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.

The Coronavirus Diaries

Head on over to Nature to read my diaries under Coronavirus Lockdown:

Week 1: Who I am https://www.nature.com/articles/d41586-020-01076-3

Week 2: On being a scientist without a lab https://www.nature.com/articles/d41586-020-01138-6

Week 3: On home schooling https://www.nature.com/articles/d41586-020-01293-w

Week 4: On getting distracted https://www.nature.com/articles/d41586-020-01323-7

Week 5: Things I don't miss https://www.nature.com/articles/d41586-020-01395-5

Week 6: People I do miss https://www.nature.com/articles/d41586-020-01476-5

Week 7: Getting ideas https://www.nature.com/articles/d41586-020-01555-7

Week 8: Getting rejected https://www.nature.com/articles/d41586-020-01624-x

Week 9: Taking a break not a holiday: https://www.nature.com/articles/d41586-020-01696-9

Week 10: Back to the lab again: https://www.nature.com/articles/d41586-020-01782-y

Week 11: Learning from my son: https://www.nature.com/articles/d41586-020-01867-8

Week 12: Unsocial Media: https://www.nature.com/articles/d41586-020-01948-8

Let it grow (Frozen Parody)

The DNA glows orange on the gel tonight

Not a fingerprint to be seen

A kingdom of eukaryotes

And I’m looking for the gene

The centrifuge is howling because it's unbalanced inside

Couldn't get the genes in, heaven knows I've tried

Won't let my genes in, won’t work for me

Be the good clone you always have to be

Anneal, don't heal, won't bloody grow

And they still don’t grow

Let it A, let it G
Can't clone shit anymore
Let it T, let it C
Turn away and slam the incubat-or
I don't care what they're going to say
Let the Taq rage on
The heat never bothered it anyway

It's funny how Magnesium makes every band less small
And the PCR that once controlled me can't get to me at all
It's time to see what I can do
To insert that gene and break on through
No blue, all white, great clones for me
I'm free

Let it A, let it G
I am one with the DNA
Let it T, let it C
You'll never see me cry
Here I stand and here I stay
Let the project rage on

My power flurries through the lab and all around
My science is spiraling from my pipette to my hand
And one thought crystallizes like an icy blast
I'm never going back, the past is in the past

Let it A, let it G
And I’ll pipette like I’m a boss

Let it T, let it C
That perfect gene is cloned
Here I stand in the light of day
Bring the western on,

Molecular biology never bothered me anyway.

How does flu affect poo?

There are lots of motivations to do science – to solve a grand global challenge, to answer a fundamental question about how the world works, because it’s a job and you’ve got to do something before pub opening times. For me, it is about solving puzzles – piecing together a coherent story from a jumble of observations.

In our most recently published paper, we got to do exactly that, and best of all, we got to draw it all on a white board, like in CSI.

Solving science problems, one whiteboard at a time

We started with an observation (from a previously published paper). When mice get viral lung infections, the bacteria in their guts (the gut microbiome) changes. This was quite surprising. So in the follow up we wanted to understand why, but also to understand if the changes in the microbiome affected anything.

But first of all, why we did care at all. As a brief reminder, it is entirely normal to have gut bacteria, in fact various estimates put the number of cells of gut bacteria as higher than the cells of person surrounding them. The gut bacteria do a whole range of important things, from breaking down your food for you to regulating your immune system.

Back to the story. One other thing we did know was that when infected with a virus, mice lose weight. In fact, relative to body size they lose quite a lot of weight, up to 25%, which they can put back on very quickly. This was our starting point and we speculated it could be due to a number of reasons, including the increased effort of breathing. Helen (the student working on the project) made the very simple step of measuring the amount of food eaten. She found that over the course of the infection, the mice stopped eating and it was this that caused the weight loss. When we mimicked this reduction in eating by reducing the amount of food the mice had per day, we saw an identical change in the gut microbiome. So problem one solved.

However, this then led to the next question – why do the mice stop eating? We drew on our previous studies, in which we had showed that the immune response to infection was associated with weight loss after infection. Specifically we were interested in an immune cell called the CD8 T cell and a signalling molecule called Tumour Necrosis Factor (TNF), which the immune system releases to activate other cells. We used antibodies (molecules that are recognise other proteins very specifically) to block CD8 T cells or TNF to see if the immune response was responsible for weight loss. To cut the story short, T cells were important, TNF not so much. It still begs the question, why does the immune system cause weight loss. At this point the simple answer is, we don’t know.

We then switched our attention to the downstream effects. One thing we wanted to see was if the change in the gut bacteria, changed susceptibility to other gut infections. In our hands, they didn’t – when we infected mice with a lung virus, there was no effect on a subsequent gut infection. However, we did observe one difference after infection. There is a complex network of chemicals in your guts, called the metabolome. After infection, these biochemicals in the guts changed. What was intriguing was that some of the chemicals that increased have previously been described as anti-inflammatory. One crazy speculation from this is that by stopping eating the mice actually get better, but we have no proof that this is true and it might just be a correlation.

So what did we learn? When mice are infected with a respiratory virus (in their lungs) their gut microbes change. The gut microbes change because they lose weight. They lose weight because they stop eating. And they stop eating because of something to do with the immune system. So problem solved, sort of.