What is up your nose?

We are interested in the contents of your nose, not at the level of hair, bogey and the occasional finger, but at the level of the complex microbial community that lives there and how it is associated with respiratory infection. The makeup of this community has been interrogated through sequencing (the airway microbiome) with indications that some bacterial communities may be associated with health and others with disease.

A bacterial diet

However, what the bacteria in the airways eat to survive is less well understood. One tool that may help us to characterise which biochemicals in the airways bacteria can use as food is called metabolomics. This uses liquid chromatography, to separate the biochemicals, and then mass spectrometry, to interrogate what they are. Comparing the mass spectrometry data against a curated library, we can then determine which individual biochemicals are present and their relative abundance. This tool has been used widely to investigate changes in the blood but has not been used much to interrogate the airway.

Blotting paper 2.0

The aim of our recently published study was to compare methods for sampling the airway metabolome. We looked at two standard techniques – nasal lavage (flushing a millilitre of saline through the nose and recovering whatever you can – quite a lot never comes back!) and induced sputum (getting people to breathe in an expectorant and then spit in a cup). We also used a newer technique, that had never been used for metabolomics sampling, called Synthetic Absorptive Matrix (SAM) strips. These are hi-tech blotting paper and have been used to recover other types of sample from the airways, including antibodies and cytokines. You can watch a video of their inventor having them put up his nose here. We looked at the use of these SAM strips in both the upper airway (via the nose) and the lower airway (via a bronchoscope). In the traditions of Barry Marshall (though I doubt I will get a Nobel prize for this), I volunteered to be one of the subjects for the sampling; the nasal wash, induced sputum and upper airway SAM were all fine, but having a bronchoscopy was fairly unpleasant.

It’s good to share

Having collected the samples, we then outsourced the running of the metabolomics to a company, called Metabolon in the US. This choice had mixed reviews, but I think it is ok to outsource, increasingly labs are outsourcing some of the more specialist analysis approaches – sequencing, transcriptomics, metabolomics. This makes sense in terms of time, expertise and access to equipment. Specifically in the case of metabolomics, outsourcing gave us access to a much larger curated library of samples, giving us more information from our samples, the biochemicals were also grouped into families, enabling us to interrogate the data more easily.

Sooo much data

From the point of performing the study to publishing it has been a lengthy process. In part this was due to the complexity of the dataset. We had approximately 14,000 data points – which may be small compared to some types of project, but when you are used performing focussed studies on individual mediators it was quite a step change. This was combined with a bewildering list of biochemicals, most of which we had never heard of – 1-stearoyl-2-arachidonyl-GPC anyone? In the end, through the power of the R programming platform and a very talented PhD student, we have ended up with a paper that uses a wide range of graph types, all of which aimed to compress the data into a meaningful form.

Food for the Pseuds

So what did we find? In total, 581 biochemicals were recovered from the airways belonging to a range of different families. When we compared the relative abundance of the these biochemicals between the different sampling techniques, we saw that the SAM strips gave us a much greater recovery of biochemicals than the other approaches. Since we were interested in how the airway metabolome enables bacterial colonisation, we screened some of these biochemicals for their ability to support bacterial growth. 35 of these biochemicals were able to support growth of the opportunistic airway bacteria Pseudomonas aeruginosa, including a number of sugars and amino acids.

A microcosm in a nostril

The airways represent a fascinating ecosystem because they are nutritionally more restricted in terms of the range and specific concentrations of any one biochemical compared to say the gut, but at the same time the nutrients are constantly refreshed. The balance of biochemicals in the airways shapes the bacteria that can live there, and we believe that this could be dysregulated in disease. By developing the tools to sample the airway metabolome, we are now one step closer to understanding how changes in airway biochemistry affects infection.

How do you build resilience

This was a co-authored piece with Dr Cecilia Johansson (Imperial College London)

At the recent British Society for Immunology (BSI) Early Career Training session in London, we were tasked with talking about tools to help immunologists improve their resilience. This was identified  by the BSI’s ‘Careers in Immunology’ report as an area that early stage (and middle and late stage) immunologists struggle with throughout their careers. So you probably don’t need us to tell you that a career in science can be difficult. Whatever stage you are at, there are always new hurdles to surmount and rejections to overcome. Part of the phenotype of the successful scientist is resilience: resilience in the face of experiments failing, resilience in the face of papers being rejected, resilience in the face of short term contracts, minimal wages and a terrifying lack of job security. As resilience is "the capacity to recover quickly from difficulties" – how do we build/enhance our resilience?

We have identified three sources of resilience that you can draw upon: within yourself, outside yourself and outside your work.

The Struggle Within

The first source of resilience has to come from within yourself. There are a number of tricks that we think can help:

1. Mindset. Carol Dweck is a Professor of Psychology at Stanford University; in her book MindSet,1 she identifies the strength of a growth mindset, which means looking for the opportunities to improve yourself in any situation. So instead of saying ‘reviewer 2 is an idiot’, reframe the situation to say ‘how could I have made my writing more clear so that even reviewer 2 could understand it’.
2. Other people. Other people’s success can be a source of strength, or not: we have two different approaches to deal with it.
   1. Never compare up (John’s approach). With the internet to hand you don’t have to look very far to find a more successful immunologist than yourself. It is then very easy to slowly sink into despair as you read their endless CV of success. Don’t do this! Alice Prince at Columbia very clearly describes how people’s CVs are not an honest reflection of the route they took.2
   2. Inspiration (Cecilia’s approach). Use amazing people around you as role models. Have a lot of them and use their skills/behaviour/mindset as motivation.  
3. Behaviour. It is not what happened, it is how you react to the situation that decides the amount of resilience needed. Your values, mindset, beliefs, and current state of mind all influence how much resilience you have: when you are super stressed and over-worked it is much harder to cope. Reflect on how and why you react to a particular situation and think of how you can improve your coping strategies.
4. Celebrate. Make a point of celebrating successes big and small: papers, grants, experiments for both yourself and everyone around you. Apply the perspective of time to your progress: taking a longer view smooths out the lows and demonstrates an upward trajectory. Pause and take stock of the past three months, one year, five years and identify what went right.
5. Make plans. It is difficult to assess your progress without a plan. What do you want to achieve in the next three months, one year, five years. The granularity of the detail can fade as you look further into the future.
6. Pause and take care of yourself. In a stressful life/period, it is very easy to forget yourself. Find ways of manage your time (as time is precious and we never have enough) and your stress levels. Mindfulness (essentially meditation) can be a very helpful tool. It doesn’t need much more than closing your eyes and focusing on your breath or the background noises for a few minutes to re-wind and re-set.

All of these approaches link to good reflective practice – studying your own experiences to improve the way you work. There are times when everything can get on top of you and you have to take time to step back. However, occasionally, it is not possible to do this alone and this is where you need to the second source of resilience, other people.

Everybody needs somebody

We all need support from other people. The Ancient Greek language has multiple different words for love/ support, and while the type of support we need most will vary from person to person and with time of life, these different types provide a useful framework for thinking about our interactions with others. This support can come from both within science and from your broader circle of friends and family.

Agape refers to love from a parent to a child, but more broadly reflects support from a senior figure to someone more junior. Don’t restrict yourself to one role model or mentor, you don’t even need to have met them (e.g. CJ looks to Cheryl Sandberg, COO at Facebook3; JT has learnt a huge amount from Stephen King’s book On Writing4). Take every opportunity to meet new and inspiring people. But also look inwards, most organisations (including the BSI) run mentoring programs. And remember different people will be useful for different types of advice/perspectives.

Eros describes the love of a partner. Now this is far from being a lonely hearts column, but we both draw great strength from our partners. The family network (partner, children, parents, cousins etc) is also a huge source of support.

Finally, but not least, Phillia love of a friend. Assembling a group of like-minded individuals is really important. Start in your PhD. Long hours spent moving colourless liquid around in labs are the perfect time to bond. Immunology is not a big field: as you progress with your career, it is amazing the times your paths will cross and re-cross. If nothing else, your PhD cohort are good for free beds in foreign cities. But the hope is that you can rise together on a common mutually supportive wave.5

Hit the road Jack

The final source of support is the realisation that this is just a job. If can feel all consuming, but it is still just a job. It helps to take a broader perspective. Again this comes back to good reflective practice. In parallel it is vital to have a life outside work (more work to live than live to work). This is not always easy, especially if you are juggling work and family commitments. But find outlets that you enjoy, without feeling the pressure to excel at them: bake but don’t aim to win Bake Off, run but don’t aim to win marathons. These other activities serve the same purpose as mindfulness – they break the loop when work is getting on top of you. Try to remember why you are doing/chose to do this job and the many positive aspects it brings.

A career in immunology has peaks and troughs. It’s ok to find it tricky and to admit to other people that you find it tricky. Recognising and celebrating the highs and learning tools to negotiate the lows can really help.

John Tregoning, Senior Lecturer in Immunology, Imperial College London. Twitter: @DrTregoning

Cecilia Johansson, Senior Lecturer in Respiratory Infection, Imperial College London. Twitter: @cjohansson_lab 

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Further reading

You can read more articles from John on his blog: drtregoning.blogspot.co.uk. References for the article are below.

1. Dweck, C. S. Mindset  the new psychology of success. Updated edition. edn,  (Random House, 2016).
2. Prince, A. Omissions from a National Institute of Health (NIH) biosketch. PLoS Pathog 14, e1006896, doi:10.1371/journal.ppat.1006896 (2018).
3. Sandberg, S. Lean in: women, work, and the will to lead. First edition. edn,  (Alfred A. Knopf, 2013).
4. King, S. On writing: a memoir of the craft. Scribner trade paperback edition. edn,  (Scribner, 2010).
5. Tregoning, J. No researcher is too junior to fix science. Nature 545, 7, doi:10.1038/545007a (2017).

Buy one, get one free: Vaccinate the mother, protect the child

Flu vaccine the best way to protect

Infection with influenza virus, the causative agent of flu, is particularly severe in pregnant women and newborn children. If they do get infected, they are far more likely to get severe disease leading to hospitalisation. For the pregnant mother, the simplest approach to avoid this is to get the flu vaccine as soon as it becomes available. However, these vaccines are not licensed for children under 6 months of age – leading us to ask the question, how do we protect newborn children against influenza infection?

Maternal vaccination, protecting both mother and child

Luckily, the body has already come up with a solution. During pregnancy, mothers pass on immunity to their children. This passive protection is transferred in the form of antibodies, which are proteins made by the immune system that are highly specific for the molecules that make up the coats of viruses and can prevent the viruses from infecting our cells. This antibody transfer occurs in the second and third trimester of pregnancy and has evolved so that the newborn child has some early protection against whatever infections the mother has been exposed to. We can utilise this system with maternal vaccination. If we vaccinate the mother, she will make antibodies that recognise the virus in the vaccine and some of these antibodies will pass from her to her baby. This maternal immunisation approach has been seen to be very effective in reducing the burden of infection with tetanus and pertussis (whooping cough) in babies. Maternal immunisation has also been recommended as a method of reducing influenza infection in babies since 2005.

When is the best time to vaccinate?

One important question is when is the best point during pregnancy to vaccinate the mother to ensure the maximum transfer of antibody to the baby. It was originally thought that early in the third trimester (weeks 25-36 of pregnancy) was best as this was the peak of antibody transfer, but recent studies investigating pertussis vaccination of mothers saw higher levels in babies if the mothers were vaccinated in the second trimester (weeks 13-24 of pregnancy). We wanted to explore the best time to immunise mothers with influenza vaccine. In our latest paper, we measured the level of influenza virus specific antibodies in both mothers and babies at the time of birth. We compared babies born to mothers who were vaccinated in the first, second or third trimesters with babies born to unvaccinated mothers. We saw that there was significantly more influenza specific antibody in babies born to vaccinated mothers than in those born to unvaccinated mothers – demonstrating that maternal flu vaccination is highly effective at boosting the protection against influenza infection in the baby. We then investigated timing and observed that the high levels of antibody were seen in children born to mothers vaccinated in either the second or the third trimester, suggesting that either timepoint was equivalent, though there was less antibody transferred if the gap between vaccination and birth was less than four weeks.

Flu the ever changing

However, there is a complication with influenza virus; unlike the other pathogens for which maternal immunisation is recommended – pertussis and tetanus, the influenza virus changes. These changes in virus necessitate a new flu vaccine each year to match the viruses that are circulating. Flu is also seasonal – you are much more likely to get flu in winter months (in temperate climates). This seasonality had an effect on the levels of immune protection in our study: children born during the flu season had higher levels of antibody than those born outside it. 

The time is now

When we put the seasonality of influenza together with the best time to vaccinate mothers to pass antibody to children, we see that the current practice of offering flu vaccine to mothers as soon as it becomes available gives the best balance of protection to both mothers and their babies at the times when they need it most. This is because the flu season is 6 months long and pregnancy is nine months long. Whilst immunising mothers in the first trimester does not pass on the most antibody to the baby, immunising the mother at the start of the flu season gives the mother maximal protection for the whole flu season and they will give birth outside the flu season, so the baby requires less protection. Mothers who are in the second or third trimester at the start of the flu season will benefit from the protection of the vaccine themselves and pass antibody protection to their baby.

Therefore our study supports the current practice of offering influenza vaccine to mothers as soon as it becomes available.

No Laughing Matter: Use of humour in lectures

We were asked to come up with the best and worst examples of lecturing, either our own or those we’ve attended. Clearly my lectures are textbook examples of tertiary content delivery and probably deserve prizes (worth a try). So I thought back to when I was the recipient of lectures (a long time ago). But since I went to a research focussed university in the mid 90’s where teaching was at best seen as a chore, the quality was fairly universally m’eh. There was, however, one standout lecturer who I still remember, and not because of the content, something to do with action potentials in nerve cells (holy moly I remembered something), but because of his delivery style. Each lecture had a carefully crafted hilarious diversion (normally about walking in the Alps). This in turn got me thinking about using humour in lectures, which I try, and sometimes succeed, to do. Here are some tips:

1.       Simple is best. You don’t need to be Jonathan Swift to get a laugh out of 200 bored undergrads. To be honest, most of the jokes I use work as well with primary school audiences as they do with postgraduates (particularly my carefully curated library of pictures of snot). My most successful joke uses the power of slide animation to transform “B for boring cells” into “B for brilliant cells”, this even gets applause! But beware, jokes, if they work, disrupt the flow and it can take a couple of minutes to settle the room afterwards.

2.       Context is important. Students are not necessarily expecting humour and so may not process it as such. When, in a fit of pique, I told one cohort that their dissertations needed to be handwritten and have the first letter illustrated by monks, the course organiser had a busy afternoon reassuring them that this wasn’t the case.

3.       Be culturally aware. Most jokes work because of some common ground, knowledge or experience; which the students may not have in common with you. Age in particular is a big barrier. I started working at Imperial before most of the current students were born, so my references to pop culture often draw blank looks. I once told a PhD student that “I love it when a plan comes together” and they looked confused, apparently unaware of the wisdom of Colonel John “Hannibal” Smith.

4.       Visual jokes work, but can take time. I love cartoons and have tried to use them from a range of sources (Piled higher and deeper, sketching science and @redpenblackpen all being favourites). But cartoons take time to read - don’t just flash them up and expect instant gratification. Memes work better: since they come with a preloaded meaning, they tick the shared common ground box. They can even be educational – if Boromir is saying it, it must be true.

5.       Align with teaching. One does not simply throw in a joke and expect it to work: you need to link the joke to the content. Humour can be memorable, but it can divert memory away from what you are trying to teach. This is why 20 years later I can remember my physiology lecturer but not my physiology lectures. I managed perfect joke-content alignment once, by tenuously linking UKIP, Brexit and the EU to T cell immunology. 3 years later, the students came up and said they remembered my lecture from the first year – both the joke and the concept.

On the whole, humour is a useful tool, but there needs to be a thread, however unlikely between the learning objectives and the laughter.

This article first appeared in Times Higher Education

Turn off your e-mail and social media to get more done

Distractions are a fundamental aspect of the modern world, but we don’t have to become hermits to avoid them.

We are all busy, seemingly all the time, with a never-ending stream of e-mails to answer and meetings to attend. But are there better ways to do busy? Cal Newport, in his book Deep Work (Piatkus, 2016), says “yes”. Here’s what I’ve learnt from him.

Newport argues that, in the new world of work, the only thing we have to sell is our capacity to think rather than our capacity to do. But this ability to think does not come naturally or easily, and, unfortunately, the interconnected world that we live in throws big barriers in the way of big thinking.

Newport spends a lot of time exploring this point in Deep Work. But I suspect you need look no further than your swollen e-mail inbox or your back-to-back schedule to see that your precious time is being frittered away. And that is not counting social media, which has many ways to make us dumber: how many times have you lost a great idea, distracted by that little red Facebook notification?

The solution

Fortunately, Newport has a number of evidence-based ‘life hacks’ to combat this. Fundamentally, they come down to one thing: remove all distractions. You might think you are already doing this by turning off your phone occasionally. But you need to go further: don’t just turn off your phone; put it in a lead-lined box and bury it at the bottom of the ocean. Quit all social media. Isolate yourself from all modern life. Smash the Wi-Fi router. Move to a small island. Then, and only then, through a state of pure asceticism, might you get some work done.

However, this perfect state of deep thought might not necessarily be achievable if you want to keep your job, in which case some of the following suggestions might enable you to get the most out of your brain.

E-mail better

Shake the habit. E-mail is the worst attention thief. It has myriad means of misdirection, from the on-screen pop-up, to the envelope icon, to the alluring bold font in the unread e-mail folder. There is some ‘brain reward centre’ stuff happening with e-mail — it tells you that you are important and wanted, even if it is only an invite to write for a “presgitious new jorunal” [sic]. The easiest way to limit e-mail’s impact is to turn it off completely.

Burst transmission. That said, you still need to be in touch with the outside world. I try to limit myself to bursts. I can sustain focus for about 50 minutes, after which I reward myself with 5 minutes of e-mail, which inevitably turns into 10. No, this is not perfect and yes, resetting after 10 minutes is tricky, but it is much more effective than having the e-mail monkey on your back for the whole day.

Short and sweet. E-mail overload is universal and often exponential. ‘CC alls’, imprecise e-mails leading to immediate clarification and e-mail ‘tennis’ while trying to settle on a date all add to this burden. Making your e-mails concise and final means everyone wins. For example, instead of suggesting a time to meet, send a calendar invite directly. One question I don’t have the answer to is when to say ‘thank you’, balancing the need not to upset someone with not getting stuck in a further round of acknowledgment and counter-acknowledgement. Send better e-mail and ye shall receive better e-mail.

Do it later. E-mail is an insatiable beast; it feels like it needs immediate action: it doesn’t. Scan read, flag things for later and do it in batches.

Not now

Batching non-essential tasks can be applied to more than e-mail. I’ve found there is no way to stop the random thoughts coming, but it is possible to reduce their derailing impact. If a thought crops up, I scribble it onto a Post-it note and then batch busy work into times of the day when I am normally less productive.

Find a space

Your shared office maintained at slightly the wrong temperature, next door to a chatty neighbour with a penchant for pickled fish, might not be the ideal place to achieve the Zen of deep work. Try working elsewhere: libraries, cafes, at home. I get a surprising amount of writing done on the train to work — an added benefit of London commuters not talking to each other.

But it is not just about work. Making your brain better is more than 9 to 5. The Internet has invaded our lives to the extent that we cannot switch off. And you might argue that it is just downtime, but the habit of endlessly checking devices leads to a loop of inattention and a dilution of focus during working hours.

A lot of a scientist’s job relies on creativity, which in turn relies upon your subconscious doing some of the work. But it can’t do this when overloaded with cat videos, envious thoughts about your friends’ self-reported quality of life and pictures of someone else’s lunch. Stepping back from social and work media after certain times of day both help.

More radically, aspire to be bored. Put your phone away and if you have five spare seconds, keep them spare. Being click-baited to generate advertising income for unscrupulous publishers doesn’t do any good to you or the world.

Health warning

At the beginning of the summer, I tried the full ‘academic monk’ thing and failed. There were some mitigating circumstances for my lack of focus, but then again I’m sure there will be next summer, and the summer after that.

Clearing your head has clear benefits: better productivity; being more present with friends and family; brilliant ideas. It is also slightly addictive in itself — achieving deep focus and really working through a problem is intensely satisfying. We’re all working hard enough. It’s time to work smarter.

This is an article from the Nature Careers Community.

What are science?

Apparently we all fucking love science, or at least we love pretty pictures, anecdotal facts, chemical explosions and slightly preachy environmentalism.

However, science is none of these things. Science is the generation and testing of ideas; normally disproving them, in the process generating more ideas that need more testing.

Science junkies

Sadly, the day job of a scientist is nothing like the programs ‘Bang goes the theory/Tomorrow’s World/Johnny Ball Reveals All’ (delete as appropriate depending on your generation): in my 20 years being a professional scientist, there has been no time at work when I have blown anything up, thrown heavy weights into bowls of custard or put Mentos into bottles of Diet Coke.
To be honest, blowing things up at work is frowned upon and the management go to some lengths to prevent us blowing up the building (just another example of health and safety gone mad).
Highly visual demonstrations of chemical reactions are educational if phrased properly – if I do this, what do you think will happen and why? And these demonstrations can be effective for attracting the impressionable to a life of science. In effect, flashy chemical reactions are the gateway drug to scientific addiction.
At school we had a teacher who once a term gave us unrestricted access to the chemical store and a Bunsen burner; I imagined this was what it would be to be a scientist. Nowadays I don’t even get to do experiments, and yet I identify more as a scientist now than when I was doing my PhD as a space-filler before getting a “real job”.

Indoor work, no heavy lifting

So if the day-to-day of science isn’t setting things on fire, what is it?
It is immensely varied, and depends upon both the stage of your scientific career and the field you work in. But the main work of science is testing ideas. Some of which involves being in a lab, but most of which involves sitting in an office analysing the results from your experiments or coming up with new ideas because your experiments haven’t turned out as expected.
Since 99% of these ideas come from other people, another major strand is evaluating other people’s ideas and building on the back of them. And since other people need to evaluate the ideas we have, we need to be able to effectively communicate them, as written articles (papers), as sales pitches (grants) or in person (conferences).
So disappointingly, the day to day work of science is not so far removed from other professions, though we do get to wear a white coat occasionally. You need to be able to read, to write and, terrifyingly, interact with other people – very much none of the things that got most of us into science in the first place.

No researcher is too junior to fix science

Here is an article from Nature about how we can work together to improve science

https://www.nature.com/news/no-researcher-is-too-junior-to-fix-science-1.21928

How will you judge me if not by Impact Factor

Here is an article I wrote for Nature on the lack of clarity about replacing impact factor

https://www.nature.com/articles/d41586-018-05467-5

From Parade ground to PI

Here is a piece I wrote for Science on how being an officer in the British Army reserve helped prepare me to run a lab

http://science.sciencemag.org/content/359/6373/362

Flu and our poo

There are various outlandish estimates about the numbers of bacterial cells there are on your body compared to the number of your own cells. Wikipedia informs me that current guestimates put it at a 10:1 ratio, with approximately 100 trillion bacterial cells per adult human; which is the kind of number that a stressed scientist makes up when the answer “I don’t know but it’s feckin’ loads” won’t suffice. Our guts are particularly rich in bacteria, and it is estimated that 30% of every poo is dead bacteria. We don’t really know for certain what all these bacteria do, quite a lot of them are probably just along for the ride living off dead skin cells and sweat. But there is a small proportion of these bacteria that we rely upon for all kinds of useful things, like breaking down our food properly, training our immune system and fighting off the bacteria that make us sick. Finally there is another group of bacteria that are just waiting in the wings to cause infection, often pouncing when we are at stressed or tired.

Collectively the bacteria that live on or in us are referred to as the microbiota and the ecological communities that they make up are called the microbiome. Our knowledge of this superficial (using its proper meaning of at the surface) second life has exploded in the last decade, mainly because of our ability to read DNA cheaply and easily. There has been a huge number of studies that have reported a link between our bacterial fellow travellers and a huge range of body functions. Some of which make some sense as the bacteria at least live at the same site as the disease including obesity, diabetes, asthma and tooth decay and some that require a more conceptual leap including mental health and autoimmunity. These links have also led to some outlandish ideas for new therapies, including faecal transplant (which is almost precisely what it sounds like) to reduce gut bacterial infection and ‘vaginal seeding’ of C-section babies.

Now that I have mentioned the obligatory facts about the microbiome – it outnumbers us, it has something to do with health and people are utilising it for weird therapies – I can concentrate on what we did in our recent paper. Given the myriad associations between the microbiota and health/ disease it is important to understand what shapes these bacterial communities. In particular we wanted to know if infection at one site, the lung, would change the bacteria at another, the gut. We looked at two important respiratory pathogens, respiratory syncytial virus (RSV) and influenza. Following lung infection, we observed a transient but significant change in the bacteria present in the guts.

One of the offshoots of studying the microbiome is that you need to learn (or relearn) your Linnean classifications (which for those of you that can’t remember go Domain-Kingdom-Phylum-Order-Family-Genus-Species: so for example humans are Animals-Chordates-Mammals-Primates-Hominids-Homo-Homo sapiens). We saw a shift in the bacterial phyla with a big decrease in the Firmicutes phyla and an increase in the Bacteroidetes phyla. Further subdividing within these phyla we saw a decrease in the Lactobacillaceae family and an increase in the Bacteroidaceae family. More strikingly, when we analysed at an approximation to the species level, we saw different species profiles with each experimental repeat. This suggested that lung infection wasn’t specifically affecting one or two species, rather it was changing the gut environment in such a way that one phyla of bacteria (the Bacteroidetes) would benefit at the cost of another (the Firmicutes). This change was acute and transient and by the time the mice had recovered from infection, their microbiome had also recovered.

Like most of science, this study acts as a starting point, asking more questions than it answers. What does it all mean? Frankly your guess is as good as ours. There is some suggestion that Lactobacillus are ‘good bacteria’, mostly from Yoghurt manufacturers who are trying to claim that a fruity, milk-based pudding is in some way good for you. One speculation is that if the bugs in our gut produce things we need to be healthy, lung infection, by disrupting the gut microbiome, may amplify sickness. But we would need to replace the ‘good’ Firmicutes and see an improvement of disease outcome to demonstrate this. Why is this happening? Again, we don’t have an answer. We had one tantalising result, which was that there was an increase in proteins associated with airway mucus in the guts, which occurred at the peak of point of bacterial change. Many of the bacteria in the Bacteroidetes phyla can utilise mucus as an energy source and so the swallowed mucus may support their growth. As I type, we are following up on both of these questions – so stay tuned and we might just have the answers, or more likely more questions!

Running up that hill: running, pop-songs and mental health

I wanted to share how running helps my mental health. I’ll admit this is a pretty self-indulgent piece, but since having a blog in the first place is self-indulgent, that shouldn’t be too much of a surprise. That said, you should definitely read on, even if only to test your knowledge of pop music.

The overstated health benefits of running!

I am focusing on the mental benefits as I am not entirely sure of the long term physical benefits of running: I am currently laid up with a torn calf muscle, my ankles and knees are pretty ruined, my tendons have shrunk so far that I can barely touch my shins let alone my toes, I’m pretty sure I’ve broken a bone in my foot more than once and the less said about my toenails the better.

However, running does, for me, have clear mental health benefits:

1.       Lose yourself. I have a pet theory that my sub-conscience does most of my problem solving; which is a convenient excuse when I am caught staring into space. But in order to problem solve, my sub-conscience needs some space in my head. Mindfulness (the corporately acceptable face of meditation) comes to the same thing – clearing the thoughts from your head. For me, running, particularly to music, clears everything else away. Occasionally, I take this to extremes by running in the woods at night with a head torch and music cranked to 11, which earns a few odd looks, but is amazing. Some people claim to power their way through work problems whilst they run, but I am too busy concentrating on remembering to breathe and the effort of putting one foot in front of the other to do this.

2.       Working 9-5. We are all productive at different times of the day. I get my best thinking done in two blocks 9-12 and 4-7: there is often dead time between these blocks and problems stay unsolved regardless of the effort spent forcing them. It is far better for me to do something else in the intervening time. This is where having a set of running stuff at work really helps, when I hit a low ebb I can head out the door for 30 minutes and come back refreshed (mentally if not physically).

3.       A small victory. Academia is beset by failure: be it experiments, grant or papers. Sometimes I need little wins. Running can provide wins through running fitter, further or faster. Apps have revolutionised incremental gains in running and whilst there are few wins smaller than knowing you were the 17^th fastest person across Waterloo bridge on a wet Wednesday in November, it beats the old method of ‘winning’ against random strangers running in the park who don’t even know they are in a race (though admittedly I do this too).

4.       Thank you. One of the major stressors at work is in comparing myself to others, losing sight of what I have achieved in the comparison. Running provides moments of wonder and gratitude: turning the corner to see the sun rise over the sea, or the light dancing on a wheat field or even just the smell of rain on the London pavements. Likewise, going on the same route year round gives a great sense of the changing of the season. Admittedly the endless slate grey of the British Autumn/Winter/ Spring can get a bit monotonous but eventually the joyous day comes when the greenery bursts into life. Restoring the perspective that I often lose.

All of these benefits are variants on a theme: they take me out of myself, focusing my thoughts on simple things. I am at my least healthy when I get caught in a loop: be it funding, staffing or logistics. Interrupting this loop with something else can be enough to shut it off or get me to focus on the solution not the problem.

Of course there are other ways I can achieve the same state. They are mostly outside: walking, camping, gardening, playing football or listening to live music. But where running has the edge is the ease and convenience. You don’t need anyone else; you only need a pair of trainers. It is also incredibly flexible, it can be squeezed in as part of the commute - though my fellow commuters on the 6:24 from Waterloo may be less grateful as I sweat my way home. It is also highly portable, I make every effort to take my running things when I travel with work and this has led to some of my favourite runs – along the seafront in Reykjavik as the sun sets over the sea, in the rain in Brussels, on a beach in California as dawn breaks.

Sunset over Iceland

Daybreak in California

As I said from the outset, this was largely a self-indulgent piece, I enjoy running, it helps me and wanted to share that feeling. Of course the reality falls short of the picture I paint here. There are often times when I don’t want to leave the house, when all my muscles ache and there was even a time when I got overtaken by someone dressed as a rhino. And while it’s not for everyone, I think the underpinning idea – doing something that takes you out of yourself is enormously beneficial. And if you found this a bit preachy, remember it could be worse – I could be a cyclist.

PS – did you spot them:

Runing up that hill: Kate Bush

Lose Yourself: Eminem

Working 9-5: Dolly Parton

Thank you: Dido

And a bonus point for spotting the Spinal Tap reference.

Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease

Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease:

Chronic Obstructive Pulmonary Disease (COPD) describes a
group of lung conditions that make it hard to breath. The major cause of COPD is
smoking. Nearly 1.2 million people in the UK suffer with COPD, costing the NHS
more than £800 million a year. Bacterial lung infections are particularly common
in COPD patients. There are a number of reasons that COPD patients are more
susceptible to infection but most research has focussed on failures of the
immune system. We propose an alternative mechanism in our latest paper in the
Journal of Allergy and Clinical Immunology (JACI).

Bacteria, like all living things, need food to grow. The
bacteria that infect us are no exception to this and their food source is us!
The airways are surprisingly rich in nutrients for bacterial growth, some of
this comes from the food we eat (micro-inhalation) and some leaks out from the
blood or cells lining the airways. In healthy lungs, glucose is actively pumped
out of the lungs maintaining it at a low level, but in damaged lungs the flow
of sugar into the lungs exceeds the amount of sugar that can be pumped back out.
Using model systems we have linked this increased lung glucose to increasedlung infection. We think that this works a little like
leaving a jam jar open – bacteria can colonise and grow on the available sugar.

We have now extended these results to patients with COPD. We
measured glucose in samples from COPD patients and found that airway glucose was
higher compared to individuals without COPD. Moreover when COPD patients had an
acute viral infection of the lungs (called an exacerbation) the glucose
concentrations were even higher, probably because the virus further damages the
lung. There was also a direct relationship between the amount of glucose and
the amount of bacteria in the COPD patient samples. We think that
mechanistically, the glucose is elevated because of lung inflammation –
essentially COPD lungs are more leaky, the glucose moves from the blood into
the airways with an impact on bacterial growth.

Why is this
important?

Antibiotics are commonly used to treat infections in COPD,
contributing to the rise in antibiotic resistance. Antibiotic resistant
bacteria (bacteria that are not killed by antibiotics) are a crisis in global
health. If antibiotics stop working, as well as an increase in the severity of
infections that are treatable, much of the medical advances of the last 50
years including surgery and transplants also become ineffective. We therefore
need new ways of killing bacteria. Demonstrating that bacteria are need the
sugar in the airways to grow opens up a new line of attack, cut off the
bacteria’s source of sugar. Potentially this would prevent bacterial infections
in the first place, circumventing the need for antibiotics.

Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses

Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses

Make your own vaccine

With pandemic infections we are always behind the curve,
particularly when it comes to developing vaccines. Vaccines work by inducing a
protective immune memory to an infectious agent so you have to know what the
infectious agent is and which part of the infectious agent the body is going to
recognise to make an effective vaccine. Having identified that, you then have
to make the vaccine, test the vaccine and ship it to the sites where it is
needed in order to give it to people before they are exposed to the infection.
This all takes time.

Manufacture = time

A particularly time consuming hurdle is vaccine manufacture.
This is because most vaccines that we use are protein based, which can be
difficult (and expensive) to manufacture. There are however alternatives. One
approach is to utilise our understanding of how proteins are encoded in our
cells. The source information for proteins comes from genes (encoded in DNA
molecules), this genetic material is copied into an intermediary messenger
molecule called ribonucleic acid (RNA). Remarkably, if you inject either DNA or
RNA into a muscle, that muscle starts making the protein encoded in the DNA.
Even more amazingly, your immune system can then recognise the protein that is
made in your muscle cells and develop a protective response, in the same way
that it would to an injected vaccine.

RNA vaccines

The injection of RNA in particular, seems to be very
effective at triggering an immune response. In our recently published
paper, we looked at ways to improve how these RNA vaccines work. We compared
two different approaches, the first approach is to make synthetic RNA molecules
that look exactly like the messenger RNA (mRNA) your body makes when it is
making a protein. The second approach is to adapt a trick from a family of
viruses called the alpha viruses, which use the machinery of the cell to make
copies of themselves. We can insert vaccine genes into a safe version of the
alphavirus, which when injected makes multiple copies of the vaccine in the cells
it has been injected into. We call these vaccines self-amplifying as they are
able make more copies of themselves after they are injected.

We compared the two RNA approaches to see which one would
make the best influenza vaccine. Both the mRNA and the self-amplifying RNA
based vaccines protected against influenza virus infection, but strikingly the self-amplifying
vaccines gave the same protection when 60 times less RNA was used. This dose
sparing could potentially be really important in the face of an epidemic where
many people need to be vaccinated in a short time period. We also show that the
vaccine was able to protect after a single dose and it is possible to combine
multiple strains of influenza virus in the same vaccine and protect against all
of them.

We think RNA vaccines show great promise for the future and
this study gives us confidence to move forwards into human studies.