How the snake got his venom

Aside from its supposed complexity (see previous post), one of the reasons I started working on snake venom was the apparent prevalence of gene duplication and neofunctionalisation (where a gene is duplicated and one of the duplicates evolves an entirely new role) in the evolution of venom toxins. Again and again in the literature one sees claims of snake venom evolving via the duplication of a gene encoding a physiological or “body” protein with subsequent recruitment of one of the copies into the venom gland. Neofunctionalisation is an incredibly rare process in most animals (plants too for that matter) so the fact that it seemed to be happening over and over again in venomous snakes made them an excellent group to study to try to get to grips with how evolutionary novelties arise. However, things turned out to not quite be as advertised.

We’ve recently published a paper1, based on gene expression analyses in venom and salivary glands and various body tissues of venomous and non-venomous reptiles, where we show that snake venom toxins likely originated from pre-existing proteins that were expressed in a number of body tissues, including the salivary gland of non-venomous species. The genes encoding these proteins were duplicated, and the expression of one of the duplicates was restricted to the venom gland, where natural selection acted to develop or increase toxicity. This goes against the previous, widely-accepted view that snake venom toxins had been recruited to the venom gland from other body tissues. It might seem a relatively minor, semantic difference between restriction and recruitment, but from the point of view of the genetic mechanisms involved it’s fairly significant – these genes are undergoing subfunctionalisation, not neofunctionalisation (basically they are taking on parts of an ancestral role (or, more, accurately, losing aspects of the ancestral role), not evolving new ones).

In addition to our own data, we also took a look at the existing data that had been used to underpin the recruitment hypothesis and found that there was little to no support for a body gene undergoing gene duplication and one of the duplicates subsequently being pulled into the venom gland. This surprised us as one of the key papers2 behind the recruitment idea has been cited 236 times (as of 01/08/2014) – can all those people really have missed what seemed to us to be obvious issues? This got us thinking about the role of the attractiveness of an idea in its initial propagation and longevity. There’s no question that the idea of a “body” gene undergoing duplication and one of the copies being recruited into the venom gland where a previously non-toxic gene can give rise to a potent venom toxin is an elegant, intuitive and attractive hypothesis. Could that be the reason?

In 1902 Rudyard Kipling published his ‘Just So Stories for Little Children’, which included stories such as “How the Whale Got His Throat”, “How the Leopard Got His Spots” and “How the Camel Got His Hump” and since then many things have been referred to as evolutionary just-so stories (one of the more recent ones was the idea that the human hand may have been shaped by punching). Strictly speaking however, many are not actually just-so stories, as these are defined (by the almighty Wikipedia no less) as:

“…an unverifiable and unfalsifiable narrative explanation for a cultural practice, a biological trait, or behavior of humans or other animals.”

In many instances however, these stories are testable, verifiable and falsifiable (Ryan Gregory picked up on this point in a 2008 blog post). I would argue therefore that it is sometimes an unwillingness to test hypotheses as much as an inability to do so that is responsible for the continued existence of just-so stories in evolutionary biology. Scientists are humans after all and most of us love a good story and the idea of a gene that has a fairly mundane job elsewhere in the body turning into a potent venom toxin is the ultimate genetic Cinderella story. Who wouldn’t want it to be true?

Unfortunately, it’s not. Snake venom has evolved (and presumably continues to evolve) via the duplication and restriction of genes. Subfunctionalisation trumps neofunctionalisation again.

 

1. Hargreaves AD, Swain MT, Hegarty MJ, Logan DW and Mulley JF (2014) ‘Restriction and recruitment – gene duplication and the origins and evolution of snake venom toxinsGenome Biology and Evolution doi: 10.1093/gbe/evu166
(Pre-print version)

2. Fry BG (2005) ‘From genome to “venome”: Molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteinsGenome Research 15: 403-420

 

 

Advertisements

Simplifying complexity

There are a couple of reasons why I decided to start working on venomous snakes, and the apparent complexity of snake venom, together with the role of gene duplications in the origin and evolution of venom toxins was one of the main ones.

Over the past few years we’ve been working on various projects associated with snake venom, based largely on transcriptomic data, but increasingly using bits and bobs of genomic sequence. We’ve now got a couple of papers submitted, another in prep and data for a few more in the pipeline and we’ve found some surprising things so far… Watch this space is all I’ll say for now.

However, one of the things that’s surprised me the most has been the fact that a vast amount of data already sitting out there in the literature just isn’t being used by people. This typically takes two forms; either people cite papers claiming that they say a certain thing, but when you read them properly you find that they don’t actually say that (in this way things end up being stated as fact that just aren’t supported, and often never were) or key papers just aren’t being cited, even though they’ve been sitting at the end of a Google search for years.  Given the ever-increasing availability of these older papers online I’m just not sure what the reasons for this latter are, except that what’s cited by some people seems to be cited by others, so perhaps some people just aren’t doing as comprehensive a literature search as they should be.

Anyway, perhaps the clearest example of this relates to the alleged complexity of snake venom. You’ll often find claims in the literature about snake venom being a complex cocktail or an incredibly complex mixture of proteins, etc etc (just a couple of examples there – try a Google search for yourself for more). These terms evoke visions of hundreds of diverse proteins, of all shapes and sizes and all kinds of function, all contributing to making snakes horrible, horrible little buggers to get bitten by. When you actually read around on some of the characterized snake venom proteomes though, you find that actually most snake venoms consists of only a few dozen gene products, and that most of these are from basically the same gene families. Our trawl through the literature suggests that snake venom typically contains between 24-61 toxins in 6-14 families (based on 12 species, including both vipers and cobras). Given that the bulk of the toxins actually derive from one or a few genes families (three finger toxins, phospholipase A2, metalloproteinases etc), with assorted other families contributing one or two toxins at most it all adds up to snake venom actually not being that complex after all. When you think about it though, this kind of makes sense – why throw the kitchen sink when you can throw a knife? If you’ve got a toxin or a family of toxins that can do the job (immobilizing prey) perfectly well, surely natural selection is going to act on those toxins to make them even better. It’s highly unlikely that everything that we currently see in snake venom is essential for rapid prey knockdown and that there exist some evolutionary equivalents of hangers-on, which don’t contribute much but just haven’t been lost yet.

Alternatively of course, some of the proteins that we see in snake venom may not have a toxic role at all…

The wandering academic

As I prepare to travel to Goa tomorrow for a conference, it occurs to me that all this travel business was not something I was particularly aware of back in my undergraduate or even early post-graduate days, when I was pondering my future career.

In my admittedly still quite short time in academia I’ve had the opportunity to travel (for conferences and/or fieldwork) to Louisiana (twice), Japan, Chile and now Goa, as well as various locations throughout Europe including Paris, Cuenca, Ghent, Prague, Valencia and Galway.

Sealions

Posing with sealions in Valdivia

I wonder if this opportunity for travel is something which prospective academics at undergraduate and postgraduate level are aware of nowadays, and whether it should be seen as a constant benefit or occasional curse. Certainly leaving my 9 month old son to travel to India a few days before his first Christmas has its downsides…although Air India willing I’ll be back on the 22nd.

 

Islands in the stream

There has been an increasing trend towards larger and larger class sizes in UK Higher Education institutions over the past decade or so – according to the Higher Education Statistics Agency (HESA) there were 1,928,140 undergraduate students in the UK in the 2011/12 academic year, compared to 1,541,225 in 2000/1. Although figures are missing for some of the earlier years, the number of academic staff appears to have increased at a much lower rate (see the graph derived from the HESA numbers below).

Image

In his September 1999 speech to the Labour Party conference, Tony Blair set “…a target of 50 per cent of young adults going into higher education in the next century.” With the Higher Education Initial Participation Rate (HEIPR) now standing (provisionally at least) at 49% for the 2011/12 academic year, it looks as though we are creeping ever closer to that supposedly magical number.

I don’t know about other institutions, but as a result of these ever increasing student numbers we’ve started to encounter capacity issues more and more frequently, especially when it comes to accommodating students in our teaching laboratories for practical classes. As a result we now run some sessions multiple times, with students split randomly into groups, often alphabetically by surname. Splitting students into groups like this took me back to my school days at St Chads Secondary School (long since demolished and replaced with an Academy) where each year group was split into six sets or streams (S, T, C, H, A and D) according to ability. I can’t remember exactly when and how this ability was assessed, so I can’t comment on how rigorous the process was that placed someone like me in the top set, but that’s not really the point. My point is this:

Why don’t we stream students according to ability in Higher Education?

Repeating identical classes is boring for the staff involved and, although I don’t have any figures to support it, I doubt that quality (and effort?) are maintained across subsequent sessions*. Are we therefore disadvantaging students in the later sessions? Or perhaps the quality of the sessions improves with repetition, in which case, are we disadvantaging the early guinea pigs? Can we perhaps be more imaginative than simply repeating the same teaching session again and again? Could we tailor individual sessions to best support the abilities and “learning styles” (urgh) of the students in them? Might the best students benefit from more background information, a freer hand and less step-by-step guidance and might the less able students benefit from a more dedicated approach based on repeated exposure to fundamental concepts?

I think this is where we hit the problem – how do we assess student ability? How do we categorise the best, the average, the less able? And when should we do this? Although the quality of teaching received by an individual student may actually improve because it is more tailored to their ability and learning style (urgh) how would we justify this to them in a way that wouldn’t negatively impact our results in the National Student Satisfaction Survey?

There’s a lot of questions there and I’m afraid I don’t actually have any answers. Without some good quality research on the benefits (or otherwise) of streaming HE students I doubt it’ll ever really happen and we’ll therefore probably keep on with a one-size fits all approach that potentially fails those at both ends of the ability scale.

Slight postscript – while writing this, it dawned on me that we do actually practise a kind of streaming already: to be able to progress onto their final year research project, our students have to pass a project preparation stage. If they don’t, they have to do a non-experimental project and another module instead. Perhaps the idea of splitting according to ability is not quite so alien in HE as it first appears?

*In theory this should be relatively easy to study – I wonder if anyone has ever done it?

iPad, myPad, yourPad

Every now and then I see on the news that another UK school has issued its pupils with an iPad (interestingly, it’s always an iPad, never one of the cheaper Android-based tablets, even though they would give the school control over the operating system…Apple educational discount deals at work?). There was another one today, about a primary school in London that is going to look at how technology can boost learning. A quick scan of the BBC News website threw up a selection of other recent-ish stories (links – 1, 2, 3, 4, 5), including one that highlights the potential drawbacks of having all this expensive kit laying about the place.

All of which adds to a growing sense that technology is becoming more and more integrated at school level in the UK, that more and more school leavers are likely to be pretty tech savvy and, perhaps more worryingly, that all these students are going to have certain expectations about what a 21st century education involves. The student perception that they’re paying £9k a year for their degree and want something tangible to show for it (aside from that oh so valuable time with our good selves) is also something we can’t ignore.

I’ve been discussing similar issues with colleagues for a while now, mainly around the problems we may face when all of these students start applying for our degrees – should we be issuing our bright-eyed and bushy-tailed (not to mention incredibly young looking) first years with their own shiny bit of kit during welcome week? We briefly toyed with the idea of applying for some Higher Education Academy funding to try to run a new module built around tablet computers, although we never got it off the ground in time to apply for that round. The story in the news today reminded me of all this, so I thought I’d have a little dig round to see if any UK university had taken the step of issuing its incoming students with an iPad (or similar).

The first thing I found (and something that I hadn’t previously considered) was a laptop and iPad loan scheme at the University of Nottingham. Perhaps enough students are coming to university with their own tablet that they we don’t actually need to issue everyone with one, but instead ensure that no one is disadvantaged when teaching and learning is dependent upon the technology? I’d worry though that those students without their own iPad might feel a bit like second class students, and that wouldn’t do them any good as they start their academic careers (nor would it do us any good later on when they fill in the National Student Survey).

A link on the University of Manchester website to pay a £100 fee to replace a lost or damaged iPad suggested that MA Social Work students at least were being allocated a tablet (although a £100 fee to replace a >£300 bit of kit is an interesting bit of economics). Students on the MA Documentary Practice programme at Brunel were loaned a tablet for the duration of their course and the University of Leicester seems to be taking advantage of iPads in a distance learning MSc. My brief search wasn’t able to find any evidence of iPads being issued to incoming undergraduates en masse in the UK, but it looks as though this is happening at the University of Western Sydney – I just hope they got a hell of a discount on their 11,000 iPads.

Personally, I think it’s only a matter of time until this happens here in the UK (my guess would be at a Russell Group University in the first instance, probably of the light or dark blue variety, although I’m not discounting a particularly enterprising and ambitious former polytechnic taking the leap first) and I for one would welcome it. The opportunity to move out of our dark underground rooms and deliver lectures almost anywhere, to record images and videos on field trips and in practical classes and to produce interactive handouts and other teaching resources, with embedded hyperlinks or video files would possibly help to drag some of our teaching practices into the 20th (if not actually the 21st) century.

 

PS if anyone actually knows of a UK university that is issuing its undergrads with iPads (or similar), please let me know. I’d be interested to know what they’re doing with them, and whether they’re actually an integrated part of the course or a bit of a gimmick at the moment…