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Zee Upton

Zee Upton joined IMB as a Research Director in July 2015 to establish, along with David Leavesley, the Tissue Technologies Group in the IMB. She is a biochemist by training, a tissue engineer, an inventor and entrepreneur who is internationally renowned for her research in molecular, biochemical and cellular aspects related to growth factors, extracellular matrix proteins and tissue repair. She is passionate about ensuring research delivers benefits, is taken up and utilised, as well as champions interdisciplinary approaches; she believes that innovation commonly arises in the “white spaces” between disciplines. She also has an interest in frugal innovation, and to this end she is working closely with collaborators in India and China on projects related to tissue repair, scar remediation and diagnostic technologies.

Prior to relocating to Singapore she was a senior research leader and research manager at the Queensland University of Technology (QUT) in Brisbane, Australia, where she held various roles, including Assistant Dean (Research) in the Faculty of Health. She also established the Tissue Repair and Regeneration Program at QUT, and plans to similarly build a highly inter-disciplinary consortium of researchers focused on tissue integrity from the fields of life, engineering, mathematical, IT, clinical and social sciences at IMB. More recently her research has moved to the development of diagnostic/prognostic/theranostic technologies to detect, preempt, monitor, interrupt or better manage disease/injury/health.

Since the award of her PhD in Biochemistry from the University of Adelaide in 1994, she has developed a significant record of innovative and quality scientific research that has yielded: $27+ million in research funding from both competitive grant schemes and industry; 120+ manuscripts; the successful supervision of 34 PhD students; the mentoring of numerous post-doctoral and mid-career researchers; the receipt of many awards including the inaugural 2013 Banksia Scientific Regenerative Medicine Award, 2011 Life Sciences Industry Queensland Excellence Award, 2010 Australian Society of Biochemistry and Molecular Biology Discovery Science Award, 2009 Women in Technology Biotech Outstanding Achievement Award and 2004 Queensland State Government “Smart Women – Smart State Award”; regular sponsorship as an invited speaker to diverse national and international forums; the establishment of new innovative collaborative research projects, including leading establishment of the $108 million Wound Management Innovation Cooperative Research Centre in Australia; 13 patent families; and the founding of a now Australian Stock Exchange-listed biotechnology company, Tissue Therapies Ltd. 

David Leavesley

David Leavesley joined IMB as a Senior Principal Investigator in July 2015 to establish, along with Zee Upton, the Tissue Technologies Group in the IMB. His research has been focussed on how cells interact with their environment and he is recognised for significant contributions to fundamental and applied medical science, particularly in cell migration and tissue repair. He has always worked with end-users, patients, clinicians and industry partners, seeking practical and affordable solutions that are fit for purpose. He actively collaboratives across disciplines, particularly primary-healthcare providers, engineers, mathematicians and clinical practitioners, as well as across institutional and geographical boundaries and has long-standing collaborations in India and China.

David graduated with Honours (BSc Hons) from Flinders University of South Australia in 1982. He joined Enterovax Pty Ltd, a joint venture with F. H. Faulding & Co, which developed the first oral vaccines for Cholera and Salmonella sp. He relocated to University College London, to undertake his PhD at the Imperial Cancer Research Fund laboratories (now CRUK), and thereafter to The Scripps Research Institute, La Jolla, Ca. At Scripps he invented the popular Transwell® cell migration assay, using it to discover the cooperative and dynamic interactions of integrins, particularly during cell migration. He returned to Australia in 1992 and used his understanding of  cell migration to improve stem cell harvesting techniques (enabling it to replace bone marrow transplantation) and ambulatory peritoneal dialysis (for patients with renal failure).

In 2001 Dr Leavesley relocated to Brisbane to take up an academic appointment in the School of Life Sciences at the Queensland University of Technology. In additon to designing and teaching courses in Cell and Medical Biotechnology, he teamed with Zee Upton to establish the Tissue Repair and Regeneration Program. This evolved into a highly inter-disciplinary consortium of researchers from the fields of life, engineering, mathematical, IT, clinical and social sciences focused on clincial challenges associated with skin and tissue integrity. The discoveries made during this period included the development of the VitroGro™-ECM technology platform, underpinning the establishment of Tissue Therapies Ltd. He was also key research leader involved in the estabishment of the world’s largest wound research cooperative, the AU$108M Wound Management Innovation Cooperative Research Centre. David and Zee intend to create a similar inter-disciplinary consortium of researchers in Singapore, to collectively address many of the existing and emerging health challenges encountered by Singaporeans and those in neighbouring regions. 


 

Our current understanding of the biological processes underlying tissue repair and remodelling, along with maintenance of tissue function, is limited. Our research group is focussed on addressing this knowledge gap and is pursuing diverse approaches to improve our understanding of tissue biology to facilitate development of next generation tissue repair and tissue integrity technologies and products. These span: consumer-focussed skin maintenance products; diagnostic, prognostic and theranostic devices and tools to better manage tissue integrity and clinical care; and novel therapies and dressings. We have a particular focus on human skin and wounds, and emerging interests in musculoskeletal tissue.

While the research activities are largely “biology” focused in the first instance, as the projects progress to the technology “proving” stages there is an increasing emphasis and need for collaboration and input from diverse disciplines such as materials scientists, engineers, clinicians, economists, information technologists, health service providers and regulatory authorities, as well as an absolute requirement for input from industry and end-users. We recognise that the convergence of the bio-, nano-, engineering, clinical and social sciences is critical to enable “innovations” or “discoveries” to be adapted to outputs that have relevance and pathways to utilisation. Similarly, the emerging opportunities for: better use and integration of data; an increasingly personalised approach to healthcare; and integration of automation and digital technologies to transform, disrupt and create new industries and business models, is at the forefront of our thinking as the research projects progress and evolve. The overall goal is to conduct innovative research that delivers outputs that improve human health and wellbeing, while at the same time enhance Singapore’s positioning as the leading regional player in basic and translational research.

Some of our group’s current research activities are briefly described below:

  • Growth factor interactions with the extracellular matrix: We are investigating the structure-function relationships of growth factor-extracellular matrix (ECM) interactions, and their associated signalling pathways and biological functions. We have examined these interactions in a range of cell and tissue types, and have applied this knowledge to develop: tissue repair therapies, including a novel multi-functional chimeric protein that has been successfully clinically trialled as a topical wound therapy; and agents that disrupt dysregulated tissue growth, such as occurs in the metastasis of tumours. 

  • Inflammation and Non-healing Wounds: Non-healing wounds are often described as ‘stalled’ in the inflammatory phase of the healing cascade. Our research is directed at characterising specific pro-resolving mediators in exudate samples from healing and non-healing wounds. In particular, this project is examining if these factors can be manipulated to enable resolution of inflammation. 

  • Development of a novel scar-remediation treatment: Shikonin is a Traditional Chinese Herbal Medicine that has been used anecdotally for hundreds of years to remediate scars. Using a range of molecular and biochemical approaches we have established that Shikonin selectively decreases proliferation and increases apoptosis in dermal fibroblasts, suggesting that these actions may underpin the anecdotal success of its use in scar remediation. Our current research is directed at: i) development of an appropriate delivery formulation/strategy; and ii) conduct of a pre-clinical study to test the efficacy of Shikonin as a scar therapy.

  • Development of a novel therapy for venous ulcers: Using advanced metabolic profiling technologies we have discovered that elevated levels of uric acid are present in exudate from non-healing venous leg ulcers and have shown that xanthine oxidase, the enzyme involved in the generation of uric acid and toxic free radicals, is elevated in non-healing wounds. Currently we are evaluating the use of allopurinol, a xanthine oxidase inhibitor, as a novel topical therapy for these wounds. We have successfully completed a human safety trial assessing topical application of allopurinol to venous ulcers and planning for a clinical trial to test efficacy is currently underway. 

  • Diagnostic and prognostic biomarkers of wound healing: Currently there are no biochemical- or molecular-based technologies available to assist the diagnosis and management of wounds. Prior research we conducted in our laboratories at the Queensland University of Technology (QUT), Australia, involved the proteomic analysis of hundreds of wound fluid samples and associated clinical data, leading to the identification of a highly promising fingerprint for identifying wounds that are on a healing versus non-healing trajectory. This is being further developed as a clinical diagnostic tool in conjunction with our Australian collaborators.

  • MicroRNAs in wound healing: Another molecular-based technology with potential to assist in the diagnosis and management of wounds are non-coding RNAs. We have characterised the microRNAs present in patients with healing and non-healing wounds and have found changes in the microRNA population in wounds that are consistent with cell type, injury and healing. We are currently validating these microRNA candidates with a view to developing them into a clinical diagnostic tool. We anticipate future studies will expand to also include long non-coding RNA species.

  • Biomarkers to intercept and interrupt musculoskeletal injury: The goal of this project is to develop a tool that can be used as an indicator of musculoskeletal health and to better manage musculoskeletal injury. The underlying hypothesis is that physical activity-related micro-trauma to musculoskeletal tissue can be detected early using urinary biomarkers. This project is using advanced proteomic technologies to discover biomarkers of musculoskeletal micro-trauma in laboratory-controlled exercise studies, as well as in labour-intensive work environments such as mining, transport, construction, defence and elite athletes. The project builds on research we conducted at QUT and will continue to involve our QUT collaborators. 

  • eSkin/Tissue Engineering/Sensor Technologies:  Leveraging off our experiences in the development of therapies and diagnostics we are currently building a new collaborative interdisciplinary research project focused on next generation tissue integrated/interfaced diagnostic technologies. This project seeks to incorporate advanced sensors, diagnostics, scaffolds, surface technologies, 3D printing and tissue-materials interfaces in innovative combinations to create diagnostic technologies fit for the 21st century. This project will focus on the development of technologies that enable disease interception and interruption, and promote health and wellbeing.

  • Characterisation of skin repair and tissue integrity using and ex vivo human skin equivalent model: Our team has developed a “ex vivo human skin equivalent” model that recapitulates the key features of skin. Through the use of skin tissue discarded from elective surgical procedures we incorporate various cell types and construct a simplified model of human skin. This ex vivo living human skin tissue has been used to evaluate the in situ responses of skin cells in studies assessing: fundamental cellular pathways and mechanisms in a 3D environment; UV radiation; novel wound therapies, dressings and biomaterials; and, for contract toxicology testing of proprietary compounds.

 

 

 

 

 


Fernandez ML, Stupar D, Croll T, Leavesley D, Upton Z. Xanthine Oxidoreductase: A Novel Therapeutic Target for the Treatment of Chronic Wounds? Adv Wound Care (New Rochelle). 2018 Mar 1;7(3):95-104. doi: 10.1089/wound.2016.0724 Link
Than UTT, Guanzon D, Leavesley D, Parker T. Association of Extracellular Membrane Vesicles with Cutaneous Wound Healing. Int J Mol Sci. 2017 May 1;18(5). pii: E956. doi: 10.3390/ijms18050956 Link
Chen Q, Zhou H, Yang Y, Chi M, Xie N, Zhang H, Deng X, Leavesley D, Shi H, Xie Y. Investigating the potential of Oxymatrine as a psoriasis therapy. Chem Biol Interact. 2017 Jun 1;271:59-66. doi: 10.1016/j.cbi.2017.04.020 Link
Wager LJ, Murray RZ, Thompson EW, Leavesley DI. A fence barrier method of leading edge cell capture for explorative biochemical research. Cell Adh Migr. 2017 Sep 3;11(5-6):496-503. doi: 10.1080/19336918.2016.1269997 Link
Yin L, Liu W, Xia H, Jia X, Leavesley D. (2017). Down-Regulation of PER2 Increases Apoptosis of Gliomas after X-Ray Irradiation. Chemo Open Access 6:228. doi: 10.4172/2167-7700.1000228 Link