It’s Alive!

If baldness is really a genetic trait, then I am well and truly screwed. I come from a long line of cue balls; every male in my family over the age of 30 is bald or balding. Especially worrying is the fact that both my Dad and my maternal Grandfather started thinning in their mid twenties, a fact my Dad takes particular glee in pointing out to me at every available opportunity.

Thus, I greeted a couple of recent articles in Nature Genetics with an air of optimistic hope. Of particular interest to me is the paper by Pasternack et al (citation below), which details a complete a start-to-finish study on the genetics of a rare hair loss disorder, beginning with a genome wide linkage analysis and ending in functional characterisation of the candidate gene: P2Y5. A simultaneous article in the same journal also looked at the involvement of this gene in hair growth, but from a different functional perspective, as covered over at Gene Expression.

Due to the commonality of baldness and the complex pathophysiology of hair growth disorders, finding a genetic cause with therapeutic potential is extremely difficult. This is why studying rare heritable hair loss disorders, such as the specific alopecia condition analysed in this study, offers a unique opportunity to pinpoint some of the key components involved in maintaining normal hair growth.

A powerful approach to advance our understanding of the pathophysiology of human hair loss is to identify genes underlying mendelian isolated alopecias. Investigation of this type of hair loss offers the unique opportunity to identify factors that are not only necessary for, but also specific to, hair growth.

Using an affected Saudi Arabian family, the group mapped the disease locus to a 28Mb region on chromosome 13. Candidate gene sequencing revealed a truncating mutation in the sequence for P2Y5: a gene that codes for a G protein-coupled transmembrane receptor. Normally located on the cell membrane, the group showed accumulation of the truncated protein in the endoplasmic reticulum, suggesting loss of function.

Aside from the solid genetic analysis carried out, the real strength of this paper lies in the further functional analysis of the protein, which did not have a clearly understood function. Through a reporter gene assay and A radiolabelled binding experiment, the group identified lysophosphatidic acid (LPA) as the ligand for the receptor. In addition, they demonstrated in vitro that the truncated version of this protein is unable to elicit the cellular response normally observed after binding of LPA to P2Y5, likely due to the loss of a number of intra-cellular loops that are known to be involved in G protein activation.

LPA is known to bind a number of receptors alongside P2Y5, with a downsteam effect of enhanced cell proliferation and migration. Broadly, these receptors can be classified into two subgroups: LPA1, LPA2 and LPA3 in one group, and LPA4 and LPA5 in the second group. The authors propose the placement of P2Y5 in with this latter subgroup due to its amino acid sequence homology and the similar downstream signalling pathways.

Interestingly, of the latter group of receptors, LPA4 and LPA5 are not expressed in the hair follicle. Thus, a loss of the one member of the group that is, P2Y5, leads to a complete loss of LPA signal transduction through the specific pathway mediated by the group. Further characterisation of this pathway is now required in order to understand how its impairment results in the alopecia phenotype observed in affected individuals however.

Ultimately, the most important question to arise from this study to me is: could it eventually culminate in an effective treatment (or even a cure!) for baldness? While it is conceivable that this paper offers the possibility of identifying potential inducers of the LPA-P2Y5 mediated pathway in a hope of enhancing hair growth in balding individuals, more realistically it offers potential for further elucidation of the complex pathways involved in hair follicle development and function.

Thus, I don’t think I’ll be seeing any wonder-drugs in the crucial next few good-hair years I have left in me that will cease the inevitable chrome-domia before it advances into chronic cue ball-ness.

Pasternack, S.M., von Kugelgen, I., Aboud, K.A., Lee, Y., Ruschendorf, F., Voss, K., Hillmer, A.M., Molderings, G.J., Franz, T., Ramirez, A., Nurnberg, P., Nothen, M.M., Betz, R.C. (2008). G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nature Genetics, 40(3), 329-334. DOI: 10.1038/ng.84

Edinburgh is world famous for a bunch of things: the Fringe Festival, terrible weather, more castles per square mile than anywhere else in the world (…probably), David Hume, terrible weather, Hogmanay, the Edinburgh Tattoo, Robbie Burns, and terrible weather.

Aside from the obvious listed above, and a few drunken anecdotes from friends, I didn’t really know much about the place before moving here from the Edinburgh of the South: Dunedin, New Zealand. Over the last six months I have spent settling here in the Edinburgh of the North I have realized just how different this place is to my old university town. Yes Dunedin was settled by Scots and a bunch of the streets have the same name, but the similarities pretty much end there.

First of all, let me get this out of the way: the weather here is total bollucks. If you ever come here, bring something warm and waterproof. I cannot stress this enough. Edinburgh isn’t the coldest place in the world, but be prepared for some utterly miserable weather. Rain, sleet and snow are standard fair throughout the depths of the winter months, and are usually accompanied by a vicious arctic gale that’ll whip your kilt off. Also, don’t bother with an umbrella; those things are good for about 10 seconds over here. Actually, a balaclava and a snowsuit is probably the way to go. The silver lining in all this is that it really does make you appreciate the 5-10% of the time when the weather is actually half decent.

Gripes about the weather aside, Edinburgh really is a pretty sweet place for a student to live, not least of all because of the abundance of pubs, bars and clubs all eager to get their hands on whatever student loan you have left after paying your course fees for the year. Around the Old Town (the main university area) in particular you can find a diverse mix of delightfully seedy old-man pubs, try-hard bars full of freshers, and boho-chic establishments full of patrons that have been at university for way too long. And if drinking indoors gets too much for you (and you don’t mind being outside in the cold), then Edinburgh has an abundance of outdoor festivals, including the carnage of the Hogmanay Street Party. On this unique occasion you can celebrate the New Year in true scottish style: crammed into Princes street with 10,000 other drunken revelers.

As far as local cuisine goes, there are two varieties: deep fried, and everything else. For every pub in this city, there is a ‘chippie’ which will sell you a wide range of amorphous deep fried entities. Some local favourites included deep fried pizza, haggis, and my own personal favourite, deep fried Mars Bars (which has a calorie content equivalent to a roast dinner but fits right in the palm of your hand). And no matter what you say it all comes drowning in vinegar and brown sauce. A couple of weeks on this diet and you’ll probably knock a good decade or so off your life expectancy.

Fortunately, the traffic and road layout here in Edinburgh is rubbish, meaning that you will (by necessity) be able to walk off all those pints and pies. The scenery of the place does make for a pleasant stroll though. Aside from the main drags of the Royal Mile and Princes St, Edinburgh contains an interconnected 3D lattice of back alleys, staircases and closes that reveal a city bursting at the seems with outrageously old school architecture (remember, I’m from New Zealand, where anything built over 50 years ago is considered a historical monument). Seriously though, while the main touristy landmarks are well worth the visit, you can get a much deeper feel for the place for free by simply walking up, down, and around the streets. To be perfectly honest I haven’t even visited Edinburgh Castle yet, I’m waiting for my parents to come visit me so they can pay my entrance fee.

(Part of the latest edition of Carnival of Cities hosted by GrrlScientist)

Further to one of my earlier posts, which has received a pretty decent volume of web traffic thanks to a link from Sciencepunk, here is a brilliant video I was emailed the other day that demonstrates the everyday problems faced by Tuscan Raiders.

Bitesize Bio has an interesting post about the need for science grad students to explore alternatives to research oriented careers while at grad school, and the importance of developing a more diverse set of skills in order to increase one’s employability in non-research career paths. 

Completing a PhD makes you the world expert on the minutia of your specific research field - and the intricacies of the various pieces of arcane equiptment found in your lab - but it doesn’t, in mine and other’s opinions, give you the skills necessary to take your knowledge of science out into the “real” world. 

Most grad students (myself included…to a certain extent anyway) are so engrossed in their academic work, that exploring other avenues of career development takes a back seat. This is entirely expected though, because as Dr Free-Ride so eloquently points out in part one and part two of her “being a grown up scientist” blog series, the learning curve from wee undergrad to big scientist is tremendously steep and involves a huge amount of raw effort, leaving little time or mental capacity to fritter away on anything that is not directly relevant to your thesis. 

While a lot of universities have cottoned on to this and are actively offering a host of practical skills courses to students, many of us lack the initiative and the motivation to participate. In addition, a lot of these courses are complete rubbish anyway. I went on a “communication for scientists” course at my uni and it was a very boring waste of time that would have been better spent trying to finish the mountain of immunohistochemistry I was buried under at the time. While I don’t doubt for a second the importance of broadening our education through such means, I get the impression that a lot of these courses are at best a token effort. 

So what is to be done with us? Well for a start I think it’s definitely a bonus to have a supervisor who actively encourages this sort of thing. After all, the supervisor is a pretty influential figure in the life of a grad student. My masters project supervisor was actively involved in a bunch of local biotech firms, which is how I ended up spending one summer as a marketing assistant at one. Not the most exciting job in the world, but definitely rewarding in terms of what I learnt about the commercialisation of research.

But at the end of the day, the onus is on the student, and herein lies the big problem. A lot of students are bound by their grad school blinkers and don’t actually realise that they may not be destined to a career in academic servitude. And until they do, they aren’t going to be dropping the pipettes any time soon to learn about how best to run a kiddie science fair or how to make millions with a spin-off biotech company. 

Pig Out are a fun lectro-pop outfit based in Auckland who have stormed through the NZ indie scene over the last couple of years with the release of their 2006 mini album Club Poems. They are definitely one of my favourite live acts from recent memory and will be taking their sweet sweet sounds to the South by South West music festival in Austin, Texas in a months time. This clip is a song called Disco Bag, one of the singles from said album.  

Just in time for Valentine’s Day, here’s my latest article written for Null Hypothesis, which takes a brief look at the tip of the iceberg of biology behind the bizarre rituals that entail human dating behaviour. 

It’s Valentine’s day again, and as a single guy it really is my prerogative to go on a bitter and cynical rant about how lame the whole thing is and how it’s pretty much lose-lose for guys whether you’re in a relationship or not. But, that sort of spleen venting is done to death at this time of year in almost every single medium one can think of. Instead, I decided to do something a bit more constructive so have written an article for Null Hypothesis which takes a fleeting glimpse at some of the science behind dating behaviour. Unfortunately, I didn’t finish it till late and it hasn’t been edited and put up on the site yet. Woops. 

However, I did manage to find a couple of interesting links for Valentine’s Day show-and-tell. Firstly, for all you weird coupley-type people, here’s something different you can do together tonight (or as a back-up option for the evening since you probably forgot to make dinner reservations again and everything is pretty much booked up). The Queens Of The Stone Age are running a youtube make-out competition to coincide with the recent release of their music vid for Make It Wit Chu (clip below). All you have to do is record yourselves making out to the song and then post it on youtube for all to enjoy. Not surprisingly, as of today, nobody has posted an entry yet. 

And then for those that, like me, will probably be spending this Valentine’s Day at home with their arm around a bottle of beer/wine/scotch/all of the above, then here’s a list of recommended anti-valentine’s day movies to keep you mildly entertained and to drown out the noise of that annoying couple you live with “celebrating” Valentine’s Day in the next room. 

It’s that special time of year again, when we all sit under a phylogenetic Darwin Day tree exchanging Darwin Day gifts to celebrate the birth of Science’s version of Jesus Christ. Like many, I always struggle to find that perfect Darwin Day gift, which is why I was totally stoked when I stumbled across this!

Can you imagine anything cooler to have sitting on your lab bench or on the dashboard of your car than a Charles Darwin bobble head? They’re only US$17 and are being sold through Southern Illunois University. I know what I’m hoping to find under the tree this Darwin Day! 

One of the things I miss most about New Zealand (aside from the weather and the fact that it’s summer there right now while I’m stuck in the eternal Scottish winter!) is the music. While at uni I was a DJ/presenter for Radio One, the Dunedin branch of the BNets, a bunch of alternative and indie stations with a big focus on local music. And because NZ is so small the music community is very tight, meaning that I personally knew a lot of the artists involved and was consistently getting new and fresh music coming across my desk.

Now that I’m literally on the other side of the world, I can’t help but feel slightly removed from all this. But thanks to teh internets I am able to stay somewhat informed and share the awesomeness with others. So, I will be posting up a NZ music video (most of which are independently made on amazingly low budgets but with pretty impressive production value) every Friday as a regular feature. The first one is by a cutsey-pop group from Auckland called The Brunettes who were recently signed to Subpop records. These guys have been around the NZ indie scene for a few years so it’s great to see them making it big over in the states. Plus the lead singer, Heather, is probably the most beautiful girl in the world. This song is called Her Hairagami Set and is off their new album Structure & Cosmetics which came out last year. Enjoy.

Below is the lay-abstract from a recently completed project as part of the masters year of my PhD here in Edinburgh. It is pretty much the culmination of 10 weeks of solid immunohistochemistry on mouse fetuses (feti?). While Wnt activity is well established as a major component of forebrain development, it’s actual interactions are less understood. This project aimed to elucidate the link between Wnt and Gli3, on of the myriad factors known to interact with Wnt. (Got my grade back today. It is good. I am pleased.) 

Canonical Wnt signaling exhibits a dynamic pattern during forebrain development and is disrupted in the extratoes mouse mutant 

The brain is one of the most complex organs in the human body, made up of a number of interacting regions. The most easily recognisable of these regions is the folded structure that takes up most of the room in the skull called the forebrain. The most evolutionarily advanced region of the brain, it is responsible for processing the enormous amounts of sensory data acquired by the five senses and mediating the appropriate cognitive and physical responses. Even more impressive than the functional power of the adult forebrain though, is the fact that it develops from no more than a single sheet of cells in the early embryo.

The process of going from this early neural tissue to the complex adult forebrain is regulated by a large number of interacting genetic pathways that are highly conserved across species as divergent as the fruit fly and the mouse, indicating their importance in brain development. This evolutionarily importance is reflected in the severe brain abnormalities observed when the function of some of the key genes is lost. One of these genes, Gli3, plays a vital role in the correct formation of the top part of the forebrain and is associated with human syndromes such as Pallister-Hall syndrome and Greig cephalopolysyndactyly syndrome when mutated.

This research project presents a detailed analysis of the activity of a specific genetic pathway, the Wnt pathway, known to be very active in the development of the top part of the forebrain, and how it is affected by the loss of the gene Gli3 in a mouse model. Our results show that the loss of Gli3 function causes a vast reduction in the activity of this pathway, shedding light on how the loss of Gli3causes the characteristic structural brain abnormalities at a molecular level, which in turn provides valuable information for understanding the basis of the human syndromes associated with loss of this gene.