Abstracts of research projects offered for October 2026
Candidates are advised to read about the research interests of members of the Department in conjunction with the following information.
Please find information about funding opportunities here.
Projects on offer:
- From Stem Cells to Heart Cells: mRNA Engineering for Cardiomyocyte Generation
- Study of Ion Channels and Biologic Partners – PhD only
- Tandem-repeat proteins: Physiological and pathological functions, therapeutics, and synthetic biology
- Towards a personalised view of GPCR drug response
- Anti-obesity drug discovery using human neuronal models
- Mechanisms and inhibition of bacterial multidrug transporters
- Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)
- Platelet procoagulant activity: regulation and inhibition
- Mechanisms of nociception
- Innovating Protein Technologies for Therapeutic and Vaccine Design
- DNA Nanostructures
From Stem Cells to Heart Cells: mRNA Engineering for Cardiomyocyte Generation
Key words
mRNA, cardiomyocytes, transcription factors
Project description
Cardiovascular disease is the leading cause of death worldwide, and in vitro cardiomyocyte models are vital for drug development, disease modelling, and regenerative medicine. One method for generating cardiomyocytes is through the differentiation of embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC). However, current protocols using small molecules and growth factors are costly, variable, time-consuming and often generate cardiomyocyte linages that are mixed or inaccurate models. An alternative approach, which has the potential to accelerate differentiation, involves introducing lineage-defining transcription factors to stem cells.
The Wilson group has been pioneering the use of novel messenger RNA therapeutics to elicit cardiomyocyte proliferation and recover cardiac function following ischemic heart failure and has a wealth of experience in mRNA design and application. Recent rapid advances in biomedical engineering and molecular medicine have enabled the production of almost any functional protein or peptide by delivering mRNA directly into the cytoplasm of cells and enabling the protein to be quickly expressed, enabling applications in medicine, diagnostics, and therapeutics. The 5’ cap, length of polyA, and types of regulatory cis-elements included are all determined by the researcher, and there is a range of additional tags and manipulations which can be made. Importantly, mRNA has no potential risk of accidental infection or opportunistic insertional mutagenesis.
This project will use RNA engineering to design and construct artificial RNA molecules to control the cellular processes of cardiomyocyte differentiation. The student will experience a broad range of experimental techniques including cell culture (ES cell culture, iPSC cell culture, differentiation of pluripotent cells), molecular design, bacterial cloning, computational codon optimisation, mRNA synthesis, In vitro translation, microscopy and flow cytometry. This biomedical engineering research is crucial for advancing the field of cardiac studies and for developing innovative therapies for heart conditions.
Study of Ion Channels and Biologic Partners – PhD only
Ion channels play myriad functional roles in fundamental biology, for example by coordinating and powering muscle contraction, by generating axon potentials, and by mediating synaptic communication between neurones throughout the peripheral and central nervous system (CNS). As such, ion channels represent major therapeutic targets with small molecules against them being the third best-selling group of prescribed drugs. Despite this, only a tiny fraction of channels are currently targeted from the estimated 400 predicted human ion channel genes. In recent decades antibody therapeutics (biologics) have rapidly risen to prominence in the drug market. One reason for the success of these agents is improved target specificity. However, no biologics against ion channels have yet made it into the clinic. Technically, ion channels represent challenging targets for the generation of useful biologic binders and modulators, in part due to difficulties in protein production of native forms, and in part due to a lack of penetrance of biologics into the CNS. The impact of breakthroughs in this area cannot be underestimated. Currently, the Miller Group’s research is aimed at using electrophysiological, biochemical, protein engineering and structural biology (Cryo-EM) approaches to understand and develop novel antibody (nanobody) modulators with unique pharmacological properties against therapeutically relevant targets such as GABAARs, glycine receptors and sodium channels. Linked to this, we are also studying and engineering natural protein toxins into useful pharmacological tools. These ion channel types play important functional roles in the central and peripheral nervous system and are high-value targets for new therapies against anxiety, chronic pain and many other neurological disorders. Naturally, following on from these studies aims are to test these proteins in relevant systems to uncover their impacts on neuronal function and to realise their therapeutic potential. A relevant example paper is: https://www.nature.com/articles/s41586-022-04402-z. Funding would be via application to Gates Cambridge, Cambridge Trust, Vice Chancellor’s Awards, or similar (see www.graduate.study.cam.ac.uk/finance/funding for more details and deadlines).
Should you wish to apply for this opportunity or learn more about it then please contact Dr Miller (pm676@cam.ac.uk). Funding can be via Cambridge Trust or Gates or other routes.
Keywords: Cryo-EM, ion channels, electrophysiology, antibody modulators
The major focus of my group’s research is a class of proteins with very distinctive architecture, known as tandem-repeat proteins, that are frequently deregulated in human diseases and whose simple modular architecture makes them uniquely amenable to the dissection of their biophysical properties as well as their rational redesign. The following projects are available:
- Artificial proteins for applications in synthetic biology and molecular therapeutics (e.g. engineered repeat proteins to harness the cell’s waste-disposal machinery to drive the destruction of disease-associated target proteins; self-assembling repeats proteins as genetically encoded phase-separating bioreactors)
- Peptide inhibitors to target disease-associated repeat proteins
- Protein engineering and design to decode structure-function relationships (e.g. repeat-protein sensors for mechanobiology)
Our research is at the interface of biology and chemistry; we also collaborate with computational groups and synthetic chemistry groups, and therefore students will be able to learn a broad range of techniques and approaches, including molecular biology, protein engineering, recombinant protein expression and purification, biochemistry and biophysical analysis, single-molecule techniques, cell biology and medicinal chemistry.
Keywords: protein engineering, protein design, targeted protein degradation, cancer, biotherapeutics
Selected references:
1. Burbidge et al. Structure (2025). Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a. DOI: 10.1016/j.str.2025.07.017
2. Eapen et al. Elife. (2025). Development of D-box peptides to inhibit the anaphase-promoting complex/cyclosome. DOI: 10.7554/eLife.104238
3. Ng et al. Chemical Science (2025). Tandem-repeat proteins introduce tuneable properties to engineered biomolecular condensates. DOI: 10.1039/d5sc00903k
4. Diamante et al. Chemical Science (2021). Engineering mono- and multi-valent inhibitors on a modular scaffold. DOI: 10.1039/d0sc03175e
5. Xu et al. JACS (2017). Macrocyclized extended peptides: Inhibiting the substrate-recognition domain of tankyrase. DOI: 10.1021/jacs.6b10234
6. Synakewicz et al. ACS Nano (2022). Consensus tetratricopeptide repeat proteins are complex superhelical nanosprings. DOI: 10.1021/acsnano.1c09162
Research topic for potential rotation projects: Designed peptides and proteins as molecular therapeutics and research tools (e.g. bifunctional peptides for targeted protein degradation; self-assembling proteins as genetically encoded phase-separating bioreactors; nanoparticle-protein hybrids; force sensors for mechanobiology).
Towards a personalised view of GPCR drug response
Due to their capacity to respond to a wide variety of extracellular signals including light, odour, ions, neurotransmitters or hormones G protein-coupled receptors (GPCRs) have been an extremely successful protein family through evolution capable of detecting cues from the extracellular environment and ensuring cell-to-cell communication. Thanks to their key role as regulators of cell physiology, GPCRs have extensively been exploited as drug targets, with over 1/3 of available drugs in the clinic targeting one of these receptors.
Although we now know many details on the molecular basis of receptor signalling, key questions on their function remain unresolved, thus hampering our understanding of GPCR function and drug action: notably, it is still not clear how age and sex-dependent differences in GPCR pathway composition can alter receptor physiology and drug responses. In this computational pharmacology project, you will integrate existing resources in the lab charting the molecular wiring of receptor pathways, with information on drug-receptor interactions, multi-omics datasets, and drug efficacy and safety readouts to obtain an unprecedented view on personalised GPCR drug responses which could shift the way we therapeutically exploit these highly successful targets.
Please contact Dr Marti-Solano to discuss potential MPhil or PhD projects before applying and, to ensure you can be considered for studentships, at least 3 weeks before the relevant funding deadline (see https://www.postgraduate.study.cam.ac.uk/applying/application-deadlines for more details).
Keywords: computational biology, systems pharmacology, multi-omics integration, receptor signalling, personalised medicine
Anti-obesity drug discovery using human neuronal models
Many drugs used to treat obesity and type 2 diabetes (T2D) act on appetite-regulatory neuron populations, likely including pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus that secrete the peptide melanocyte stimulating hormone (MSH) to inhibit appetite. In the mouse brain, POMC neurons are activated by metabolic signals including the hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), and leptin. To facilitate the study of human POMC neurons, we developed methods to generate them in large numbers from human induced pluripotent stem cells (iPSCs). We found that these iPSC-derived POMC neurons (iPOMC) closely resemble their counterparts in the human brain in terms of the genes they express, their processing of POMC into MSH peptides, and their functional responsiveness. Specifically, we used calcium imaging and electrophysiology to characterize their responses to hormones and drugs, and found that they are robustly activated by GLP-1, GIP, and their derivative drugs semaglutide and tirzepatide. More recently, we have developed functional assays to facilitate the identification of new treatment combinations and novel targets to reduce appetite by modulating these appetite-regulatory human neurons. We propose several projects related to these new research directions.
Project 1 (funded PhD studentship with AstraZeneca)
To maximise discovery potential with human iPSCs, AstraZeneca and the Merkle lab will improve existing cellular models to generate hypothalamic neurons more quickly, efficiently, reproducibly, and at higher level of functional maturity by combining existing directed differentiation protocols with the targeted expression of candidate transcription factors (TFs) involved in cell type specification and maturation. This project offers the successful student the opportunity carry out part of their studies in a pharma environment, and the possibility of generating new cell populations to underpin new drug discovery efforts.
Project 2 (not funded)
To discover new potential therapeutic targets for obesity, we will leverage the scalability, functional relevance, and genetic and environmental accessibility of iPSC-derived neurons to carry out CRISPR and small molecule screens with the help of recently-developed scalable phenotyping assays. We will then validate hits alone or in combination with known drugs using more detailed morphological, electrophysiological, and omics-based methods and advance the most promising leads to animal models of obesity. This project is envisioned as a PhD project, but a more discrete body of work to follow up on existing candidates could form the basis of an MPhil project.
Key words: obesity, appetite, iPSC, differentiation, transcription factor, neuron, POMC, screening, target validation, drug discovery, mechanism of action
For more information, please visit our website or contact Florian Merkle at fm436@cam.ac.uk.
References
Merkle et al., Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development, 2015, 10.1242/dev.117978
Abay-Nørgaard et al., Generation of human appetite-regulating neurons and tanycytes from stem cells, BioRxiv 2025, 10.1101/2025.05.23.655442
Mazzaferro et al., GLP1R agonists activate human POMC neurons. BioRxiv, 2024 10.1101/2024.04.02.587825
Herb et al., Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus. Science Advances, 2023,10.1126/sciadv.adf6251
Tadross et al., A comprehensive spatio-cellular map of the human hypothalamus. Nature, 2025, 10.1038/s41586-024-08504-8
Mechanisms and inhibition of bacterial multidrug transporters (MPhil/PhD)
Multidrug transporters are membrane proteins embedded in the plasma membrane, where they play a key role in expelling therapeutic agents from the cell interior to the exterior. This extrusion process helps cells resist the toxic effects of antibiotics, enabling continued growth. These transporters contribute significantly to antibiotic resistance in pathogenic bacteria and other microorganisms, and also play a role in the development of resistance to anticancer drugs in tumours. In addition, they influence drug toxicity and pharmacokinetics across all forms of life, from bacteria to humans.
Understanding the structure–function relationships of bacterial multidrug transporters is therefore of broad relevance and forms the central focus of our project. By exploring these relationships in detail, we aim to uncover insights that could support the development of new strategies to combat antibiotic resistance and improve the effectiveness of current antibiotics.
Our research focuses on multidrug transporters from the ABC, MFS, and MATE families, investigating their roles in bacterial antibiotic resistance using a range of microbiological methods. We also employ biochemical and genetic techniques to purify and reconstitute both wildtype and mutant proteins into artificial lipid systems, including proteoliposomes, lipidic nanodiscs, and peptidiscs. To understand the mechanisms of antibiotic binding and transport, we use biochemical, biophysical, and structural approaches.
This work is carried out in collaboration with leading research groups in the UK and internationally. Together, these multidisciplinary strategies are helping us address fundamental questions about multidrug resistance.
Keywords: Antibiotic resistance; multidrug transporters; mechanisms; inhibitors.
Targeted protein degradation by the Ubiquitin-Proteasome System (UPS) - PhD Only
Targeted protein degradation occurs through ubiquitin-mediated pathways that bring about the destruction of ubiquitin-tagged proteins at the 26S proteasome. Research in the Lindon group seeks to understand how these pathways interact with the cell cycle, and how they can be harnessed for novel therapeutic strategies. One major focus of the lab is the cell cycle regulator Aurora A kinase (AURKA). AURKA is a target of ubiquitin-mediated degradation by the APC/C-FZR1 ubiquitin ligase, a key player in several types of cancer, and a potential target for new oncology drugs.
One novel class of drugs, often referred to as PROTACs (Proteolysis Targeting Chimeras), harness the UPS to induce the degradation of clinically relevant target proteins, and the group are studying a number of PROTAC compounds effective against AURKA. Although there is much excitement about the therapeutic potential of this approach, there is still much to learn about the relevant ubiquitin-dependent pathways that operate within the cell to bring about target destruction. Research in the Lindon group therefore aims to discover more of the cell biology of PROTAC action to assist in the design of successful PROTAC-based therapeutic strategies.
These questions are studied using quantitative molecular and cell biology techniques, including timelapse fluorescence microscopy and cellular ubiquitination assays, and involves collaboration with chemists, biochemists and computational biologists. Please see the lab pages and recent publications for more information. Interested candidates should contact Dr Lindon to discuss potential PhD projects.
Key words: ubiquitin, mitosis, APC/C, Aurora kinase, degron, proteolysis, targeted protein degradation, PROTAC
Platelet procoagulant activity: regulation and inhibition
Platelets are necessary for normal haemostasis but platelet activation at the wrong time or place drives arterial thrombosis, leading to heart attacks and ischaemic stroke. One of the prothrombotic roles of platelets is to enhance coagulation by exposing phosphatidylserine (PS) on their outer surface and by releasing procoagulant extracellular vesicles (EVs).
In the Harper lab, we aim to understand how platelet PS exposure and EV release are regulated, and whether we can pharmacologically inhibit these dangerous processes to reduce thrombosis. Our recent work has identified that ‘supramaximal’ Ca2+ underlies platelet PS exposure, identified the platelet ‘flippase’ as a novel approach to reducing coagulation, and explored a diverse range of potential antithrombotic molecules.
Future research projects will involve continuing to further our understanding of platelet PS exposure and EV release. Please contact Dr Harper to discuss potential MPhil or PhD projects before applying to discuss potential research directions.
Keywords: platelets, thrombosis, novel therapeutics
Innovating Protein Technologies for Therapeutic and Vaccine Design - PhD Only
Inspired by extraordinary molecular features from the natural world, the Howarth Group’s research develops new approaches for disease prevention and therapy. By engineering and evolving proteins, projects range from fundamental analysis through to clinical application. There are PhD projects in various areas and the group is keen to design with you a project connecting to your interests.
- The group's Plug-and-Protect vaccine platform has entered clinical trials for malaria, coronavirus and CMV. One project is to tailor antigens and protein nanoparticles, to induce the most potent cell signalling and maximize protection for the most important global health challenges.
- The group’s SpyTag/SpyCatcher technology for covalent ligation is being widely applied for basic research and biotechnology. A new project uses SpyTag to enhance how antibodies can be combined for combinatorial control of CAR-T and cancer cell signalling. A key goal is to modify the cell surface to improve CAR-T cell selectivity in killing of solid tumours.
- The gut is highly effective at degrading proteins, preventing the use of antibodies for targeting in the gastrointestinal tract. The group has established a new antibody mimetic with exceptional protease resilience. One project will use library selection and computational design with machine learning to advance the targeting platform, towards tackling important challenges in autoimmune disease, infection or microbiome modulation.
Keywords: protein engineering, synthetic biology, cancer, infectious disease
Antibiotic resistance is a growing worldwide human health issue with major socio-economic implications. A review from the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit estimates that by 2050 the global cost of antimicrobial resistance will be up to $100 trillion and will account for 10 million extra deaths a year, reinforcing the urgency of finding novel and efficient ways to treat this problem. The Mela Group explores the potential of DNA nanostructures, both as a sensor that binds to bacteria in a specific and efficient manner and as a platform to deliver active antimicrobials to bacterial cells.
DNA nanostructures are made by exploiting the base-pairing property of DNA to construct two- or three-dimensional nanostructures that can be easily customised to deliver a variety of payloads and also to carry “anchors” that will enable attachment to specific targets
Project 1
This proposed project aims to investigate the interactions of 3D DNA nanostructures of different sizes with bacterial targets, and the potential of these nanostructures to enter the bacterial cell. The nanostructures will be tested for targeting potential both “naked” and encapsulated in liposomes. We will then functionalise the nanostructures with active antimicrobials and explore the relationship between size and cargo in the efficiency of these nanostructures as antimicrobial drug delivery vehicles.
Project 2
In this project, we aim to use DNA nanostructures that have the ability to change conformation depending on environmental conditions. We will functionalise the nanostructures so that they can tightly bind on the bacterial membrane and then induce conformational changes (linear to spiral structures). We will assess and quantify the effects of these conformational changes to the membrane integrity of bacteria and therefore their viability, and develop these nanostructures as potential antimicrobial nano-robots.
Keywords: Antibiotic resistance, DNA nanostechnology, microscopy, drug delivery