Here you will find some case studies and reports from selected awardees of the BSI Career Enhancing Grants. These highlight some of the successful projects and activities undertaken with whole or part support of this grant scheme. We hope these will give you some inspiration and ideas for your own potential applications.
Dr Ben Lindsay
Visit to The Ordovas-Montanes Lab at the Harvard Stem Cell Institute
Thanks to the British Society of Immunology I was able to visit Jose Ordovas-Montanes lab within the Harvard Stem Cell Institute to develop a Clinical PhD fellowship application. This lab is using a variety of novel techniques to study how inflammation can drive memory formation within mucosal tissue. This fantastic opportunity, made possible by The BSI’s Career Enhancing Grant, allowed me to get direct exposure to new lab techniques, shape my research ideas and network with leading international scientists.
I’d initially planned to visit for 1 month however like many post-2020 plans it was delayed because of COVID! Fortunately, the lab was very understanding and able to rearrange dates. Although, due to personal commitments I visited for a slightly shorter time of 3 weeks. Once I arrived, I was instantly welcomed by the team, all of which found time to discuss my research ideas and let me shadow their experiments.
During my PhD I intend to study how recurrent viral infections can induce inflammatory memory and lead to adaption with the nasal mucosa. Starting out with a fellowship application as a junior academic is a daunting task. Having to come up with a question, think about potential future experiments and map out 3 to 4 years of research time requires a lot of work and support. Having this opportunity to immerse myself in a new research group investigating similar questions was invaluable and really helped bring my application together.
One of the key aims of the visit was to observe research techniques that I could apply within my fellowship. The main methods I planned to see were single cell RNA sequencing, isolation of cells from nasopharyngeal swabs and culture of respiratory basal cells (a stem cell like progenitor cell). Getting the opportunity to see these techniques allowed me to quickly see important benefits and limitations and think about how they may fit within my research proposal. After returning from Boston it also enabled me to rapidly set up some of these methods within my current lab.
Beyond the obvious benefits of learning new techniques, the opportunity to network and connect with a new group of researchers will have a large impact on the next steps in my career. It’s easy to forget the benefit of face-to-face interaction after the rapid adaption to virtual communication that the COVID19 pandemic necessitated. This was my first professional trip since COVID19 and I really benefited from being able to meet people in person, share ideas and have creative conversations.
The BSI’s Career Enhancing Grant is unique and opens up so many possibilities through its broad remit. The minimal number of rules and pre-requisites really does allow researchers to put together tailored experiences that can have significant impacts on career development. I hope this grant can continue in the future and have recommended it to many colleagues.
I’m really grateful to Jose and his lab for this opportunity and for the BSI for supporting the visit. The lab is doing some really exciting immunology and have a very friendly and collaborative culture. I’ve taken a huge amount from this visit and look forward to continuing collaborating with the group in the future. I do feel I achieved more in the 3 week visit than I would have with 3 months at home and it has put me into a much more competitive position for my PhD fellowship application. The Career Enhancing Grant has definitely lived up to its name.
Dr. Damian Perez Mazliah
Studying Pathogen-specific And Autoreactive B Cells Side-by-side With Single-cell RNA Sequencing
Dr. Damian Perez Mazliah (Hull York Medical School, University of York) is an early career researcher working to establish an independent research programme looking at B cell immunity in Chagas disease. The BSI Career Enhancing Grant has provided Damian with timely support to conduct a most valuable single-cell RNA sequencing (scRNA-seq) proof-of-concept experiment and complete the foundation required to apply for larger extramural research Fellowships. Thus, this grant has been a great aid to Damian’s endeavour of becoming fully established and continue working on his research, aimed at improving the quality of life of people suffering with neglected tropical and autoimmune diseases.
Cardiovascular diseases are the leading cause of death globally. Caused by Trypanosoma cruzi, Chagas disease is the leading cause of infectious heart disease worldwide and the highest-impact parasitic disease in the Americas. Chagas disease is now spreading globally; currently, no vaccines are available and treatment is limited and frequently leads to adverse effects. Chagas disease affects mainly people living in poverty in rural areas and generally receives little attention from governments, despite affecting ~8 million people worldwide (in context, more than the estimated amounts of people suffering from Parkinson's disease or lupus). T. cruzi causes a life-long chronic infection that in some ~30% of individuals leads to different degrees of heart disease, ranging from mild to severe and even death. It remains unclear why some individuals develop heart disease while others remain asymptomatic upon T. cruzi infection. Similar to human infections, different strains of mice develop different degrees of heart disease in response to T. cruzi infection, thus allowing us to model different clinical outcomes. Therefore, we combined mice and scRNA-seq to study and compare the immune responses associated with mild vs severe Chagas heart disease. A BSI Career Enhancing Grant to Dr. Damian Perez Mazliah covered the sequencing costs for this scRNA-seq experiment.
B cells, white blood cells that are part of the body's immune system, produce antibodies that protect us from infections. In rare occasions, some B cells, called autoreactive, begin producing antibodies that instead of fighting infections, attack the body's own tissues, leading to autoimmune diseases (e.g. lupus and rheumatoid arthritis). T. cruzi infection activates the immune system to produce both antibodies against the parasite and against the body’s heart. Thus, B cell immunity is important to protect us from T. cruzi infection, but might also contribute to the development of Chagas heart disease. To better understand how the B cells that fight the infection and those that attack the heart develop, we generated novel experimental strategies (B-cell tetramers) to isolate and study in mice both kind of B cells side-by-side. Our data shows that parasite-specific and cardiac-specific autoimmune B cells are drastically different. T. cruzi-specific B cells activated by the infection are able to interact with T cells and give rise to germinal centre responses leading to long-lived memory. On the other hand, autoreactive cardiac-specific B cells do not interact with T cells and give rise to short-lived responses. Thus, continuous parasite stimulation is required for autoimmunity to persist. Moreover, our scRNA-seq experiment showed that mice that develop mild Chagas heart disease and those that develop severe Chagas heart disease show striking differences in their immune response to the parasite, with B cells dominating these differences. Importantly, severe Chagas heart disease leads to a striking accumulation of recently activated autoreactive B cells in the spleen, as well as accumulation of recently activated B cells in the heart.
Our future work will focus on studying if cardiac-specific autoreactive B cells activated by T. cruzi infection can contribute to heart tissue damage either by autoantibodies or by migrating into the heart. This research will generate foundational knowledge that will help us produce novel treatments to improve life quality not only of people suffering this neglected tropical disease, but also autoimmune diseases in general.
Mikołaj Kocikowski
Molecular modeling techniques for computational screening of canine anti-cancer antibody candidates
My name is Mikołaj Kocikowski and I’m a PhD student at the International Centre for Cancer Vaccine Science (ICCVS) – a joint project between The University of Edinburgh (UK) and The University of Gdansk (Poland). ICCVS is an inter-disciplinary and highly collaborative research centre that aims to train future leaders and teams in translational science and medicine. The main focus is research on molecular mechanisms in cancer immunology. My research project aims to characterize canine (occurring in dogs) cancer types and to develop therapeutic antibodies against them through a combination of laboratory and computational methods. Limitations of cancer immunotherapy that we have described recently likely stem from the inadequate, artificial murine models used in drug discovery and development.
Meanwhile, spontaneous cancers occur in dogs with high prevalence and usually resemble their human counterparts closely. Contrary to classic phylogenetic trees, the human genome is more similar to the canine than the murine one. The same holds for the immunoglobulin locus, making dogs prime candidates for immunotherapy development. Careful development of dog cancer treatments could be an invaluable knowledge source for human medicine while filling the gap in the veterinary oncology arsenal. Importantly, dogs are not treated as “laboratory animals” but as oncological patients in need of effective treatments. This concept, termed comparative oncology, matches contemporary and interdisciplinary approaches to problem-solving such as One Health – “collaborative efforts of multiple disciplines working locally, nationally, and globally, to attain optimal health for people, animals and our environment”.
Our team raised antibodies against targets present in both human and canine cancers: PD-1 and CD-20. The use of the mouse hybridoma system resulted in a mouse-characteristic amino acid sequence, foreign and hence immunogenic for a dog. For each, I had to modify the sequence so that it resembles natural canine ones from a previously developed database. I performed this process – called caninization – computationally through multiple proprietary methods. Antibody engineering comes with a risk of a drastic reduction in target affinity. Producing all the designed protein variants for biological activity screening is not economically viable. Hence, I decided the best drug candidates will be chosen based on modelling the molecules and in-silico screening. In the next step, we will produce and characterize the most promising ones in vitro.
To this aim, I first took a course in computational antibody design offered by the Schrodinger company. Excited by the capabilities of modern molecular modelling software, I decided to dive deeper. I applied for a British Society for Immunology (BSI) Career Enhancing Grant with a project titled “Molecular modelling techniques for computational screening of canine anti-cancer antibody candidates”. The received funding enabled me to get advanced training in molecular modelling for drug design and development. I gained a new understanding of the enormous breadth and capabilities of molecular modelling techniques. It is clear to me now, that this beautiful and extremely complex art can take long years to master. However, understanding its importance and potential for real drug development and selection of therapeutic molecules will tremendously enhance my current project and future research ideas.
Dr Rachel Tanner
Characterisation of non-specific responses induced by BCG vaccination and M.tb infection
Bacille Calmette-Guérin (BCG), the only currently licenced TB vaccine, may exert beneficial non-specific effects (NSE) in reducing morbidity and mortality due to non-mycobacterial infections including COVID-19. Randomised and observational studies indicate lower all-cause mortality rates for BCG-vaccinated neonates; most consistently associated with a reduction in cases of sepsis, respiratory infection and fever. The advent of the COVID-19 pandemic triggered a resurgence of interest in NSE of BCG vaccination, and more than 20 clinical trials are assessing the efficacy of BCG vaccination against COVID-19.
The immunological mechanism underlying the NSE of mycobacterial stimulation is unclear but may involve cross-reactive/antigen-independent heterologous lymphocyte responses and/or ‘trained’ innate immune memory mediated by epigenetic changes. The latter is being extensively studied, but there is a paucity of literature on the role of humoral immunity. Improved immunological understanding is essential because: a) NSE could be exploited, mimicked or augmented using novel vaccines and immunological therapies; b) novel TB vaccines must be non-inferior in their NSE, in addition to being efficacious against TB; c) discontinuing BCG vaccination programs due to a decline in TB prevalence may have detrimental knock-on effects; and d) BCG vaccination may have value in the early control of future emerging pathogens.
This BSI Career Enhancing Grant allowed me to generate pilot data investigating the potential contribution of humoral immunity to non-specific effects, characterising antibody responses induced by BCG vaccination and Mycobacterium tuberculosis (M.tb) infection against a number of heterologous pathogens.
No heterologous IgG responses were observed in UK adults vaccinated with BCG in intradermally (ID), and only IgM specific to S. abortus and E. coli increased significantly post-vaccination. Non-human primates (NHPs) vaccinated with BCG by the ID route of BCG also lacked heterologous antibody responses. We attempted an in vitro stimulation of PBMC collected from human volunteers pre- and post-BCG vaccination but were unable to detect measurable PPD-specific antibodies in the supernatant following stimulation with PPD, BCG or SARS-CoV-2 antigens in either vaccinees or controls, suggesting that the assay requires further optimisation.
Interestingly, we show for the first time that NHPs experimentally-infected with M.tb had significantly increased levels of both IgG and IgM against SARS-CoV-2, cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and tetanus toxoid, and of IgG against respiratory syncytial virus (RSV) compared to pre-infection. To determine whether these antibodies are functionally relevant, we assessed neutralisation capacity and avidity against SARS-CoV-2. We were unable to detect neutralising antibodies, perhaps due to levels falling below the cut-off for assay sensitivity, but we did observe a non-significant trend of increased avidity against SARS-CoV-2 spike protein following M.tb infection.
To better understand the discrepancy between the BCG and M.tb findings given the high degree of homology between these two mycobacteria, we explored whether the effect observed in M.tb-infected animals could be induced by BCG administered to NHPs by the same route as M.tb (aerosol) or by a 10x higher dose administered intravenously (IV). In neither case did BCG induce heterologous antibody responses. We then performed sequence homology analysis to determine whether the responses induced by M.tb were due to non-specific antibody cross-reactivity due to antigen similarities between M.tb and the heterologous pathogens, and found no significant whole genome or protein sequence homology.
We hypothesise that the mechanism underlying the heterologous antibody responses could be non-specific polyclonal activation of memory B cells triggered by ongoing antigen stimulation during M.tb infection, and future work will seek to better understand this using flow cytometry. It would be particularly interesting to assess responses following vaccination of NHPs with the novel TB vaccine candidate MTBVAC, which is an attenuated strain of M.tb, to disentangle the relevance of transient versus ongoing antigen challenge and the role of M.tb-specific antigens. If MTBVAC is able to induce similar heterologous antibody responses as M.tb infection, this could have significant implications in terms of its superiority compared with BCG and other TB vaccine candidates.
This grant has been extremely valuable as it has supported research costs between my Fellowship ending and beginning a new post. During this time I had a Health Research Bridging Salary Scheme Award which funded my salary but did not cover consumables. As I am at a critical juncture in my career transitioning to independence, the opportunity to pursue this research direction which diverged from the main interests of my host group has been particularly useful. The pilot data generated is promising and will form the basis of a larger grant application and a manuscript on which I will be senior author; both of these aspects are critical to my career development.
Sylvine Lalnunhlimi
PRINCE2® Foundation and Practitioner, 6th edition (Project management course), University of Westminster
Being a Research Assistant for over 5 years was great, I learnt a lot, but it was not something I wanted as a career, and I felt like something was missing. During my career in research, I was involved in several
research projects including observational studies. I worked with clinical trials team from various organisations, and I learnt the importance of work beyond research in the laboratory. I was deeply
inspired by the kinds of job that a trial management team does and the value of their contributions towards delivery of a successful clinical trials. The experiences I have gained through working in a research
environment have boosted my interests in pursuing clinical project management as a career. I started exploring opportunities to help me develop the skills and qualifications I need.
A good friend of mine recommended me to undertake PRINCE2®️ project management course, a globally recognised qualification which is often one of the essential requirements for project management jobs.
However, after researching more on this, I quickly realise how expensive the course is and I was looking for a way to fund myself. Luckily, the BSI Career Enhancing Grant scheme was rolled out. It was the perfect
time for me and after reading through the guidance notes, I decided to apply. To my surprise, BSI kindly offered me the grant and I was able to register for the course without having to pay for it from my pocket.
I signed up for PRINCE2®️ Foundation and Practitioner course, ran by University of Westminster. The course ran for 5 Saturdays, followed by an exam for both Foundation and Practitioner. The exams were
not easy, especially Practitioner exam and requires investing a lot of time to read and practice. But it was worth it and I passed both exams. I learnt many new things about project management in general, such
as proper planning, managing risk and amendments, maintaining high quality standard, monitoring progress and proper documentation. Most importantly, it has boosted my confidence to a great extent.
I started applying for jobs and was fortunate enough to be offered two. One as a Tissue Procurement Specialist at Guy’s and St Thomas’ hospital and the other as a Research Manager at University College
London. After a long debate and contemplating between the two, I decided to go for the first one as I still wanted to be involved in clinical studies and a more hands-on job rather than an office-based job. At my
current position, I am responsible for managing translational studies that run in our department. In addition, I am also involved in cell therapy trials where tumour tissue sample is required for the production
of ATMIPs.
PRINCE2® training has provided me the skills and knowledge to better manage these on-going studies that I am responsible for as well as new projects in set up. It has given me a successful transition from
laboratory-based work to trial management and is a stepping stone to achieving my career aspiration. Having this qualification has immensely enhanced my employability in a field of my choice. Most
importantly, this training will enable me to manage clinical research projects more effectively and deliver successful outcomes that will benefit patients as well as research teams.
I am grateful to British Society for Immunology for providing this Career Enhancing Grant scheme and for choosing me as one of their successful candidates. I am thankful for their support and providing the fund
to enabling me to become PRINCE2® qualified. I encourage everyone to explore this golden opportunity and use it to your advantage to help achieve your career goals and aspirations.
Veronica Matei-Rascu
Single cell RNA-sequencing analysis training supported by the BSI Career Enhancing Grant
Expertise in the field of bioinformatics and computational biology are rapidly becoming core skills for early career researchers. I had planned to incorporate these into my PhD, carried out at the University of
Birmingham, to aid both my research aims and personal development. However, the project modifications necessitated by the COVID-19 pandemic made my original plans impossible. Instead, I identified an
opportunity to spend 6 months learning singe cell RNA-sequencing (scRNA-seq) analysis. Following introductory training in the use of programming languages, command lines and statistics, this project was to
take place in the labs of Professors Chris Buckley and Mark Coles at the Kennedy Institute of Rheumatology, University of Oxford. These groups are home to several bioinformaticians and PhD students experienced in
Next Generation Sequencing (NGS) techniques.To take full advantage of this training opportunity I sought to be fully embedded within my host groups.
However, the funding I secured was not sufficient to cover accommodation costs. As a result, I applied to the BSI Career Enhancing Grant scheme which, with its broad remit to aid personal development, was perfectly
placed to support this work. Following initial training the project was designed to be completed in two phases. First, being exposed to analysis of a large human scRNA-seq
dataset, and second, analysis of newly generated data. Joining my host labs in person, enabled by the Career Enhancing Grant, meant that I was exposed to analysis of large-scale data created as
part of a clinical trial and even got to join parts of this process. Through this work I gained familiarity with scRNA-seq analysis workflows, new programming languages, scRNA-seq analysis
packages and, most importantly, troubleshooting key processes such as clustering and annotation. I then further developed these skills by analysing a
new dataset generated by my PhD host lab, led by Professor David Withers, in collaboration with the Coles Lab. This data, based on cancer models that enable tracking of lymphocyte movement between tumours and
draining lymph nodes, was to be used to interrogate tumour-egressing lymphocyte population heterogeneity at the transcriptomic level. Through this process, that is still ongoing, I applied my new skills and developed
further ones while troubleshooting my own analysis. Joining my host groups by moving to Oxford for the duration of this training meant that 1:1 help and guidance was readily available. Consequently, I gained
independence in using a range of programming languages, including R and Python, as well as in identifying appropriate pre-existing packages for the analysis of NGS datasets and incorporating them in my own work.
On top of the stated aims of this project the Career Enhancing Grant has also enabled me to grow my network by spending an extended duration of time within a new institute and university. These connections, forged
outside the scRNA-seq project, have helped me identify new wet-lab techniques that I plan to incorporate into my own research projects. In addition, by being present during lab meetings and informal discussions, I
was able to provide my own expertise in advising other students on their experiments.
Overall, the BSI Career Enhancing Grant enabled me to develop a new interdisciplinary skillset, meaning that I can now marry wet- and dry-lab techniques to best advance my research. In addition, my experience in a
range of fields means I can not only carry out in vivo, in vitro, and in silico work independently but also understand the needs of colleagues with varied backgrounds. I believe this ability to easily communicate with
others will greatly benefit my work and future career.