On mutation and namings

Viruses are unusual; unlike other organisms which always use DNA to pass information between generations, viral genetic material isn’t always DNA. Some viruses use RNA, which human cells mostly use to transmit information from the nucleus to the machinery that makes proteins. These differences in the way in which viruses encode their genes have a profound impact on viral evolution. When human cells make copies of themselves, they use proofreading to ensure that the DNA copies are identical to the original code, this reduces the rate of mutation. However, viruses that use RNA to transmit their genes lack this proof-reading capacity, leading to a much higher mutation rate. Whilst this can be deleterious for an individual offspring virus, for the population as a whole it is extremely effective. This comes down to numbers, higher species only produce limited numbers of offspring, so each one needs to be as good possible. Viruses go for safety in numbers, really big numbers. Each infected cell produces approximately 10,000 new viruses. Therefore, there is a huge stock of different offspring, a small number of which will be fitter than their parents. This high degree of mutation means it can be tricky to apply the Linnaean system to group viruses. We can loosely group viruses on a range of different characteristics or the similarity of their genes, but because they change all the bloody time, they are hard to pin down exactly.

Viruses can be named after the disease they cause: influenza virus is named after influenza and yellow fever virus after yellow fever, this is admittedly confusing, but reflects how the disease was known before the causative agent. Alternatively, viruses are named after the part of the body they infect, in Greek to make it sound more sciencey, hence rhinovirus rather than nose virus (rhino is the Greek word for nose). Finally, viruses have been named the geographical region where they were discovered (Ebola after the Ebola river, Lassa after a village in Nigeria). The geographical naming of viruses stopped due to the stigma attached, which is why SARS-CoV-2 took three months to be named and wasn’t called Wuhan virus. Though a different approach has been used recently of using Greek letters for the SARS-CoV-2 variants of concern.

 Excerpt from Infectious: Pathogens and how we fight them

Signalling failure delays training of antibody in early life

 

This may come as a surprise, but there are other viruses that infect our lungs than COVID! One of them is called Respiratory Syncytial Virus (RSV). This innocuously named virus is THE leading cause of hospitalisation in children during winter months, but somehow doesn’t get the same level of attention as its sexier relatives influenza and SARS. One of my colleagues Prof Peter Openshaw has previously suggested it be called ‘deadly killer virus’ to get it the attention it deserves.

One of the interesting aspects about RSV is that it is possible to get re-infected with the same virus. This is unusual because the assumption is mostly that once the immune system has seen a virus once it is then better trained to deal with it in the future, preventing further infections. However, some viruses such as RSV (and also coronaviruses, like the one that causes COVID) can reinfect. We don’t fully understand why this is the case, but one contributing factor is a protein in the blood called antibody. Antibodies are highly specific molecules made by the immune system that can bind and kill viruses.

Antibody molecules are produced by a white blood cell called the B cell, but in order to produce the best possible antibody, B cells need help from another type of cell called the T cell. The conversation between T and B cells happens in the lymph nodes – which is why you get swollen glands after infection or immunisation. In our recent work, ‘Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity‘ recently published in the Journal of Experimental Medicine we explored this interaction. Specifically, we asked the question are there differences between the T-B cell crosstalk in early life – the time of greatest susceptibility to RSV.

We found that baby mice infected with RSV produce less antibody than adult mice infected with the same dose. This lack of antibody left the mice susceptible to re-infection with the virus. Side by side with the reduction of antibody, there were fewer of the helpful T cells needed to train the B cells. If we specifically removed those helpful T cells (called T follicular helper cells or Tfh) from adult mice before RSV infection, we saw a very similar effect – re-infection.

We dug deeper as to why these handy Tfh cells are not so active in early life. We identified a role for a molecule that cells use to talk to each other called interleukin two (the sequel to the commercially more successful, but less interesting interleukin one). There is more of this molecule sloshing around in early life and it may play a role in training the early immune system what is good and what is bad.

Overall, out findings may help us to develop better vaccines that work from the moment babies are born and stop them catching viruses such as RSV.

The COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape

 We tried to capture the state of play of coronavirus vaccines, it was extremely mercurial - so much data is coming out all the time. But if you want a snapshot it is here https://rdcu.be/ctIwh

In summary - all good, as long as the doses are given to people we will be ok!

Coronavirus diaries: the COVID 19

One of the reasons (pandemic asides) that I have been quiet on here is that in 2020-21 I was writing a recurring column for Nature Careers called the Coronavirus Diaries.

You can access them here

INFECTIOUS

 My book: INFECTIOUS: PATHOGENS AND HOW WE FIGHT THEM is Out on 14th October!

Pre-order at Waterstones or Amazon

Double Trouble: IFI44 and IFI44L

An important component of host defence against viral infection is cell intrinsic immunity. This type of immunity is mediated at a cellular level rather than requiring recruitment of other cells to restrict the infection. It is characterised by the induction of an anti-viral state, which limits the ability of viruses to enter cells, make copies of themselves within the cell or exit the cell having replicated. The induction of this anti-viral state is triggered by a signalling molecule called interferon. Interferon signalling leads to the expression of a multitude of interferon stimulated genes (ISG). Many of these ISG are uncharacterised in terms of function.

Technological developments over the last twenty years have changed the way that we investigate how cells work. In particular, the use of transcriptomics, where the messenger RNA (mRNA) in a sample is measured. mRNA is important because it is the intermediary between the cell nucleus, where the genetic information is stored and the ribosome, where proteins are made. Transcriptomics gives an overview of what the cell is doing. However, transcriptomics is a broad-brush tool that does not necessarily give the fine detail of what individual genes do in the prevention of infection.

Over the last few years we have undertaken a program of work to understand the role of individual ISG in the control of viral infection. In particular we are interested in respiratory syncytial virus (RSV). RSV infects the lungs of children – all children will be infected with it before the age of 2 years old, most before 6 months of age. Some of these children will get extremely sick with RSV infection and we hypothesized that this is because they fail to control the virus early on during infection. However, prioritising which ISG to investigate was an issue, especially given the large amount of data available. We therefore used a screening process to identify those genes which are more commonly associated with RSV infection (https://doi.org/10.1128/mSystems.00051-16).

This screening process led us to work on a pair of genes called Interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L) which we published in the Journal of Virology (https://jvi.asm.org/content/early/2020/06/26/JVI.00297-20). We confirmed that the genes were induced following RSV infection and then set about exploring whether they played a role in the control of infection. The first question was what would happen in the absence of either gene. Using two different gene-knockout approaches, CRISPR-cas and siRNA, we showed that when you reduce expression of either gene, the virus replicated better. We then did the opposite experiment, increasing the amount of both genes in the cells, this led to decreased viral replication. These initial findings were supported by studies in mice and children. Mice lacking the IFI44 gene were more susceptible to RSV infection and children with lower expression levels of the gene, as determined using transcriptomics on their blood, were more likely to have a more severe infection – though this was a weak association.

The question remains as to how IFI44 and IFI44L prevent viral infection. One of our observations was that altering the levels of the two genes altered the ability of cells themselves to replicate. When there was more IFI44, the cells replicated more slowly, when it was removed they replicated faster. We think that this gives us a clue as to their function – somehow they limit resources that both the cells and the virus need to make more copies of themselves. We are now looking to understand exactly how this happens. What is fascinating is that there are so many different genes involved in the prevention of viral infection and an important question is how do they interact to protect us.

It takes a Village

First published in Times Higher Education

The greater prominence enjoyed by scientists during the Covid-19 pandemic has led to some individuals gaining a high profile – with the attendant praise and demonisation that this can bring. But these public figures are just the visible tip of a huge iceberg of effort taking place to combat the pandemic.

To convert one bright idea into 7.5 billion doses of vaccine will take a huge team of people. This includes not just the lab team developing and test the vaccine, but also the animal care staff enabling the pre-clinical studies, the safety staff maintaining a safe environment to work with a potentially fatal pathogen, the lab managers ensuring that essential reagents are available, the administrators preparing the relevant grant applications, the ethics boards reviewing the trials and the trial managers, doctors, nurses, med-students and volunteers. Not to mention the contracts team negotiating with equipment manufacturers, the accountants moving the money around, the security officers keeping the doors open and the communications experts informing the public of progress.

That is just at one institution. And the work is not performed in isolation: there are external funders, suppliers, manufacturers, regulators, toxicologists, shippers, couriers and warehouse staff, all of whom are vital to the process.

Unlike the standard image of an old white academic, staff in professional roles tend to be more diverse with more women, more BAME and more LGBT. But, in the UK, they will be excluded by the government’s proposed post-EU new immigration rules. This would be deeply counter-productive: if the pool of skilled individuals is reduced, there will be a clear impact on the ability to deliver cutting edge research, particularly in a time of crisis.

Highlighting the role of these critical core staff is vital. They are often under-represented in the media. For example, coverage of the recent UK pension strikes focused on the academics taking part, rather than on all the other higher education staff who shared the picket lines with them.

As well as not accurately reflecting science as a collective endeavour, a focus on individuals can, in fact, be toxic. Much of what is wrong with academia is driven by the narrative that it is a zero-sum game, where only one person can come out on top. This leads to the back-stabbing, bullying and bitchiness that characterises the very worst of our sector.

Now as never before, kindness in the workplace is critical. Developing the vaccine that the world so desperately needs can serve as a demonstration that great things can be done collaboratively rather than competitively, belying the inaccurate depiction of it in some places as a race between different universities. In the UK’s case, the race is supposedly between the University of Oxford and Imperial College London – but the fact that some of the ChAdOx (Oxford vaccine) trials are being performed at Imperial tells a very different story.

Thinking ahead, maybe we can use this time as a trigger to rethink the whole of academia. The first step is acknowledging that it is about more than the academics. It’s been said before, but when you look at the numbers, academia is actually the alternative career for science trainees: most enter other sectors – including academic support roles. All these paths should be supported and celebrated equally.

If none of the above persuades you, then consider this. Representing the team nature of science de-risks the process for the individuals, the institutions and the ideas themselves. People sometimes make mistakes, often unrelated to the science itself, but this can tarnish the idea. In an increasingly combative media space, any perceived fault can be manipulated to damage a broader theme. Demonstrating that science is collective removes one tool from the arsenal of those that seek to discredit ideas that have universal benefit, such as vaccination or combatting climate change.

The Wellcome Trust’s Reimagine Research campaign is currently looking into ways to rebalance the research space. But you don’t need to be a funder to make a difference. We can all play our part to make higher education kinder and more inclusive. Take time to say thanks. Reach out to teams outside your immediate remit. Be public in your praise, raising awareness of the whole team, not just the star signing. Applaud the whole community of effort.

Let me start and make an Oscars style acknowledgement of some of the amazing team at Imperial (and sorry if I missed you) – thank you Kasia, Kat, Kai, K, Krunal, Kostas, Catherine, Tessa, Anna, Hannah, Hadi, Michelle, Glenda, Genevieve, Paul, Paul, Carolyn, Ruth, Jennifer, Tom, Lesley, Sharron, Jesses, Leon, Aaron and Jo –I know that most people reading this will not know who they are, but without them we might never get back to work.