1 March 2021. Dr Mairi Kilkenny is with the Department of Biochemistry, School of Biological Sciences. A PDF version of this Issue is available here.
Research focus: Structural biology of human DNA replication
My particular area of interest is geared towards understanding, at the molecular level, how DNA replication works in human cells. It’s important, at a fundamental level, to understand how the cells in our body replicate DNA (the information storage molecule) prior to cell division. This is key to ensuring that each daughter cell has a complete and accurate copy of the genetic material. There are also more translational aspects to our research, relevant to human health. Cancer is a disease of uncontrolled cell growth and division, requiring high levels of some DNA replication proteins. We are currently investigating whether some of these DNA replication proteins would make effective targets for anti-cancer therapy. We have also recently discovered that some of our DNA replication proteins interact with SARS-CoV-2 viral proteins, which may help us to deepen our understanding of COVID disease progression and severity.
What made you decide to pursue research?
I didn’t really have a “eureka” moment – I enjoyed my undergraduate degree to the extent that I knew I wanted to give a PhD a go. My PhD was a stimulating, collaborative experience, so I thought well, I’d quite like to continue to a post-doc. I’ve moved research fields (and locations) a fair bit: from inorganic chemistry (undergrad/Masters, Cape Town), to bacterial biosynthetic pathways (PhD, Cambridge), to human DNA repair (post-doc, Institute of Cancer Research, London), to human DNA replication (senior research associate, back in Cambridge!). I really enjoy taking on a new research project, working in a collaborative team to put the pieces of the puzzle together to arrive (eventually!) at the big biological picture. And I still enjoy my research work, but I’m now balancing that with other roles: Assistant Director of Teaching in the Department of Biochemistry, and Tutor, DoS and Supervisor at St Catharine’s College. I enjoy the variety that these different roles bring, and it’s really fun teaching and supporting a wide range of students.
One piece of advice…
If you think a career in research could be for you, be persistent about seeking out extra curricular research experience – use your network (DoS, supervisors), apply for funded internships in academia/industry, email individual group leaders and simply ask if they have any summer internship opportunities available – email again if you don’t hear back (academics are often drowning in emails, so don’t be scared to drop a reminder email). Don’t be afraid to change field – the diverse experience can make you a better scientist. There is some fascinating work going at the interface between fields – chemistry, biochemistry, physics, mathematics and computer science. Join societies (like SciSoc!) – build a network. Don’t worry if you’re not sure WHAT you want to do – the Careers Service is a great place to start looking for all sorts of different/varied opportunities.
8 February 2021. Dr Tina Potter is with the Department of Physics. A PDF version of this Issue is available here.
Research focus: High-energy physics
I am searching for signs of new particles that may briefly form in the high energy proton-proton collisions at the Large Hadron Collider. The lack of a discovery to date tells us that any new physics may not be easy to find; whether it be Dark Matter which makes up 85% of the mass of the universe, or other new particles which decay to Dark Matter. The possible signatures of new particle production can be complex and difficult to pick out of the abundant Standard Model processes. My research focuses on the design of novel and sensitive searches for new physics, such as Supersymmetry, using the ATLAS detector. Supersymmetry offers a potential solution by introducing many new particles, the lightest of which is an excellent dark matter candidate. I push the sensitivity of our searches for Supersymmetry and new physics in general, with the ultimate goal of a discovery of a new particle that will help us understand the composition of our universe.
What made you decide to pursue research?
For me, it’s simply my personal drive to understand the as-yet unexplained Dark Matter in our universe. Ever since I learned the huge number of open questions we still have about fundamental aspects of our universe, I felt a strong need to contribute and help find the missing pieces of the puzzle. The Large Hadron Collider was soon to start up as I finished my undergraduate degree and the timing was perfect to step into this huge experimental effort and make an impact.
What would be your advice to aspiring researchers?
Research can all too often have a narrow focus as we try to solve the day-to-day problems to reach our final goals. My advice would be to keep an eye on what is happening in your wider field to understand the bigger picture and put time aside every week to simply think.
22 February 2021. Dr Alexi Crosby is with the Department of Haematology, School of Clinical Medicine. A PDF version of this Issue is available here.
Research focus: Making platelets from inducible pluripotent stem cells
My current research is focused on making platelets (which are important in blood clotting) from inducible pluripotent stem cells. The rationale behind this is that there is a constant demand for the transfusion of platelets (as well as other blood components) and supply is limited by the number of donors, their shelf life (they can only be kept for < 7 days), and their compatibility with the recipient (the recipient may produce antibodies against the transfused platelets). More specifically I am looking at ways of making these platelets ‘more effective’ by loading them with proteins that are involved in blood clotting. This idea is to enhance blood clotting in areas where there is bleeding. Prior to this, I worked on a disease called pulmonary hypertension, which is high blood pressure in the lung circulation. This can cause right-sided heart failure. There are few effective therapies available and I was looking at the role of the bone marrow (where various blood cells are made) in this disease and the potential for bone marrow transplants as a therapy.
What made you decide to pursue research?
I decided to pursue research as I found my degree in human biology fascinating and wanted to carry on learning more. I also wanted a varied career and research is definitely that! My job involves coming up with hypotheses, devising experiments, doing experiments, analyzing data, writing papers and writing grants to obtain funding. In addition, I also supervise graduate research students and undergraduates. I wanted to a ‘make a difference’ and any finding, no matter how small, does just that. I come from a family of Scientists and I think that rubbed off on me!
One piece of advice…
My advice to any aspiring researchers would be to go for it! I would also say try to get some experience in a research lab if you can. Undergrad practicals are good, but research is a totally different ball game as you will find out during part 2! There are various 4 year PhD rotation programmes and these are really great as they enable you to rotate around 3 labs for the first year and then choose which lab you would like to go to for your PhD. This gives you great exposure to different labs and no 2 labs are the same! Not only are the projects you work on different, but also the people and different labs have very different ways of working and it’s important to find a lab that you ‘fit in to’.
18 January 2021. Dr Jingwei Zeng is with the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB). A PDF version of this Issue is available here.
Research focus: Intracellular antibody receptor TRIM21 role and function
My PhD topic focused on studying the role of the intracellular antibody receptor TRIM21 in antiviral immunity and the molecular mechanisms of TRIM21 functions. Antibodies are classically described as molecules of the humoral immune response that are capable of activating extracellular effector functions to prevent infection. However, work in the James lab over the past decade have shown that antibodies are carried into cells during infection by viruses and intracellular bacteria. This ground-breaking discovery has revolutionised our understanding of antibody immunity and has important implications for future vaccine and gene therapy design.
In addition to antiviral immunity, the natural function of TRIM21 as a cytosolic antibody receptor has been exploited to enable the utilisation of off-the-shelf antibodies to achieve fast degradation of cellular proteins in a technique known as “Trim-away”. This technique has enabled functional studies of proteins that were previously intractable to genetic-based techniques such as RNAi and CRISPR.
My first project was to study the importance of the TRIM21 system in human immunity to viral infection by investigating the impact of naturally occurring missense mutations on TRIM21 function. The outcome of this study showed that human TRIM21 is a highly conserved compared to other immune genes and that the vast majority of coding mutations did not have a detrimental effect1. This finding provided evidence that TRIM21 mediated antiviral immunity is important and conserved in the human population.
My second project focused on the molecular mechanisms by which TRIM21 is regulated and activated upon detection of virus-antibody complex and how the subsequent catalysis occurs2 to activate downstream intracellular immune signalling and effector functions.
What made you decide to pursue research?
I have long had an interest in viruses and how they interacted with their host. It seems bizarre to me how something that is as simple as a virus particle, on the border of life, can wreak havoc in complex multicellular organisms such as ourselves. For example, HIV which persists in its human host using a mere nine genes and fifteen viral proteins but causes catastrophic immune failure if left unchecked. The Cambridge pre-clinical medicine course has equipped me with the necessary theoretical knowledge, and a successful Part II project experience made me decide that I wanted to pursue further research. I really enjoyed the process of formulating research questions, designing and performing the necessary experiments and getting first-hand results.
I did a PhD as part of the Cambridge MB/PhD programme, which enabled me to integrate doctoral research into my medical training. For my PhD, I joined Leo James’ group at the Medical Research Council Laboratory of Molecular Biology (LMB). My reasons for working at the LMB were mainly three-fold. Firstly, Leo had an interesting project that was practical and realistic for a PhD student with a fixed deadline. Secondly, the James lab was very friendly and had a good dynamic when I visited to discuss potential PhD projects. Thirdly, the building only opened in May 2013, which meant nice modern offices and facilities. The other benefits of working in the LMB are the availability of lab support services, access to specialist equipment and core funding which were incredibly helpful and allowed me to work efficiently and focus on my experiment at hand.
What would be your advice to aspiring researchers?
My advice would be to make sure that research is something that you truly enjoy doing before embarking on a lengthy PhD study. Get involved in shorter-term research such as summer project, Part II project or even a master’s project to help you with your decisions. You should also think about the subject area that interests you and try to get some experience in the relevant field if possible. Don’t be afraid to step outside your comfort zone and try something different but bear in mind any time limitations and what you can realistically achieve. You should plan ahead and research available funding options. Lastly, who you work with is just as important as what you do, so make sure that you do some background research and arrange to meet your potential supervisors if at all possible.
Selected Publications
Zeng, J., Slodkowicz, G. & James, L. C. Rare missense variants in the human cytosolic antibody receptor preserve antiviral function. Elife 8, (2019).
Kiss, L. et al. A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases. Nat Commun 10, 4502 (2019).
15 February 2021. Dr Alex Copley is with the Department of Earth Sciences. A PDF version of this Issue is available here.
Research focus: Earthquakes, and the geological evolution of the continents
I study what happens during earthquakes, and what controls their locations and characteristics. This work forms the backbone of a larger enterprise to understand what controls how the Earth’s continents evolve through time, for example during periods of mountain-building.
What made you decide to pursue research?
I was attracted to this topic because the big unsolved questions all revolve around things we can see, touch, and visit (for example mountain ranges, basins, and the
fault-lines that produce earthquakes). I also enjoy the mixture of observational and modeling work that the topic involves, and the chance to work with a wide range of datasets, including my own field observations, global geophysical monitoring networks, and satellite data. The societal relevance to understanding earthquakes, and the controls on the locations of the natural resources that will underpin the transition to green energy, are also strong motivators for me.
One piece of advice…
Keep your knowledge broad, as many breakthroughs happen on the interface between disciplines.
