What we do at the MRC Toxicology Unit | University of Cambridge
What we do at the MRC Toxicology Unit | University of Cambridge
What we do at the MRC Toxicology Unit | University of Cambridge
Unit Mission
Our mission is to conduct mechanistic toxicology research. We aim to uncover the links between exposure, molecular initiating events, and adverse outcome pathways. Exposure to environmental chemicals, radiation, and new medicine platforms are of particular interest. Our research groups use an interdisciplinary systems-based approach to address key research questions in these areas. The Unit continues to work with partners in industry to translate basic research into outcomes that benefit public health.
Our Research Themes
Safety of Advanced Therapeutics
Advanced therapeutics use nucleic acids to target specific DNA and RNA molecules in the cell, enabling treatment of previously undruggable diseases. Increased understanding of the processes involved in disease development and improvements of nucleic acid therapy (NAT) platforms, have resulted in a rapid increase in NAT studies and drug approvals. However, adverse events have resulted in the failure of some clinical trials. We aim to gain a deeper understanding of how NATs work at the molecular level to enable a more efficient drug discovery process with reduced likelihood of adverse events in treated individuals.
In collaboration with other academic institutes and industry partners, the MRC Toxicology Unit is working to make NATs safe-by-design, using unique tools and methodologies to understand and ameliorate their safety liabilities, unlocking their full potential to transform healthcare. As part of this research, we are examining chromatin based and post-transcriptional responses to NATs, including RNA-binding proteins, regulatory RNAs, and cellular stress response pathways. We also are seeking to understand the immunological responses to NATs, with a focus on individuals with obesity, immunodeficiency and immunomodulatory treatments such as immune checkpoint blockade. We are working together to improve the efficacy of NATs and develop methods to reduce off target effects.
Approaches
Understanding the off-target effects of therapeutic RNAs
Professor Anne Willis OBE
The Willis Lab is working to understand the off-target effects of new modalities such as therapeutic RNAs. In particular, they are investigating the delivery and safety of oligonucleotide-based therapies.
Transcriptional control of cellular stress response to advanced therapies
Dr Ritwick Sawarkar
The Sawarkar Lab studies how cells sense advanced therapies and respond at the genomic, epigenetic and transcriptional level. Focusing on RNA therapeutics like anti-sense oligonucleotides and mRNA vaccines, they aim to identify how to mitigate the side-effects of these drugs.
Improvement of vaccine efficacy and toxicity in mice and humans
Dr James Thaventhiran
The Thaventhiran Lab is developing methods to make mRNA therapies including vaccines more efficient and reduce the risk of adverse events caused by mistranslation. They are also investigating why some groups are not as well protected by vaccination, including obese individuals, those with inherited immunodeficiency, and patients treated by immune checkpoint blockade therapies.
Mechanisms of cell death in response to toxic injury
Dr Marion MacFarlane
The MacFarlane Lab aims to provide novel insights into the mechanisms of cell death that underlie the toxicity of advanced therapies. They are working to identify the key proteins and pathways that control cell fate decisions and mediate the toxic effects of advanced therapies. In addition, they are working to define the signalling networks involved in drug induced mitochondrial toxicity and cell survival in the liver. Through this they are informing strategies to mitigate the side effects of both existing and new therapies.
Microbiome mediated toxicity of advanced therapies
Dr Kiran Patil
The Patil Lab investigates how the microbiome interacts with advanced therapeutics. They are working to understand reciprocal interactions between host and gut bacteria at the molecular level. They aim to understand how the microbiome contributes to inter-individual variability in drug effectiveness and toxicity.
Molecular Impact of Environmental Exposures
We are investigating how environmental exposures impact biological systems at the molecular level. In our modern world we are exposed to various substances in our environment including particulate matter in the air, chemicals from industrial processes and food additives. These non-biological substances or xenobiotics can enter our bodies through inhalation or ingestion and interact with our cells and our gut microbiome.
The purpose of this research is two-fold. First, we aim to understand how xenobiotics may have adverse effects on health by looking at how they alter biological pathways. Through this we can provide evidence for updated safe limits for xenobiotic substances, generate predictive models for adverse outcomes, and inform development of safer alternatives. Second, we use these findings to understand more about how our cells work at the molecular level to inform the creation of novel therapies. We use complementary research approaches, benefiting from combining our different expertise and perspectives towards making our environment safer.
Approaches
Post-transcriptional control of gene expression in response to injury
Professor Anne Willis OBE
The Willis Lab is working to understand the role of post-transcriptional control in response to toxic injury with a focus on RNA-binding proteins, regulatory RNA motifs and tRNAs. They use mechanistic approaches to develop models that can predict adverse outcomes.
Chromatin control of environmental stress response
Dr Ritwick Sawarkar
The Sawarkar Lab aims to understand the different ways in which our cells respond to chemicals from the external environment. They focus on the cell stress response, looking at how cells alter gene expression using transcription factors, chromatin modifications and non-coding RNA to adapt to changing environments. They aim to gain novel insights and mechanistic understanding of transcriptional response to stress and toxins.
Molecular mechanisms of cell death
Dr Marion MacFarlane
The MacFarlane Lab are working to understand how environmental exposures influence cell life/death decisions at the molecular level with the aim of delivering field-changing mechanistic insights into toxicology and disease. This includes investigating how particulate matter and inhaled fibres induce toxicity.
Microbiome mediated toxicity of pollutants and other xenobiotics
Dr Kiran Patil
The Patil Lab investigates how the gut microbiome responds to exposure to environmental substances including chemicals from industrial processes such as pesticides and PFAS ‘forever chemicals’, as well as common food additives. They are using a combination of computational and experimental approaches to systematically uncover how microbial metabolism and inter-species networks are impacted by xenobiotics.
Mechanisms of fibre toxicity
Dr Marion MacFarlane/Professor Anne Willis OBE
The MacFarlane and Willis Labs are using their combined expertise to understand the degree to which fibres, including engineered nanofibers are toxic. They are exploring which of these fibres lead to the development of diseases such as mesothelioma using mechanistic studies to identify pathways to toxicity, key molecular changes and biomarkers.