The President's Excellence Fund for Frontier Research

Dr David Ayuso, Professor Joshua Edel, Dr Alex Ivanov, Professor Michael Bearpark, Professor Jon Marangos

Chirality—the property of an object that cannot be superimposed on its mirror image—is ubiquitous in nature. Like our hands, opposite versions of the same chiral molecule (R and S enantiomers) behave identically unless they interact with another chiral object. Molecular chirality is rapidly becoming essential in nanotechnology, e.g. for developing molecular motors and spintronic devices. The unbalance between R and S biomolecules on Earth (amino acids, sugars, DNA, etc.) supports life. This homochirality gives different biological activities to opposite versions of a chiral drug or pesticide, with profound implications for pharmaceuticals and agriculture. Moreover, abnormal enantiomeric ratios of chiral biomarkers have recently been linked to cancer, Alzheimer’s, diabetes, and other diseases.
Having efficient tools for rapid chiral discrimination is therefore vital. However, current optical methods are inefficient because they rely on the (chiral) helix that circularly polarised light draws in space. The pitch of this helix—determined by light’s wavelength—is ~10,000 times larger than the molecules. Consequently, the molecules perceive the helix as a flat circle, hardly feeling its chirality. This results in weak chiral sensitivity, typically <0.1%, which presents major limitations. For instance, enantio-quantification in samples containing several chiral molecules requires their time-consuming pre-separation in chromatographic columns. These columns are specific to the molecule type and require regular cleaning and disposal, contributing to additional waste. For synthetic applications, the challenges are even greater, and using light’s helicity to control the outcome of a photochemical reaction is simply unfeasible. Instead, one must start with enantiopure reagents or utilise specific chiral catalysts.
We can overcome these limitations with synthetic chiral light, where the electric-field vector traces a chiral trajectory in time. This new type of chiral light can drive ultrafast chiral currents inside the molecules, which interact with the chiral molecular skeleton in a highly enantiosensitive manner, leading to 100% chiral sensitivity. At Imperial, we pioneered the first experimental realisation of synthetic chiral light using ultrashort and ultrabright lasers and advanced 3D shaping techniques.
We aim to harness this extraordinary sensitivity for practical applications by developing on-chip microfluidic devices based on extreme lensing. Microfluidic platforms enable a range of imaging applications with minimal liquid sample consumption. Importantly, curved (e.g. cylindrical) microfluidic channels can act as a lens. However, unlike conventional lenses, microchannels are typically smaller than the laser spot size. Thus, the incident light rays entering the channel can experience its full curvature (extreme lensing), creating promising opportunities for 3D polarisation shaping that remain unexplored.
Our ambitious goal is to engineer microfluidic devices that generate synthetic chiral light within their channels when illuminated by a standard laser—eliminating the need for chiral, ultrabright, or ultrashort light sources. By removing the reliance on large-scale optics and specialised expertise, we aim to enhance scalability and accessibility. If successful, this project will lead to sustainable, scalable, compact, and user-friendly technology that can disrupt optical methods for chiral discrimination, with major industrial implications.

Dr Jack C Gartside, Professor Riccardo Sapienza

The growing demand for AI computing power is critically unsustainable with current energy-hungry hardware. Neuromorphic computing leverages complex physical dynamics to efficiently perform AI, drawing inspiration from the brain - the most efficient computer. However, existing neuromorphic approaches rely on single physical systems, limiting performance when AI tasks do not align with the system's physics. To address the urgent need for versatile, energy-efficient AI solutions, innovative approaches are required.
In HYMN, we propose a new paradigm: a ‘hybrid’ neuromorphic approach that leverages the complementary strengths of multiple physical systems, delivering a new class of energy-efficient AI hardware that excels across diverse tasks. Our team will show that photonic semiconductor lasing networks, hosting many lasing modes which act as photonic neurons, can be sensitively controlled by optically-switched nanomagnetic arrays. By reconfiguring lasing modes via programmable nanomagnetic fields, we will intelligently tune lasing dynamics & hence AI processing, using neuromorphic algorithms developed by the Gartside group. This will vastly improve the power & flexibility of neuromorphic performance to enable bio-inspired AI with real-world impact. We will validate our approach via challenging AI vision tasks, including biomedical image diagnosis with extremely scarce training data - critical for patient care but underserved by current AI systems.
Leveraging synergistic expertise in nanomagnetism, neuromorphic computing & magneto-optics (Gartside), network lasers (Gartside/Sapienza), and complex nanophotonics (Sapienza), HYMN will establish hybrid magneto-photonic networks as a key to breakthrough neuromorphic performance: vastly reconfigurable magnetic arrays provide memory and task adaptivity, while photonic lasing dynamics grant exemplary image processing.
We will exploit nonlinear coupling between vast numbers of lasing modes in graph-like InP waveguide networks to engineer highly sensitive systems, where even small magneto-optic effects from integrated magnetic arrays enable deep photonic reconfigurability. Different magnetic states will configure synapse-like coupling between lasing modes via Faraday, Voigt, and nonreciprocal phase shift effects. This resolves two key limitations of photonic neuromorphic systems: lack of memory, and reconfigurability - resolved here via the persistent, programmable magnetic microstate.
Our approach is high-risk and high-reward, ideal for the frontier ambition of this fund. Hybrid neuromorphic systems have not been demonstrated, magnetic control of III-V lasers is underexplored & local nanomagnetic lasing control has never been attempted. If successful,
HYMN will deliver a paradigm shift in physical neuromorphic AI and reconfigurable lasing control. Our strong preliminary experimental data and supporting numerical simulations mitigate risk & prove feasibility.
We will evaluate recent hypotheses on ‘neuronal heterogeneity,’ which suggest that diverse neuronal dynamics enhance few-shot learning. By mimicking the diversity of biological neurons, HYMN’s hybrid neuromorphic approach will enable rapid learning from minimal examples, unlocking new capabilities in adaptive AI.
HYMN will ignite the next-generation of neuromorphic AI hardware, unlocking the potential of hybrid systems that surpass the sum of their parts while addressing the crucial global need for sustainable AI. Our goals sit closely aligned to Imperial’s ‘Science for Humanity’ strategy, as well as the core aims of the School of Convergence Science in Human & Artificial Intelligence.

Professor Sophia Yaliraki, Dr Matthew Child, Professor Mauricio Barahona, Dr Louise Walport, Professor Ed Tate

In biology, allostery describes how a functional site on a protein can be influenced from a physically
distant position on the same protein – a so-called allosteric site. For example, the catalytic activity
of an enzyme can be regulated by interactions physically distant from the enzyme’s catalytic
centre, or ‘active site’. Thus, allosteric modulation of proteins is an important aspect of their
functional regulation. How allosteric sites regulate protein function is fundamental to our
understanding of the rules of life, and represents a unique therapeutic opportunity; allosteric sites
are typically less conserved, and have unique sequences. This means that related families of
proteins typically display more variance at these positions, with this sequence variation enabling
selective targeting of otherwise highly related proteins. Thus, allosteric sites provide an opportunity
to drug proteins in a highly selective manner that can discriminate between closely related proteins.
This has relevance to drug discovery, where some targets of high therapeutic and economic value
have so far eluded therapeutic intervention, often due to these undruggable targets being members
of highly related protein families.
Differences in allosteric regulation and the opportunity to exploit these differences for drug
discovery could circumvent the challenge of undruggable targets.
A new approach for de novo identification and validation of allosteric molecular pathways offers
game-changing potential for drug discovery against these undruggable targets across all areas of
disease. Here, we will integrate emerging computational and experimental technologies from our
labs to establish the first high-throughput platform for universal discovery, validation, and targeting
of functional allosteric sites. Proof-of-concept for this multidisciplinary approach will be
demonstrated through the generation of the first allosteric modulators of human protein translation,
deepening our understanding of the rules of life governing functional allostery as well as
underpinning novel approaches to drugging intractable targets.

Dr Jun Ishihara, Dr Adam Celiz, Dr Victoria Salem

The delivery of exogenous insulin has been the only treatment available for type 1 diabetes (T1D) for a hundred years. The development of novel pharmacological formulations of insulin and technologies to aid the monitoring of blood sugars and accurate dosing of insulin have been revolutionary, but do not feel like a “cure” for people living with the disease. This application will focus on the root cause of T1D and aims to develop a T1D vaccine that will prevent its onset. 

In the proposal, we will establish a new approach to achieving immune tolerance in patients at risk of or with early T1D based upon Treg-mediated antigen non-specific immunotherapy (TrANSIT). Our approach is to develop an immunotherapy composed of: 1. Antigens made of beta cells, 2. A protein to induce tolerance. These will both be combined inside a gel implant which controls the release of the components over time to rewire our bodies immune system to accept beta cell transplants. We have engineered a modified immunosuppressive protein, interleukin (IL)-35, which will allow prolonged survival in the bloodstream providing a more effective immune response. Uniquely, we will use an antigen made from beta cells to capture the heterogeneity of T1D for a broad a tolerance as possible.  

Our team possesses unique protein engineering technologies which have been leveraged for large scale production of IL-35 and prolonged bioactivity. This has enabled therapeutic benefits in mouse models of autoimmune arthritis without systemic side effects. In this project, we develop and optimise TrANSIT as an effective vaccine for T1D. 

We hypothesise that co-delivery of long-acting IL-35 with slow-release antigens in people at risk of T1D will lead to immune tolerance and an abrogation of the autoimmune destruction of beta cells. We have assembled a multi-disciplinary team of protein engineers, materials scientists, bioengineers, immunologists and clinical diabetologists to test the antidiabetic effects of our engineered immune suppressor IL-35 in various animal T1D models and immune cells extracted from T1D patients. 

Professor Alexandra Porter, Dr Theoni Georgiou, Professor Mary Ryan, Professor Terry Tetley, Professor Omar Usmani, Professor Brian Robertson and Professor Robert J Wilkinson

Globally, Tuberculosis (TB) is one of the biggest infectious causes of death, with one death every 20 seconds. Tragically, ~1.5 million people die and ~10 million new cases are diagnosed every year; figures that have changed little despite the drugs and vaccines available. TB control is a multifaceted challenge: lacking timely diagnostics, a single licenced vaccine that performs poorly in high burden countries, and a multi-drug treatment (with 4 drugs) that is prolonged (6 months) with side-effects making it difficult for patients to complete the drug course. Where TB and HIV co-infection are common a significant number of pills must be taken every day (Figure 1). If people stop taking their medicines, then multidrug resistant TB (MDR-TB) can develop as the bacteria mutate. Treatment of MDR-TB requires a more demanding regimen, including injectable drugs, with more severe side effects, for longer periods up to 24 months. Thus, a radically different approach is needed to overcome current treatment problems. We bring together a diverse group of scientists, clinicians, engineers, and infectious disease specialists to design an inhalable drug formulation that has 3 prongs: [1] current and new drugs, [2] antibacterial metals and [3] an inhalable microcapsule. By delivering an augmented drug treatment directly to the site of infection in the lungs, we will shorten treatment from the current 6 months and improve the therapeutic index, with lower doses of drugs that will limit many of the current side-effects including liver toxicity, anorexia, diarrhoea, nausea, and vomiting, that make TB drug treatment physically difficult for people who are already ill.
To achieve our ambition to improve national and global health, we will design and create an inhalable aerosolised nanomedicine to treat TB. TB is caused by inhaling the bacterium Mycobacterium tuberculosis (M.tb), which is ingested by immune cells (macrophages) within the airways, to fight the infection. However, some bacteria escape and proliferate, and the efforts of our immune system to fight the infection can lead to lung damage. Our inhalable nanomedicine will deliver antibiotic drugs as a Trojan horse inside the M.tb infected macrophages at the site of infection in the lung (Figure 2). This will be the 1st inhalable TB drug therapy with a multi-functional approach to deliver potent cocktails of conventional drugs along with small amounts of silver (which has complementary antibacterial properties) to destroy the organism without unwanted lung injury or the drug side-effects that impact quality of life. Combining cocktails of drugs with engineered antibacterial silver nanoparticles (ENPs) will increase the potency of drug formulations. The ENPs weaken the bacterial cell-wall enabling efficient entry of antibacterial drug-combinations into M.tb, reducing the dose of antibiotics required to kill the bacteria. We will use materials that are FDA approved for human use and non-immunogenic polymers to avoid unwanted side effects.
This project will be an absolutely novel approach developed at Imperial, which will be patented with Imperial IP. We will also develop and refine existing human lung cell based models for use with M.tb to aid in the development of better inhalable drugs formulations to treat TB. Our approach will improve treatment outcomes for patients with TB by reducing treatment times and side-effects. This platform approach could be used in future to treat other lung diseases.

Dr Laura Barter, Dr Rudiger Woscholski, Professor Nick Long and Professor Oscar Ces

This proposal aims to pioneer catalytically-enhanced nutri-uptake (CENUP) technologies that will underpin a true world first: fertilisers for plants that simultaneously act as catalysts. CENUP will transform crop security across the globe and enable plants to exceed performance levels that are limited by in-built pathway inefficiencies, currently only being addressed via expensive & often perceived as controversial genetic engineering approaches.
CENUP crop enhancement technology is a fertilizer, but unlike traditional fertilizers, it is also a catalyst. It will enable plants to take up nutrients, in this case CO2, at levels beyond that set by their natural performance, by increasing nutrient concentrations at the site of action. Mimicking the behaviour of an enzyme, CENUP’s catalytic nature means that it is able to increase the cellular CO2 concentrations, without itself being consumed. CENUP will target the inefficient process of photosynthesis and in particular the wasteful photorespiration reactions, where O2 competes with CO2, lowering photosynthetic efficiency by ~50%. CENUP will mitigate this by increasing local CO2 concentrations, minimising photorespiration and thereby increasing photosynthetic efficiencies and crop yields (figure 1).
Our proposal capitalises upon our team’s pioneering expertise and recent breakthroughs in the design and synthesis of novel chemical mimetics that are able to capture and release CO2, thereby unlocking the possibility of developing CENUP technologies. This will be complemented by our world leading expertise in understanding the molecular interactions limiting photosynthetic efficiency and the development of high throughput screening platforms that can predict the efficacy and transport properties of de-novo molecules in plants.
Addressing Global Food Shortages: The need for CENUP based technologies is paramount as gains in crop yields provided by technology advances of the first Green Revolution have reached a ceiling at a time when the global population continues to rise. Starting in the 1960s, the introduction of scientifically bred, higher-yielding varieties of rice and wheat meant food production in developing countries kept pace with population growth, with both more than doubling. Yet today, despite these demonstrable achievements, over 800 million people consume less than 2,000 calories a day, live a life of permanent or intermittent hunger and are chronically undernourished. If nothing new is done, the number of poor and hungry will grow. Even on the best land where farmers are obtaining yields close to those produced on experimental stations, there has been little or no yield increase of rice in recent years. Available agricultural land is also depleting, due to urbanisation and climate change. The Covid-19 pandemic, and more recently the war in Ukraine, have also highlighted the sensitivity of the food system to external factors and shown the importance of (i) building resilience & (ii) increasing local productivity. To ensure the world's poorest do not still go hungry in the 21st century, we therefore aim to usher in a 2nd Green Revolution underpinned by the development of CENUP.
A step change in agri-tech is required and the development of CENUP delivery vehicles, able to act as catalytic fertilisers, offering a completely novel approach to supercharging photosynthesis & increasing crop yields could provide a solution.

Dr Malcolm Connoly

Quantum computers are special-purpose machines that will revolutionise our ability to perform simulations and cryptography tasks that are practically impossible with classical hardware. It remains to be seen, however, whether current technologies are sufficiently scalable to satisfy the demands of applications such as the design of drug molecules and energy-efficient materials, or optimising search algorithms and securing communications over a quantum internet. Quantum data is processed by shuffling tiny packets of energy between qubits, quantum mechanical switches that can be on and off simultaneously. The main problem is that qubits are corrupted by the environment more quickly than their classical counterparts.  

Technology companies such as Google, IBM, and Intel aim to solve this problem by encoding data in the distribution of energy in a large two-dimensional array of superconducting qubits, a leading technology based on thin films of metal that can conduct electricity without loss when cooled to low temperature. Much as a dance routine with many performers helps conceal minor footwork errors, a large qubit array can tolerate errors if they are kept below a certain threshold. Qubit performance is reduced in an array and the magnetic field control strategy currently used to route energy packets are challenging to scale, limiting array size to a few hundred qubits. This strategy is sufficient for near-term applications but not for realising the most significant economic and societal impacts. Fundamentally new ideas and scientific breakthroughs are thus essential to ensure superconducting qubits reach their full potential.  

In this President's Excellence Fund for Frontier Research (PEFFR) proposal I will lay foundations for a revolutionary type of qubit based on exotic Majorana quasiparticles that emerge when superconductors are combined with magnetic and semiconducting materials. I will use the Quantum Science and Device Facility, a suite of state-of-the-art microscopy and microwave measurement tools, recently won as an EPSRC Strategic Equipment bid, that is specifically designed for this purpose. My recent lectureship appointment and modern refurbished lab equipped with state-of-the-art equipment sets the stage for Imperial to be a significant player in this arena, with the PEFFR providing the essential expertise and resources to achieve this effectively, innovatively, and on a timescale relevant to this fast-moving and highly-competitive frontier. 

Dr Robert Hoye, Professor Rongjun Chen, Dr Peter Petrov, Professor Jerry Heng and Professor Peter Haynes

The delivery of exogenous insulin has been the only treatment available for type 1 diabetes (T1D) for a hundred years. The development of novel pharmacological formulations of insulin and technologies to aid the monitoring of blood The current COVID-19 pandemic has laid bare our severe vulnerability to pandemics, and the critical importance of vaccines to counter their associated societal and economic effects. Developing and deploying new vaccines will be essential to mitigate the current pandemic, as well as the future pandemics that will inevitably occur. Whilst vaccine development has dominated recent headlines, passing clinical trials is only the first of many challenges. Equitable vaccine deployment worldwide is equally important, but perhaps more challenging to achieve, owing to the extremely limited stability of many vaccines. This necessitates cold chains, which are notably absent in many developing nations.
Our vision is to eliminate the need for cold chains and make vaccines that normally require refrigerated/cryogenic storage stable at near-ambient temperatures. We propose to do this through a combination of: 1) vaccine encapsulation and delivery using multifunctional liposomes and 2) vaccine packaging in nanoporous storage packaging (nano-packaging). The Chen Group has recent proof-of-concept results showing that multifunctional liposomes can achieve efficient RNA vaccine delivery in vitro and in vivo. Our hypothesis is that the thermal stability of vaccines can be improved by storing vaccine-containing nanoparticles in precisely-fabricated nanopores through molecular interactions with the inner surface of the nanopores (confinement effects). The nanopores could also prevent nanoparticle agglomeration by fitting only one nanoparticle each. This project will test this hypothesis by developing proof-of-concept nano-packaging for vaccine nano-formulation storage and identifying the key parameters for controlling vaccine stability.
To fulfil our overarching goal, we have three work packages (WP1): 1) nano-packaging manufacturing with precise control over nanopore dimensions and density, 2) vaccine nano-formulation development and 3) nano-packaging surface functionalisation to optimise nanoparticle loading/unloading from the nano-packaging. In WP1, we will precisely fabricate nanopores through focussed ion beam milling and electron-beam lithography, making use of the new Royce@Imperial facilities. We will investigate the effect of nanopore width, depth and spacing on loading/unloading efficiency and stability of vaccine nano-formulations. In WP2, we will investigate the role of particle size, charge and composition on loading/unloading of the vaccine nano-formulations in the nanopores and evaluate the effects of storage in the nanoporous packaging on vaccine stability. Surface functionalisation in WP3 will be achieved by conformally covering the nanopores with oxides grown by a novel atmospheric pressure chemical vapour deposition (AP-CVD) technique developed by the Hoye Group. The isoelectric point and surface charge will be fine-tuned by changing the material from TiO2 (weakly acidic) to Al2O3 (close to neutral) to NiO and ZnO (alkaline). Across all WPs, vaccine loading/unloading will be measured with a quartz crystal microbalance to generate the adsorption/desorption isotherms and kinetics.
Fulfilling the objectives will deliver a revolutionary new approach to improve vaccine stability and eliminate cold chains, which will lead to vaccine equality worldwide. The proof-of-concept results that validate our hypothesis will form the basis for us to secure follow-on funding to focus on the large-scale manufacturing of nano-packaging.

Professor Mark Crimmin, Dr Becky Greenaway, James Bull and Professor Oscar Ces

Our ability to design and synthesise new molecules has led to unparalleled improvements in our
quality of life. Modern synthetic chemistry allows the construction of molecules with precise control
over their properties and three-dimensional shape. Such control is necessary for targeted
applications in numerous fields including drug-discovery, medical imaging, materials science and
catalysis. However, synthetic methods can often be cumbersome, inefficient, and a bottleneck in
discovery processes. Complex compounds are typically constructed through multi-step
approaches in which parts of the molecule are built up step-by-step. Within this approach, even
seemingly simple modifications – such as replacing a carbon atom with a nitrogen atom – require
repeating the entire synthesis with modified chemical building blocks. We can do better. The
revolution in gene-editing technology (CRISPR-Cas9) has led chemists to revisit their ambitions
for synthesis. Practitioners are now asking if they could directly edit complex molecules to modify
their properties. Just as CRISPR-Cas9 can be used to selectively replace a single gene in DNA,
could methods be developed to selectively add, delete or replace any atom (or group of atoms) in
any molecule at will?
In this project, we will address this grand challenge, and define the field of ‘molecular editing’. We
will pioneer an approach to molecular editing in which new types of reagents are used to edit
aromatic ring systems. Aromatic rings are highly stable entities that are common in both drug discovery
and materials chemistry. We will use reactive fragments based on main group or
transition metals to edit aromatic rings. These reactive metal fragments can be thought of as both
molecular scalpel and sewing kit, allowing us to cut aromatic rings in a desired position and then
stitch them back together. At the end of the process none of the metal fragments remain in the
molecule but the structure itself has been altered. We will show that it is possible to add carbon or
nitrogen atoms to expand heteroaromatic ring systems – resulting in their transmutation from one
ring type to another. We will develop new routes for the selective deletion of bonds in aromatic
rings, resulting in the modification of the shape of molecules. In the most ambitious part of this
project, we will achieve new approaches to divide aromatic ring systems in two allowing the
construction of two rings from one.