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 injuries range from blistering and scarring to full limbs requiring amputation and are often the result of tissue destruction caused by cytotoxic (cell killing) snake venoms. This tissue destruction is called necrosis and is caused by snake venom cytotoxins inducing cell death in the affected tissues: typically skin, muscle, and even bone. Such injuries can be devastating to victims, families, and communities. Conventional antivenoms – the only specific treatments for snakebite – are ineffective at stopping this necrosis. These antivenoms are (i) composed of large polyclonal antibodies, which limits their penetrance into the peripheral tissues most affected by cytotoxic snake venoms, (ii) animal-derived (typically horse), often resulting in a strong immune response from the patient which can result in severe side effects including death due to anaphylaxis, and (iii) must be administered intravenously, limiting treatment administration to hospitals or other healthcare facilities with trained medics which take a snakebite victim an average of 5-9 hours to reach. In short, new pre-hospital therapies are desperately needed to treat the local envenoming pathologies caused by cytotoxic snake venoms. While small molecule drug inhibitors and recombinant antibodies have shown impressive anti-cytotoxic snake venom activity in recent years, it is unlikely that any one drug or antibody targeting a single toxin family – no matter how potent – will be sufficient to inhibit the tissue destruction caused by the bite of any of the hundreds of snake species with cytotoxic venoms. Due to the immense diversity and complexity of snake venoms, we hypothesise that a rationally designed polypharmacological combination therapy, containing multiple drugs and antibodies that target and inhibit multiple toxin families simultaneously, will be required. Using cell-based cytotoxicity assays and fluorescence imaging, the PhD candidate in this project will assess the efficacy of drug inhibitors of snake venom toxins, including varespladib, marimastat, 2,3-dimercapto-1-propanesulfonic acid (DMPS), and tinzaparin, combined with novel recombinant antibodies designed to target and inhibit specific snake venom cytotoxins against a range of snake venoms: from spitting cobras to saw scaled vipers to pit vipers. The candidate will perform experiments to determine which combinations exhibit the greatest pan-species efficacy and whether they exhibit pharmacological synergy – where the overall effect of a treatment is greater than the predicted sum of their parts – between the drug and antibody used in each unique combination. To further improve treatment potency, efficacy, and pan-species effectiveness, higher order combinations (3+ drugs/antibodies) using the top performing two-therapeutic combinations will then be rationally designed with the goal of creating a treatment with significant cytoprotective activity against a global panel of snake venoms. In other words, a globally effective cytotoxic snakebite therapy that could be used anywhere in the world. In the later stages of this project, the candidate will test the best-performing combinations of therapeutics in a mouse model of local envenoming (i.e. skin and muscle necrosis), to determine if the pan-species cell-protective effectiveness is translatable to whole organisms. If successful, the PhD candidate’s work could pave the way for a future snakebite therapy with the potential to save thousands of snakebite victims from the life-changing effects of cytotoxic snake venoms every year. The successful applicant will join Dr Steven Hall’s laboratory at Lancaster University. They will also be co-supervised by Dr Stefanie Menzies (Lancaster University) and Prof. Nicholas Casewell (LSTM). 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 |
| Methodological Aspects |
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| 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, whilst also helping our labs to attain future funding through funders such as MRC, Royal Society, or 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 contribute to engagement activities, such as teaching the public about snakebite and the work we do to reduce its burden on victims. Finally, there is the very real possibility that we will discover a powerful new combination therapy with the potential to improve the treatment of snakebite in the real world, ultimately having life- and limb-saving impact on snakebite victims worldwide. |
| Training Opportunities | 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. Dr Menzies will provide training in antibody discovery and protein production. In addition, the division of Biomedical and Life Sciences (BLS) at Lancaster University, in which both Dr Hall and Dr Menzies are faculty members and the student will primarily be based, is a very collaborative division which includes over 30 academics and dozens of research students with a wide variety of expertise and with whom the student will be able to train in techniques with which Dr Hall and Dr Menzies are unfamiliar. Prof Casewell is the director of the Centre for Snakebite Research and Interventions (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, the 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. |
| Subject Areas | Snakebite, Neglected Tropical Diseases, and Drug Discovery and Development |
| 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 Menzies, S. K.; Patel, R. N.; Ainsworth, S. Practical progress towards the development of recombinant antivenoms for snakebite envenoming. Invited review in Expert Opinion on Drug Discovery. 2025. 1-21; DOI: 10.1080/17460441.2025.2495943 Khalek, I. S.; Senji Laxme, R. R.; Nguyen, Y. T. K.; Khochare, S.; Patel, R. N.; Woehl, J.; Smith, J. S.; Saye-Francisco, K.; Kim, Y.; Mindrebo, L. M.; Tran, Q.; Kedzior, M.; Bore, E.; Limbo, O.; Verma, M.; Stanfield, R. L.; Menzies, S. K. et al. Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins. Science Translational Medicine. 2024. 16(735) DOI : 10.1126/scitranslmed.adk1867 |