Ashley M. Buckle, Ph.D.

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Research Focus

Dr. Ashley Buckle is a translational scientist and entrepreneur focused on advancing fundamental discoveries into clinical applications. His work broadly addresses how proteins contribute to human health and disease, and how they can be engineered into therapeutic agents. With over 30 years of expertise in structural biology and protein engineering, Dr. Buckle has led multidisciplinary teams in both academic and industry settings.

He earned his PhD in Biochemistry at the University of Cambridge under Sir Alan Fersht, a pioneer in protein engineering, where he studied the structure and function of the ribonuclease Barnase. His postdoctoral research at the MRC in Cambridge focused on the structural biology of molecular chaperones, leading to the first detailed structural model of GroEL-substrate interactions and insights into the allosteric mechanism of the GroEL-GroES-ATP complex.

In 2003, Dr. Buckle joined Monash University in Melbourne, Australia, where he established a diverse research program encompassing:

1. Protease Biology and Inhibition:
Key contributions include the structural characterisation of several forms of the Myeloid and Erythroid Stage Specific serpin MENT, elucidating the structures of thermostable serpins; characterisation of the disease-causing Z mutation of antitrypsin; creation of a synthetic serpin, providing insights into disease-causing serpin misfolding and aggregation, and the discovery of an allosteric mechanism of kallikrein inhibition, resulting in the development of an antibody-based inhibitor.

2. T-Cell Receptor–MHC Interactions:
His research provided structural insights into the immune synapse, revealing how peptide–MHC (pMHC) complexes interact dynamically with T-cell receptors, thereby shaping immune recognition.

3. Engineered Monobodies:
Dr. Buckle led innovative research into the development of fibronectin type III (FN3) monobodies—engineered protein scaffolds derived from the FN3 domain that offer antibody-like specificity with superior stability and manufacturability. His work has focused on leveraging FN3 monobodies as precision tools for modulating immune responses and targeting disease-relevant proteins. Through rational design and structure-guided engineering, his team has developed FN3 variants capable of binding immune checkpoints and other clinically significant targets, with potential applications in oncology, autoimmunity, and regenerative medicine. This platform complements his broader efforts in designing synthetic proteins to create next-generation immunotherapies.

4. Type 1 Diabetes and Autoimmune Disorders:
Focusing on GAD65, a key autoantigen in Type 1 diabetes, his team used hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography, molecular dynamics, and cryo-EM to uncover its unique conformational flexibility. These studies revealed how epitope stabilization upon antibody binding drives immunogenicity, informing therapeutic strategies for autoimmune diabetes and related neurological conditions.

In 2021, Dr. Buckle joined Replay, a San Diego-based genomic medicine startup, as Vice President and Head of Protein Engineering & Structural Biology. There, he led efforts that secured $1.5M from the Bill & Melinda Gates Foundation to develop a discovery platform for hypoimmunogenic iPSC-derived cell therapies. His work was central to Replay’s successful $55M seed funding round in 2022 and led to five patents and the founding of a new gene therapy startup, where he now serves as co-founder and Chief Technology Officer.

His current research focuses on developing novel therapeutic modalities that modulate the immune system. In particular, he is pioneering the design of engineered immune shields to create hypoimmunogenic cells for use in cell therapy and regenerative medicine.

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Publications

View the full list of Dr. Buckle’s publications on Google Scholar

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Education

PhD (Biochemistry) – University of Cambridge, UK (1990 – 1994)
Bachelor of Science (Honours, Chemistry) – Kingston University, UK (1986 – 1990)

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Professional Experience

2025 – Present Adjunct Professor, San Diego Biomedical Research Institute
2024 – Present Chief Technology Officer & Co-founder, stealth biotech startup
2021 – 2024 Vice President & Head of Protein Engineering and Structural Biology, Replay
2020 – 2023 Founder & CEO, PTNG Consulting
2021 – 2023 Founder & CEO, Biovidera
2020 – Present Adjunct Associate Professor, Dept of Biochemistry & Molecular Biology, Monash University (link)
2007 – 2020 Head, Protein Engineering and Design Lab/Associate Professor, Dept of Biochemistry & Molecular Biology, Monash University

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Honors and Awards

2014: Visiting Professor at the Sapienza Università di Roma, Italy
2013: Visiting Professor (Erskine Fellowship), University of Canterbury, New Zealand
2012: Visiting Professor, Ecole Normale Supérieure de Cachan, Paris, France
2012: NHMRC Senior Research Fellowship (Level B). Monash University
2007: NHMRC Senior Research Fellowship (Level A). Monash University
1990: Medical Research Council (UK) Postgraduate Scholarship, University of Cambridge