Transforming molecular biophysics with mass photometry

Understanding how biomolecules, drugs and other molecules work together is one of the most important areas of study in the life sciences - central to our understanding of basic biology and to developing new drugs. However, it can be difficult to obtain accurate information about these different interactions. To make this possible, we need tools that have three key features. They should be: i) highly sensitive and accurate, ii) able to capture changes over time rather than only static snapshots, and iii) able to operate in the natural environment of proteins or in comparable conditions. In recent decades, much work has gone into developing such tools and researchers have made huge progress in this area. Still, none of the tools available now encompasses all three of the features we urgently need.
Our group has developed a completely new tool that could solve this problem, with the potential to revolutionise how we study molecular interactions. We call the approach 'mass photometry' (MP) because it uses light (in a microscope) to measure the mass of molecules in a liquid sample. From the amount of light scattered by a molecule, we can calculate its mass with a very high level of accuracy. This technology amounts to only the third way of measuring mass, after gravity-based methods and mass spectrometry.
MP has already attracted high levels of interest from fellow researchers working in universities and in the pharmaceutical industry. It has also led to the creation of a successful spinout company, Refeyn.
Still, for the potential of this cutting-edge technology to be fully realised, we need to make critical improvements. For this fellowship, we have set objectives to improve four key aspects:
1. Measurement resolution;
2. Measurement precision;
3. The range of sample concentrations for which MP is applicable; and
4. How we analyse the data and process the images we obtain.
It is these improvements that will transform MP into a potentially revolutionary approach for studying biomolecular structure and function. We will conduct this work over five years at the University of Oxford's Department of Chemistry. Our team will consist of the fellowship holder, who will guide and oversee the study, and four postdoctoral researchers, who will lead research on each of the four objectives alongside two PhD students.
Our ultimate goal is to advance MP from a proof-of-concept technology to a well-accepted, transformative tool for researchers working across the life sciences - from those doing biological discovery research to those developing drugs and clinical diagnostics. In support of that goal, we will also engage in two major collaborative/outreach activities for the duration of this fellowship. First, we will work with a major pharmaceutical company, exploring how MP can support their drug development work. Second, we will operate a MP facility in our university department, which will be open to all fellow researchers to use in their own projects at minimal cost. These two activities will help us validate our techniques, test MP on different applications, gather feedback from MP users, and spread the word about our technology and what it can do to the broader research community.
This fellowship will enable Philipp Kukura to build on what he has been working towards since becoming an independent academic a decade ago: changing our perception of what we can measure with light, and opening up new inroads in diagnostics, biological discovery and drug development. Bridging the advanced optics and life sciences communities, he will use this fellowship to solidify his position as the global leader in this field, share his vision with the next generation of researchers, and create an MP powerhub in Oxford. Ultimately, this will not only benefit the research community, but the UK economy as well, with the creation of local jobs, boosting the UK's prime life sciences industry and advancing health.

We expect that the adoption and use of our technology will pave the way to wider societal impacts in terms of health and prosperity. A major area of application for mass photometry (MP) is biologics, which are the most rapidly growing part of the drug market, due to their remarkable selectivity and specificity. These features bring major benefits for treatment of conditions such as cancer, where they reduce the likelihood of side effects. Unlike small molecules - which have traditionally comprised most of the drug market - biologics are often large, complex macromolecules and are much more challenging to characterise. Our technology mitigates this challenge by enabling highly accurate, dynamic mass measurements of single molecules in solution. Representing seven of the world's ten top selling drugs in 2018, biologics are immensely economically important, particularly in the UK, where the life sciences is a critical area of industrial activity.
MP has already generated significant economic impacts. The underlying technology has been patented and commercialised by Refeyn Ltd, an Oxford-based spinout company. Founded in 2018, Refeyn attracted significant seed funding and has grown rapidly. It now employs 25 people in the Oxford area (and a further 3 in the US), with more than 20 of its instruments sold and in operation in laboratories spanning the life and physical sciences around the world. To build on these economic impacts, further commercialisation opportunities arising from this work will be pursued through our existing links with Refeyn, with appropriate IP protection and licensing agreements.
In the near to medium term, an important group of beneficiaries from our work will be its direct users, primarily life scientists within both academia and the pharmaceutical industry. Through the development work we plan to undertake as part of this fellowship, we envision that MP will provide unique capabilities to life scientists working in discovery science, drug development and clinical diagnostics. It will give researchers a powerful new approach for studying molecular interactions, enabling them to characterise molecular complexes and dynamics at an unprecedented rate and level of detail.
As evidence of this immense potential, since introducing MP, we have been regularly approached by life scientists interested in using it. More than 30 academic visitors have come to use the equipment in our group in the past 18 months, and there has also been considerable industrial interest. To capitalise on this high level of interest and generate impact during the fellowship, we will i) establish a MP facility in our Department, open to all researchers, and ii) initiate a large-scale collaboration with a major pharmaceutical company, AstraZeneca. These activities will allow our work to generate significant impacts over the course of the fellowship beyond the traditional routes of dissemination via publications and seminars. They will also lay a strong foundation for the wider adoption of MP - by engaging potential users from a range of fields and gathering feedback about how they will use the technology and the key performance characteristics they expect.
Overall, we expect this fellowship to generate impacts on three levels: UK society will benefit from economic and health impacts; the wider life sciences research community will benefit from access to a powerful new tool for biophysical characterisation enabling new science; and the biophysics community will benefit from the fellow's leadership in this area and from the creation of novel methodologies based on MP.