Dr Jonathan Phillips
Senior Research Fellow
Living Systems Institute
Skills Development Fellowship Vision
A Fellow will have demonstrated excellence and already be in possession of extensively developed skills in their core discipline that provide an opportunity for tremendous insight to be gained by their application to a key challenge in another space within biomedical science. They must be intellectually agile and not only able, but curious to explore and learn information and skills that fall outside of their prior focus areas. In this way, I anticipate they would see significant growth and broadening of their skillset – perhaps even becoming uniquely qualified.
The solid basis from their previous training would allow them to be autonomous in some aspects of the project: for example a mathematician would be expected to benefit from more guidance and mentoring in gathering and curating experimental datasets and in the strategic aspects of where they hope to have an impact on the field, yet may be quite autonomous in developing models to fit or explain the data. Naturally, this will require excellent communication skills and engagement with networks to forge casual and formal collaborative relationships that evolve the project towards its goals.
Ultimately, the Fellow will develop a thread of research that has the potential to expand into a rewarding and interdisciplinary exploration – one that poses as many questions as it answers and which will form the basis of their own research group.
- BSc biochemistry.
- PhD chemistry (molecular biophysics).
- Post doc in synthetic biology (protein design).
- Industrial fellowship awarded to develop physical chemistry methods for the study of protein dynamics (AstraZeneca).
- Senior Research Associate at University of Cambridge.
The study of control in nature and in medicine. Control of biological systems is naturally achieved most often by controlling how proteins move. This gives us higher order functions, such as vision, movement and growth. Now, the majority of new approvals for medicines are for protein drugs, whose behaviour must also be tightly controlled. So, although there are many advanced techniques to elucidate protein structure at high resolution, it is actually protein structural dynamics that underpins much of biomedical function.
Therefore, it is important and interesting for us to understand how proteins alter their posture dynamically and interactively between forms that are functionally distinct. In the Phillips lab we develop experimental methods (focused around hydrogen/deuterium-exchange mass spectrometry) to measure protein movement at the highest possible spatial and temporal resolution. We have previously combined this with mathematical/statistical models to describe protein structural changes.
In the future we will look to apply this to more complicated molecular systems, such as biochemical pathways, neurodegenerative disease (Parkinson’s disease) and synthetic protein switches. This presents a skills and knowledge gap as we seek new models to explain increasingly rich data that is inherently too complex to be sufficiently represented by the models that were previously so successful.
- Klein T et al. (2015) Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase. Nature Communications 6:7877.
- Edgeworth MJ et al. (2015) Global and Local Conformation of Human IgG Antibody Variants Rationalizes Loss of Thermodynamic Stability. Angew Chem Int Ed Engl 54(50):15156–15159.
- Millership C, Phillips JJ, Main ERG (2016) Ising Model Reprogramming of a Repeat Protein’s Equilibrium Unfolding Pathway. J Mol Biol 428(9 Pt A):1804–1817.
Ongoing Projects & Grants
- Structural plasticity of alpha-Synuclein in biology and in Parkinson’s disease.
- An automated system for hydrogen/deuterium-exchange mass spectrometry with a 1000-fold increase in temporal resolution.
- Design and engineering of protein switches.
- The structural dynamics that underpin infectivity in Botulinum toxin.
- Dr G. Kaminski (University of Cambridge) – Neurobiology/neurodegeneration.
- Dr S. Gamblin (Crick Institute) – Kinase biology in metabolism and diabetes.
- Dr S. Jackson (University of Cambridge) – Protein folding.
- MedImmune Ltd – Antibody folding and stability.
- Ipsen Ltd – Botulinum toxin biology and biomedicine.
- Applied Photophysics Ltd – Automated high temporal resolution instrumentation.
Research Group Connections