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Sunday, 4 December 2016

The Beijing lineage of M. tuberculosis is the villain in a movie sequel. Nastier, scarier, harder to kill. You thought tuberculosis (TB) was bad? Think again. The Beijing lineage is that little bit worse, associated with a speedier disease progression and increased antibiotic resistance.

I’ve always had a thing for studies that attempt to pick apart the origins of infectious diseases. So when I spotted a paper on the makings of the Beijing lineage, my excitement levels came close to when I discovered there’s going to be a Guardians of the Galaxy 2.

A while back, a paper came out suggesting that the Beijing branch of the TB family tree emerged some 30,000 years ago in Southeast Asia. Then, as the Han Chinese population embraced farming as a way of life, BOOM! The Beijing lineage exploded in northern China and started its journey towards worldwide misery.

Another study, however, put the approximate age of the lineage at around 6,600 years old. Suffice to say, attempts to date the M. tuberculosis family tree are notoriously unreliable. They all rely on some pretty big—and pretty shaky—assumptions, mainly based around how quickly the bacterium accumulates changes in its DNA.

So on to this new piece of research. It takes advantage of the increasing availability of whole-genome sequencing to look at how the pathogen has evolved in fine detail. The researchers were interested in a specific branch of the Beijing lineage—the central Asian clade, which recently reared its evil little head in Western Europe.

Like previous studies, I doubt that the molecular clock used in this study was calibrated accurately. But what’s clever about work like this is that it’s possible to superimpose expansions in the bacterial population size over big human upheavals. More bacterial diversity=worse living human living conditions. TB basically takes advantage of low points in human history. Anything that results in poor health, overcrowding, decaying healthcare systems, etc etc.

The study suggests that back in the 1950s to 1960s, the central Asian clade first appeared in the former Soviet Union. Then, thanks to the Soviet-Afghan war, it entered Afghanistan 1979-1989. Following the American invasion in 2001, the clade spread further as people were displaced from their homes and former lives. As Afghan refugees found their way to Europe, so did the central Asian clade of the Beijing lineage.

Back in the former Soviet republics, the clade had been similarly busy taking advantage of the fall of the Soviet Union. When it comes to historical events with huge ramifications for TB, the implosion of the Soviet Union is among the big ones. Bye bye, decent public healthcare and TB control; hello, drug resistant TB. Even today, multi-drug resistant TB is a gigantic issue in many ex-Soviet countries.

What studies such as this one demonstrate is how easily M. tuberculosis rides upon the back of political instability, war, population displacements and all the other crap us humans heap upon each other. And based on current events, none of that crap is going anywhere. So where does that leave TB?

Eldholm V, et al. (2016) Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis. PNAS 113(48):13881-13886.

Saturday, 26 November 2016

In Agra’s slums, community volunteers are visiting the houses one-by-one and asking the occupants a simple question: “Have you been coughing for more than two weeks?”

Of the ten million new cases of TB every year, one-third remain invisible to the public health authorities. India currently holds the dubious title of World’s TB Capital and accounts for one million of those missing patients. Many of those whose TB goes either undiagnosed or unreported are lost somewhere among the muddy streets and flapping fabrics of the poorest urban communities.

Much of India’s TB problem is socioeconomic—poor housing, poor sanitation, overcrowding, and unhealthy populations both at higher risk of developing active TB and with limited access to adequate healthcare. Active case finding among these marginalised and vulnerable populations is part of the solution to ensuring that people receive treatment and do not continue to transmit their infection to others.

A short paper published last week describes the lessons learnt from a pilot project looking for active TB cases among the half-a-million inhabitants of ‘Agra city’. Community volunteers were offered incentives to visit house-to-house and educate the inhabitants on TB, collect demographic details, and ask if anyone had been coughing.

Where the answer was ‘Yes’, potential TB patients were referred to a local health facility for further testing. What surprised me about the results of the study was that only 40% of those referred actually went of their own fruition. The other 60% had to be accompanied by the community volunteers, who returned to the homes of those not self-presenting within one week.

The study also revealed that levels of TB knowledge among the 3,940 households surveyed were actually very high. Ninety-percent of respondents had heard of TB; most of these people knew that coughing was a symptom. Yet the volunteers still managed to find 382 potential TB patients who hadn't sought out a diagnosis.

When questioned, most of the families said they relied on private healthcare providers for medical care. India’s private sector is highly variable, encompassing world-renown TB doctors all the way down to unqualified charlatans. The combination of patients not seeking out medical care and, when they do, turning to someone who won’t necessarily provide them with a correct diagnosis begins to explain why so many cases of TB go undetected.

It was beyond the paper’s scope to discuss why patients don’t seek out a TB diagnosis but, for me, this is one of the most important questions. What are the barriers that stop people living in Agra city—or in any other part of the world, for that matter—from approaching the health services with symptoms of TB?

Because new drugs, vaccines and diagnostics aren’t going to eradicate TB alone; not when millions still don’t receive the existing treatments and people continue to die from what is a curable disease.

Prasad et al. (2016) Lessons learnt from active tuberculosis case finding in an urban slum setting of Agra city, India. Indian J Tuberc. 63(3):119-202

Sunday, 20 November 2016

You know when you drive an unfamiliar car and you have to find your way round all these knobs and buttons to make the car go in the direction you want it to go in? M. tuberculosis has the same problem when it comes to the human immune system. This can make things tricky as it’s a pathogen that practices immune subversion rather than immune evasion—driving the immune response in its own favour rather than hiding.

A lot of the time, specific lineages of TB stick to the human genetic backgrounds that they’ve grown-up infecting. Even as global travel increases and the world gets smaller, these associations between TB lineage and their preferred flavour of human host persist. Over millennia, specific lineages of M. tuberculosis have evolved alongside specific human populations, learning all our secrets and finding ways to navigate our immune systems. Faced with an unfamiliar host, however, the pathogen can struggle.

But some lineages and sub-lineages are better at adapting to new host backgrounds than others. They’re the ‘generalists’ of the TB family. In comparison, the less-adaptable strains are known as ‘specialists’ and more or less stick to geographically restricted populations. They’re the ones who, if they ever go on holiday, demand a hire car exactly like the one they have at home. ‘I can’t be dealing with these fancy Japanese cars’, they say. ‘Give me a nice, British-made Rover.’

This idea of co-evolution and adaption is one I talk about in more detail in my book Catching Breath - The Making and Unmaking of Tuberculosis. The book is basically a scientific biography of TB exploring how M. tuberculosis came to be the world’s biggest infectious disease killer and how science is going to kill it right back. It comes out next summer as part of the Bloomsbury Sigma imprint of popular science books.

Here, though, I wanted to mention a new paper that came out last week from Sebastian Gagneux’s lab in Switzerland. In it, he looks at the success of M. tuberculosis lineage 4. It’s the most adaptable lineage, making its home on every inhabited continent—a generalist lineage that’s found its success thanks to both biological and social phenomena, according to Sebastian’s study. 

The team used SNP-typing and targeted whole genome sequencing to look at the genetic differences between 3,366 lineage 4 strains isolated from 100 different countries. They used the differences to break down lineage 4 into several sub-lineages. Some were generalists found in multiple locations; others, in comparison, were more isolated and rarely strayed outside of small regions of Africa, for example.

Like I said, M. tuberculosis doesn’t hide from the immune system. It wants to be recognised so the bits of the pathogen on the immune system’s watch list don’t tend to vary much at all. But Sebastian’s study showed that the generalists are more immunologically versatile than their specialist counterparts. This is likely because they have evolved to deal with a wider range of host genetic backgrounds and have had to come up with ways to ensure they get their own way no matter who they infect.

The paper was also interested in the sub-lineage known as L4.1/LAM. L4.1/LAM, like Starbucks, is on a mission to take over the entire world. It’s found everywhere from Africa to Australia. The scientists used the genetic differences between members of L4.1/LAM to predict its geographical origin. According to the results, it first emerged in Europe then, as us troublesome Europeans spread around the world, we took our TB with us.

It’s a common story when it comes to TB. The disease is among the world’s oldest and its history is twisted up with that of us humans. The spread of TB around the world tracks with human migrations; explosions in M. tuberculosis populations overlay with human upheavals. Understanding the co-evolution of M. tuberculosis and the human immune system has consequences for, in particular, vaccine design. How do we vaccinate against a pathogen that uses the immune response for its own benefit and how do we make sure any vaccine works in every population where not only the predominant lineage differs but so does the host’s genetic makeup?

Stucki D et al. 2016. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sub-lineages. Nature Genetics.

Yu Y et al. 2015. RASP (Reconstruct Ancestral State in Phylogenies): a tool for historical biogeography. Molecular Phylogenetics and Evolution. 87: 46-49

Sunday, 26 July 2015

One week old baby

The other day I commented to the father of my child that having a baby is a little bit like going to prison. Not the ‘nice’ sort of prison where they let you do Open University courses and try to make you a better person. A Victorian-style prison where the inmates are forced to turn a crank thousands of times a day or walk on a treadmill for hours and hours with no end product to show for their labours. You do your time and then you’re released into a world you no longer recognise, having lost half your hair and a year of your life.

You know, writing that makes me realise why my partner looked at me with his ‘What the fuck?’ face. Yes, yes, I have a one year old miniature human to show for all those hours spent pacing to and fro sob-singing Somewhere over the Rainbow while the baby screamed because she was so flipping tired that she just couldn’t sleep. And, yes, all that panic-Googling because said baby has a highly disturbing habit of rolling her eyes over white when it’s windy wasn’t entirely wasted. I now know more about neurological disorders in infants than the average neurologist.

But I can’t say the first year of my baby’s life has lived up to my expectations of motherhood. Don’t get me wrong—it’s been totally worth it. My child really is the best baby in the world, even taking into account that month-long phase where she got so fat that all our baby photos look like we’ve dressed a small pig in human clothes. Or that way she hisses and bares her teeth whenever there’s a bright light nearby, like some blood-sucking vampire grub. Or the time she gave me Hand, Foot and Mouth disease that adults totally aren’t meant to get, which I totally did get, and am in fact currently typing with a fingernail that is totally going to fall off any day now, and urggggghhh.

I know what you’re thinking: if this is Kathryn’s first foray into Mummy-blogging then, Dear God, nooooo. You’re alright, don’t worry. I am fully aware that, while I’ve somehow managed to find myself in possession of a predominantly happy and healthy toddler, it has not been thanks to any previously dormant Mother-skills that need to be unleashed upon the world. I barely know what I am doing when it comes to my own child, so I am most definitely not in any position to offer parenting advice to others.

What I do want to talk about is how wasted time isn’t always wasted time. I worked in scientific research for, what, 8 years as a post-doc and for 12 years total if you count the time spent working towards my PhD. And of all the work I did during that time, maybe 5% amounted to something useful. Maybe less, depending on your feelings towards basic tuberculosis microbiology. All those hours in the lab, all that funders' money. You can’t be scared of failure if you want to be a scientist. 

I’ve read papers before where years of work have been condensed down into a few lines. The protein could not be crystallised. A gene deletion mutant showed no phenotype. Compounds showed poor activity in vivo. No one gets into science to spend their days performing the grunt work that provides the filler for the rare discovery that changes the status quo. But the reality of working in the lab is that taking the easy road rarely leads to the really interesting results, but taking a risk—trying something completely new—will often lead absolutely nowhere.

Now that I’ve left the lab and am embarking on a new adventure in the form of writing a popular science book, I am getting to see science from a new perspective. It’s dizzying to see how much research there is out there that no one outside the field ever hears about. Work that’s published in the best journals can still be just another drop in the ocean. Years, sometimes decades, of work. Even the biggest discoveries can sometimes look very boring from the outside. It’s enough to make my own work feel very small and insignificant.

But somehow, while you’re hunched over the lab bench, it doesn’t feel like you’re wasting your time. Two weeks struggling to make a protein expression vector. Two months purifying a protein so that you can get started on the real experiments. Two years screening inhibitors only to conclude that the protein you picked at the start wasn’t the best drug target after all. Go back to the beginning and try again. From the outside, it looks like wasted effort but, along the way, there were small successes. New techniques that will improve future attempts. Students trained who will go on to do their own research. Interesting side projects that may or may not lead to something exciting.

I’d rather hoped that the lessons science taught me about the value of failure might translate into a bottomless well of patience when it came to stay-at-home-parenting. Hypothesis rejected! One of the issues is that reproducibility goes out the window when it comes to babies and there’s an inverse relationship between how much research you do and how good the outcome is. But, like my scientific career, I sometimes look back on the first year of my baby’s life and wonder where all the time went. What have I achieved? Could I have done more?

Now that I’m coming out the other side of the baby period and starting to piece back together my own life and ambitions, I can see why so many women find it so difficult to juggle motherhood and a career. Pre-baby, it seemed so simple. I couldn’t understand why some women seemed to cease to exist as an individual once they had kids. Now? I can’t decide whether those failures in the lab would feel like time that could have been better wasted at home with my daughter, or vice versa.

So instead of returning to work for someone else, I am going to attempt to carve out a freelance writing career that will let me work on something I want to work on while also being around to clean spaghetti off the walls. No doubt there will be plenty of failures along the way and I am sure there will be times where I regret wasting my time on something that leads nowhere. But, hopefully, in a year’s time when I look back, it will have all have been worth it.

Sunday, 22 February 2015

In a small chapel just outside Prague, a chandelier made from every bone in the human body hangs from a garland of skulls like the world's creepiest wind-chime. Nearby, a coat of arms features an almost comical bone bird—its wings a human hand and its neck a gnarled vertebrae—that pecks at a skull's eye socket. In each corner of the room, several thousand, maybe more, bones are tightly packed into huge bell shaped mounds.

Back in 1278, the abbot of the Sedlec monastery sprinkled some earth from Jesus' supposed burial site onto the abbey graveyard. The effect was much like the opening of a new crossrail station in a previously affordable London borough. One moment, fashionable types wouldn't be seen dead there; the next there's a trendy pub opening up with artfully stained sofas and an influx of skinny jeans. Or, in the case of the Sedlec graveyard, corpses. Suddenly, it was the place to go and die, much like Southwold only without the beach.

By the 16th century, the Black Death, or plague, had deposited so many bodies in Sedlec that there was literally no more room. So a partially-sighted monk was tasked with digging up all the bones crammed into the graveyard and stacking them up in neat little piles. The remains of 40,000 people eventually found their way into the ossuary (I like to imagine that each and everyone was moved by that one dedicated monk). Later, during the 19th century, a local family employed a wood carver to make the bones pretty. Clearly this wood carver was a distant relation of Tim Burton, and his creations were eerie and strange, and surprisingly beautiful.

Is that shameful to admit? The Black Death, after all, has to be one of history's most terrible killers, decimating huge swaths of the population over the centuries. Shouldn't the remains of all those dead invoke feelings of solemnity and sadness, not awe?

This is an issue which, as a scientist working on a killer disease, I've often wondered about. Can an infectious agent that kills millions ever be beautiful and the subject of admiration and respect, or should I have felt horror and disgust with every swirl of the culture flask, every squirt of my pipette? After all, there were days when confessing my profession to a stranger left me feeling a little like I’d just admitted to marrying a serial killer in a prison chapel.

I worked on a different type of plague to the Black Death—the White Plague, or tuberculosis. Even today, tuberculosis kills almost two million people every year. Despite this, I’ve always held a strange affection for the bacterium. There's something amazing about peering into the minuscule world of the viruses and bacteria and, like an astronomer looking out into space, feeling wonder at the complexity and elegance present in each and every tiny species.

Recently, an artist called Luke Jerram created blown glass sculptures of various killer viruses and bacteria. He didn’t make one of the Black Death bacterium, Yersinia pestis, but he did create an Ebola, Smallpox, and HIV, among others. While many people marvelled at the beauty of his art, more than one person raised the question of whether it was distasteful to admire diseases responsible for untold misery.

Perhaps a better way of looking at it is that it is the science that is beautiful. Once, we believed that the Black Death was a judgement from God or a curse from the odd lady down the road with tangled hair who talks to cats (don't we all?). Now, we can look this tiny killer in the pilli and see it for what it is—an amazing creation of nature that walks the fine line between horror and beauty. The more we understand, the less there is to fear.

When I look at the Sedlec Ossuary, I see the humanity in the careful way that the bones have been arranged, and am reminded of how fragile and fleeting life can be. I see a memorial to all the lives claimed by diseases such as the Black Death and I remember how far we’ve come since the days when the plague killed between 30 and 60% of the European population. The bones aren't beautiful because they are dead but because, once, they were alive.

Saturday, 20 December 2014

Scientist spends 8 years training for a career in research. Scientist gives up said career to embark on her greatest experiment yet—an adorable squishy baby! Only the scientific method no longer works and that Excel spreadsheet titled “How I will raise baby” is woefully inadequate…

1. Your PhD did not prepare you for this 
At no point in all your years in the lab did you encounter a problem that required you to wrestle your boob into another human’s mouth while they screamed to the point of liquefaction. Transferrable skills my ass.

2. To do lists now consist of ‘Keep baby alive’ and ‘Remember to eat’ 
Once, you juggled multiple projects; now, it’s time to burn that list of things you planned to do on maternity leave. Learn French? Ha ha ha. Have another Jaffa cake.

3. Virkon-ing your child is frowned upon  
Interesting fact: microbiology labs and babies are often interchangeable when it comes to their smell. Only no one sells pink powder that can be sprinkled on a human child to decontaminate it.

4. You’re the annoying student and there’s no postdoc to help 
Instead, you have your mother’s thirty-year-old parenting advice. Remember that time your PI decided to run a gel for ‘old time’s sake’ and set two undergrads on fire…?

5. There’s no peer-review for baby articles 
One minute you’re researching developmental milestones; the next, Google has diagnosed your little troll with goat plague spread by vaccination.

6. Evidence and reason no longer apply 
My baby has goat plague! What do you mean only goats can get it? Oh my god, I think my baby’s a goat.

7. No one cares about your results anymore 
And here’s a photo of her sticking her right foot in her mouth. And I’m teaching her to grab the left one too! I think there’s a picture somewhere here if you just…wait, where are you going? 

8. Reproducibility is a distant memory 
One day, you can pace to-and-fro shushing like a deranged librarian and It Sleeps! The next? You get the ‘Like that’s going to work on me, Mother-Creature’-look of baby contempt.

9. The baby doesn’t give a shit how smart you are 
Like the plot to the sequel of ‘Flowers for Algernon’, you’ve experienced a career where using your brain is kind of handy and now you’re singing ‘You are my Sunshine’ for the thousandth time.

10. I don’t remember what this one was going to be 
So I read the draft of a paper the other day and got half way through before I realised that I’d written the damn thing. The old me. The one who had an attention span long enough to…huh what?

Saturday, 5 October 2013

Chimp holding a skull
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.