Just hanging about

Presumably the question you are asking yourself is what determines persistence in acute RNA viruses? If not, why not?

Viruses have been shown to persist – stay present in the body, potentially after the symptoms of infection have passed. Most of the evidence and mechanism for viral persistence has been collected for DNA viruses and retroviruses (that is RNA viruses that convert their RNA genome into DNA and insert it into the host). However, there is clear evidence that non-retroviral RNA viruses can persist (see the review here). We normally think of these acute RNA viral infections as being short lived, cleared by the host and only succeeding if they can transmit to a new individual. However, this strategy has limitations, particularly if there are no new individuals who haven’t been infected by the virus. Therefore, viruses need to have evolved a way to maintain a reservoir, this is particularly important when we consider that viruses are obligate parasites – they have to use host cells to replicate and survive. It is particularly interesting to think that the viruses can persist in spite of selective pressure from the host immune response which is trying to clear the virus.

The question we set out to answer in a recently published study, led by Prof Rick Randall and Prof Steve Goodbourn, was how RNA viruses can switch between an acute and persistent state. The work focused on parainfluenza virus (PIV), which is a member of the paramyxovirus family. Viruses require specific proteins to make copies of their genetic information, which is described as the polymerase complex. The imaginatively named P protein of parainfluenza virus is a core part of the viral polymerase. If the P protein was phosphorylated (a mechanism by which cells can control protein activity), then the virus no longer replicated in the cells, but and this is important, the viral RNA was maintained within the cell. We then demonstrated that the phosphorylation status of the P protein and was determined by a single amino acid within the protein, if this changed then the protein could be activated or de-activated. Since amino acids are determined by the genetic code of the virus, specifically by 3 nucleotides, a single nucleotide change can alter the amino acid sequence, in turn affecting the phosphorylation of the protein and whether it is active or not. So in essence there is a switch that can control whether the virus makes copies of itself within the cell, given that RNA viruses have leaky polymerases (they make inaccurate copies of their own genes), this flip between active and inactive states can occur readily during the infection/ replication cycle. The switch may be driven by immune pressures, we demonstrated that lytic viral variants replicated to higher levels in a mouse model but were cleared much faster, whereas the persistent variant led to a prolonged infection. We proposed that the virus may start in an active state producing lots of copies of itself, before switching to a persistent state to develop a reservoir.

This was in essence a piece of basic research addressing a fundamental question in virology, but it does have broader impact, understanding why and how RNA viruses persist has implications for infection epidemiology as well as potential for developing novel vaccine platforms.

Breathe it in

Influenza is a serious cause of death and disease, contributing to the winter healthcare burden. One approach to reduce this is vaccination. In addition to the injectable influenza vaccine, which is given as an intramuscular injection there is an intranasal vaccine. This vaccine is also referred to by its initials LAIV – live attenuated influenza vaccine. The vaccine is a live vaccine, that has been adapted to reduce its pathogenicity. Specifically, the vaccine virus was adapted so that it can only replicate at lower temperatures. This is important because there is a temperature differential across the airways: the nose, because it is drawing in cold air is cooler than the lungs. The nose is at approximately 30°C, compared to the lungs which are at 37°C. This means that viruses that can replicate at 30°C are restricted to the upper airways and therefore cannot cause severe disease. The vaccine virus is then administered by a nasal spray syringe, once it gets into the nose, it replicates and this replication is important in the induction of an immune response.

However, one of the problems with influenza is that the virus changes season on season, sometimes in small steps (antigen drift) but sometimes in much bigger jumps (antigen shift). This changing of the viral strain necessitates new vaccines each influenza season. Most of the variation comes through the surface antigens, haemagglutinin and neuraminidase, which are the H and N of influenza virus nomenclature. Luckily the same temperature sensitive attenuated vaccine virus strain can be used as a backbone into which different H and N genes can be substituted. However, to achieve greater coverage three or four (depending on manufacturer) different virus strains in the vaccine, normally two A strains (H1N1 and H3N2) and two B strains.

In the UK, LAIV has been recommend for all primary school age children (up to 11), and some other high risk groups. This decision is based in part on the herd protection that this vaccine could potentially have, protecting the elder generation by reducing the infectious reservoir. However, in recent years there have been some concerns with the efficacy of the LAIV – particularly in the USA where efficacy dropped from 85% before 2009 to 17% in 2013-14 which led to a reversal of the American  Advisory Committee on Immunization Practices to recommend suspension of LAIV between 2016 and 2018. We wanted to understand factors that affected the immunogenicity of this vaccine.

In a previous study, we had described how nasal antibodies, specifically of the IgA type were associated with reduced viral shedding after influenza infection (https://www.frontiersin.org/articles/10.3389/fmicb.2017.00900/full). So  now we wanted to look into the effect of immunisation of children with LAIV on IgA. In our recently published study (https://onlinelibrary.wiley.com/doi/full/10.1111/cei.13395) we saw that three out of the four strains in the vaccine were able to induce a significant increase in IgA. Interestingly the only strain not to induce an increase in IgA – H1N1 – was the one for which concerns have been raised for protective efficacy. Though it was not clear in this study why the H1 strain might behave differently.

In a separate study (https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(19)30086-4/fulltext) in collaboration with Dr Thushan da Silva in Sheffield, we looked into potential reasons for the differences. By happy coincidence, Thushan ran clinical trials with LAIV over 2 seasons and the H1 vaccine strain was changed between the years from A/17/California/2009/38 (Cal09) to A/17/New York/15/5364 (NY15). This gave us an opportunity to understand a bit more about how vaccine strain changes can affect immunogenicity. Strikingly the change in vaccine led to a significant increase in vaccine response and this was linked to how good the vaccine was at replicating – the newer strain (NY15) replicated better both in vivo and in vitro and this was associated with stronger immune responses.

Based on these studies, we want to look at how vaccine replication is associated with immunogenicity and what viral factors enable enough replication to work as a vaccine without causing infection themselves.

Postscript
Interestingly the uptake rate for the free LAIV vaccination in schools in the UK is only 30% (as at 16/12/19). This vaccine has been opt-in rather than opt out. One question is if it was made the default and then people had to opt-out would uptake be higher?

Protective protozoa

Flu, caused by the influenza virus is unpleasant. Even in non-pandemic years, it causes 290,000 to 650,000 deaths. In the absence of a ‘universal’ vaccine that could provide protection against all possible variants of the virus, new vaccines need to be selected and manufactured each year. The majority of these vaccines are manufactured using eggs. Influenza virus is grown in chicken embryos inside the eggs which are then cracked open prior to purify and inactivate the virus for vaccine use.

There are a number of limitations to this approach. Firstly, it is complex to scale up, for example during a pandemic. It can also induce a selective pressure upon the vaccine virus – chicken cell and human cells have slightly different receptors for influenza on their cell surface and co-factors within the cell. This means that in order to replicate efficiently in egg cells the virus may undergo some slight changes. If these changes are in regions of viral proteins recognised by the immune system,  for example haemagglutinin, then the vaccine virus might induce a memory immune response which does not recognise the virus that is actually circulating in the wild. The final problem is that some viruses, in particular the highly pathogenic ones (H5N1 and H7N9) are deadly to birds and kill the chicken embryos before enough virus is made for the vaccine.

Therefore alternative manufacturing approaches are required. One tool that has been widely applied across all fields of biological drug manufacture is the use of recombinant cell culture – where genes from one organism are expressed in cells of another. There is a licensed influenza vaccine (Flucelvax) which is manufactured using the MDCK cell line. These cells were originally isolated in the 1950s from a dog kidney, specifically a cocker spaniel, by S.H. Madin and N.B. Darby – hence Madin-Darby Canine Kidney (MDCK) cells. Growing cells from mammals has advantages compared to embryonated chickens, but there is value in developing alternative methods.

We investigated an alternative manufacturing approach in our recently published study Recombinant Haemagglutinin Derived From the Ciliated Protozoan Tetrahymena thermophila Is Protective Against Influenza Infection in Frontiers in Immunology. Working with a biotech company based in Germany (Cilian, AG) who use a protozon ciliate called Tetrahymena thermophila for the manufacture of biologics. This system has a number of potential advantages, it uses conventional manufacturing equipment, the same as that used for both bacterial and yeast based manufacturing systems.

However, it was possible that viral proteins manufactured using a protozoan might not induce a good vaccine response. We therefore set out to test the immunogenicity of the ciliate derived material. We demonstrated that immunisation with recombinant haemagglutinin could protect against an infection with a matched influenza virus. We saw this with haemagglutinin derived from either influenza A or influenza B viruses.

This proof of principle study therefore opens that path for further development of the Tetrahymena thermophila platform for vaccines. The major next step will be to work the platform up to a good manufacturing practice (GMP) grade material so it can be tested in clinical trials.

First cut is the deepest

Grant rejection didn’t improve my scientific output, but it did improve my scientific career.

I had a reasonably frictionless track from undergraduate to PI, which I attribute to personal brilliance and dashing good looks, but was more likely a combination of hard work, luck and privilege. I had had some rejections along the route but nothing that felt derailing. There were rejected papers, but by and large rejected papers always find a home, maybe not as prestigious as I’d hoped, but a home nonetheless. I had also put out a few speculative job applications for posts that I was dramatically underqualified for, and was rightly turned down. But essentially, I got to lecturer without any big career rejections.
But rather than being a #humblebrag, I am trying to set the scene for what came next. As a freshly minted PI, flush with my own self-confidence, I submitted a research grant to a popular medicine-based science council. It came back with what I thought were reasonable scores and so I answered the reviewers’ comments, resubmitted and went to a conference in Thailand (again an important detail not just showing off).
On day 2 of the conference, I made the terrible mistake of opening my inbox. ‘We regret to inform you…’. Cue full on meltdown. To quote Nick Hornby, ‘I lost the plot for a while, then the subplot, the script, the soundtrack, the intermission, my popcorn, the credits and the exit sign’. I attribute this to several factors. I was away from my support network, 8 hours out of sync and it was pre-Skype so I couldn’t talk to them anyway. Secondly, it was the first big thing I had applied for that I hadn’t got. And finally, being new, inexperienced and somewhat melodramatic, I completely over-estimated the importance of any single piece of research funding on my academic career. There were a number of sleepless nights contemplating my ruined career and how I would never get over it.
I did get over it.
And whilst I wouldn’t go as far as describing it as a blessing in disguise, grant rejections (and time) have changed how I do my job. Rejection has had a humanising effect, having been ‘there’, I know what it feels like to undergo grant rejection and can sympathise better with other people undergoing the same experience. Having had (many) grant rejections and still being employed makes each individual rejection feel less make or break. I now have a longer perspective to see that some of my ideas are just plain bad and don’t deserve to be funded (obviously none of the ones currently under consideration), some ideas went to the wrong place and have now found a home, and some ideas are worth fighting for so that they get done, one way or another.
My first failed grant laid the foundation for how I now cope with future rejections and I am now failing better. There is a mourning period, which may sound like a strong term, but I think appropriate – if you don’t care enough about a grant, you are never going to submit it in the first place. After the mourning period, which I have managed to contract to 24 hours, I try to step back and take on the reviewers’ feedback as constructive. This is a challenge, but I have made progress since writing profanities about each reviewer’s parentage on the grant and then accidentally leaving this tirade on my desk for my students to see.
However good I get at failing, getting my grants rejected is still tricky – but never as traumatic as that first time.

(This first appeared in Times Higher Education)

20 Years at Imperial: what have I learnt?

On 1 October 1999, I walked out of South Kensington tube station in London, fresh-faced and ready to start my PhD. 20 years later as I walk out of the same tube station to the same campus of the same university (still fresh-faced I like to think), the question is, have I learnt anything? 

Spoiler alert – the answer is yes, but a guarded yes, from a staggeringly low starting point, like Marianas Trench low. Some of what I have learned is fairly niche and only useful if you work in a biomedical lab – like how to open a tightly screwed plastic tube with one hand whilst avoiding infecting yourself with influenza, some are a bit more generally applicable to having a career in science, especially if you are or want to run your own research group, and some grandiosely I think might be applicable to everyone.  

1.       School’s out. Working in a university, this may be a bit unnecessary to point out, but education never ends: we are continually learning and evolving. Even if you were able to recall all the facts from school into adulthood it is likely that they are now either outdated or completely irrelevant to the work you do. We need to retrain: to become parents, to become managers, to change roles, to retire gracefully. And for these new roles, there is no pass/fail test to say how well you have done, it is all a bit woolly. So we need effective strategies to learn for life: both for ourselves and for the others – students, children, co-workers – that we might need to train.  

2.       The skills to pay the bills. The skills you need for your PhD are not enough for the rest of your career. Being good in the lab or field or computer terminal is important, but at some point, you need more. You need social intelligence too (sometimes called soft skills): being able to work with other people. A lot of the PhD might focus on generating scientific results but given that most PhD students leave academia (estimates are between 95 and 98%) it is important to develop your whole self. 

3.       The Future’s so Bright I gotta wear shades. As Professor Martyn Kingsbury (Head of Imperial Education Development Unit) puts it so eloquently: your PhD is when you move from being a consumer of knowledge, learning what other people have done, to a provider of knowledge, producing data that other people will have to learn. My first experience of this was during my BSc project: I was looking at my squashed flies and feeling a bit uncertain about what the point of it all was when my supervisor came into the microscope room and said: “you see that, the thing you have just done – you are right now the only person in the world who knows that”. And that is what science is about, that flash of discovery, that satisfaction when the pieces of the puzzle fit together, the glow that however briefly you are the only person in the world who knows something. Doing a PhD had some of these moments and now as a lab head, I try to guide others to have them too. 

4.       Race for the Prize. The standard metaphor is that a PhD is a marathon not a sprint. But this draws on the wrong sport. A PhD is much more like a football season. It’s about consistency over a longer period, not constantly winning – you can even lose occasionally and still do well. The football analogy can be stretched a bit further over the length of a career, with each year a chance to reset and start fresh. One of the advantages of being in science for a longer time is that you get to see projects through to fruition. The ideas that you have which were initially rejected can be polished up, resubmitted and eventually find a home. 

5.       We’re going to be friends. I consider myself incredibly fortunate to work at Imperial, this is fundamentally driven by the people. I have met and worked with brilliant, kind, funny, supportive scientists, without whom this job would not be half as good. This connection began during my PhD and my fellow students now form the nucleus of a collaborative and supportive network that spans from Brisbane to Cardiff. Nurture your friendships. 

6.       Don’t Leave. No one ever really leaves Imperial. I did briefly try. For three years between 2008 and 2011, I worked at St George’s in South London. Luckily, I ignored the churlish temptation to say something along the lines of “screw you guys, I’m leaving”, as three years later I was back again – albeit one floor up from where I had been before. The science community in London is quite small, everyone knows everyone. This can be great because the network you build can help you out in all sorts of unforeseen ways. But it does necessitate some care, the person who you complain about one day, may end up being your office buddy the next.  

7.       London calling. I spend a lot of time dashing between St Mary’s Campus in Paddington and the mothership at South Kensington for some or other meeting. But this isn’t as onerous as it sounds, as I get to walk through Hyde Park and see the changing of the seasons. Which is just a fragment of the amazing things just on our doorstep. A lot of which is very easy to miss in the daily grind. But make time, go for lunch in the remarkable Art Deco café at the V&A, and if that is too far – go to the physics building for a cup of tea for fantastic views across Hyde park and beyond. 

8.       9 to 5. One of the best things about doing science is also the worst. Science is open-ended, fascinating and mostly you get to set the direction of what you are exploring so build on your interests. But this can mean that you can end up thinking about work all of the time, with no defined beginning or end of the day. Which is fine when things are going well. But when the inevitable setbacks pile up, there can be little respite. It can often feel like the best approach is to just do more work. At times like these, stepping away from the bench, taking some time out, for example by going for a run in one of London’s parks can help. 

9.       Life happens. In the process of doing my PhD, I met my future wife. While doing my postdoc, we married. When I started my group, I also started my family. And just recently there has been my first lab marriage (not actually in the lab, though I did offer to give the bride away). If you are too busy focussing on the job, you will miss these moments. 

10.   When I grow up. It is very easy to look at other people further down the track than yourself and assume they had life mapped out from the outset. This isn’t helped by the endless social media bombardment of success, which luckily didn’t exist when I was starting. Looking back, my career looks fairly linear, but at no point during my PhD did I think I would want to run a research group at the same university. I wrote up and then applied for a whole range of different jobs. In the end I took a postdoc position, mostly on the rationale that I had trained in science for three years, so I ought to see what it was like as a job. Even then I didn’t look much further forwards. I certainly didn’t have a single topic of research I wanted to work on. There is no harm in having a vague plan but being open to opportunities is vital. 

So in summary, have fun. Take time out, make friends, work to live rather than live to work. This way you will get the most out of your PhD and beyond. 

Post Script 

I was asked whether anything at Imperial has changed. Beyond my being older, the biggest change has been the space. The buildings have had a massive overhaul in the last 20 years, going from quite tired to shiny and new. I miss the old Holland Club and Southside bars, but I think that is more nostalgia for a time when I could pop out for a drink (or two) after work without having to race home to collect the children.  

My ability to predict the future is extremely low, things never quite work out as I imagine them. I honestly do not know what the next 20 (or even 5) years hold. A blend of opportunities, successes, disappointments, tantrums, scientific breakthroughs and scientific dead-ends no doubt, backdropped by a cast of wonderful colleagues and students. 

PS - can you name the 10 artists that sang the 10 lessons?

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How to win a research grant: Hone your sales pitch

I tend to think of my lab as a small business, with me as the entrepreneur at the helm – although I am probably closer to Del Boy Trotter than to Mark Zuckerberg.

This is just one of the many tortuous analogies I use to make sense of an academic career (because, let’s face it, academia doesn’t make much sense). Grants are the sales pitch that shore up the lab’s cashflow, and while I am not advocating passing off Peckham’s tap water as spring water, even genuine spring water won’t sell unless you market it properly.

As such, your grant applications have to target the customer. What complicates matters is that there are at least two different customers, with different requirements. Your sales pitch needs to be detailed enough to convince peer reviewers that you know what you are doing, but it also needs to be exciting enough to convince the panel to select your application ahead of other, equally scientifically valid, proposals. Here the lay summary is key. Sure, it is mislabelled: no lay person is ever going to read it. But it is your chance to sell the project to the panel.

Within a small business model, you also need to consider the cost of application. Our most precious commodity is our time. The endless hours absorbed by grant writing could be spent teaching, researching, writing papers or even having a life outside work!

The decision regarding whether to bear that opportunity cost should be taken in light of consideration of the chance of success versus the return if funded. Small grants with long application forms and a low hit rate should be ignored, no matter how desperate you get. I keep a tally of grants I have applied for, recording the grant value and the time invested. This has helped me to concentrate my efforts.

The sales pitch mentality stretches to how I review grants. I want to know what I am buying. First and foremost, I want to see a hypothesis. Not buried on page seven after the justification of resources, but on page one, line one, in bold. I then want my pulse quickened with a unique selling point. Why does the work need to be done? If it is a fundamental question, why does it need answering? If it is translational, how will answering it make the world a better place?

If that isn’t clear, no amount of technical competence will save you. So get out there and get selling!

This was first published in the Times Higher Education

#FailTales: Beyond resilience

A career in research is riddled with failure. The fact that there is a blog series about academia entitled #failtales suggests that failure in research is common. If the idea of failure being part of academia comes as a surprise to you, you are either too early on in your career to have been beaten down by it – in which case my condolences - or you are so hyper-successful that it has never impinged upon your exponential upward trajectory – in which case we are now mortal enemies.

First things first; it is OK to fail. Science isn’t easy. Science careers are not easy. We therefore need ways of dealing with failure.

Black Swan

I’ve recently been reading Antifragile, a book by Nicholas Taleb who is a self-styled errant business philosopher. His other book, The Black Swan, is about the surprising frequency of rare, extreme events and the disproportionate impact they have: the book takes its title from the fact that black swans exist, even if you have never seen one, i.e. absence of evidence is not the same as evidence of absence.

Antifragile

Antifragile takes this idea further, exploring how to deal with these random events. The book is not an easy read, but the underpinning message is revolutionary. In between the weird analogies about Fat Tony, a prominent character of the book who embodies the anti-intellectual trader who understands risk without theories, and references to obscure Greek Philosophers, Taleb makes a case for changing our approach to extreme events.

The author splits the world into 3 categories: fragile, resilient and antifragile. Fragile systems respond very poorly to extreme events, and according to Taleb this includes high finance and research that is directed with a particular result in mind. Resilient (or robust) systems, including opportunistic research and privately owned businesses, can cope with such extreme events and recover after they have occurred. Antifragile systems actually benefit from these same extreme events. His examples of antifragile systems include the net economic value of Silicon Valley tech start-ups and the net democratic value of feudal city states, both of which are characterised by agility in the face of changing conditions because of their relatively small size. They also benefit from having a large number of starting options upon which selection can choose the fittest. Interestingly a recent study in Nature suggested that scientific disruption is driven by small rather than large teams (https://www.nature.com/articles/s41586-019-0941-9)

So how does antifragile link back to scientific careers?

Failure is the linchpin of success.

Without some ideas failing, no ideas are going to succeed. This is very much in line with what Jon Tennant says in his article about the scientific record. Without better knowledge of what went before, we as a community are doomed to repeat ourselves.

A nuance of this is that failure is required to optimise an experiment: nothing works first-time. One of my more useful contributions to science literature was a technical note about in vivo imaging; a technically challenging process that is published in static beautiful images in a way that says, “this is easy, everyone can do this.” In actual fact, it turns out that there are a number of ways to mess it up. We managed to do all of them; fluorescent mouse turds, reflective ink in the pens we used, mice that were scientifically speaking too hairy, not enough anaesthetic, and so on. It would have been really helpful if someone had made this clear earlier. Only through failing were we able to get the studies to work and publish our own beautiful images, though it seems a shame that we failed to mention the pain we had been through to get them.

There is of course a separate conversation about failing fast, when it is right to drop a project if it isn’t working, and how information about the failed project can then be shared. Alternative publishing models and partial paper repositories where things can be put together from a group of studies are appealing, but they aren’t fully viable yet.

Back to the failure.

The aim of antifragility is to go one step further and make setbacks beneficial. It is easier to see how this works at a systems level. My failure and its publication helps other people. Likewise, in the context of grants, there have to be winners and losers – competition is important. If the system is working properly, only the strongest ideas survive and thus the field moves on. While that is great for research as a whole, what about me and my career?

At an individual level, how do you become antifragile? The aim is to make every situation a win-win. Taleb describes a barbell – a bimodal distribution of risk, basically reducing the cost of failure. He says “If I have ‘nothing to lose’ then it is all gain and I am antifragile.” For example, if you are going to invest in a project, reduce the emotional cost and make sure the return is high. Likewise, for antifragility in terms of experimental design, plan your investigations so that the outcomes are always interesting, rather than tightly focused on a hoped-for outcome.

We all fail. Grants are rejected. Papers bounce. Experiments explode. It is clear that we want to avoid the extremely negative impacts of failure. Part of this is moving away from fragility: not having our happiness and mental well-being pinned to a single outcome outside of our control. This means we need to move up the spectrum towards resilience. To achieve this, we can do a number of things: have a growth mindset, don’t take things personally, and build a good network of support for a start. Moving beyond resilience, antifragility can be built into your career. Place yourself so that regardless of external events, you succeed (or at least fail less). This involves not tying yourself to one single idea, too narrow a research field, a single funder: instead, hedge your bets strategically so that if one area goes down, others may be coming up. This is not easy, but at least thinking about it may protect us the next time failure calls.

This first appeared on Digital Science

Nature wants you dead – here’s how vaccines work to help keep us all alive

Nature wants you dead. Not just you, but your children and unborn children and everyone you have ever met.

It wants you to cough and sneeze and poop yourself into an early grave. If it can, it wants you your blood vessels to burst and pustules to explode all over your body. Put simply, Nature is trying to kill you.

And until relatively recently, it was really good at doing this. The average life expectancy of a human in 1900 was 31 years. I should already be dead.

But then science intervened with two critical innovations, clean water and vaccines, and changed everything. Clean water has had the biggest impact, but vaccines are a close second.

Vaccines work by tricking your immune system into thinking it has seen a bug before, so that if you ever see the real thing, it can kill it before it kills you. They are the coolest thing humanity has ever done, that and Magnum ice creams – choc ice on a stick, genius!

Vaccination’s greatest hits

In 1967, there were 10-15 million cases of smallpox a year – this is the equivalent every single person in London. The image above shows two 13-year-old boys in the early 1900s – the one on the right was vaccinated against smallpox, the one on the left wasn’t. The results couldn’t be clearer.

Since 1979, no one has died of smallpox, or even been infected with it. Putting that into context, in the same time 40 year period, more people have been killed by lava lamp explosions, allergic reaction after intercourse with a dog, suffocation after being wedgied, sacrificial goats and whipped cream cans.

Yes, the eradication of smallpox is the biggest success, but the hits just keep coming.

Pretty much everyone wears seatbelts because they save lives. Since 1988, they have saved about 450,000 lives in the USA alone. Vaccines do the same, in the same time period the number of cases of wild poliovirus reduced from an estimated 350,000 cases to 33 reported cases.

But it’s not just polio and smallpox. In 1940, there were more than 60,000 cases and 3,283 deaths from diphtheria in the UK. By 2002, vaccination had almost eliminated it – there were just 2 deaths from diphtheria between 1986 and 2002. Meningitis C has been virtually eradicated, as has invasive pneumococcal disease, Haemophilus influenzae B and rotavirus. And a very recent study showed a 90% reduction in cervical cancer since the introduction of the HPV vaccine – that’s 10 times fewer people getting this type of cancer.

Biological seatbelts

But vaccines only work if you take them. Which is kind of obvious. But the problem is that, as I have just established, vaccines reduce illness, dramatically. This means that the likelihood of people knowing someone who has had a vaccine-preventable illness is very low, which can then reduce the incentive to vaccinate. This is understandable, but wrong and it is particularly wrong because vaccines are a public health measure. By getting yourself or your family vaccinated you are doing a civic duty and protecting others. Because vaccines reduce the transmission of infections – the likelihood that an infected person will infect someone new, they reduce the overall numbers of infections. If you want to see what happens when people stop getting vaccinated, look no further than the reappearance of measles.

Changing the world

So far, so good. But we at Imperial College London want to go further. We want to make new vaccines against diseases that haven’t even emerged yet, preparing for ‘Disease X’ – an unknown pathogen which may cause disease and potentially an epidemic in future. We want to make micro-manufacturing units that can be put in a shipping container and moved to pandemic hotspots. We want to stop HIV and kick Influenza to the curb.

We are working to stabilise vaccines so they don’t go off in the sun and to scale manufacturing processes to make vaccines for all. We want to know when is the best time to vaccinate pregnant mothers to protect their children and the best time to vaccinate children to protect their grandparents. We work across borders with partners around the world to achieve these goals. And I get to work with these brilliant people, doing brilliant things on the coolest thing that mankind has ever done, sometimes whilst eating a Magnum. Happy days.

Natural antivirals

Before the immune system is activated, cells have their own intrinsic defence against viral infection. This comes in the form of proteins that can inhibit various stages of the viral life cycle. Some of these proteins are constitutively expressed and others are inducible – activated by signals from other infected cells as part of the early response to infection. Many of the proteins that provide this cell intrinsic immunity are expressed in response to signalling by a family of cytokines called interferons, in particular interferons alpha, beta and lambda. These antiviral genes are collectively known as interferon stimulated genes (ISGs). There are a large number of these genes (upwards of 300), but knowledge of what viruses they restrict and how they do it is limited, many genes have unknown functions.

In our recently published study we investigated the role of a specific ISG called IFITM1 (short for interferon induced transmembrane protein 1). IFITM1 is one of 3 IFITM proteins expressed by human cells and they appear to have a role in restricting early events in viral ifnection. We followed up previously published work, investigating where in the cell the protein was expressed and showed that unlike the better characterised IFITM3, IFITM1 was found on the plasma membrane, suggesting it prevents direct viral entry. We demonstrated that for a wide range of RNA viruses that infect the respiratory tract, including Respiratory Syncytial Virus, Influenza and Measles, increasing the level of IFITM1 in the cell reduced the level of viral infection. Interestingly we showed that IFITM1 was able to prevent infection with a virus with a DNA genome (Herpes Simplex Virus), suggesting IFITM1 function was associated with its cellular location rather than an effect on specific viral families. The importance of the location of the protein with in the cell was supported by studies that reduced the ability of IFITM1 to localise to the cell surface, leading to increased infection. These studies were supported by increased levels of infection in mice lacking the IFITM1 gene.

Understanding more about the function of interferon stimulated genes can help us to understand how viruses infect cells and may provide insight into strategies to prevent viral infections. In the case of IFITM1, we have shown that human cells make a robust anti-viral response at the cell surface and this can help to reduce viral infections.

Enter the Lab

So, there I was, pipette in hand, doing actual labwork for the first time in a year. How had it come to this? When I started out, I was convinced I was not going to be one of those PIs who is never in the lab: a common sentiment if you speak to late stage postdocs/ early stage PIs. My initial determination to stay lab active was in part caused by the disconnect between the training you receive as a post-doc and the reality of being a PI. Labwork so dominates the life of the postdoc that it is hard to imagine a job without it, skewing your sense of what a PI does and should be doing.

It can be tricky to come to terms with but as you progress in academia your job is no longer at the bench. There is a blunt reinterpretation of Adam Smith’s division of labour: “why have a dog and bark yourself”, which means you can’t do everything. As the leader of the group, your main responsibility is to support your team through ideas, funding and papers. Whilst it may be possible to have ideas and troubleshoot from the lab bench, there are some things that cannot be done, particularly writing. I find it very hard to alternate between bench and desk – and when I do try, fail to do both.

As time progresses, I have gotten to the point where my presence in the lab raises eyebrows and prompts various sarcastic comments along the lines of “labwork eh, try not to break anything”. Which I have to answer with as good grace as possible. However, there was one great occasion, when I had been teased all day by a postdoc about PIs not knowing anything, after several hours of this “banter” the same postdoc made a truly basic mistake in their experiments whilst my experiment went as planned, much to my amusement.

The move out of the lab comes with downsides. The lab is the heart of the group: it’s where all the gossip happens. Long experiments are great opportunities to get to know the team. Ensuring you have shared time together through other activities e.g. tea breaks, lunches and socials can help. As you step away from the bench, there is an inevitable skill fade, both in the techniques you do know and newer techniques that you do not. Losing lab skills is problematic on a number of levels. Psychologically, our success as postdocs was so closely linked to our success in the lab, losing the lab skill set before mastering the PI skill set is tricky. It can also affect our ability to lead in terms of legitimacy as group leaders which is in part based on our technical expertise, when this fades it can increase the ever-present imposter syndrome, but also not knowing how a technique works limits the ability to give feedback when it doesn’t. The best solution to this is to hire brilliant people.

There are still times when you can justify your presence in the lab, particularly in training. When you are getting established and it is just you and one or two other members of staff, the majority of lab know-how resides in your head. At this early career stage, there is a tension between good training and good results. You need to build a solid platform, so that your staff can function independently in the future: but every second you are not generating your first paper feels like wasted time, especially with the probation/ fellowship/ tenure clock ticking down. If you survive this first stage, the training can be self-perpetuating with existing staff training the newbies. This is very satisfactory but comes with the caveat that you need to think about quality assurance. The techniques I taught to my first PhD students 10 years ago have morphed over time. Normally this is for the best – things change after all, but it is worth checking occasionally. The training role never entirely disappears, because people selfishly leave from time to time and unless you have a succession plan in place take all that knowledge with them.

It is really hard to strike the balance. There are times when you are best out of the lab and other times when your presence in the lab might be the key difference between success and failure, or at least helping limit the levels of stress that your team have during bigger experiments. Erring on the side of absence builds independence in your team much more quickly – though this can be tough on them. One approach is to treat yourself to some labwork every now and then. Especially if you pick something that you can still do, that generates quick, easy results for use as preliminary grant data. These short bursts in the lab are refreshing. Unlike a PI’s day which involves some meetings, thinking a bit and maybe some writing, labwork has a set timetable with a clear endpoint to the day. Labwork can be simple and clean and it is reassuring to still be good at something, since a lot of being a PI involves external forces telling you are rubbish. It can also remind you why you got into science in the first place, especially if you generate some novel data. But lab time is best treated as a luxury rather than a key part of the job.

There are also upsides to leaving the lab behind. We tend to paint our lab time in a rosy shade as the best time of our life. But if you go back for longer than a day or so, you remember that it can be frustrating, especially when things don’t work. But more importantly, being the head of a lab enables you to do more of the research you want to do. As an early career researcher, you are working on someone else’s project and there is just one of you. When you get your own lab, you can put as many people as you can get funded onto the tasks you want to do. You also spread your losses, if it is just you, when an experiment fails it is devastating, when there are 5 people working for you, any one failure is offset by other successes.

The fact is that your role changes. As your group grows there is less need for you to be in the lab (and this is ok). You have to come to terms with the fact that most of the time you are best serving yourself and your team outside the lab. So if you are not leading a group yet, enjoy the labwork while you can because, as odd as it may sound right now, one day you will miss it.

This article first appeared on Digital Science