Coronavirus Q and A

What is the ‘Wuhan coronavirus (2019-nCoV)’ and what do we know about it so far?

Dr John Tregoning from Imperial’s Department of Infectious Disease spoke to the School of Public Health’s Prof Steven Riley about the ‘Wuhan coronavirus’ outbreak that recently began in China.

·       Who has been working on the outbreak epidemiology at Imperial College London?

SR: I work as part of the MRC Centre for Global Infectious Disease  Analysis and the Abdul Latif Jameel Institute for Disease and Emergency Analytics centre with Professor Neil Ferguson, Dr Natsuko Imai, Dr Ilaria Dorigatti and Dr Anne Cori.

·       So what is the ‘Wuhan coronavirus'?

It is a viral infection that was first discovered in the Chinese city of Wuhan in 2019 that has been associated with a number of cases of pneumonia – an infection of the tissue in the lungs. You might see it being called ‘2019-nCoV’, which stand for novel (or new) coronavirus. More information has been provided by the World Health Organisation.

·       What is a coronavirus?

JT: Viruses are infectious organisms that rely upon the cells in our bodies to replicate. A virus needs to enter our cells and hijack them to make copies of itself. They enter our cells by sticking to the outside of the cell, using viral proteins to recognise proteins made by the human cells.

Coronavirus are respiratory viruses, which means they are viruses that infect the nose and the lungs. They are a large family of different viruses causing a range of different illnesses from colds to more severe diseases. The coronavirus family is known to be potentially zoonotic, so able to jump between different species. They are from a broader group of viruses called RNA viruses, which means their genetic material is carried on RNA molecules, not DNA molecules, which is important when it comes to thinking about how they can mutate.

·       What are the symptoms?

SR: Since nCoV is a respiratory virus, it will cause symptoms ranging from a cold (blocked nose) and a cough, to chest infection and pneumonia. Fever (a temperature over 38°C or 100.4°F) has been commonly observed with nCoV infections. As the virus was first identified in a cluster of pneumonia patients, we can probably assume that it can cause pneumonia in the more severe cases.

·       Is it anything like SARS, MERS or Ebola?

SR: The novel coronavirus (nCoV) associated with this outbreak, is somewhat similar to SARS (Severe acute respiratory syndrome) which emerged in 2003 and MERS (Middle east respiratory syndrome) which emerged in 2012. Both of these infections, SARS and MERS, are caused by coronaviruses and are respiratory infections.

It is nothing like Ebola, which is caused by a different virus type altogether (Filoviridae). Ebola spreads from person to person by contact with bodily fluids from infected individuals.

·       How does nCoV spread?

SR: We don’t fully know. However, we can compare it to other respiratory viruses. Most of which are spread by respiratory droplets, for example from a sneeze to a hand to a surface, which is then picked up by a new person who then touches their face. Sometimes the virus can be airborne and then inhaled, but it’s more difficult to measure how much transmission happens this way.

·       How was it discovered?

SR: There was a cluster of pneumonia cases in Wuhan, China. Genetic material was isolated from these patients and this coronavirus was found. The team that found it have rapidly shared this information with the global research community, which has enabled research towards new vaccines and diagnostics.

·       How do you test patients for a new virus like this?

SR: Following the identification of the virus causing the infection, we can use pre-existing technology called PCR to test patients. PCR (polymerase chain reaction) is a highly specific test that recognises a genetic sequence and amplifies it so that its presence can be detected.

·       Where did it come from – did it ‘jump’ from reptiles or bats?

SR: The first cases have been closely tied to a specific market in Wuhan. These no reliable evidence for it coming from snakes. The closest known virus is found in bats, but we don’t know for sure if this is where it came from.

·       And how did it jump to humans?

JT: Viruses, and in particular RNA viruses, mutate over time. This is because when they use your cells to make copies of themselves they have poor proofreading, so each copy is not quite the same as the original. Most of these changes will make the virus less infectious, but some might enable them to infect a slightly different type of cell or species.

SR: For other zoonotic viruses (viruses which spread between animals and humans), the viruses normally move from a species with which we are closely physically associated, so for example influenza can move from pigs and chickens to people. The huge number of animals raised for meat and their close physical proximity to people can make these jumps more likely.

·       How is it spreading now?

SR: One of the tools we use as epidemiologists is the R0 value. This is the number of new individuals infected by the first infected person. So for example an R0 of 2 means that each infected person infects 2 more people: in an unbroken transmission chain these 2 people would then infect 2 more each – so 2 becomes 4, which becomes 8 and so on. We then want to apply behavioural and treatment approaches to reduce the R0 to less than 1 so the infection contracts. We do not know the R0 value for nCoV yet and it is too early to be confident about what it is.

·       Is the virus mutating?

SR: It is very hard to tell. Viruses mutate all the time as part of their replication process. It’s very difficult to detect significant mutations that really change the behaviour of a virus.

·       Is this virus any more or less dangerous than seasonal flu?

SR: We don’t know. We are concerned that it is more dangerous than the 2009 strain of influenza, which was milder than other influenza pandemics. One way to think about this is the difference between case fatality rate and infection fatality rate. Very roughly speaking case fatality rate (CFR) is the number of deaths per confirmed cases of the virus (so in this example people who have gone to a doctor or a hospital and had a confirmed diagnosis of the virus). Infection fatality rate (IFR) is the number of deaths of all the people who have been infected.

·       Why is the difference between IFR and CFR important?

JT: If the majority of people who get infected with the virus do not have severe enough illness to need to go to hospital or the Doctor, then the case fatality rate will be higher than the infection fatality rate and the disease will be less serious than it appears. Essentially clinical cases, those that require medical assistance is the tip of an iceberg and the question is how big is the underlying iceberg? If most people infected don’t develop any symptoms, then it is a mild disease, if most people infected need hospitalisation, it is a cause for concern.

·       Why don’t our existing vaccines or antiviral drugs work?

JT: Vaccines work by training your immune system to recognise specific features (called antigens) of the virus it is protecting you against. Since this is a new virus, which looks different to other viruses and has different antigens, current vaccines cannot provide protection.

·       Why don’t we have a new vaccine?

JT speaking to Professor Robin Shattock (Imperial College London). Vaccines take time to manufacture, even with our best new platforms, any new vaccine takes at least 3 months to manufacture enough material to test in people for safety. It is then a big step from there to manufacture enough doses of vaccine to cover the world population.

Likewise, antiviral drugs target key components of the viral replication. They have been developed for other families of viruses and so are not necessarily specific enough to inhibit the coronaviruses.

·       Is there anything people can do to reduce their risk: for example wearing facemasks or washing hands?

JT: Masks are important in clinical settings when properly used, however they have little value for the general public. Handwashing and reducing contact from hands to face can be helpful, as this helps stop the spread of the virus through respiratory droplets from coughs and sneezes.

·       Will the quarantine in Wuhan work?

SR: It is an unprecedented step, so we have no evidence either way. But it is a strong statement from the government and this will increase the awareness of the infection and therefore reduce spread.

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