What actually prevents viral lung infection?

The protection provided by our immune system against infection is multi-layered. Each individual cell has a degree of self-defence where it is able to recognise and kill infectious pathogens, this is called intrinsic immunity. Then there is a rapid response called the innate immune system that recognises infection in general. Finally there is a pathogen specific response tailored to each individual virus subtype called adaptive immunity. In turn the adaptive immunity has several elements to it there is a cellular arm made up of two flavours of T cells (CD4 and CD8) and an antibody arm which is also divided into 5 different subtypes based on the structures of the immunoglobulin molecule produced, these are called IgA, IgD, IgE, IgG and IgM. Why they are not called IgA,B,C,D and E is unclear to me, but then again much of immunology nomenclature is opaque (think of the HLA/MHC gene numbering system – or don’t): some might say is deliberately difficult to keep out interlopers from other fields.

HAI

Whilst we know that these different components exist, what produces them and how they work to kill infections, we don’t have a complete picture of the relative contributions each component makes. Thanks to studies performed in the 1970’s in the common cold unit, Porton Down (in the rolling Wiltshire countryside of the UK), we do know that antibodies in the blood protect against influenza infection. In these studies, volunteers were deliberately infected with influenza and the rate of infection compared with antibody levels in the blood. The researchers found that volunteers whose blood scored greater than 40 on a particular test called Haemagglutination inhibition (HAI), which measures the functional activity of antibodies, were significantly less likely to get infected. This benchmark number of 1:40, is now used to assess new vaccines. However, the HAI test only assesses one of the arms of the immune system – IgG. We were interested in the role of other components.

IgA

In order to assess the role of another antibody subtype, IgA, in our recently published study we went back to human challenge studies. Working with a biotech company – Altimmune – volunteers were deliberately infected with influenza. However in this study, individuals were deliberately selected who had a sub-protective HAI titre. This enabled us to look at the role of other components without the masking effect of blood IgG. Having screened the patients to have low levels of functional antibody in the blood, one prediction might be that they should all get infected. However of the 47 volunteers infected, fifteen had no recoverable virus or symptoms of infection. This suggests that there are indeed other factors that can protect against infection. We measured influenza specific antibody and found that volunteers with high levels of flu binding IgA antibody in their nose or their blood produced less virus over the course of the study. This suggests that IgA can also protect against flu.

CD8

However, there were patients with low IgA and low IgG who didn’t get infected, suggesting that there are additional factors contributing to protection. We have data that suggest that CD8 T cells could also be playing a role. CD8 T cells are also called cytotoxic T cells, they work by recognising little bits of virus that are displayed on the surface of infected cells as little flags of infection. Recently it has been shown that there is a special population of T cells that live in the lungs and are primed to recognise and prevent infections. We found high levels of these cells in the lung after a viral infection (Respiratory Syncytial Virus: RSV, which has a very large burden of disease in children). What was really striking was that by transferring these cells alone from one animal that had been exposed to RSV to another animal who hadn’t we could also transfer protection against infection. This means that CD8 T cells are also able to protect against infection, the full study is described in our paper in Mucosal Immunology.

A model: 

So where does this leave us? We think there is a layered defence against infection. IgA, which is mostly found in the upper airway, forms a barrier to the virus getting into cells in the first place. If this barrier is breached, then the IgG prevents the virus from moving from the upper to the lower airway. If the IgG fails to prevent infection of the lungs, CD8 T cells resident in the lungs rapidly kill the infected cells reducing the burden of disease. What this means is that when designing vaccines for these infections, we need to target all three components of the immune response for the best protection.

Time and how to organise it better

Organisation

Time, next to grant funding, is the thing for which most academics would sell their soul. Everything is a PRIORITY that needs doing NOW. This can be overwhelming, especially if you are caring for someone at home who also needs all of your time NOW.

The self-help literature shelves are awash with advice on how to better organise your time. So much so you’d need a whole second life just reading them. Luckily I have read the abstracts, looked at the front covers, chatted to a mate and condensed all this collected knowledge down to 3 easy steps and 5 superpowers.

Time being short, let’s begin:

Step 1, The List. Everyone has a list, be it on scraps of recycled paper or blue roll, lab gloves, google notes or a specially designed pad. The list may only exist in the ether, your head or your PA’s head (if you are lucky enough to have one). But somehow, somewhere, you need to register everything that needs to be done. If you are not even doing this, then you are truly lost. Make a list: write down everything, big or small, home or work, trivial or world changing.

Step 2, The Main Effort. Having written your list, step back and decide what it is you want to achieve. Not only by the end of today, but at the end of the year, in 5 years’ time and if possible over your whole career. Whatever your goal is, from finishing your PhD on time, through getting that paper out and becoming a PI to winning the Nobel Prize, define the activities you need to achieve it and put all your effort into those activities. In military circles, this is called the main effort (or Schwerpunkt): a centre of gravity, where a decisive result is to be achieved.

Step 3, Triage. Inherent in the main effort approach is the need to sacrifice other fronts to achieve the goal. You therefore need to prioritise your work into 4 categories (I use an adaptation of triage).

Red (Immediate): These tasks directly contribute to you achieving the main effort; spend as much time as possible doing them.

Yellow (Delayed): It’s helping, but indirectly; or someone is really screaming at you to get it done.

Green (Minor): It is not on the main effort but needs doing.

Dead: There are some tasks that a) seem urgent but aren’t or b) even if you tick them off the list come back to bite you at the end of the day. Don’t do them!

For example, my goal is to get promoted, to do this I need to publish papers and get grants (my main effort). I split my list into papers, grants, lab and admin (i.e. everything else). Where possible I prioritise doing papers and grants.

So now that you defined your goal and prioritised the tasks that will help you achieve it, you still need to find the time to do them. And this is where my timefighting superpowers come in.

·         Bullet Dodge. Say no. If it doesn’t get you where you need to be, don’t do it. Use this superpower sparingly. Part of being an academic is being a good citizen. If you are a superstar, you can be as selfish as you like, but the rest of us need to keep our jobs in order to achieve our goals and part of keeping your job is saying yes to things you don’t want to do. EO Wilson in his letters advises us to “avoid departmental level-administration…make excuses, dodge, plead, trade”.

·         Hyper-alert. There are parts of the day in which you will do your best work. For me it is in the morning up to lunch (strictly at 12 noon) and after 3 pm. So I schedule deep-thought for those periods and busy work for 1230-3. (If you are in my group and reading this and I have scheduled a meeting for 2…of course I value our time together).

·         Hyperfocus. Time flies when you’re truly engaged in a piece of work. Sometimes you get into a magical state where the ideas crystallise into words on the page. This Zen state of intense focus/ productivity is named as ‘flow’ by Mihály Csíkszentmihályi. Do everything you can to attain and remain in this state, for as long as possible.

·         Immunity to internet. Having identified your priorities and found your perfect time of the day, don’t let others or yourself come between you and flow. Some tips: divide your time into 45 minute chunks and in those segments, turn off the email, turn off the internet, block social media accounts, hide your phone, have a note pad so if something urgent but not task related comes up you can write it down and move on and focus. If you can’t get away from distractions in your office, work in the library, work from home, put on headphones, get away from that person who always ‘just needs’ to ask you one thing.

·         Let go your over-critical self. Some tasks are never going to be finished to perfection, there are times when you have to accept that 80% and submitted is better than perfect and still on your C drive as the final-final-final.doc. Not everything is achievable in a day; if you have pushed a task as far as it will go, put a mark next to it to remind you more is needed or you are waiting for someone else. One of the best pieces of advice to reduce stress about incomplete tasks is to go home at a sensible time every day and if things are not finished to repeat the mantra ‘I’ll just try harder tomorrow’.

So what are you waiting for? Identify your goal and don’t let anything (including yourself) get in the way!

This first appeared on Digital Science blog, May 2017

No scientist is too junior to fix the system

This first appeared in Nature: May 2017

The March for Science filled the streets on a Saturday afternoon. The next steps should come at research institutions and universities, says John Tregoning

                Last month thousands of researchers took to the streets. It is time to channel this collective energy to shape the culture of science.

                We all love to complain how the system for doing science thwarts ideal practice. Prestigious publications are rewarded more than sound work. Everyone ends up chasing trends and asking the same questions. Broader multidisciplinary research might achieve more, but it is harder to publish and less well rewarded. We end up sticking to the path of the prestigious paper and big grant at the expense of worthier endeavors.

                Why don’t we just change the system to something better? After all, science is uniquely self-regulating. The people who set the science agenda are scientists, the people who allocate funding are scientists, and the people who decide what gets published are scientists. The tool we hold in highest regard is peer-review: we are judge, jury and executioner.

One reason for stasis is that scientists value consistency. The scientific process requires controlling variables as tightly as possible, even down to those unlikely to have any impact on an experiment. I know people who won’t change the order in which they use pipette tips; they are unlikely to change the research system.

Another reason is that we’re too busy just getting by in the current system to pause to fix its flaws. Grant submissions and experimental timepoints—tasks that reward the individual and have strict deadlines--will always win against some nebulous effort for the common good.

But most of all there’s the sad reality that those who most feel the need for change have the least power to create it. It’s all too easy to justify putting off activism. The time to fix the system, we tell ourselves, is after we have gained actual influence. If a PhD student shouts in frustration, are things going to change, or will she just be marginalized as a rabble rouser?

This leads to a pernicious inertia: moving up the ladder shifts your perspective. Making tenure puts you in a position to make change, but can inure you to the status quo. The principal investigator tells the postdoc that finding a permanent position is nothing compared with the angst of getting a grant. The postdoc tells the PhD student that defending a thesis is nothing compared with the angst of finding a permanent position. The higher you rise, the smaller the problems of those in the levels below seem. In other words, research traps young scientists in a suboptimal system, but if they plan to advance their careers before setting it right, nothing will change.

Within the last twelve months, separate groups of researchers have made headlines [http://www.nature.com/news/the-mathematics-of-science-s-broken-reward-system-1.20987] by applying evolutionary fitness metaphors to show that scientists are driven to less rigorous but more ‘productive’ practices. They portray science as a zero-sum game: everyone is so busy competing that no one revises the rules. Those who spend their time lobbying for change rather than collecting data will find themselves scooped of the recognition required for resources.

But evolutionary theory also suggests a potential way out: reciprocal altruism. The key is to use whatever influence you do have to help your peers, and to trust that your peers will do the same. I have reaped the benefits. One example was relinquishing a key authorship position on a paper in order to maintain a productive collaboration. At the time, I felt I was losing out, not fighting hard enough in the struggle for the scarce resource of credit to which I felt justified. But the small sacrifice paid off. I continued to work with my co-authors, and we wrote a successful grant together. The immediate reward of prime authorship would have been less beneficial in the long run.

More broadly, I am collecting a group of like-minded colleagues that consciously try to be less self-focused and support each other. In practice, this comes down to small things that even a pipetting-compulsive can handle: we read each other’s drafts, accept a fair share of committee posts so no one has an undue burden, take the time to forward relevant grant announcements, or just to go out for a drink. We just each try to work a bit more toward a collective good: I happen to be enthusiastic about identifying broken stuff in the building that everyone else ignores (burnt out lights, squeaky doors, blocked sinks) and seeing that they get repaired.

Start now. Don’t wait on your senior colleagues, and definitely don’t wait until you become the senior colleague. Build a network of like-minded people. Identify something that doesn’t work and fix it. It can be as small as leaky tap or as big as peer review. Believe that idealism can be catching.

Reciprocal altruism may seem idealistic, but focusing solely on your own advancement can come back to bite you. Academic promotions and appointments to senior positions require recommendations from colleagues, and I’m sure I’m not the only one who has heard of ambitious individuals who would never be considered for department chair because they have stabbed too many people in the back.

Let’s strive to stand together. Historians called last month’s worldwide march to defend science unprecedented in terms of its scale and breadth. That energy and optimism need not dissipate – it should be funneled into making the overall system function better. The payoff may not occur immediately, but play the long game and we all can win.