An interview with Henry Barrow and Ben Butt
Henry Barrow and Ben Butt are both PhD students in the lab of Professor Stephen Graham at the University of Cambridge (UK) and members of the Microbiology Society. In this interview, they explain how their research is helping to treat viruses and antiviral medication.
Where did your interest in microbiology come from?
Henry: It was my lecturers at university that launched my fascination into the inner workings of a cell, and the pathogens which so expertly manipulate them. I was hooked by how something so relatively small and basic could overcome a host’s defences and manipulate cellular machinery for its own benefit.
Ben: Likewise – during my undergraduate degree, I became fascinated with how viruses have evolved to manipulate the 'rules' of cell biology, in order to overcome the limitations placed upon them by their hosts.
Tell us about your research.
Ben: We work on pUL7 and pUL51, a pair of tegument proteins from herpes simplex virus (HSV)-1 that form a complex during infection. The pUL7:pUL51 complex has multiple functions, including promoting membrane wrapping of virus particles during secondary envelopment, and stabilising focal adhesions to maintain the morphology of infected cells. I use biochemical, biophysical and structural techniques to probe the molecular function of the pUL7:pUL51 complex during secondary envelopment.
Henry: My PhD focuses on the role the complex has in manipulating focal adhesions. Focal adhesions are situated at the interface between the cell and extracellular matrix, and are important for maintaining cell shape and adhesion, amongst other things. My research uses primarily virology and cell biology approaches to probe how and why the virus is manipulating these structures.
What is a typical working day for you?
Ben: I use a wide variety of techniques, so my days are varied. You might find me purifying proteins in the cold room, setting up crystallisation trials or collecting X-ray diffraction data remotely. I also do some computational work, so you are equally likely to find me at my desk writing code!
Henry: My days are similarly varied! I could be setting up or passaging cells in tissue culture or infecting them in the virus room. I could be carrying out immunofluorescence microscopy, performing co-immunoprecipitations or preparing samples for mass spectrometry. This is interspersed with meetings and diverse seminars.
How can this research potential have an impact on the production of antiviral medication?
Ben: We are interested in herpesviruses because they are excellent cell biologists. Millions of years of co-evolution with their hosts has provided them with a wide array of techniques, to manipulate and subvert host cell biology. By using viruses as tools, we are able to gain insights into fundamental aspects of cell biology. However, this also illuminates novel aspects of herpesvirus biology that underpin the next generation of vaccines and antiviral drugs. pUL7; for example, has a novel fold, which may make it a promising antiviral target with limited off-target effects.
Henry: Cell–cell spread is particularly important for HSV pathogenesis, as it’s the primary mode of spread and is essential for the establishment of latency. We believe the modulation of focal adhesions by the pUL7:pUL51 complex, plays a key role in this cell–cell spread.
If the complex is important for cell–cell spread and the establishment of latency, then this opens up the possibility of engineering a virus that robustly replicates in epithelial cells, but is not neuroinvasive, and thus cannot establish latency. This could provide a novel avenue for HSV vaccine development.
What qualifications did you obtain before starting your role?
Henry: I obtained an undergraduate Master of Science (MSci) in Biological Sciences from University College London. After a year as a Research Technician, I started my PhD programme; of which the first year was a Master of Research (MRes).
Ben: I studied Natural Sciences at the University of Cambridge, specialising in cancer biology and virology during my final year. As part of my virology studies, I undertook a research project investigating the propensity of a potyvirus polymerase to 'slip' during virus genome replication and transcription before starting my PhD. During the first year of my PhD programme, I was able to carry out three 10-week rotation projects – during the last of these, I worked in my current lab and discovered my interest in protein chemistry and structural biology.
What are the professional challenges that present themselves and how do you try to overcome them?
Ben: Most of my technical experience before my PhD was in cell-based assays, so I found moving into a field heavily based on biochemistry, biophysics and computational biology particularly challenging. However, with support from my excellent supervisor Dr Stephen Graham, I was able to pick up (and enjoy!) these new techniques quickly. I think having good mentors is critically important at all stages of a research career.
Henry: Failure is by its nature very common in research, and so staying motivated through failure can be difficult. I find the best way to get over these downs is to make sure I make time to relax, spend time with friends and family and get out in the fresh air.
Tell us about your biggest professional achievement(s) so far.
Ben: During the first year of my PhD I solved the crystal structure of the HSV-1 pUL7:pUL51 complex, providing some of the first structural insights into secondary envelopment, a poorly understood stage of the herpesvirus life cycle. Of course, this would not have been possible without a huge amount of work from previous members of our lab and the Crump Group, with whom we collaborate closely.
Henry: Being only a matter of months into my PhD; it’s probably being accepted onto my PhD programme.
You are both members of the Microbiology Society – tell us more about your involvement.
Henry: I plan to attend future Annual Conferences and so far, this has been the extent of my engagement with the Society and its members, but I look forward to expanding on this in the future.
Ben: Funding from the Microbiology Society has allowed me to attend a variety of meetings and conferences that I would not otherwise have the means to attend as a student. The Microbiology Society’s Annual Conference also provides an excellent opportunity to gain productive feedback on my work and to network with students at a similar career stage as well as more established researchers.
Why is it important to be a member of an organisation like the Microbiology Society?
Ben: The Microbiology Society and similar organisations provide an incredibly important support network of like-minded researchers. As an early career researcher, this is a vitally important resource for discussion and future collaborations.
Henry: The Microbiology Society is a community of people with diverse academic and research backgrounds interesting in solving a diverse range of questions. The biggest questions in microbiology require us to take a diverse range of approaches and bring together people with different expertise.
Why does microbiology matter?
Henry: Microbes play key roles in many aspects our lives, notably in health and food. Every day we are becoming increasingly aware of this importance as research sheds a light on their role in our ecosystems. We live in the era of the microbe.
Ben: Microbiology remains an incredibly important field. Basic science and translational research in this area has provided humanity with drugs and vaccines against an array of pathogens and continues to make progress against less tractable or novel targets. Emerging viruses such as SARS-CoV-2 will continue to provide challenges in future, but the kinds of research carried out by Microbiology Society members continues to make us more prepared than ever.