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Spotlight on ECRs: Dr Mariana Diniz and Dr Leo Swadling
Mariana and Leo of the Maini Lab share their achievements in the fields of immunology and infection and advice for early career researchers.
4 November 2022
Interview by Dr Marie-Belle El Mdawar, UCL Respiratory
In this episode, we chat with two members of the Maini Lab about their research, recent academic achievements, the advice they have for ECRs and their life outside the lab.
- Mariana, a senior research fellow at UCL Division of Infection and Immunity, received an award from the TIN Pilot Data Scheme for her innovative plans to engineer human NK cells to fight liver cancer more efficiently.
- Leo (@Leo1401j) has recently become a junior group leader at UCL Institute of Immunity and Transplantation (Pears building), and secured funding to develop his ideas for a pan-coronavirus vaccine.
Thanks very much Mariana and Leo for joining us today to talk about your respective careers and achievements.
Research questions:
1. We will start at the beginning of your research journey. What led you to pursue a research career in immunology and infection? (Common question for both)
Mariana: First, thank you so much for the invite and for the chance to speak here. I think I was interested in immunology and infectious diseases since I started university. I studied biology as an undergraduate and since my first year, I already was interested in human health.
Then, once I had my first class of immunology, I knew that was the research area that I wanted to follow. I also joined a laboratory as an undergraduate and was working on immunotherapies for cancer, and have been working in this area since then.
Leo: I had a roundabout way to get into academic research with immunology. I started out doing an undergraduate in zoology, and then my first job after university was in a small contract research organisation in Oxford. I really enjoyed the lab work, but it wasn't so stimulating for me to be working on other people’s projects. So, I went to do the graduate scheme at the Health Protection Agency, where I had more input into the design of experiments and did rotations to experience different types of science such as molecular work, proteomics and immunology. That is when I discovered that immunology was by far the most interesting to me and that's when I got interested in vaccines, something that everyone experiences and is related to everyone's life. So, step by step, I became more and more academic and more immunological in my work.
2. Mariana: You were awarded a TIN Pilot Data Scheme for your innovative plan to engineer human NK cells to fight liver cancer cells more efficiently. Can you tell us a bit more about this award and the project you are working on?
The TIN pilot scheme is an internal UCL grant application. It is dedicated for research work that is more in the preliminary stage; when you need initial help to develop preliminary results to then apply for bigger grants.
I found out about it by the UCL emailing list and once I got in touch with them [scheme team], the team was very well organised and helpful; they have networking groups and preparation courses that you can access and you can also receive news and learn about other opportunities.
The process to apply was quite straightforward after, with a form that you need to fill and write a small research project.
My award was to follow on some work that I previously developed in the lab. I was studying how NK cells can regulate T cell responses in hepatitis B and we saw a potential to manipulate these NK cells a bit further to improve their role in fighting not only infectious diseases, but also cancer.
I applied for this scheme to start establishing the next step in the NK cell therapy. The idea was to transduce or engineer these NK cells to express two proteins. One is CXCL6, which will allow NK cells to infiltrate better the liver cancer tumours. The cells would also secrete anti-PD1, which is a checkpoint blockade molecule that is already being used in clinical trials for cancer and other diseases.
Leo, you recently became a new Group Leader at UCL Institute of Immunity and Transplantation and secured funding to work on your ideas for a pan-coronavirus vaccine. Can you tell us more about the process you went through, what it is different now that you are a PI, and the project you want to develop?
I was actually really lucky. Mariana and I have moved with our previous group to a new building institute at the Royal Free Hospital: the Pears Institute. As part of opening the new building, the Pears Foundation donated funds for a senior post and a new group leader post. Like other fellowships, there was an application process and an interview, and I was really fortunate to be selected so that I could make that step from being a postdoc to a recognised group leader at UCL.
UCL have another scheme for new group leaders, which basically pays for your salary and some consumables. It is to give you the freedom and the time to concentrate on getting substantial funding to establish a research group. I am funded personally for three years but it doesn't come with any extra staff. When you are busy also presenting data and grant writing, you need an extra pair of hands. So, I applied for the therapeutic accelerator scheme to get my first technician in the lab and now I have someone who I can train and work with to keep the project going.
Becoming a PI was kind of a gradual process for me. There is a lot more work to do that isn’t at the bench, but you start to do more of this a bit as a postdoc. Now, I definitely notice that I spend more time presenting the work and engaging with collaborators to tell them what we have done and what we want to do next. There is more managerial work: managing staff and managing the grants.
For my group, I am interested in T cells’ contribution to protection against viruses. Recently, we had a really interesting cohort which we were lucky to work with, where we identified that some individuals resisted developing a SARS-Cov2 infection. And what was unique about these individuals was is that they were exposed to the virus, but they cleared it very quickly because they had some pre-existing immunity. These are T cells generated by something that they had previously seen which is related to SARS-CoV-2. The work we want to do is to try and understand more about these T cells; why some people have them and others don’t, can we recapitulate the immunity that these people had with vaccines? So, by studying these people who could clear the virus very early in the infection, before it could be detectable, is a good way to identify the best type of immunity that we want to generate with vaccines.
3. Do you have any students working with you on this project? And if so, what kind of relationship do you have with them? (Common question for both)
Leo: I think like transitioning to a PI, your relationship with the other members in the group changes gradually. Mariana and I are both junior scientists, so we try to be quite approachable and we work really close with the students because we are really the ones training them in the lab and working side by side with them on the projects. But I think the further you go in your career, the more hands off you become. At the moment, we try to give them a good understanding of what science is; doing robust and reproducible science, the technical aspects of it, but also to introduce them to the importance of telling other people about what research you do and putting your research in the context of what other people do around the world.
Mariana: As Leo was saying, because we are still doing a lot of the research work in the lab, I think we work very closely to them, but usually that is quite different when you are working with a more senior PI, where the students don't feel they can approach them all the time, and more likely they have to arrange meetings.
Follow up question: Do you think you would keep this interaction when you become more senior or do you think you will follow up with the pass of being less approachable?
Mariana: I think you can always try to be approachable, but maybe not physically so close, because as things evolve we will have other postdocs or PhD students in the lab that can train more juniors students. So, you make sure there is always someone working very closely with new students and you are there for advice, but not necessarily at the bench.
Leo: In science, you are asked to do lots of different jobs: training new researchers, teaching, keeping your own research going, being involved in research strategy. From the group we have been in, they really concentrate on training new staff members because although they might not stay and work directly with you, you hope that you can train scientists that will go on to do good work and that maybe you will work with in the future. And immunology is such a small community that you inevitably come across them later. My mentors have always stressed the importance of training others well, so that they can hopefully go on to contribute to the scientific development as this is really a great output from what you do, not just to concentrate on publications and your personal output. It is something I would hope to keep up.
4. Can you tell us something amazing about liver (Mariana) and vaccine (Leo) that people may not know?
Mariana: I think one thing that is very important in the liver is that it receives a lot of microbial products from the gut. So, the liver is specialised to be a tolerogenic environment, and not to respond to a lot of these antigens that it receives and also antigens that come from our food, for instance. It is specialised in kind of silencing a lot of the immune responses. This specificity is good from one side, as it helps in dampening the response to commensal bacteria antigens, but at the same time it can create a problem when we try to solve infections to pathogens that actually populate the liver.
Leo: What I find fascinating with SARS-CoV-2 is how we are living now with different variants of concern, slightly different versions from the original virus, which have evolved over time but that are almost identical in their sequence. It is really small changes, small differences from the original virus but which cause such clear differences in disease and viral characteristics; changing 0.01% of its [virus] sequence, it can become more transmissible or infect upper or lower respiratory tract in different ways, evade immunity etc. I think that is kind of fascinating, such few changes have big impact.
5. Can you tell us about a setback that you might have encountered as a researcher and how you were able to overcome it? (Common question for both)
Leo: I think science is competitive because there is a small amount of money that people can use and, in particular, a lot of the money come from charities and the government. So, it should be competitive because we want to make the best use of this limited resource. And that means when you apply for grants and you want to publish papers, you have to expect setbacks. For instance, for our pan-coronavirus funding, this wasn't the first source that we tried. Even though we think it is an idea worth trying and something that needs to be done quickly, it wasn't awarded funding with the first grant application. But you can restructure your proposal, take the feedback and then try again. And we were lucky that we did get funding to pursue it!
Mariana: To add on that, sometimes the specific project ideas that you work on in the lab don't always go as well as planned, so then of course you need to change your approaches or change the strategy. Always try again and differently.
6. Can you share some interesting work that you read about recently? (Common question for both)
Leo: I was reading a paper this morning where they were trying to match TCR specificity to antigen specificity. In T cell research, we have these immune cells, T cells, in our body which recognize a small part on the virus using unique receptors. We can sequence these receptors really well. But what we are not very good at, is taking a receptor sequence and telling which part of the virus it recognizes: is it a T cell which is going to recognise cells infected with SARS-CoV2, or CMV or HIV or something else? And they [the authors] have used all of the data that we have available for SARS-CoV-2, where we can match a T cell receptor with the part of the virus it recognised, and they’ve used that to predict what similar receptors would recognise and have found that those predictions work really well. It is a lot of bioinformatic work, but it is some of the first exciting data where we could potentially use this really high throughput technology to work out what parts of the virus the immune system is recognising in different people (https://pubmed.ncbi.nlm.nih.gov/35841887/).
Mariana: For me it is a new more targeted way to deliver cytokines as immunotherapy. Cytokines have been trialled previously in different settings, like vaccines and cancer treatments, but they can induce systemic toxicity and induce severe adverse effects.
What this group tried, was constructing a chimeric protein to deliver IL-15, which is the cytokine that can make T cells and NK cells proliferate. They constructed a chimeric IL-15 fused to anti-PD1. The idea is that the CD8+ cells expressing PD1 will bind to these anti-PD1 antibody that is fused to the IL-15. Then, the IL-15 will be internalised and used by these PD1 high CD8+ cells, which is a population of exhausted and dysfunctional CD8+ cells.
With this kind of therapies in cancer, but also in hepatitis B for instance, it is a way of giving IL-15 more specifically to this dysfunctional population that you want to try to recover, avoiding systemic effects, like cytokines enhancing proliferation of other T cell populations that we are not necessarily interested in inducing (https://rupress.org/jem/article/219/12/e20220745/213502/An-engineered-concealed-IL-15-R-elicits-tumor).
Personal / Opinion questions: (Common questions for both)
1. What are you most proud of attaining or achieving in your research journey?
Mariana: I have always been very pleased and proud when my students or students I co-supervised pass their thesis viva and publish papers from their thesis projects. One thing I like about research is that it can be transmitted, and then when people working with you also are passionate about their work and generate nice results is very rewarding.
Leo: I am most proud of the work we did on SARS-CoV-2 because we had access to such a unique cohort, and felt the pressure to produce something quite novel and really make the most of it. I feel quite lucky that we could get some way to addressing the questions or hunches we had with our work and provide some novel understanding of immunity to viruses.
2. Do you have any advice for PhD students and/or early career researchers who are starting their PhD/research journey?
Leo: I think sometimes people think the purpose of a PhD is to produce publications, whereas really it is more useful to think of a PhD as a training scheme to give you the skills to be a researcher, whether you are staying in academia or going to industry or even going to do something completely different. I think PhD students should concentrate on gathering all the skills, trying lots of new things and really developing both analytically and experimentally and in their reading and writing skills in science.
Also, it is a long process, so think about where you are going do it. You can get excited about any research question as long as you are at the forefront of knowledge, but there are different environments and different ways of running a research group, so think hard about how you like to work and who you want to work with before you commit.
Mariana: I would add to that, try to learn more techniques that don't necessarily fit your research line, go to seminars and hear about different work projects because sometimes you can come across some difficulties that maybe you have seen other people dealing with so it can help you. Be open to collaborations and asking for help.
3. What research skill are you most proud of as a researcher?
Mariana: It may be a bit polemic because there is a lot of resistance to working with animals, but I think I have always liked doing animal work with mice. It was easy for me to learn the different techniques and it is something that I have done most in my research life, working with different immunization routes and different surgeries, always trying my best to avoid pain and stress for the animals.
More recently, I started doing a bit more of molecular biology work, which I hadn’t done before, like constructing different viral vectors and doing primary cell transductions, and it got me interested.
Leo: Now I am probably most proud of my ability to present my research effectively. It was something I struggled with a lot as a research assistant and PhD student, and something that nearly put me off a career in academic research. But it is amazing what practice can do. And as soon as you’ve given a talk to a big audience, everything smaller seems easy. So, don’t worry if you’re not a natural presenter, in my experience it gets easier and easier.
4. Outside research, what interests and activities do you like to pursue?
Mariana: I like to travel. I like to do some sports when I can; Leo and I used to go running, we need to start doing that again. I also enjoy going to the cinema and exhibitions.
Leo: We have a book club in our group; we have a coffee lottery that was set up because we like to drink coffee a lot. We also as a lab have been to a few music festivals because there is lots of people into music, and we have a running club.
5. In recent years, the importance of mental health at work is becoming more and more important. What do you find helpful to keep your mental health in the lab?
Leo: I have got really good colleagues to talk to, to keep everything in perspective. I think science is a really slow process and everyone is so enthusiastic they want their results straight away; so they want to do all the experiments in one week and it is very easy to work too hard and burnout. I think keeping everything in perspective and talking is really important. Doing exercise is also a good distraction and a good way to clear your head when you can't stop thinking about the science.
I also help to organize a postdoc network in London and one of the main purposes of that is to try to promote wellbeing and to offer a social and support network for researchers, but also to encourage people to collaborate across London (https://londoninfection.wixsite.com/home; @LondonPostdoc).
Mariana: We spend most of our time that we are awake at work, so I think it is really important that we have good relationship with our colleagues and have a work environment where you are not stressed all the time. I enjoy also building personal relationships rather than just being all the time discussing about work. I think for me, it also helps a lot to find some moments of quietness, like when we are reading something or going for a walk.
6. Do you have a favourite quotation or memo that you would like to share with our readers?
- Leo: Someone said: “If we knew what it is we are doing, it would not be called research.” It frees you up to accept that you don't know exactly what is happening all the time.
- Mariana: “Philosophy, art, and science are not the mental objects of an objectified brain but the three aspects under which the brain becomes subject.” - Gilles Deleuze.
