Refocusing the Microscope

I grew up staring out at the stars through my parents’ antique telescopes; marvelling at the tiny pinpricks of twinkling light and how, on a clear night, the Milky Way streaked across the sky. There are more than 100 billion stars in our galaxy, and more than 1,000 billion galaxies in the universe. How many of them, I used to ask myself, contained planets that were home to life like our own sphere of rock and ocean? It was always the potential for life that fascinated me, be it aliens with copper in their blood and sulphurous breath, or plants with red leaves and a taste for nickel. It felt like us humans were just a small part of something infinite in its vastness and, when I thought about it too hard, I became a lone comet tumbling through 46 billion light years of unknowable space.

When I grew tired of feeling small, I played with my parents’ brass microscopes, with their chipped lenses and seized knobs. At first it was leaves and hair and globules of pond water dripped directly onto the mirrors. I never saw very much but the hidden microscopic world fascinated me as much as looking out at the stars. I must have been about ten when the concept of bacteria first took hold of me. I think it was via a book mentioning Anton Van Leeuwenhoek who, back in the 17th century, had fashioned himself a homemade microscope to look at what he described as ‘wee animalcules’ and ‘cavorting beasties’ in fresh water. Of his animalcules, Leeuwenhoek said ‘ten thousand of these living creatures could scarce equal the bulk of a coarse sand grain.’ My view of the universe we live in stretched a little further, much like it had the moment when I’d realised the stars could all be someone else’s sun.

I grew up to become a microbiologist and not an astronomer. From a distance, both fields looked similar to me. Both saw the universe through lenses and mirrors, only one was looking up and the other down. I wanted to see the smallest living creatures in the world because, if we don’t even understand the extremes of life on our own planet, how can we hope to comprehend the breadth of life to be found throughout the rest of existence. The microbial universe was as beautiful as the night sky, with the way Bacillus subtilis formed fractal-like patterns across an agar plate or the rainbow hues of cyanobacteria radiating from the edges of the Yellowstone hot springs. Even the pathogenic species could be wondrous in the way that, wherever you look, life has found a way and a home.

I didn’t intend to work on a pathogenic species at first, but the days of Leeuwenhoek observing his animalcules are long gone. Microbiology, on the whole, is all about using our knowledge of microbes to better humankind—by finding a cure for tuberculosis, in the case of my own research. I envy astrobiologists their timeline, in a way. How they are still explorers who, one day, may be the first to see alien cavorting beasties in a droplet of water from Neptune or the traces of past life in a sample of silica from Mars. But I suppose any field can lose its shine when you zoom in to focus on the minutiae. That’s what happened for me, at least.

From the world’s biggest infectious disease killer, to a yellowy suspension of cells shaking in an incubator, to a fingerprint of proteins making dark bands on a Western blot. Somewhere in my ten-plus years in the lab, the beauty of the microbial world got lost among diagrams of signalling pathways and overly simplified models to distill the behaviour of bacteria down into something predictable. Does it remove some of the wonder of the solar system to understand the physics that hold our planets in orbit around the sun? Only if you spend so much time hunched over your mathematical formulae that you forget to look up at the sky from time to time.

So I left. There were other factors involved in my decision, of course. The birth of my daughter, for one, which re-centred my view of the universe around this one, impossibly bright point of light. But mostly it was that I’d spent too long looking down that microscope and had lost sight of everything else. The day after I handed in my resignation, a publisher at Bloomsbury messaged me to ask if I’d ever thought of writing a popular science book. Two years later, Catching Breath - The Making and Unmaking of Tuberculosis is on its way to publication. I started out intending to shine a light on how Mycobacterium tuberculosis, the bacterium behind the disease, is the cleverest of them all. Only, the gravitational pull of my own cavorting beastie kept changing my focus. It’s no longer M. tuberculosis that fascinates me, but the place it occupies in the world.

I used to think of the microbial universe as something separate from us, to be observed from a distance. Only, microbes—the ones on our skin, in our guts, floating around in our drinking water, or causing infections such as TB—make up the fabric of our lives. We exist in a vast, interconnected world in which no one species lives its life in isolation. There’s no good guys and bad guys here, not really; just a huge tapestry of life that isn’t always sewn in humankind’s favour. Catching Breath isn’t a zoomed in review of the scientific research into M. tuberculosis. I’ve taken a step away from my own work and tried to tell a story of how TB fits into the rest of the world and, in doing so, I’ve remembered why I got into research in the first place.

Scientists find the gene for…

 

Steve Jones begun his talk at the Henley Literature Festival by breaking the news that he was not the same Steve Jones who played guitar in the Sex Pistols. I was personally quite glad about this because it would have made writing this article on genetics somewhat difficult.

The Welsh geneticist and snail fan-iteration of Steve Jones has a new book out called The Serpent's Promise: The Bible Retold as Science. In the words of one of his reviews, it is a “re-cranking of the Darwinian barrel organ – accompanied by the monkey of New Atheism as it screeches petulantly at religion.” Sounds awesome, right?

His talk focused on the role of genetics in the nature versus nurture argument, using the bible as his starting point. Are we born already tainted by Adam and Eve’s transgressions in the Garden of Eden or, to put it in more scientific terms, is it worth trying to fight the genes we’re dealt at conception or are we all screwed before we even get started?

What does genetics tell us?

Are you sitting with a few others? If so, check out the two people closest to you. Statistically speaking, two out of the three of you are going to die as a result of your genes. Cheery thought, right? Although, in Shakespeare’s time, two of you would already be dead so that’s something to be thankful for. It was with this introduction that Jones begun his discussion of what genetics can—and what it can’t—inform us about who we are.

Clearly plenty of human attributes are linked to our genes. Thanks to my parents, I am at risk of developing high blood pressure and have my mother’s nose (in a jar on the mantelpiece, mwah ha ha). But it’s not a simple case of Genetics=Destiny, despite what certain scientists and members of the media would lead you to believe.

“Ignorance more frequently breeds confidence than does knowledge.”

Type ‘Scientists find the gene for’ into Google and more than 10,000 pages pop up. Among the hits is the slightly dubious premature ejaculation gene. Jones was quick to explain how this kind of reporting contributes to the public misunderstanding of genetics.

Overhyping the role of genetics is what was behind the UK’s disastrous Eleven Plus education policy in which they attempted to identify the ‘naturally talented’ kids worthy of a decent schooling. Take a class of kids and measure their IQ and there’ll be a natural variation in their scores. But we now know that, during childhood, genes can only explain 10% of this variation (interestingly, this goes up to 70% in the 65-70 age range). You see this when you look at twins adopted into different families—their environment plays a far bigger role in academic performance than genes do.

So the Eleven Plus didn’t really measure a child’s potential, all it did was deprive some kids of an education that could have drastically changed their life.

Extreme poverty drags everyone down regardless of genes

The part of the talk that stuck with me the most has to be how the contribution of genes to IQ differs dramatically depending on how rich you are. Among the top percentile for income, the contribution of genes to the population’s variation in IQ comes in at 0.7 (70% of the variation can be explained by genetic variance). Bottom percentile for income, and it drops to 0.1. For these people, their genes don’t make the damnedest bit of difference. Cue embarrassed shuffling from some members of the entirely middle- and upper-class audience.

It’s a similar situation when you consider the ‘gene for criminality’ found in half of the population. Yup, that’s the one responsible for testosterone production in the violent, dangerous creatures otherwise known as ‘men’. If you look at murder rates by age for men and women, those in possession of a Y chromosome commit around 10 times more murders than women. The peak age for criminality is between 20 and 30, gradually tailing off into ‘grumpy old men’ as Jones put it.

Compare the graphs for the UK and Detroit, and they look identical until you notice the scale of the Y axis. In the UK, the peak murder rate is 25 in 1 million. In Detroit, it’s 1000 in 1 million. Men still commit 10 times more murders than women but something about the environment has changed the scale of the problem. I’ve never been to Detroit and, after listening to Jones’ talk, I am not sure I want to.

Do our lizard brains impact on criminality?

Setting aside the limitations of brain scanning as a science, it can be used to demonstrate something really clever about how genetics can influence criminality. There’s this primitive little bit of the brain called the amygdala responsible for emotional responses and, if you surprise someone in an MRI scanner, you can make this region light up.

The degree to which the amygdala is activated depends on levels of a protein called monoamine oxidase A (MAO-A)—an enzyme involved in the transmission of nerve impulses. Those who are genetically programmed to produce low levels of MAO-A tend to respond more strongly to sudden shocks, giving them a worse temper than those who produce normal levels of MAO-A.

But MAO-A levels are not deterministic when it comes to aggression and criminality. There are plenty of people who make low levels of MAO-A (Steve Jones, for one) who don’t run around fighting and murdering. And there are people with normal levels who, thanks to their circumstances, end up taking a less than virtuous path in life. The interesting difference appears when we compare the effect of stress and trauma on antisocial behaviour in those who make low and high levels of MAO-A.

Normal levels of MAO-A + unstable childhood = 3 times higher rates of antisocial behaviour.

Low levels of MAO-A + unstable childhood = 20 times higher rates of antisocial behaviour.

It seems that, in this case, genetics can predispose someone towards violence but environment plays a huge role in deciding if a person will live up to their ill-fated inheritance. Should genes, therefore, be taken into account in the justice system? Should upbringing? Or are we all ultimately responsible for making the best of whatever cards we are dealt?

"We don’t need more geneticists, we need more theologians"

With genome sequencing becoming easier and cheaper, Jones believes that we will soon reach a point where it is possible to sequence the DNA of every child born in Britain. The problem is that this won’t tell us very much. No matter what genes we are born with, nurture still gets a look in. It’s why I get frustrated every time I see newspapers sloppily reporting scientific developments with headlines such as Are you a victim of the hunger gene? It misleads people into thinking that human behaviour can be explained in genetic terms when it is far, far more complicated in reality.

Survivorship Bias in Science

Let’s imagine for a moment that uncertain job prospects and too much caffeine pushes me over the edge and I gather up every monkey in the world and shut them in a room with a bunch of computers. Sometime later, I return to a lot of flung poo and, among all the random strings of letters typed by the unfortunate (and now cannibalistic) monkeys, I discover that one capuchin has typed the sentence: “HELLO KAT”.

This is a version of the Infinite Monkey Theorem, which basically states that a monkey hammering on a keyboard for an infinite amount of time will eventually type out the complete works of William Shakespeare. It’s all about probabilities.

Give a million monkeys ten years, and the probability that one of them will type ‘HELLO KAT’ entirely by chance is 1 in 2. The same as guessing the outcome of a coin toss*. Throw in all the other 9 character sentences that can be made from the letters on a keyboard, and the likelihood of one of the monkeys NOT typing something meaningful by chance is practically zero.

But what happens if I now take that one, single monkey, and I publish a paper saying that I have found the world’s first literate capuchin? Disregarding all the random sentences typed by all the other monkeys, I proclaim that there was only a 1 in 1.8x10⁷ chance that my monkey could have randomly typed ‘HELLO KAT’. Those odds are so slim that surely this particular monkey must have intentionally hit those particular keys?

This is an example of Survivorship Bias, in which only focussing on the successes while ignoring the failures can lead you to make incorrect conclusions.

The same thing happens when it comes to careers. I can’t count the number of times I’ve listened to a leading scientist explain how they made it to the top using their formula of:

(Being smart) x (Choosing the right field) ^{(Hard Work)} + (Networking) = Success

The thing is, this doesn’t take into account all the people who are plugging the exact same numbers into the exact same formula and coming up with entirely different results. When something is heavily dependent on chance and luck, you can’t make conclusions based only on the survivors—you need to check the graveyard too. The road to permanent scientific positions is littered with the tombstones of postdocs who have fallen along the way and I can’t believe I didn’t notice them until the point at which I was down on my hands and knees, scrabbling around in the dirt.

The stupid thing is that others did try to warn me when I started out, but I didn’t want to listen. Looking back, I wish I hadn’t been so quick to disregard the experiences of older scientists finding themselves in the same position I am now in. It was all too easy to presume that they’d done something wrong; that they hadn’t tried hard enough or they simply weren’t very good at science. Understanding the role that luck plays in a scientific career wouldn’t have stopped me from becoming a scientist, but it might have made me less of a dick.

Now that I am picking myself back up and heading off for pastures new, I am experiencing yet another example of Survivorship Bias. People who know that I write science fiction novels in my spare time keep sending me articles about self-publishing success stories. Why are you trying to find a traditional publisher when E. L. James self-published 50 Shades of Grey and look at her now! What they don’t realise is that, for every wannabe author who becomes famous from self-publishing, there are hundreds of thousands who fail miserably.

When it is a scientist who tries to tell me how to be successful as a writer, I ask them if they would self-publish a scientific paper that had been rejected by a few dozen journals. It’s not the same, they say, science isn’t subjective like writing. You either do it right or wrong. Then I sit back and wait for them to do everything right and find that it still isn’t quite enough.


*Let’s just say there are 50 keys on my keyboard. So the probability of that monkey hitting the first ‘H’ is 1/50. The probability that the ‘H’ will be followed with ‘E’ is (1/50) X (1/50) and so on. I worked it out, and the overall probability is 1 in 1.9x10¹⁵, which in the grand scheme of things is extremely close to zero. But let’s say that a monkey can type at a speed of 200 characters a minute and it manages to type around 100 million strings of 9 characters over one year. If we work out the probability that the monkey will type ‘HELLO KAT’ at some point over the year, it works out at 1 in 1.8x10⁷ – still very, very unlikely. But what if we give a million monkeys ten years? Now the probability that one will type ‘HELLO KAT’ entirely by chance is up to 1 in 2.3. Entirely doable.

Scientific Stockholm Syndrome

Science embodied as a person would be a rubbish date. You’d be so dazzled by Science's awesome that you’d not only end up paying for dinner, but you’d find yourself promising them your undying loyalty. Then, before you know it, you're feeling guilty for not spending all of your time with Science and Ohhh that Kool-Aid looks really tasty*.

Misplaced loyalty to a career undoubtedly isn’t unique to scientists, but it does sometimes seem to be worryingly common in my profession. How many non-science people do you know who’d continue to work when they’re no longer being paid? Not many, yet it is all too common for end-of-PhD students and sometimes even postdocs who need to do that last experiment for the paper. And don’t get me started on the long hours and weekend work that seem to be the norm in most research laboratories.

We tell ourselves that we’re doing it for our own benefit—because we love what we do and want to give ourselves an edge in a very competitive environment. But lab heads and universities happily take advantage of this devotion to our careers and there comes a point where they are benefiting far more than the temporary scientisit. Like the vampires inexplicably romanticised by young adult fiction, of course employers aren't going to say no to willing victims eager to be sucked dry of their intellectual creativity*. But maybe they should.

Sure, less PhDs would get funded because it would cost a hell of a lot to keep paying every student until the moment they submit their thesis. Some papers wouldn’t get finished if universities couldn’t find extra money to keep on postdocs at the end of a grant. And the scientists would be the first ones to complain and defend their right to be exploited. 

With four months left in the lab, I’m not sure what scares me more—coming to the end of my contract and not having a new career to move on to, or finding a new position with time to spare and having to leave my project unfinished. Come December 31st, neither my current boss nor my research career is going to be buying my New Year’s Eve beers, so why do I feel like I would be letting both down if I don’t stick it out until the very last chime of Big Ben?

I’m sure that there are few lab heads out there who, if offered the professorship of their dreams, would turn it down out of loyalty to their postdocs and PhD students. So why do some temporary staff like me feel so guilty at the prospect of jeopardising a lab’s future grants and papers by making a selfish decision that would be in our best interest? It's like I have to keep reminding myself that my contract with the university is for a three year postdoc and not my soul. 

My relationship with Science has reached the point where I’m sat comfortably on the sofa in jogging bottoms, with barbeque sauce smeared around my face. Science is out there being all sciencey and cool, and here I am, clinging on to the memories of all our happy times together*. I keep telling myself that loyalty is only worth as much as the rewards it yields, that I could be so much happier in a new relationship, but it is so hard to not feel guilty about leaving. 

*I blame impending unemployment for all this melodrama. If any potential employers are reading this, I really am entirely sane. Please give me a job. 

Swan (Dive) Song

On leaving laboratory science and why it’s going to be awesome (but first a rant)

A few years ago, I went on this residential course for postdocs whose years’ experience was greater than their output of Nature/Science/Cell papers. We made paper bridges for hamsters and drew our innermost feelings on giant shields for a reason I can’t quite fathom. Later, when we’d all got to know each other through the medium of unrelenting pessimism and beer, we went around the room and stuck post-it note ideas for alternative careers on everyone else’s shields.

My alternative career suggestions? Science fiction novelist, science journalist, or primary school art teacher.

Today, with five months left of my contract and the decision made that it is time to move on to a new career, I find myself looking back on those suggestions and thinking how absolutely, ridiculously naïve they were. We all know that there are more postdocs than there are permanent research jobs, and that most of us will have to pack up our ‘transferrable skills’ in a little knotted handkerchief and venture out into the big wide world. But this enthusiastic ‘You can do anything you want with a PhD!’-mentality doesn’t help anyone. It’s right up there with patting a five-year-old on the head and telling her that of course she can grow up to be an astronaut if she Just Dreams Big Enough.

It’s the science journalist suggestion that bugs me the most because I hear this from students. All. The. Time.

“What are you going to do after your PhD?”

“Oh, you know, I’ll probably just go into science journalism.”

No experience, no training, no particular interest in science communication. But, for some reason, there seems to be a prevailing attitude among a worrying proportion of scientists that having Dr in front of our name somehow qualifies us to hop out of the lab and easily pinch someone else’s hard-won career. It might be our plan B, but it will do. And I worry that it makes the rest of us look like dicks by association.

This is my big problem with PhD training.

Universities are churning out all these slightly entitled 25-year-olds with no idea of how the real world works. Students are paying more and more for their undergraduate courses, and the teaching is becoming increasingly structured with teaching fellows taking the lectures instead of researchers. To me, it feels a bit like we’re spoon-feeding people who should be able to learn independently by this point in their life. Then some start a PhD and a small minority never pause to consider that maybe they should stop thinking of themselves as a student and start acting like an adult.

No one really fails a PhD—I've seen far too many poor students saunter through their vivas with no problems after spending 3 or 4 years treating their PhD like a hobby rather than a professional job. And this devalues the PhD for everyone else. With so many of us wanting to use our skills in other careers, I'd kind of like it to represent the pinnacle of scientific education and not become an esoteric qualification unworthy of respect.

It's hard enough for the best and the brightest scientists to secure fellowships or lectureships, so why are we letting people continue wasting their time and money on a pointless PhD that won't help them become a scientist and hasn't taught them anything they couldn't have learnt better in the workplace?

There is no grading for a PhD but maybe there should be. Or maybe the standards just need to be higher and more consistent. Would I have passed if this was the case, or even got a project in the first place? I like to think I'd have risen to the challenge but we will never know. 

But what does this bitter little rant have to do with me leaving science?

At the end of the day, it’s not the poor job prospects and uncertainty that got me (although that didn't help). No, it’s being part of a system that spews out more and more PhDs despite knowing that there just aren’t enough jobs, then tells us that we can do anything we want with our little qualification and starts again with the next batch of naive wannabe scientists. Throw enough people at Science and a few will stick. Everyone else? Transferable skills!

It lets everyone down—the students who don’t have a clue and the postdocs who become demoralised at the thankless task of mothering adults who don't know why they’re doing a PhD in the first place. Science and scientists are complicit in a system that screws over postdocs in more than one way and it's shit.

So I'm going to take all my 'transferable skills' and find a job that makes me happy instead of frustrated; challenged instead of used; that respects me for the things I am good at instead of treating me like a disposable scientific thinker, broken equipment tinkerer and exhausted nursemaid.

I’ve always felt like leaving science and starting something new would feel like I’d failed. And I guess this is part of the reason why I’m jumping before I am pushed. But, now that I’ve told my boss that this postdoc is it for me, I feel inexplicably happy. I have no idea what I will be doing after Christmas, and it’s going to be awesome finding out.

The Green (Fluorescent Protein)-Eyed Monster

Is there a formula for scientific success, or do some scientists simply ‘get lucky’?

When in doubt, draw a graph. This is not so much useful advice as a way of life. The pros and cons of various DNA ladders? The best flavour of soup for ten minute incubation breaks? Or the relationship between things breaking and student proximity? Questions all vastly simplified through the liberal application of pie-charts, bar graphs or, in times of great need, 3D scatter plots. In my experience, there are only two things that can't be better explained in a graphical format: cats and scientific careers.

Surely there should be a positive correlation between the amount of effort a scientist puts into their career and the likelihood of scientific success? But, no, instead of a nice straight line with an R2 value of 0.99, I keep getting something that looks like the teeth of a career-eating monster. "Aha," says Reviewer 3, "the author has failed to take an important variable into account: creativity." And, for once, he/she does have a good point. Is there any scientist out there who hasn't entertained the scary possibility that their lack of seventeen Nature papers might just be due to a lack of scientific ability?

But natural talent isn’t enough, and neither is hard work. I still can't get the numbers to add up. There's something else at work here: luck.

An extreme-graphing habit doesn't exactly leave much room for futile emotions such as jealousy. But, when it comes to scientists who seem to get all the lucky breaks, I can't seem to help but daydream about all the terrible accidents that might befall them. Contaminated cultures, ripped protein gels, background on their western blots. I know, I'm an awful person.

Yet luck is something that anyone embarking on a career in the lab needs to consider. With only 5% of early career postdocs progressing to the next level – a fellowship or lectureship – there is the very real possibility that many good scientists are going to find themselves chucked out of the lab along with the out-of-date plasmid extraction kits. Actually, that's not true – no one would throw away perfectly useable consumables just because they are past their use-by date.

Choose a slow-paced lab in which to pursue a PhD, or the wrong project in some cobwebby corner of science into which even your supervisor doesn't want to venture, and your career is already off to a shaky start. In today's competitive scientific environment, no one can afford to treat a PhD as a learning experience during which they can gradually learn how to be a fully-fledged scientist. Yet no one seems to tell you this when you're getting to grips with your pipette.

With the big grants increasingly going to big established labs, the chances of making a real impact during your PhD can depend on being in the right lab at the right time. Pick a mentor who will champion you through fellowship and lectureship applications, and you have the chance to sink or swim on merit alone. And these are the lucky guys and gals that test my composure more than temperamental cell lines. I don’t doubt that they’re brilliant, but it sometimes feels like they've had all the opportunities.

But maybe it's just that they've taken advantage of their fortuitous circumstances, and managed to get themselves in a position where luck is on their side?

We are always hearing how so many of the big scientific discoveries are down to luck. Alexander Fleming discovered penicillin when one of his bacterial Petri dishes became contaminated with antibiotic-producing mould, right? Only, what no one seems to mention is that it was Fleming's scientific curiosity (and stubbornness) that got penicillin through the ten long years it took to find a way to turn it into a drug. That wasn't luck that was, um, science.

Much of the work we do as scientists is preparing ourselves so that, when those moments of serendipity strike, we are ready for them. Perhaps the same goes for careers and the 'lucky' guys aren't lucky at all.

After the media fellowship

I recently finished a month-long British Science Association Media Fellowship, spending three weeks at Nature and one week at the British Science Festival in Aberdeen. I’ve talked more about my thoughts on this experience at the Wellcome Trust blog.

I’m now left wondering what on Earth I am going to do with all my newfound skillz. See, I exist at a leisurely gastropod-like pace, whereas the news media seems to be more of a fast-moving cephalopod. Science=three year deadlines that can meander off in an unexpected direction at any point; news=short window until it’s too old for anyone to really care. So using this blog to write about scientific advances (my pre-placement plan) is a pretty stupid idea unless I’m going to add something that isn’t already being said faster and better by a professional news outlet. Mollusc-based metaphors, sadly, aren’t quite enough; I think I’m going to have to develop opinions. We will see how that turns out.

Anyway, I’d recommend applying for a Media Fellowship to any scientists who are interested in how the news works. Then, you too, can be plunged into a metaphysical quandary about your place in the science media world.

Oh, and here’s my big self-aggrandising list of things what I wrote while on my media placement:

Nature News articles and blog posts:

Scientists do the wet dog shake
Nerve growth factor linked to ovulation
Helium reveals gibbon’s soprano skill
There are fewer microbes out there than you think
Resistance to backup tuberculosis drugs increases
Hepatitis C drug trial halted after patient death
Photosynthesis-like process found in insects

Research Highlights and News in Brief:

Rodent that cannot gnaw
Infection breaks truce
Inflamed guts boost bad bacteria
Cigarette smoke boosts biofilms
Hepatitis C halt
Resistance warning

Wellcome Trust Blog articles:

From growth media to news media
No such thing as a stupid question
When the drugs don't work

British Science Association website:

Stereotypes form by ‘Chinese whispers’
Sex and sewage
Cows and cars
Sensing hidden oil reserves
Shock – balanced diet is healthy!

Image: Neurons in the brain – illustration. Benedict Campbell. Wellcome Images

H5N1 controversy from a scientist's perspective

What's all the fuss about? Flu isn't so bad, right?
Seasonal flu is an annoyance for most people but, in the young or elderly, or immunocompromised individuals, it can still be fatal. Each year, there are around 4,000 deaths attributed to flu in the UK, despite these people having access to health care and anti-viral medicines.

So why is everyone so worried about bird flu?
The H5N1 bird flu strain has so far caused 578 confirmed infections and 340 deaths, but all of these individuals were in close contact with infected birds. The big fear is if the strain gains the ability to be transmitted between humans, which would give it the potential to cause a global pandemic. But we don't know how likely it is that this will happen, so it's very much a waiting game. Because none of us have encountered this strain before, we have virtually no resistance and the outbreak could be much worse than seasonal flu. It has been estimated that the worldwide death toll could be around 150 million and, because the strains are constantly evolving, we can't make a vaccine until the epidemic begins. The best we can do is stockpile anti-virals and put in place contingency plans for what to do if the worst case scenario should materialise.

What's this about scientists making a transmittable version of the bird flu virus?
Scientists want to understand how the virus might make the leap into being transmittable between humans and, to do this, they have created a version of the virus which can be passed between ferrets. Ferrets are a good model for flu in other mammals so there is a good chance that this virus would also be able to spread between humans (but this isn't known for sure). The two papers in question have not yet been published and there have been calls from the US government for the journals in question, Science and Nature, to censor specific details about how the research was done in case bad guys use it to reverse-engineer a bio-weapon.

So the scientists have played God and created a killer virus just because they can
Let's get this one out of the way first. It is terrifying to see just how many web pages come up if you Google 'H5N1 playing God'. Do people honestly believe scientists are power-crazed maniacs doing really stupid things for the sake of it? Because it simply isn't true. This bird flu research was designed to give us a better understanding of how a potentially deadly virus might emerge naturally and go on to kill millions. Similar research into flu has led to some awesome discoveries that better prepare us to deal with this disease. For more information, here is an article by a scientist behind one of the bird flu papers explaining why he believes this work to be so important.

These papers contain methods that can easily replicated by those that would like to use flu as a bio-terror weapon
A well accepted way to create strains that can be transmitted between animals is to repeatedly grow the virus until it accumulates the mutations that will allow it to be passed on by itself. This is effectively happening in nature right now and many believe it is a matter of time before the bird flu virus does it outside of the lab. We need to understand how this could happen in order to prepare for a situation in which it does. And failing to publish these papers won't stop terrorists from attempting this method if they really want to but it isn't a quick and simple task.

But they could use the mutations detailed in the paper to reverse-engineer a deadly strain
It's been reported that all of the mutations leading to these new strains are already published - that's because the same mutations have already been seen in the wild, albeit separately. A person with enough knowledge of the flu virus would most likely be able to make an educated guess as to how to go about engineering a similar strain but even an expert would find recreating the virus to be a mammoth task. Generally, if you've put all your effort into following the terrorist career path, you probably haven't had the time to become an expert on complicated viral genetic manipulation.

How can scientists even run the risk that someone will use this information for evil purposes?
Because the dissemination of information is a cornerstone of science. Censorship is a slippery slope which could lead us to a point where legitimate scientists cannot access information that could help their work and be of benefit to others. However, it is unlikely to provide a barrier to those intent on doing harm. If we are going to start restricting what information can be published among the scientific community, we need to know that the restrictions will work and that they are being imposed for the right reasons, rather than as a knee-jerk reaction to the slightest whiff of concern. The laboratories at the centre of this controversy have agreed to a 60 day halt in their work so these concerns can be discussed - this is an effort to show they are taking the situation extremely seriously but some have voiced worries that it is simply an empty public relations gesture. But any bad feeling between the scientific community and the public needs to be addressed - it helps no one if scientists adopt a 'we know better than you' attitude and refuse to justify themselves.

Is the work really of any benefit, though?
Predicting how scientific advances will help us in the future isn't always possible - some of the biggest discoveries in science have emerged when no one was expecting them to. Sometimes in science it is necessary to accumulate a critical level of unusable information before something comes of it and anything that improves our understanding of a disease such as bird flu can only be a good thing. So perhaps this bird flu work will lead to a better vaccine or drug treatment, perhaps it won't. Some people have suggested that it will allow us to better monitor the virus, allowing us to predict when it might start spreading between humans. In theory, this is a great idea but, unfortunately, it relies on quick and reliable reporting of infections and they are currently occurring in parts of the world not well known for their organisational skills when it comes to keeping track of viral infections.

It is inevitable that some of these strains will get released by accident and we'll all die
Safety measures in every category 3 laboratory are extremely tight, training is extensive, and every scientist I've met takes safety very seriously - none of us want to infect ourselves, after all! We all need to consider the risks versus the benefits. Yes, dangerous work does go on in scientific laboratories. No, it is not inevitable that there will be an accidental release of something deadly.

But the work isn't even happening in the highest biosafety level labs
In the country where this work was conducted, bird flu can be used in category 3 laboratories rather than the stricter category 4 facilities (used to study diseases such as ebola). This isn't an indication that the scientists in question are being stupid, it is an indication that they have considered all the possible risks and have gained permission from the relevant agencies for this work to go ahead. But I personally do find it slightly surprising that a cat 3 was used - I know in the UK, our bird flu work takes place in cat 4 labs.

And it has been reported that there are no armed guards protecting the virus!
This is true, universities and research institutes don't tend to station people with machine guns at every entrance. Yes, if armed terrorists stormed the labs, they could potentially steal these strains. But, come on guys, we can't start having armed guards stationed in all the places that everyone's currently panicking about, only to move them on when the next sensationalist newspaper article pops up. Preparing for real threats (such as the natural emergence of bird flu) is surely better than living in fear of something extremely unlikely happening?

If it gets out, this strain will kill 80% of those infected
It is surprising how much this statistic is reported. Yes, nearly 60% of the reported bird flu cases have resulted in death. But the problem here is the word 'reported'. Only those who are very, very sick go to hospital - when was the last time you reported mild cold symptoms to your doctor? So we don't know how many people have been exposed to bird flu but haven't become sick. The death rate is likely to be much lower than 60% - possibly less than 1%, in fact (see this PNAS article discussing the fatality rate, amongst other things).

There is no treatment or vaccine available
Current anti-virals are active against the H5N1 strain and there are vaccines that provide some protection against H5 strains. But it is true that, if there was a global pandemic, it would likely take 4-6 months for a vaccine against the strain to be formulated and distributed.

Nefarious governments are deliberately doing this work to create weapons
There isn't much arguing with conspiracy theorists who believe the world leaders are out to get them. But I can tell you that I've met few scientists who'd be willing to act as minion to some shadowy government organisation intent on killing off half the world's population. That probably isn't much comfort if you've already convinced yourself that the government and all scientists are inherently evil. In truth, very few of us are evil – if we were, we’d have chosen alternative career paths such as banking.

Image: Cybercobra at en.wikipedia

Thirteen things about doing a science PhD...

...that I wish I could tell my younger self:

1. It’s not going to be easy or, at least, it won’t feel easy. At some point, you’re probably going to start doubting everything about yourself, from your ability to generate high-quality data to whether that old lady on the bus moved seats because the stench of E. coli DH5a has somehow impregnated itself into your very soul. Of course, make it to post-doc status and you’ll look back on your PhD days with a mixture of nostalgia and nausea—how could you not have realised back then that pretty much everyone passes? I suppose it is a kind of rite of passage. Like the Satere-Mawe Tribe of the Amazon who endure the agonizing stings of hundreds of bullet ants to prove themselves men. Awesome.

2. Be prepared for failure. Things don’t always work in science. Even when you go it right. Don’t take it personally. Instead, add the phrase ‘optimising the procedure’ to your dictionary and whip it out any time someone asks why you have no results.

3. Don’t expect to know everything straight away. And it’s alright to admit that. By the end of the PhD, your little brain is going to be so full of esoteric information that it may have purged large portions of your childhood from your memory. But you can’t miss something you don’t even remember.

4. Take responsibility for your mistakes, and don’t try to come up with explanations until you know enough to not look like a twit. Occam’s razor—the simplest answer is usually the correct one. If your culture is contaminated, you’ve probably got your mucky little fingers too close to it. The autoclave is not the problem—it works for everyone else. If your digests haven’t worked, I can bet it’s because you’ve forgotten to add an enzyme. It’s highly unlikely that the air-conditioning is causing temperature fluctuations that set up convectional currents within the tube thus preventing access to the enzyme’s active site. Own your mistakes and then deal with them. No one else wants to sit through an hour-long lab meeting in which you describe how DNA from the air has floated into your ligation and caused mutations. Learn to do it right before you decide Science is the one who's wrong.

5. Don’t cry in the lab. How I love undergraduate project time. It always feels like a lottery—what if we get that student. Not the one who uses the last Miniprep column without ordering a new kit, or who leaves all the antibodies on their bench for several weeks. Or even the one who doesn’t actually turn up to the lab. I mean the student who (brace yourself) cries when their experiments fail. Scientists are not always known for their interpersonal skills so we have absolutely no idea how to react to a sobbing undergraduate who has just accidentally murdered ten billion bacteria by adding formaldehyde instead of glycerol to their culture. Once you get to PhD level, it’s time to get really good at learning to fix your own mistakes—the post-docs don’t need to know and we certainly don’t need to console you and tell you it’s all going to be OK. It’s not.

6. You’re not an undergraduate anymore so don’t act like one. That ‘I’m still a student’ safety net is great, don’t get me wrong. But now is the time to take responsibility for your own work and start acting like this is a real job. That means turning up on time when you need someone to help you, solving your own problems, and coming up with your own ideas. Asking lots of questions is one thing but you need to ask yourself if they generally take the form of: "I did [insert something dumb here] to my experiment, will it still work?" This is basically asking for reassurance in the same way that a freshly xmas-fattened person asks if they have put on weight: it's not something a co-worker wants to discuss with you and you don't want the real answer anyway. Just do it again. This brings me on to…

7. A post-doc is not your mother. Post-docs have their own jobs to do and supervising students in the lab is not top of their priorities. If you can’t find something in the freezer, what makes you think they will have any more luck? OK, yes, they will probably find it because they’ll do this amazing thing known as ‘looking properly’. Lost your lab book? Same answer. Expecting someone else to drop everything to do something for you that you could do yourself is kind of crappy.

8. If you think all your work is brilliant, it probably isn’t. Self-criticism is the best skill you can learn. No one likes an arrogant PhD student and we’re unlikely to be sympathetic when your viva examiners rip you to pieces. Mwah ha ha.

9. No one else is responsible for your PhD, but be thankful for any input you get. When it comes to the viva, you’re pretty much on your own. So what if your supervisor came up with the original project and the post-docs made suggestions for what controls to include? Your examiners won’t care if you can’t defend the work. ‘Because I was told to’ is never a valid answer. However, there’s a fine-line between taking control of your own project and walking on the faces of people who have helped you. Failing to acknowledge someone else for the work they’ve done for you doesn’t make you look more productive, it makes you look like an ass.

10. Cutting corners will come back to bite you. Think it doesn’t matter that some of your graphs have error bars the size of the moon? You think you’ll have so many brilliant results after 3-4 years that none of the setup will make it into the thesis? Think again. A PhD thesis is a weird document—you may well end up including all those negative results that would never make it into a paper. Attempting to use Photoshop to reconstitute the seventeen pieces of your protein gel into something that doesn’t look like cack is not going to end well. Just run the gel again to start with. Or don’t drop it in the sink in the first place.

11. You might be stressed but so is everyone else. Your PhD, your mini breakdown. I remember starting my PhD and thinking everything would be alright once I finished. All those post-docs had it easy, didn’t they? So why weren’t they helping me All The Time, and putting off their own experiments so I could finish mine? But, trust me, it doesn’t get less stressful. Everyone is scrabbling for a handhold on science’s crumbling cliff face and pounding your little fists in fury only loosens the rocks. 

12. 9-to-5 isn’t a bad thing. Have you noticed how working long hours often makes a person intolerably smug about their work ethic, regardless of how many results they actually have? Yes, getting into the lab at 8 am and staying past 10 pm is all well and good, but not if you spend half that time on Facebook or go insane from never seeing daylight. Having a life outside science is not something to be ashamed of and adequate organisational skills will always trump long hours. I personally like lists—see, I even turn my angy rants into lists. Bringing me on to...

13. Those bitter post-docs – you’re probably going to be one of them. If I could go back in time and talk to my 22-year-old self, I would warn them that science is not a very reliable career path. It's all short-term contracts and far more post-docs than there are permanent positions. Hard work is all well and good, but there is sometimes a fair amount of luck involved and failing to progress past a couple of post-doc positions is not always a comment on someone’s abilities and intelligence. A backup plan is always a good idea.