Below is a list of 19 broad research areas – these research areas are an indication of research which is currently being undertaken at the Franklin, and where the project leads believe there is scope for a PhD project.
Each listing describes a selection of scientists associated with the project which begins with a project coordinator, followed by a project description and key subject areas which the project will cover.
During their application, prospective PhD students will be asked to express an interest in two research areas in their applications this year. Find out more about the application process here.
1. Cellular Compartmentalisation and Condensate Formation from Biology to Physical-Chemistry
Franklin Scientists associated: Judy Kim, Adam Nelson, Karina Pombo-Garcia, Michael Grange, Alexandre Paschoal, Andrew Baldwin, Ajay Jha
The cellular environment is a complex mix of biomolecules that organize themselves to carry out vital physiological cell processes. By compartmentalising, multiple processes can simultaneously occur in the cell, such as energy production in mitochondria and lysosomal material breakdown. In the emerging area of condensates, biomolecules are not surrounded by a lipid bilayer and behave as membrane-less organelles that phase-separate into liquid compartments that concentrate in the cell. This may occur with proteins, lipids, small-molecule drugs, and nucleic acids. This research has implications in neurodegeneration, genetic disorders, and mitochondrial diseases to name a few. This project area is one of our institute’s core challenges which is inherently cross-disciplinary – pushing the understanding of cellular function based upon chemical and morphological organelle dynamics.
Key subject areas: Condensates, Phase Separation, Cell Biology, Thermodynamics, Microscopy, Material Properties, 4D STEM, CryoET, Super-resolution microscopy, Biophysics, Organoids, High throughput synthesis, Liquid phase EM, Raman spectroscopy
2. Cell-Cell Interactions
Scientists associated: Karina Pombo-Garcia, Liang Wu, Felicia Green
One of the biggest challenges in contemporary biology is to understand how cells integrate chemical and physical signals to drive self-assembly, which underpins the formation of complex architectures such as tissues and organs. Cell-cell adhesions and Cell-matrix interactions are crucial for mechanical and chemical information exchange, and forms the fundamental basis of many biological processes, from organ development to pathogen entry. We want to understand the biochemistry and biophysics of cell-cell interactions, by looking at the proteins, lipids and sugars that make up cellular interfaces, and tracking their dynamic changes across complex physiological structures (e.g. organoids, organotypics, tissues). Major tools include light (STED, imaging mass spectrometry) and electron microscopy (cryo-ET), as well as (bio)chemical tool development to analyze and edit the molecules that make up cell surfaces.
Key subject areas: Super-resolution microscopy, Glycobiology, Imaging mass-spectrometry, Cell Adhesion, Cell Biology , Glycobiology, Microscopy, CryoET, Lipids, Nanobodies, Organoids, Dynamic Biology, ECM
3. Defining how Cells and Pathogens Interact
Scientists associated: Lucile Moynie, Shabaz Mohammed, Ben Davis, Maud Dumoux, Ray Owens, Liang Wu, Chen Huang, Alexandre Paschoal, Felicia Green, Andrew Baldwin, Michele Darrow
An essential requirement for rational development of antimicrobial drugs for the treatment of bacterial and viral infections is the understanding of mechanisms that drive pathogenesis. We aim to develop innovative strategies for incorporation of probes and labels (through biological or chemical approaches) that will be enable us to image and map molecular details of host pathogen interactions across different length scales in near-native environments ( e.g. cells ,tissue). This will be achieved using a combination of technologies developed by the Rosalind Franklin Institute such as cryo-ET, Ptychography, optical imaging, Mass spectrometry, NMR, AI. Our goal is to unravel events that influence early stages of infection and mechanism of persistence, with the aim of identifying potential antimicrobial targets and new strategies for pathogen detections and therapeutic interventions.
Key subject areas: Pathogen, Cryo-EM, Cryo-ET, Chemical biology, Mass spectrometry, NMR, Neural Networks
4. Coincidental Lattice Light Sheet Microscopy and Structured Illumination Microscopy for quantitative tissue, cellular and biomolecular dynamics
Scientists associated: Marco Fritzsche, Narain Karedla, Ajay Jha, Angus Kirkland
Quantitative correlative imaging is now mission critical in biomedical sciences. A key development is the UK’s first Biophotonic Correlative Optical Platform (BioCOP) at the RFI, based on Lattice Light Sheet Microscopy (LLSM). This advanced technology offers 100-fold faster imaging than standard microscopes and 3D fluorescence imaging with diffraction-limited spatial resolution in up to seven colours. The projects aim to revolutionize live-cell imaging by developing imaging and analysis pipelines such as Structured Illumination Microscopy and combine LLSM with Fluorescence Correlation Spectroscopy (FCS). The BioCOP will enable high throughput, multiplexed, and deep tissue imaging, advancing the study of biomolecular dynamics in membranes and solutions.
Key subject areas: Spatiotemporal Imaging, Fluorescence, Advanced Optical Microscopy, Spectroscopy
5. Electron Ptychography and Phase Retrieval in Electron Microscopy
Scientists associated: Chen Huang, Angus Kirkland, Judy Kim, Ivan Lobato, Emanuela Liberti, Jingjing Zhao, Ali Mostaed, Amirafshar Mostaghpour
Cryogenic electron ptychography uses coherent diffractive imaging techniques with computational iterative phase retrieval algorithms. New methods such as these are challenging but open the door to new tools for the scientific community. Simulations show that resolution achieved by cryo-ptychography could theoretically be decreased to 2.2 Å, but improved strategies are needed as this area of work applied to biology includes the careful balance between radiation damage and signal-to-noise. These methods could be used to examine biological structures at high-resolution using a small number of particles or over wide fields of view. We use our physics knowledge to work in the experimental, computational, and theoretical development of this field.
Key subject areas: TEM, STEM, Ptychography, Electron optics, Image simulations, Cryo-EM, Physics, Mathematics, Iterative algorithms
6. Liquid Phase Electron Microscopy for Cellular Ultrastructure, Biochemistry and Dynamics
Scientists associated: Brian Caffrey, Angus Kirkland, Judy Kim, Adrián Pedrazo-Tardajos, Tobias Starborg, Mohammed Yusuf
Fundamentally, biology is driven by transient, dynamic assemblies of biomolecules in solution. Therefore, imaging these assemblies live, either as isolates or in situ, is crucial for understanding essential dynamic processes such as chemotaxis, organellar morphology and cell division. Traditionally, these studies of cellular dynamics have remained the purview of super-resolution light microscopies and other related techniques, far from the frozen samples necessary to survive the vacuum of an electron microscope. Our work focuses on sample preparation, encapsulation and imaging techniques to enable the capture of subcellular components, live, in their native aqueous environments at nanometre resolutions across tenths of second timescales.
Key subject areas: TEM, STEM, Liquid phase dynamics, Tilt-corrected bright field imaging, SPA, EDX, EELS, Graphene
7. Electron Diffraction Based Methods of Structure Elucidation
Scientists associated: Marcus Gallagher-Jones, Angus Kirkland, Judy Kim, Jonathan Barnard, Adrián Pedrazo-Tardajos
X-ray crystallography has been for many years the primary method of revealing the atomic coordinates of biological and small organic molecules. However, there are molecules that have remained resistant to structure determination due to their inability to form crystals larger than 1 micron. Electrons, by virtue of their greater scattering cross section, can unlock the potential of nanocrystals. We are developing tools for structural elucidation from nanocrystals of proteins and organic small molecules using a variety of electron diffraction methods.
Key subject areas: TEM, 4DSTEM, 3DED, MicroED, ScanningED, Protein crystallography
8. Damage Reduction using Alternative Scanning Methods in Electron Microscopy
Scientists associated: Abner Velazco-Torrejon, Angus Kirkland, Judy Kim, Maud Dumoux, Jonathan Barnard, Amirafshar Mostaghpour
The main limitation to perform localized analysis in electron microscopy is radiation damage. Organic and biological materials are very sensitive to the energetic electrons. Radiation damage and its secondary effects such as the loss of mass occur at different time scales. The dynamic of these processes can be used to reduce sample degradation by pulsed beam illumination and alternative scanning methods. We explore these methods at different time scales and acquisition schemes, and study the damage behaviour by a diffusion model. These approaches can be coupled to electron ptychography and EDX or EELS techniques, or applied to focus ion beam.
Keyword: STEM, SEM, Radiation damage, Mathematical modelling, Diffusion models, CryoEM
9. Cryogenic electron imaging for investigating the molecular sociology within cells and tissues
Scientists associated: Maud Dumoux, Liang Wu, Michael Grange, Ray Owens, Casper Berger, Michele Darrow, Mark Basham
Electron imaging under cryogenic conditions allows cells and tissues to be imaged on multiple scales, with pristine preservation of fine molecular detail. Tools to bridge the gap between structure and cellular dysfunction are needed. We are building approaches to determine molecular structures within the wider context of intact cells and, more importantly, tissues, including novel methods for labelling and targeting molecules in the cell. We focus our approach on several biological areas, including neuroscience, host-pathogen interactions, and glycobiology.
Key subject areas: TEM, STEM, Plasma FIB/SEM, Volumetric imaging, Cryo-EM, Cryo-ET, Neuroscience, Cell Biology, Labelling.
10. Interrogating the host-microbiome interface of the gastrointestinal tract in human health and disease.
Scientists associated: Felicia Green, Anthony Devlin, Karina Pombo Garcia
This project aims to understand how the localisation of and, the interactions between bacteria present in the gut microbiome may alter the host response. The gut microbiome is home to hundreds of different bacterial species and comprises one of the most dense bacterial environments on earth. Despite this, little is known about the localisation of gut bacteria with each other, different areas of the gastrointestinal tract or near different macroscopic tissue structures. Using the unique instrumentation at the Rosalind Franklin Institute, you will develop new methodologies for detecting bacteria in situ and multiplex these with other world leading instrumentation in order to understand changes in gastrointestinal pathology and how these relate to human disease.
Key subject areas: Mass spectrometry imaging, secondary ion mass spectrometry, gut microbiome, super-resolution imaging
11. Imaging neurodegeneration using mass spectrometry to understand the mechanisms of disease in the brain.
Scientists associated: Felicia Green, Matija Lagator, Mark Basham, Helen Cooper
Given the high complexity and heterogeneity of the cells in the brain, spatial information of molecular organisation is essential for the understanding of and insights into cellular processes. Secondary ion mass spectrometry (SIMS) and native ambient mass spectrometry (NAMS) imaging are increasingly recognised as a powerful technique for visualising molecular architectures in the fields of neurobiology and cell biology. SIMS provides the advantage of analysing multiple types of molecules, with cellular resolution, without the need for a prior knowledge and tagging. This project will use the unique instrumentation available at the Franklin for the generation of images with high spatial resolution and chemical specificity.
Key subject areas: Mass spectrometry imaging, Secondary ion mass spectrometry, Neuroscience, Neurodegeneration, Correlative imaging
12. Enzyme Free Chemical Cleavage of Macromolecules for Mass Spectrometry Imaging
Scientists associated: Felicia Green, Bela Paizs, Daniel McGill, Alexandre Paschoal
Mass spectrometry imaging (MSI) is a rapidly evolving field, enabling the spatially-resolved extraction of chemical information about tissues, organoids, and other solid-phase samples. Despite its flexibility and the range of modalities available, MSI suffers from a set of limitations on top of those already inherent to mass spectrometry. In this project, we aim to utilise surface-modifying chemical methods already common in organic and synthetic chemistry in order to reveal new insights into analytes; combined with our ion mobility capabilities in BMS and data science of AI, the project promises to make a significant impact, enabling deeper probing of tissues and hence a greater understanding of metabolic pathways.
Keywords: Mass spectrometry imaging, metabolites, data science
13. Chemical Biology
Scientists associated: Ben Davis, Lucile Moynie, Liang Wu, Adeline Poh, Karina Pombo-Garcia, Shabaz Mohammed, Andrew Baldwin
Cells rely on a range of biomolecules to maintain function and respond to change. There are highly complex interdependent relationships between these biomolecules that are also incredibly dynamic. Key nodes or certain biomoelcules are key in specific circumstances. Monitoring or modulating the status (of e,g. a kinase) allows substantial insight or remedy of cellular behaviour (i.e. disease), respectively. Our groups develop a range of molecular biological and chemical approaches to monitor and/or modulate a protein’s structure in cellulo or in vivo. Often, approaches are developed to allow heightened detection within the cell/tissue and its partners by techniques such as Cryo-ET/EM, PET, EPR, NMR, Raman and Mass Spectrometry.
Keywords: Chemical Biology, Protein Chemistry, Chemical Synthesis, Molecular Biology, Cell Biology
14. Developing biocompatible chemistries
Scientists associated: Ben Davis, Adam Nelson, Adeline Poh, Ajay Jha, Shabaz Mohammed, Andrew Baldwin
Post-translation modifications (PTMs) are nature’s way of communicating and responding to a change in situation. There are several hundred chemically distinct PTMs and most can be rapidly applied or removed. They are chemically diverse and applied, by nature, in a highly selective way. Chemical approaches, despite many advancements, still face challenges related to water compatibility and substrate stability, which restrict their applicability across various protein types. To address these challenges new chemistries are needed to recreate these modifications to modulate and control cellular networks, to maintain or control function. Our research explores a wide range of light-, redox-, metal- mediated chemistries with the intention of creating a general palette of reactions that control organismal target physiology and the ability to focus on ‘trigger’ pathways.
Keywords: Chemical Biology, Protein Chemistry, Chemical Synthesis, Analytical Chemistry
15. Biophysics, Spectroscopy and Spectrometry
Scientists associated: Andrew Baldwin, Ajay Jha, Shabaz Mohammed, Ben Davis
Understanding the nature of a biomolecule requires understanding its structure and function within its native environment under a range of conditions. Intense research is being carried out at the Franklin on several analytical tools. New mass spectrometer designs are being constructed and optimised to improve sensitivity and comprehensivity. Superior designs of laser-based spectroscopies such as Raman are being developed to improve detection and classification. NMR approaches involving both pulse sequences and data processing are being developed to allow detection of dynamic (in cellulo) biomolecule interactions as well as identify modes of action of drugs. These approaches dovetail with our research into new chemistries and chemical biology. Not only to enhance the fidelity of our data but to also allow the techniques themselves to be improved. Femtosecond transient absorption and electron paramagnetic resonance (EPR) spectroscopy, for example, is used to investigate the mechanisms of radical formation. NMR and MS provide insight into selectivity and clues for better synthesis control. These insights will allow us to optimize reaction conditions and improve selectivity.
Keywords: Mass Spectrometry, Nuclear Magnetic Resonance, Raman Spectroscopy, Analytical Chemistry, Physics, Mathematics
16. High Throughput discovery and molecular informatics
Scientists associated: Adam Nelson, Ben Davis, Mark Basham, Alexandre Paschoal
The diversity of biological, chemical and physical properties that naturally occurring proteins achieve are astounding. The same can be said of the products of human driven chemical synthesis efforts, which have yielded the catalysts, pharmaceuticals, and materials that shape our modern world. Surprisingly few chemical reactions have been used by chemists and biologists to explore the utility of ‘synthetic biologics’ in earnest; a consequence of most research being principally driven by a human and thus ‘limiting’ and ‘slowing’ this endeavour. We are developing strategies for a fully diverse protein and polypeptide synthesis program through the combination of high throughput discovery using automated liquid handling and detection approaches including a range of cellular phenotype screenings (FACS, high-content confocal, robot-assisted selection, antibiotic potentiators with culture imaging) as well as classical analytical approaches such as MS and NMR. This work is augmented with AI tools to aid experimental design as well as data deconvolution and we are developing feedback approaches to allow rapid iterations.
Keywords: Chemical Biology, Protein Chemistry, Chemical Synthesis, Molecular Biology, Cell Biology, Microbiology, Programming, Algorithms, Automation
17. Image Analysis
Scientists associated: Michele Darrow, Mark Basham, Elaine Ho, Neville Yee, Dimitrios Bellos, Avery Pennington, James Parkhurst
Many different modalities lead to the generation of large amounts of 2D or 3D image data (TEM, SEM, X-ray CT, LM, etc). After imaging data is collected, there will undoubtedly be steps needed to computationally extract information from the data. This often entails image manipulation for the purpose of understanding the quality of the data or data processing pipeline, reconstructing from 2D images into 3D images, annotating or segmenting the images to identify regions of interest and taking measurements. In many cases, the image processing needs cannot be met without the development of new artificial intelligence and informatics approaches and software tools to apply these approaches to handle big data in semi-automated ways. These approaches enable faster, less subjective and novel understandings of biomedical processes and intersect with instrument development, microscope control, software engineering, and computational modelling.
Keywords: TEM, SEM, cryoEM/ET, X-ray CT, Image Analysis, Algorithm Development, Software Engineering, Big Data, Computational Modelling
18. Biological Data Science
Scientists associated: Alexandre Paschoal, Mark Basham, Alex Lubbock, Fabiana de Goes
How could we build cutting-edge AI tools to translate biological data into solutions and guide better decision-making? Our interdisciplinary approach focuses on three key strategies. First, we highlight the importance of mining public datasets using AI-bioinformatics expertise to unveil valuable biological insights that could pave the way for new therapeutics and diagnostics. This highlights the need for innovative tools to classify complex biological patterns and user-friendly databases for easy data comparison. Second, abundant data on nucleic acids and proteins provide a foundation to model factors influencing human health, such as infectious diseases and cancer. Last, generative AI offers powerful solutions for tackling complex biological problems, enhancing tasks like classification and data augmentation. Together, these approaches will enhance our understanding of biological systems through ambitious applications of AI and advanced data analysis methods.
Keywords: Bioinformatics, Computational Biology, AI In Biology, Machine Learning, Software, Prediction, Databases, Data Integration and Analysis, Generative AI
19. Experimental Artificial Intelligence
Scientists associated: Mark Basham, Laura Shemilt, Michele Darrow, Alex Lubbock, Laura Crawford, Dimitrios Bellos, Elaine Ho
The Franklin collects a significant amount of experimental data every year and it is paramount to the scientific process that the data collected is the best it can be. Artificial Intelligence tools and methodologies are employed at the Franklin to address this challenge, from effectively choosing the experiments to be undertaken, through to efficiently evaluating the data once collection is complete. Writing and developing software allows us to streamline and automate much of this complex process, which has the impact of massively reducing the time taken to discover new science, introducing new avenues for exploration or development.
Keywords: Artificial Intelligence, Algorithm Development, Software Engineering, Big Data, Computational Modelling, Optimisation