahon AP, Hamilton NA, Smyth IM, Little MH. Developmental Cell (2014) 29(2): 188–202.

An integrated pipeline for the multidimensional analysis of branching morphogenesis. Combes AN, Short KM, Lefevre J, Hamiliton NA, Little MH*, Smyth IM*. (*joint senior) Nature Protocols (2014) 9(12):2859-79.

A spatially averaged mathematical model of kidney branching morphogenesis. Zubkov V, Short K, Combes A, Lefevre J, Ju A, Georgas K, Rumballe B, O’Brien L, Hamilton N, McMahon A, Smyth I, Little M, Byrne H. Journal of Theoretical Biology (2015) 379: 24-37

Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis. Lambert B, MacLean AL, Fletcher AG, Combes AN, Little MH, Byrne HM. Journal of Mathematical Biology (2018) 76(7):16734-1697

What have been the longer lasting benefits of this HFSP grant and working with international networks?

Beyond the HFSP funding, I was funded by the National Institutes of Health both within the Genitourinary Development Molecular Atlas Project and in reBuilding a Kidney (RBK), both of which enabled continued collaboration with Professor Andy McMahon and new links with additional international kidney researchers. 

Professor Melissa Little is the Theme Director of Cell Biology at the Murdoch Children's Research Institute (MCRI) in Melbourne. An NHMRC Senior Principal Research Fellow at MCRI, she is also Program Leader of Stem Cells Australia and Professor, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, and past President of the Australasian Society for Stem Cell Research. In 2021, it was announced the Professor Little would be the inaugural CEO of the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), a collaboration between the University of Copenhagen in Denmark, MCRI in Australia and Leiden University Medical Center in The Netherlands. The new consortium is expected to stimulate a new wave of global investment in stem cell medicine and technologies, paving the way for future stem cell-based treatments.