Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci

Abstract

We propose to bring together a group of researchers across the UK and in Sao Paulo to share expertise that will allow us to understand the biology of parasites that cause neglected tropical diseases and improve our ability to intervene against them. Disease-causing microbes remain a major problem for health the world over. This is seen disproportionately in tropical countries, were a combination of environmental factors (e.g. climatic conditions supporting the propagation of insects that can transmit disease) and relatively scarce economic resource ensure the maintenance of infectious disease. Parts of rural Brazil, like other areas in Latin America, suffer from diseases caused by parasitic protozoa, which are single-celled organisms. One parasite, Trypanosoma cruzi, causes Chagas disease, affecting several million people across Latin America. Closely-related parasites, belonging to the genus Leishmania, cause a range of diseases called the leishmaniases in many parts of the world. Chagas disease is transmitted by triatomine bugs that suck the blood of mammals including humans and in the process defecate upon their victims. Parasites in the faeces then enter the body and over a long period of time, sometimes twenty years or more, the insidious Chagas disease develops. Quite often patients do not know they have the disease. In around 30% of cases though, a chronic inflammatory response to the heart or digestive system can lead to death. The leishmaniases are transmitted by sandflies through the saliva whilst they feed on their victims. Depending on which species of the Leishmania parasite is transmitted, the disease can either occur in the skin (cutaneous leishmaniasis) or else migrate to the liver and spleen (visceral leishmaniasis). Some species, including Leishmania braziliensis, causes the horrible disease known in Brazil as Espundia, where human cells called macrophages (in which the parasite resides) migrate to the mucosal membranes of our lips and nostrils and cause them to disintegrate. Sometimes, following treatment, after a lapse that can last a few years, the visceral form of the disease relapses into a form we call post Kalar-Azar dermal leishmaniasis (PKDL).

Although drugs exist to treat both Chagas disease and the leishmaniases, they are far from ideal. Some are toxic, others have to be given over a protracted period, and several are available only by needle injections. Resistance has emerged to existing drugs, and it has been known for a long time that some parasites do not respond to treatment even if resistance has not been selected.

This collaborative project aims to bring together a team of researchers across the UK and Sao Paulo to look specifically at the processes that enable parasites to thrive in the insect vectors that carry them and then within the very different environment of their mammalian host. Since the parasites keep exactly the same genome (which is the blueprint that encodes every aspect of their ultimate makeup) they need to choose which parts of the genome to express in different environments. This involves subtle changes to the structure of the protein architecture that holds their genes together, in a structure we call chromatin. In other organisms it has, in recent years, become clear that the addition of small molecules to those chromatin-associated proteins can change their function. Removing those adaptations causes them to change back again. These alterations, which do not involve modifying the sequence of the DNA blueprint itself, and yet do influence how that DNA is expressed, are described as "epigenetic" alterations. We will investigate how epigenetic alterations impact on gene expression in T. cruzi and leishmanias, and work out how we can manipulate this epigenetic process by altering the availability of the small molecule metabolites responsible for those changes. We hope to find new therapeutic drugs treatment interventions to act on these epigenetic targets.

Technical Summary

This programme of research will create a network of researchers studying the regulation of gene expression in the kinetoplastid protozoa, allowing us to dissect the processes that link metabolism, epigenetic change to chromatin, gene expression and cell differentiation. This will give insights into the processes that enable these organisms to enter a quiescent state that protects them from both immunological and chemotherapeutic intervention, and also provide novel targets against which to develop new drugs.

Specifically, we aim to characterise the range and extent of post-translational modifications to proteins (specifically histones) involved in chromatin formation in Trypanosoma cruzi and Leishmania infantum and L. mexicana cells undergoing passage through the life cycle and in response to metabolic pertubations. This will involve the isolation of chromatin from different parasite lifecycle stages, and isolation of the individual proteins of the complex (using immunopreciptation methodologies with antibodies specific for the trypanosomatid histones, and BioID approaches to identify neighbouring members of the complex). Proteomic approaches will determine the repertoire of proteins involved. Post-translational modifications (PTMs) on individual proteins will be assessed using specific antibodies and also mass spectrometry of digested proteins to seek mass changes consistent with different PTMs. The abundance of individual metabolites in cells at different cell/lifecycle stages will be determined using LC-MS based untargeted metabolomics. CRISPR/cas9 approaches will allow rapid knockout of non-essential enzymes producing metabolites implicated in PTM, and use of different metabolic substrates will also be used to modulate their abundance to asses impact on epigenetic change and gene transcription by RNAseq. Cell culture techniques will assess life cycle progression in mutants

Planned Impact

The programme we propose will bring together a group of researchers from four UK institutions and the University of Sao Paulo in Brazil to investigate a crucial and yet hitherto relatively poorly studied aspect of the biology of protozoan parasites belonging to the order Kinetoplastida. Trypanosoma cruzi afflicts millions of people in Latin American causing Chagas disease, while the leishmaniases have a distribution spanning the world's tropical and sub-tropical regions. The groups that we are bringing together have expertise in many aspects of the biology of the causative parasites and covers parasite biochemistry, molecular and cell biology, metabolomics, proteomics and nucleotide sequencing. The group collectively brings together all of the skills required to learn about the epigenetic processes that allow the parasites to remodel their metabolic pathways to survive within the different environmental niches in which they find themselves. These can include the bloodstream and different intracellular environments in their mammalian hosts as well as different anatomical locations within the insect vectors that transmit them.

Epigenetic processes are those which enable profound changes in the physiology of an organism without requiring changes in the nucleotide sequence of their genomes. Generally, epigenetics involves remodelling of the structure of chromatin, which is the combined protein and nucleic acid structure that contains the genetic information. Chromatin remodelling can involve the post-translational modification of its protein components, for example histones. The modifications to chromatin-associated proteins are generally those of addition of small molecules, derived from cellular metabolism. As such, metabolism, and the accumulation or loss of particular metabolites, have a profound impact on how cells behave.

We will identify and characterise the post-translational modification in trypanosomes and leishmanias. We will then determine how these modifications influence gene expression as parasites move from one environment to another. As metabolism is ultimately responsible for providing the molecules that modulate chromatin, we will also probe the metabolism of these cells progressing through their life cycle.

Critically, it has recently become clear that T. cruzi and Leishmania parasites can enter a quiescent, non-proliferating state where they become tolerant of both immunological and chemotherapeutic assault. It is likely this process evolved (as in other microbes) to enable protection of the population against environmental fluctuations of many types (manifest in humans as immunological or drug intervention). As changes to genetic sequence are not associated with quiescence, epigenetics must be at play.

A key outcome of discovering the processes underpinning epigenetic influence on gene expression and phenotypic variation in these parasites will be to identify the process that drive quiescence. Since this process is responsible for long-term parasite persistence and drug treatment, this information will open the way to new strategies to prevent, or reverse, the formation of quiescent parasites, and thus create new avenues to assure successful treatment that will ultimately lead to control and elimination of Chagas disease and the leishmaniases, diseases which afflict tens of millions of people across the world today.

Publications

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Acosta H (2019) Proteomic analysis of glycosomes from Trypanosoma cruzi epimastigotes. in Molecular and biochemical parasitology

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Alpizar-Sosa EA (2022) Genome deletions to overcome the directed loss of gene function in Leishmania. in Frontiers in cellular and infection microbiology

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Barbosa RL (2020) Proteomic analysis of Trypanosoma cruzi spliceosome complex. in Journal of proteomics

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Barrett MP (2019) Protozoan persister-like cells and drug treatment failure. in Nature reviews. Microbiology

 
Description We have demonstrated that Leishmania mexicana parasites respond to purine depleted medium by ceasing to proliferate and demonstrates profound changes to their metabolism associated with this state. We believe this gives insight into how new drugs can target dormant parasites believed to be critical in thwarting activity of current drugs.

Given the fact that we
(a) lost staff time to furlough during the covid19 lockdown
(b) Had staff seconded to the Lighthouse lab (Covid19 testing centre) to assist the national effort against Covid19
(c) Had financial support cut from the grant due to its being ODA associated funding
(d) were refused a non-costed extension in spite of the above hindrances
(e) Many months of repeated experimentation revealed that histone preparation from Leishmania species is not readily achieved though adaptation of standard methods.applied to other kinetoplastid parasites
(f) serendipitous discoveries in seeking modes of action of anti-kinetoplastid compounds

We altered focus of our work.

Success has been achieved in histone related work ialongside metabolic shifts impacting histone modification and vice versa n T. cruzi through our Brazilian partners. That work is reported separately through the FAPESP funding partners

With an ultimate aim of seeking new drugs that may be active against kinetoplastid protozoa we turned our attention to two pathways associated with epigenetic gene regulation in these parasites.

1. Inhibition of Coenzyme A biosynthesis. We discovered two separate compounds with potent anti-leishmanial activity that inhibit the synthesis of coenzyme A, which is the primary donor of acetyl gous used in epigenetic modifications of histones. Our discovery was achieved using a non targeted metabolomics approach to determine modes of action of leishmanicidal drugs. Elevated levels of metabolites of the pantothenate pathway and a decrease in Coeznyme A, acetyl Coenzyme A and the metabolite of the TCA cycle pointed to inhibition of either pantetheine phosphate adenyl transferase, or dephosphocoenzyme A kinase. Other changes included a dramatic increase in lysophospholipids and loss of phospholipids, associated with reduced coenyme A as a donor of fatty acyls. An unexpected increase in the pentose phosphate pathway was noted too along with decrease in cellular ATP. Addition of coeznyme A to parasite culture medium was able to rescue parasites from the activity of the new compounds. We have thus identified coenzyme A synthesis as a validated drug target in Leishmania and are currently assessing numerous additional datasets pertaining to the drug mode of action as we move towards writing up the data for publication and seeking follow up funding for further development of these compounds.

2. Inhibition of methyltransferase activity by anti-kinetoplastid benzoxaboroles. Work carried out prior to this grant on trypanocidal benzoxaboroles had indicated that exposure of parasites to the drug leads to an accumulation of s-adenosylmethionine, which is the primary donor of methyl groups in cellular processes including epigenetic modification of DNA. Benzoxaboroles are now in clinical development against human African trypanosomiasis, and preclinical development against leishmaniasis and Chagas disease. Other work (carried out prior to this grant) indicated that development of resistance to benzoxaboroles in Trypanosoma brucei was associated with an alteration to transcriptional profiles of these parasites, such that their transcriptional profile as bloodstream forms in culture actually resembled procyclic forms. We, therefore, decided to determine whether benzoxaboroles of the valylester subclass (which are under preclinical development for Chagas disease and also animal African trypanosomiasis) might also trigger resistance in a similar way and in Glasgow, where we are not licensed to work with T. cruzi, used Trypanosoma congolense as a model to select resistance to a range of benzoxaborole compounds of the valylester class. Most yielded resistance through loss of serine peptidases involved in activation of these compounds by cleavage of the linker region, releasing a carboxylate derivative of the benzoxaborole warhead. One line, however, did not carry mutations to this gene, not amplification of the CPSF3 gene believed to encode one target of these compounds. Phenotypic analysis, genome and transcriptome sequencing have not yet identified the mechanism of resistance in this line.
We have also initiated a new collaboration with Professor Gerald Spath in Paris to understand the metabolic effects of methyltransferase inhibitors designed to inhibit epigenetic processes in Leishmania infected macrophages (metabolomics data acquired, results under study). We have also conducted further collaborative work with Professor F Bringaud in Bordeaux who has developed a system whereby African trypanosomes alter their metabolism when grown in medium with glycerol rather than glucose as a main carbon source and we have conducted single cell RNA sequencing work and metabolomics analysis to determine the transcriptional and metabolic pathway alterations associated with the shift.

In late 2022 we were awarded, through the University of Glasgow, some EPSRC originating funds to help complete our work. I was delighted to be able to appoint Dr Gould, one of the original post-docs on the MRC-Newton award who volunteered to join the national effort to combat the coronavirus pandemic. He was able to demonstrate that the compounds active against coenzyme A synthesis in Leishmania target dephosphoCoA kinase. Moreover, the same enzyme is not targeted by these compounds in African trypanosomes.

A further discovery was made in that another class of compounds (the Strathclyde minor groove binders) appear to exert their mode of action binding to specific sites in trypanosome DNA indicative of a role for chromatin structure.

Additional money became available through an EPSRC grant to the University of Glasgow. We were able to use that grant to continue our work on the coenzyme A synthesis pathway and have now expressed two Leishmania dephosphocoenzyme A kinase enzymes. We were also able to conclude a crucial piece of work on Topoisomerase II as a target for novel cyanotriazole based compounds developed by Novartis, with great potency against all trypanosomatids and now proceeding through a pre-clinical drug development pathway.
Exploitation Route We plan to seek whether histone changes are related to the phenotype and metabolic changes detected. The system we have developed offers a route to screen for compounds against dormant ("persister") type parasites and we believe this can be used by others in screening for new chemicals that will be active against such parasites.

We have identified the coenzyme A synthetic pathway as a novel drug target in Leishmania. Others may seek new compounds to inhibit enzymes of this pathway (and a grant has been submitted with colleagues to take this further). The original submission was unsuccessful but a PhD student has now picked up on that work and once we have definitive evidence on the role of dephosphocoenzyme A kinase as a drug target in Leishmania we will re-submit. Our work with Novartis on cyanotriazole compounds that inhibit topoisomerase is progressing through a pre-clinical drug development. That partnership has also led to our repurposing some exceptional compounds as potential veterinary trypanocides.
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

URL https://bv.fapesp.br/en/auxilios/103479/a-network-for-an-integrative-biology-in-neglected-diseases-bridging-epigenetics-metabolism-and-cell-/
 
Description Drs Matthew Gould and Federica Giordani are employed by this grant. From May 2020 until September 18th for Dr Giordani and ongoing for Dr Gould, they took secondments to the Lighthouse lab in Glasgow where they joined the team producing high throughput testing of Covid19. Both became highly valued members of staff, leading teams in various aspects of the testing workflow. The laboratory has now performed over 10 million tests, has been instrumental in the national effort against Covid-19. Professor Barrett, the PI, was part of the team that established the Lighthouse laboratory too and lead research and training there until end of October 2020. He lead a training programme that up until that point had trained over 500 staff in the processes required to run the lab. Despite limitations arising from the COVID19 pandemic, we have been able to make significant progress with project aims. Work in Glasgow has focused on optimisation of methods to characterise post-translational modification of histones in Leishmania. We have maintained a fruitful exchange of knowledge between UK and Brazilian collaborators. Despite the secondment of research staff to COVID19 testing efforts, the involvement of Glasgow Polyomics, which has been working at approaching normal capacity apart from a 4 month hiatus (March 2020 - June 2020), has meant that we are able to collect detailed proteomic data from samples generated both in Glasgow and Sau Paulo. As a coda, we received an additional grant (part of a block grant to the University of Glasgow that was made available for proposals to pursue GCRF-Newton awards that had been operative across the pandemic. We were delighted to progress two drug development projects linked to our original plans through this "epigenetics and metabolism" grant. One, showing how a couple of anti-leishmanial compounds target the dephosphocoenzyme A biosynthetic pathway has reached a point where the data on dephosphocoenzyme A as a target are compelling. We were also able to gather the definitive evidence that a series of compounds developed by Novartis target topoisomerase IIalpha in trypanosomatids and these compounds are now being developed further by our partners.
First Year Of Impact 2023
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description Food and Agriculture Organisation of the United Nations (FAO) - Advisory committee on rolling out a Progressive Control Pathway for Animal African trypanosomiasis
Geographic Reach Africa 
Policy Influence Type Membership of a guideline committee
Impact Working towards a progressive control pathway for animal African trypanosomiasis (AAT) brings with it improvements to the welfare and health of livestock animals (primarily cattle) in Africa
URL http://www.fao.org/3/i7587e/i7587e.pdf
 
Description Membership of the Drugs for Neglected Diseases initiative (DNDi) Scientific Advisory Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a guidance/advisory committee
Impact I provide advice on programmes in drug discovery against Neglected Tropical Diseases for DNDi, the world's leading organisation in drug development for diseases of the world's poorest people
URL https://dndi.org/our-people/mike-barrett/
 
Description Sceintific Advisory Board - Drugs for Neglected Diseases initiative 2023
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a guidance/advisory committee
Impact The Drugs for Neglected Diseases initiative is developing new drugs for diseases afflicting the World's poorest people. In 2023 the drug fexinidazole received a positive opinion from the European Medicines Agency (EMA) for use in Rhodesiense human African trypanosomiasis. I Chaired the advisory board following the clinical trials that ultimately succeeded in receiving the EMA positive opinion. I also advise on their other programmes in leishmaniasis and trypanosomiasis (African and American)
URL https://dndi.org/our-people/our-governance/
 
Description A distinct mode of DNA replication initiation in trypanosomes?
Amount £756,872 (GBP)
Funding ID BB/W001101/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2022 
End 09/2025
 
Description Identification and validation of a novel drug target in the Coenzyme A biosynthesis pathway in Leishmania
Amount £46,353 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2022 
End 03/2023
 
Description Precision Medicine PhD project
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2020 
End 10/2023
 
Description Wellcome Investigator Award
Amount £1,655,328 (GBP)
Funding ID 224501/Z/21/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2022 
End 07/2027
 
Title Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi 
Description Flux balance analysis model of T. cruzi metabolism 
Type Of Material Computer model/algorithm 
Year Produced 2020 
Provided To Others? Yes  
Impact A model of T. cruzi metabolism, enabling identification of choke points to point to drug targets 
URL https://pubmed.ncbi.nlm.nih.gov/33021977/
 
Title Metabolomics dataset - Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model 
Description Metabolomics dataset at Metabolights 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact Indication of drug mode of action 
URL https://www.ebi.ac.uk/metabolights/MTBLS464
 
Title single cell analysis of T. brucei long slender to short stumpy differentiation, and of cell cycle 
Description RNA expression changes descibed at single cell level 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact 2 papers to date 
 
Description Collaboration with Novartis Institute of Tropical Diseases (Emeryville, CA, USA - note the archived address is out of date) 
Organisation Novartis
Department Institute for Tropical Diseases Research
Country Singapore 
Sector Private 
PI Contribution We have screened Novartis compounds for activity against trypanosomes and leishmania, then sought drug modes of action for example, using untargeted metabolomics. We have verified drug targets e.g. topoisomerase II using CRISPR-cas9 editing of the gene to introduce mutations
Collaborator Contribution Novartis have generated a multitude of molecules and found many active against trypanosomatids. They have initiated mode of action studies and completed full ADME-tox analysis in order to select compounds for pre-clinical and later clinical development.
Impact Publications are listed. The project is interdisciplinary. Novartis produce chemicals, screen for activity, work on mode of action, pharmacology and all key aspects of drug development. We work on identifying drug modes of action and resistance. We are also testing compounds for activity against the trypanosome species that cause veterinary disease with a view to initiate development of new compounds for these diseases of great agricultural value.
Start Year 2016
 
Description Glasgow - Nottingham collaboration 
Organisation University of Nottingham
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigating post-translational modifications and epigenetics of trypanosomatids
Collaborator Contribution Still in the phase of methods development
Impact Still developing methods. Several face to face and online conferences
Start Year 2019
 
Description Glasgow - Oregon Health Science University 
Organisation Oregon Health and Science University
Country United States 
Sector Academic/University 
PI Contribution We have tested the impact of these compounds on Leishmania metabolism and revealed them to target the Coenzyme A pathway, which we have confirmed by rescuing against drug action by addition of Coenzyme A exogenously.
Collaborator Contribution We received leishmanicidal compounds from Professor Scott Landfear which he had previously tested in vitro and in vivo and demonstrated potent anti-parasite activity.
Impact The compounds received from Professor Landfear were shown in our untargeted metabolomics platform to impact on Coenzyme A production with various knockon effects across the metabolome. Hence we have been conducting numerous experiments to confirm that it is either pantetheine phosphate adenhyltransferase, or dephosphoCoA kinase that is the target of these compounds, and have thus identified a novel mode of action for drugs against leishmania. This work will enable further drug development against these parasites. The work is interdisciplinary involving medicinal chemistry, anti-parasite drug screening and drug target deconvolution.
Start Year 2020
 
Description Glasgow - Sao Paolo Collaboration 
Organisation Universidade de São Paulo
Country Brazil 
Sector Academic/University 
PI Contribution Working to purify histones and other proteins involved in epigenetics in trypanosomatids and characterise post-translational modifications
Collaborator Contribution WE have worked on histone urification from Leishmania, the Brazilian group on Trypanosoma cruzi
Impact To date we are still in the methodological development stage.
Start Year 2019
 
Description Glasgow Bordeaux 
Organisation Bordeaux Segalen University
Country France 
Sector Academic/University 
PI Contribution We have measured the metabolome and transcriptome (to single cell level) of trypanosomes grown under differing conditions to understand the processes that drive metabolic shifts in these parasites when cultivated in different conditions (e.g. glucose vs glycerol).
Collaborator Contribution Professor Bringaud's team in Bordeaux performed the initial experiments showing changes in metabolism of trypanosomes cultivated in different conditions and have proteomics data already. The French team provided cells and culture conditions.
Impact To date we have gathered transcriptome and metabolome data currently under analysis.
Start Year 2021
 
Description Glasgow Edinburgh 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution We have performed metabolomics and RNA sequencing analysis for our colleague on this grant Achim Schnaufer
Collaborator Contribution Professor Schnaufer provided different cell lines under different growth conditions for metabolome and transcriptome analysis
Impact Datasets generated, analysis not complete
Start Year 2019
 
Description Glasgow Pasteur 
Organisation Pasteur Institute, Paris
Country France 
Sector Charity/Non Profit 
PI Contribution We have analysed the impact of a number of inhibitors of methyltransferases believed to impact epigenetic events in Leishmania parasites on their cellular metabolome
Collaborator Contribution Professor Spath's team have assessed activity of methyltransferase inhibitors on Leishmania development and sent compounds with anti-leishmanial activity to us for metabolomics testing,
Impact To date we have collected metabolomics data to assess impact of methyltransferase inhibitors designed to interfere with epigenetic processes on leishmania metabolism
Start Year 2021
 
Description Article about penicillin's first patient in the New Statesman magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article outlining the story of penicillin's first patient, the visit of his daughter to his grave and the coming crisis in antibiotics due to AMR
Year(s) Of Engagement Activity 2023
URL https://www.newstatesman.com/politics/health/2023/06/albert-alexander-legacy-penicillin-first-patien...
 
Description Conference - Epigenetics and the regulation of gene expression in kinetoplastid protozoa 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was an international conference directly related to this project where the project members were joined by over 100 other scientists with a strong postgraduate student representation
Year(s) Of Engagement Activity 2021
URL https://mobile.twitter.com/Barrett_Lab/status/1395782382511398916
 
Description Lecture on the Scottish Encounter with Tropical Disease to the University of the Third age in Helensburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a lecture outlining the role of Scottish investigators in discovering the agents of tropical diseases and was able to link to the current status of tropical infectious diseases in the world today related to important Scottish research in a global context.
Year(s) Of Engagement Activity 2020
 
Description Lecture to the Helensburgh University of the Third age on the Coronavirus pandemic 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave an overview of the coronavirus pandemic to the University of the third age in Helensburgh
Year(s) Of Engagement Activity 2020
 
Description Magazine article - About vaccination 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact THis article discussed the problems of vaccine scepticism
Year(s) Of Engagement Activity 2018
URL https://www.newstatesman.com/politics/health/2018/05/how-fake-science-costing-lives-malign-rise-anti...
 
Description Magazine article about new variants of the SARS-Cov-2 coronavirus 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The New Statesman is a UK based weekly political and current affiars magazine with 36,000 subscribers and over 200,000 online subscribers. It is read by most UK politicians.
Year(s) Of Engagement Activity 2021
URL https://www.newstatesman.com/politics/health/2021/01/truth-about-new-covid-19-variants
 
Description Magazine article about the success of new interventions against neglected tropical diseases 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact THis magaaine article summarised the successes the 21st Century has had in developing new interventions against neglected tropical diseases
Year(s) Of Engagement Activity 2019
URL https://www.newstatesman.com/world/africa/2019/08/how-world-winning-fight-against-neglected-tropical...
 
Description Magazine article discussing the discovery of antibiotics and ethics of drug testing 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers)
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/international/science-tech/2020/09/lesson-antibiotics-race-science-must...
 
Description Magazine article on coronavirus and human evolution 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This article in the New statesamn discused viral and human genetic evolution in light of the competition between host and pathogen in the context of the covid-19 causing coronavirus
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/science-tech/coronavirus/2020/03/what-makes-us-vulnerable-covid-19
 
Description Magazine article on coronavirus immunity 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers)
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/science-tech/coronavirus/2020/04/can-you-catch-covid-19-twice
 
Description Magazine article on the 200th anniversary of the death of poet John Keats from tuberculosis and its link to Covid19 today 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The New Statesman is a UK based weekly current affairs and political magazine. It has 36,000 subscribers and over 200,000 on line readers. It is read by most UK politicians.
Year(s) Of Engagement Activity 2021
URL https://www.newstatesman.com/culture/books/2021/02/why-keats-s-haunting-reflections-tuberculosis-res...
 
Description Magazine article on the UK "Kent" coronavirus variant 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The New Statesman is a leading UK based, but internationally read weekly current affairs magazine read by most UK politicians. It has a subscriber based of 36,000 plus online subscription based of >200,000 readers
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/science-tech/coronavirus/2020/12/how-dangerous-new-covid-19-variant
 
Description Magazine article on the flawed concept of herd immunity for Covid19 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article in high standing UK current affairs weekly magazine, sparked further media interest afterwards and great interest from among the magazines 36,000 subscribers (>200,000 online subscribers)
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/politics/health/2020/10/why-herd-immunity-not-option-uk-it-faces-covid-...
 
Description Newspaper article and interview on penicillin's first patient 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by the Herald newspaper, along with the daughter of penicillin's first patient, outlining the story of penicillin, the tragedy of the loss of its first patient, the boom in antimicrobials and looming crisis in antimicrobial resistance
Year(s) Of Engagement Activity 2023
URL https://www.heraldscotland.com/news/23592325.story-penicillin-told-world-congress-pharmacology/
 
Description Penicillin's first patient's daughter's visit to her father's grave 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact As part of the visit to the UK I arranged for Sheila LeBlanc, the daughter of penicillin's first patient, we were interviewed by BBC news at the grave yard in Newbury, Berkshire where Constable Albert Alexander is buried. The interview was part of a news feature covering the story of Constable Alexander, his treatment with penicillin and the ensuing revolution in antimicrobial therapy that followed the discovery.
Year(s) Of Engagement Activity 2023
 
Description Public understanding of science lecture. The impact of Covid 19 on Neglected tropical diseases. St. Andrews Clinics for children (by Zoom) 25th Jan 2022 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact In this talk I discussed the impact of the coronavirus pandemic in Africa and how it influences efforts aginst other diseases there, e.g. neglected tropical diseases. Fruitful discussion was had with members of the public that support a charity that funds chilldrens hospitals in Africa
Year(s) Of Engagement Activity 2022
 
Description SCOTLAND - RHEINLAND-PFALZ LIFE SCIENCES AND BIOTECHNOLOGY CONFERENCE 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Conference aiming to bring researchers in the Life Sciences in Scotlnd and the Rhineland closer together to explore collaborative opportunities
Year(s) Of Engagement Activity 2022,2023
URL https://sulsa.ac.uk/first-scottish-rheinland-pfalz-life-sciences-and-biotechnology-conference/
 
Description Talk on penicillin's first patient at the World Congress of Pharmacology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I organised a scientific session on the antibiotic resistance crisis at the World congress of Pharmacology. As part of the symposium a pubic engagement lecture was included at which I gave an outline on the history of penicillin and the fate of its first patient.
Year(s) Of Engagement Activity 2023
URL https://wcp2023.org/events/antibiotics-solving-the-crisis/
 
Description Talk to Wootton village history society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact As part of the visit, I arranged, of the daughter of penicillin's first patient to the UK I spoke on the history of penicillin to the Wootton history society. Wootton is the village from which Albert Alexander, the policeman first treated with penicillin came.
Year(s) Of Engagement Activity 2023
URL https://www.newstatesman.com/politics/health/2023/06/albert-alexander-legacy-penicillin-first-patien...
 
Description Talk to school. "The next pandemic" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A talk to sixth formers at the High School of Glasgow on the persistent threat of infectious diseases, contextualised around the Covid19 pandemic
Year(s) Of Engagement Activity 2023
 
Description The next pandemic 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk to sixth formers at the High School of Glasgow on the risks of a new pandemic following the Covid19 crisis
Year(s) Of Engagement Activity 2022
 
Description Times Radio interview on the meeting between Dr Livingstone and Henry Stanley in 10 Nov 1871 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by Times radio about the legacy of Dr Livingstone in medicine and exploration
Year(s) Of Engagement Activity 2020
URL https://www.thetimes.co.uk/radio
 
Description Times radio interview on the 200th anniversary of the death of John Keats and his descriptions of tuberculosis (23 Feb 2021) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed about the impact of John Keats (poet) and how the tuberculosis from which he died influenced his work, and also explained how TB continues to affect the world today
Year(s) Of Engagement Activity 2021
URL https://www.thetimes.co.uk/radio
 
Description Webinar - to New Statesman magazine readers 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A webinar hosted by the New Statesman alongside Dr Phil Whitaker and Laura Spinney discussing the Covid19 pandemic
Year(s) Of Engagement Activity 2020
URL https://www.newstatesman.com/2020/05/watch-new-statesman-webinar-pandemics-past-present-and-future
 
Description Webinar for business 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact I gave a series of five webinars in 2020 to Investec plc discussing the science behind the coronavirus pandemic
Year(s) Of Engagement Activity 2020
URL https://www.investec.com/en_gb/focus/economy/economic-webinar-replay-professor-michael-barrett.html
 
Description Webinar. Covid 19. Investec 14th Dec 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Investors and employees of Investec joined a dsicussion about the Covid19 pandemic, seeking advice on how to respond to the virus both personally and in business practice.
Year(s) Of Engagement Activity 2021
 
Description Webinar. Covid 19. Investec 30th Sept 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Webinar updating Investec and their investor community on Covid19 situation. Lots of Discussion about how individuals and businesses should respond.
Year(s) Of Engagement Activity 2021
 
Description Webinar. Covid 19.Update Investec 14th Dec 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Webinar updating on the Covid19 pandemic
Year(s) Of Engagement Activity 2021
URL https://www.investec.com/en_gb/focus/economy/economic-webinar-replay-variants-vs-vaccines.html