This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Kofi Annan called snakebite “The biggest public health crisis you’ve never heard of”. Snakebite envenoming is a medical emergency that is estimated to kill over 100,000 victims every year and maim a further 400,000. These permanent injuries range from small lesions and scars on the body to full limbs requiring amputation and are often the result of tissue destruction in and around the snakebite site. This tissue destruction is called necrosis and is caused by snake venoms containing what are called “cytotoxins” which induce cell death in the affected tissues, such as the skin, muscle, and even bone of the victim. The only venom-inhibiting treatments available for snakebite envenoming are antivenoms; expensive antibody-based therapies that must be administered intravenously in a hospital and that are largely ineffective at reducing tissue necrosis. In our labs, we have worked on discovering and developing small molecule drugs that inhibit certain venom toxins. Such compounds are suitable to be administered “in-the-field” directly after a snakebite occurs, meaning a snakebite victim could theoretically carry such a treatment on their person that could be used almost immediately in an emergency snakebite situation, slowing the venom and buying the victim time to reach hospital for further antivenom therapy. However, as snake venoms are complex and variable in their toxin makeups, it is likely that any one drug targeting a single toxin will be insufficient, and that a therapy containing multiple compounds to target multiple toxins would prove more effective. Such a treatment would ideally be effective against the venoms of many different species of snake and drastically reduce the resulting necrosis, such that a survivor would not have to live with the life-altering injuries so often associated with cytotoxic snakebite currently. While much of this drug discovery work has focused on compounds that target specific venom toxins, one potentially exploitable avenue is to inhibit a more general tissue-destructive biological effect caused by the toxins. One of these avenues is the generation of what are called reactive oxygen species, or ROS. ROS are oxygen-containing compounds that are highly reactive, such that they rapidly oxidise lipids, proteins, DNA, and any other biomolecules necessary for the proper functioning of our bodies; these can include compounds like hydrogen peroxide (H2O2) or oxygen radicals like superoxide (O2-). ROS can cause significant damage when their levels rapidly and drastically increase, and are associated with tissue injury, inflammation, and necrosis. While ROS have been extensively studied in normal human physiology and in the progression of other diseases, such as cancers or Alzheimer’s disease, their relevance to snakebite envenoming is only just beginning to emerge, with a handful of recent papers showing how certain snake venoms induce ROS activity. Antioxidants are common, readily available, cheap, and safe to use in humans. Many of them (e.g. citric acid, ascorbic acid, citric acid) are found in our foods naturally, and many are readily available for human consumption as health supplements (e.g. N-acetyl cysteine). It is certainly feasible that such antioxidants may help reduce the necrosis associated with cytotoxic snake venoms by reducing the damaging effects of venom-induced ROS activity within a victim’s tissues, and that they could be a valuable addition to future snakebite therapies. This project will therefore focus on determining if and to what extent a variety of antioxidants (including those mentioned above) can inhibit the cytotoxic potencies of snake venoms, such as those from Echis ocellatus (saw-scaled vipers), Naja nigricollis (black-necked spitting cobras), and Bothrops asper (Fer-de-lance). The extent and type of cell death caused by these venoms, and its inhibition by antioxidant treatments, will be assessed using cell culture techniques such as resazurin cell viability and propidium iodide cell death assays. Any antioxidants that do exhibit efficacy will then be combined with drugs that inhibit snake venom toxins, such as DMPS, varespladib, and tinzaparin with which we have worked previously, and using pharmacological methodologies and the program SynergyFinder we will determine if these compounds are acting synergistically against the snake venoms. Should these in vitro assays prove successful, animal studies will be considered to further prove (or disprove) the potential efficacy of antioxidants, alone or in combination with other treatments, as future snakebite therapies. The successful applicant will join Dr Hall’s laboratory at Lancaster University, whilst also being affiliated with Prof Casewell’s Centre for Snakebite Research & Interventions (CSRI) at the Liverpool School of Tropical Medicine and Dr Giorgi’s Centre for Health Informatics, Computing, and Statistics (CHICAS) also at Lancaster University. Through our combined and varied expertise, the student will earn a unique PhD that will make them a competitive candidate in whatever career path they choose to pursue upon its completion. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Expected Outputs | Publications: In addition to the successful candidate’s thesis, they will help write and edit an estimated 2-3 manuscripts based on this work for publication in peer-reviewed journals. They will also be given the opportunity and mentorship to publish abstracts and present the associated research at toxinology and pharmacology conferences, and to publish work in non-peer reviewed formats, such as in Pharmacology newsletters associated with either the Canadian or British Pharmacological Societies or in The Conversation. Funding: The work completed by the student will both help them in terms of attaining future funding through fellowships or small grants, should they decide to pursue academia, and will be help our labs to attain future funding through the MRC, Royal Society, and Wellcome Trust Research Grants to progress this work into an eventual real life snakebite therapy. Impact: The student’s published work and presentations to fellow scientists will help us to foster new collaborations to pursue further work, will educate others on the potential utility of antioxidants in the treatment of snakebite envenoming, and allow the student to grow in their confidence and abilities to help them attain their career goals. They will be encouraged to get involved in engagement activities, to teach the public about snakebite and the work we are doing to reduce its burden on victims. Finally, there is the very real possibility that we will discover a powerful new compound or compounds that can be used in combination with other drugs or antivenoms to improve the treatment of snakebite in the real world, having potentially life- and limb-saving impact on snakebite victims worldwide. |
| Training opportunies |
Dr Hall will teach the student about cell culture, drug testing, and working with venoms in wet lab experiments, and will provide training and mentoring to develop the student’s scientific writing and presentation skills. In addition, the division of Biomedical and Life Sciences at Lancaster University, in which Dr Hall is a faculty member and the student will primarily be based, is a very collaborative group which includes over 30 academics with a wide variety of expertise and with whom the student will be able to train in techniques with which Dr Hall is unfamiliar. Dr Giorgi, who is the head of CHICAS and a member of Lancaster Medical School, will be able to train the student in data handling and statistics, and connect the student with fellow academics within the Medical School should there be additional areas in which the student wishes to be trained. Prof Casewell is the head of the CSRI within the LSTM, a group of over 20 postdocs, students, and technicians, with whom the student will be able to collaborate and from whom the student will be able to learn all they can about snakebite research. Last of all, Lancaster University provides additional training for doctoral students to help them develop, and the Faculty of Health and Medicine offers a regularly occurring training programme for graduate students. In short, we will ensure the student is well-trained upon completion of their degree. |
| Skills Required | Any student with a general bioscience background, a strong sense of curiosity, a willingness to try things and make mistakes, a strong work ethic and ability to self-motivate, and a genuine interest in snakes, snakebite, or developing new treatments for a neglected tropical disease would be suitable for this position. |
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Key Publications associated with this project |
J. M. Gutiérrez, J. J. Calvete, A. G. Habib, R. A. Harrison, D. J. Williams, D. A. Warrell, Snakebite envenoming. Nat. Rev. Dis. Primers 3, 1–21 (2017). DOI: 10.1038/nrdp.2017.63 |
| R. H. Clare, S. R. Hall, R. N. Patel, N. R. Casewell, Small molecule drug discovery for neglected tropical snakebite. Trends Pharmacol. Sci. 42, 340–353 (2021). DOI: 10.1016/j.tips.2021.02.005 | |
| S. R. Hall, S. A. Rasmussen, E. Crittenden, C. A. Dawson, K. E. Bartlett, A. P. Westhorpe, L-O. Albulescu, J. Kool, J. M. Gutiérrez, N. R. Casewell, Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. Nat. Commun. 14, 7812 (2023). DOI: 10.1038/s41467-023-43510-w | |
| M. Mittal, M. R. Siddiqui, K. Tran, S. P. Reddy, A. B. Malik, Reactive Oxygen Species in Inflammation and Tissue Injury. Antioxidants & Redox Signaling. 20, 7, 1-42 (2014). DOI: 10.1089/ars.2012.5149 | |
| D. Resiere, H. Mehdaoui, R. Neviere, Inflammation and Oxidative Stress in Snakebite Envenomation: A Brief Descriptive Review and Clinical Implications. Toxins. 14, 802. 1-13 (2022). DOI: 10.3390/toxins14110802 |