Masters of Imm

Although The Institute wound up its teaching term last Friday, there was still teaching to be done.  So I spent Monday and Tuesday up in The Smoke doing four sessions on molecular evolution for the almost new MSc in Immunology.  I've done similar courses before when I was supplying bioinformatic infrastructure to the plain people of Ireland back in the last century. It was on my feet for 5 hours on two consecutive days but at least I know now NOT to kneel on the floor when getting down to the level of a student working away at a computer. If you do this in your youth, you'll finish up with chippy's knee and barely able to walk long before the end of your working life.  I had primed the students (N=19) to come with a gene of interest to work on.  So the first day they discovered where and on which chromosome their gene was located but also where the equivalent gene in mouse could be found. They found out the size and some of the functional attributes of the protein that came from 'their' gene.  But before all that I gave them a pre-quiz: asking them questions to which they would more likely know the answer after they had completed my course than before. Q4: put these five biological entities in order of size

• glucose
• T-cell
• mitochondrion
• T-cell receptor
• hypothalamus

I was relieved that almost everyone got almost everything correctly ordered.  This is different from many students at The Institute who don't seem to care/grasp that a molecule (glucose, T-cell receptor) is smaller than a sub-cellular organelle (mitochondrion) which is smaller than a cell (T-cell for example) which is smaller than an organ (hypothalamus, adrenal gland, kidney). On the second day, I asked them to estimate the relative sizes (chekkittout!) of each of the 5 objects.  Sure now, a T-cell receptor is part of and so smaller than a T-cell; but how much smaller?  A little of the "that's easy" confidence drained away because nobody could confidently tell me about how big a cell is tsk! let alone tell me how big its TCR receptor is.  Probably only half of them could instanter recall the formula for calculating the surface area of a sphere from its diameter.  The ratio between the diameters of the T-cell and its receptor is 1:5000 or this . to a large beach-ball.

The other task I gave them on day I was to name the 20 amino acids that are produced by the "Universal" genetic code: this was an obvious task because there were 19+1=20 of us in the room. The quality of this student cohort is indicated by one of them briskly pulling me up on the "20 amino acids" because she knew that in some species in some circumstances the UGA 'stop' codon is induced to produce the 21st amino acid selenocysteine.  I opened a box of chocolates, threw down a couple of markers and said they could have a sweet IF they could write the three-letter code for any of the known protein amino-acids. The quality of this student cohort is indicated by one of them asking me about taurine which is (almost) an amino acid which led to a brief discussion about other amino acids (ornithine) that have key roles in biology but not in building proteins.  It was very brief because there was an unseemly scrum of students round the white board fighting for access to markers and chocolates.  The tide didn't go down until all the dupes had been removed and the last amino acid had been identified. The quality of this student cohort is indicated by the fact that they stuck at it until they had solved the problem to their own satisfaction - the chocolates were entirely incidental.

The next day, I gave them a bit of a harangue because it's one thing the know the name of 20 somethings but that's only useful if you know their attributes - which are big, which small, which basic, which hydrophobic.  If they remember nothing else from from the day, I hope that they will have internalised Willie Taylor's Venn diagram: it is key to making sense of protein sequence data. 

These people, from all over the world but currently in Dublin, are hot.  If you senior guys in Kiev "Привіт колеги" are looking to hire bright, engaged, competent young scientists you'd better be putting a competitive package together: there are only 19 currently available.  If you young guys "Привіт прохолодні молоді люди" in Kiev are looking for a great taught Master's Program, I look forward to meeting you next year.

Trigger

Film-buffs and horsoholics may believe there is only one Trigger: the "Four-legged Friend" of Roy Rogers, but triggers feature prominently in the world of immunology and cancer.  Humans, and mammals in general, are so robustly healthy most of the time because of redundancy built into the immune system - if one ploy fails to block a pathogen, then another is waiting in the wings. But sometimes the immune system is too clever by 'arf and over-reacts.  Then you develop an autoimmune disease as the mechanisms used to attack 'foreign' cells suddenly turn on cells that have up to now been recognised as 'self'.  Clearly this doesn't happen every day or we'd ALL have lupus (SLE), rheumatoid arthritis, type I diabetes, or Sjögren's syndrome.  Whereas lupus is only really common in alternate episodes in boxed-sets of House.  One way of explaining the incidence of these troubling conditions is that you have a genetic predisposition like DQ0602 which I mentioned yesterday, and you're okay for years and then some environmental challenge jumps the immune system off the rails. You get a flush of the runs after ingesting Campylobacter jejuni from a dodgy chicken pie and your immune system mops it all up over 3-4 days. Guillain–Barré syndrome occurs because a few days later your immune system, all hyped up and spoiling for a fight, occasionally recognises or imagines a structural similarity between something on the outside Campylobacter and something on the outside of peripheral nerves. The nerve damage may take years to recover if it ever does.  It's Lombard Street to a china orange that something similar is involved in multiple sclerosis (MS), but we haven't identified the trigger there (the smart money is on a virus).

Yer takes yer chances in the rough old world of infection and immunity; sometimes you get a bad break.  But now you can choose to stack the odds in your favour in this desperate lottery by getting immunised. About 1 million people played this card in Ireland (22.5% of the population of the Republic) to avoid getting the H1N1 'flu that was certain-sure going to go pandemic in the winter of 2009-2010. They were injected with a vaccine called Pandemrix. You can see from the graphic that the urgency of the programme abruptly went off the boil for the last week of 2009, where protection from a life threatening illness took second place to having a Christmas knees-up (most of us) or lie-down (the poor overworked health-care professionals).  Some of those million immunized people may have therefore not gotten 'flu, not spent days in bed or in hospital, not died.  So that's clearly a good thing.

But in the relevant period 32 people started showing symptoms of narcolepsy.  You really wouldn't expect so many cases of this rather rare condition to blip up the HSE statistics in such a short time.  So Darina O'Flanagan and her colleagues at the Health Protection Surveillance Centre (HPSC - our equivalent of the CDC in Atlanta) carried out a retrospective study to see who had recently come into narcolepsy and whether they had been 'flu jabbed (N=30) or not had the jab (N=2).   In young people aged 5-19 the risk of narcolepsy was, from these figures, calculated at 5.7 per 100,000 person-years for vaccinated vs 0.4 per 100,000 person-years for unvaccinated: 14x more likely to get this condition if you have the jab.  But still extremely unlikely to get the condition.  81 cases of narcolepsy were revealed when notes were compared with Sweden and 79 cases when Finnish data was considered: the odds up North were similar to those in Ireland.

The vaccine Pandemrix was invented by GlaxoSmithKline GSK and patented in 2006, it consisted of an antigen from an H1N1 strain of influenza virus, an 'adjuvant' called AS03 and some preservatives. Adjuvants are often added to vaccines to goad the immune system into a response: inorganic alum (aluminium sulphate) has been used for decades for this purpose.  It looks like the immune system of the vanishingly small fraction of youngsters, who had the jab AND THEN developed narcolepsy, goes on the rampage and attacks the part of the brain that produces orexin.  Presumably they are DQ0602 positive  for starters.

These unfortunate narcoleptics were in the news last week because an apparatchik (аппара́тчик) from the megalithic Health Service Executive HSE (of which HSPC is part) issued a diktat to say that these affected narcoleptics couldn't have their legal costs (of their suit against the state) covered by the state . . . and he was promptly over-ruled by the head of the HSE: probably because The Boss recognised a public-relations disaster when it jumped up and bit him. 

Who to blame? There are plenty of lawyers who will, for a cut, offer to sue the State, the HSE, the Department of Health, and GlaxoSmithKlline and Uncle Tom Cobbley to vindicate the rights of these people and indemnify them for the results of their mis-call in the matter of whether to have the jab or take their chances with the 'flu. Do I hear you cry "moral hazard" you uncaring brute? The cases are so rare that they would be impossible to pick up in any reasonably sized epidemiological study carried out by GSK before they released the vaccine to the public.  And here's another thing: there is evidence from China to suggest that, regardless of vaccines and GSK, by contracting a dose of H1N1 flu you are more likely to get narcolepsy.  Whom do you sue then?  Set your lawyers Dewey, Cheatem & Howe on Clotho, Lachesis and Atropos?

Asleep on the job

Most of us have fallen asleep in a lecture - the lights go down, the power-points start to flicker past, the voice-over drones and . . .  zzzzzz.  I found it was fatal to eat half of a free sandwich offered to encourage attendance at lunchtime Departmental Seminars - only a quarter and I had a chance of staying awake beyond slide 5/80.   But falling asleep at inopportune moments is only one of the symptoms of nacrolepsy. Distressing as nacrolepsy  is for narcoleptics and their families, its diversity of symptoms opens a fascinating window in how our bodies work in normal circumstances and how every player in the sub-sub-microscopic genetic and biochemical landscape has to multi-task.  We only have 23,000 protein-coding genes to play with after all: about 10% more than Caenorhabditis elegans and that worm is only 1mm or 1000 cells in size.

Perhaps the least expected co-symptom of nacrolepsy is

• cataplexy - a sudden muscle weakness often under conditions of emotional stress: anger and fear, but also laughter - cataplectics really do tend to go Ha Ha Bonk

Other symptoms are sleep-related:

• nightmare-quality hypnagogic (falling asleep) and hypnopompic (coming awake) hallucinations.  
• sleep paralysis - inability to move and/or speak when falling asleep (how scary is that?)
• a real quick drop into REM (dreaming) sleep.

Then again perhaps cataplexy falls into the same bin because one of the 'symptoms' of normal sleep is loss of muscle-tone.  And the hypnagogic hallucinations could be seen as part of the instant REM sleep - we usually have 60-90 minutes of relaxation before the dream-scape starts in our head. Clearly something or somethings are regulating a lot of quite disparate effects to control normal sleep. And I think we should all be grateful that we forget most of the dreams we have. Seemingly, it's because nighttime sleep is so bitty that the body needs to catch up during the day.

And at an epidemiological rate of 1:2000 it's not uncommon!  That's a little more common than, say, cystic fibrosis (1:2500) and about the same prevalence as Parkinson's and MS; all of which get a much bigger press than narcolepsy.  But a lot of this lies hidden as sufferers and their families cope - I know quite well three people with MS and three other people with Parkinson's but I don't know anyone with narcolepsy despite the fact that there are at least 2000 in Ireland.

Narcolepsy has a clear genetic component, or it wouldn't have an OMIM number, that's for the gene NRCLP1. But it's more complex than that because there are other OMIM entries for NRCLP2, NRCLP3, NRCLP4, NRCLP5, NRCLP6 and NRCLP7.  Seven different genes at different places in the human genome have all been shown to be associated with the condition.  So you can see why scientists get petulant when the press reports that Dr Mephistopheles has found The gene for homosexuality, schizophrenia, gout or any other traits with complex causation (or etiology αἰτιολογία as we like to call it to bamboozle outsiders).

At a molecular level, nacroleptics almost always have greatly reduced levels of a neuropeptide HCTR/hypocretin/orexin (all synonyms) in the brain and the cerebro-spinal fluid.  Orexin is made by the gene NRCLP1, so that's a direct connexion - banjaxed NRCLP1 means no orexin which is known to be the main mediator of sleep and arousal, but orexin also has roles in feeding behaviour, fluid balance, and hormonal regulation.  So far, so not so simple: to switch on the gene that makes orexin must involve a cascade of other genes (probably NRCLP2-7) and if you banjax any of those then you're going to have lower levels of orexin.  This all makes it complex and difficult to a) work out what causes narcolepsy b) how to cure, avoid or treat it.  One factor that seems to predispose is what variants you carry among the HLA Major HistoCompatibility (MHC) genes.  Notably pretty much ALL European narcoleptics have variant DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 (known to its friends as DQ0602) but so do 15% of the normal population so this immune variant is necessary but not sufficient. Specific HLA variants are known to be associated with predisposition to a number of different diseases and it turns out that the same DQ0602 that does for you with narcolepsy also protects you from diabetes. There is a suggestion that narcolepsy - which often kicks in during adolescence - starts because an autoimmune reaction specifically attacks the orexin producing neurons in the brain.  That's like rheumatoid arthritis where the capsule of the joints is attacked by the body's own immune system.  But it's more like Guillain–Barré syndrome where the immune system attacks the nerves. That is triggered by exposure to Campylobacter jejuni and common cause of chicken-driven food poisoning.

If this is ringing bells, you might like to contact the narcolepsy support group at
http://www.sleepy-heads.org/; me I'm just glad I don't doze off in the normal oufeller way too often.

Follow on to this.

Not so esperanto

Today puzzle time, for the birthday that's in it.  See how much of the following tribute you can figure out before lashing the whole thing into Google translate.  I've changed colour for some proper-name clusters. If you have a little Latin, you'll find it easier than cracking the Enigma Code.

 Ludwig Lazarus Zamenhof naskiĝis Лейзер Заменгов Leyzer Zamengov en la urbeto de Bjalistoko , en kio estas nun norda orienta Pollando. La urbeto ŝanĝis manojn kelkajn fojojn kaj pleniĝis de diversaj homoj tipa por Centra Eŭropo ĉe la tempo. Li naskiĝis en la jaro de Darvino Origino de Specioj estis eldonita je 15 decembro 1859. Lia uloj estis litova judoj kaj Leyzer parolis Rusa , Jida kaj Pola kiel infano : tre eble ĉiuj samtempe , se la familio de la Amato estas io por iri de. Ili kreskis ĉe alia vojkruciĝo en la Sahelo en Okcidenta Afriko kaj Mashup ilia diskuto kun Hausa , Franca , Araba kaj la Angla. Leyzer poste lernis la Germana, Franca , Latina , Greka , Hebrea , Hispana, Angla, Litova kaj Itala . Liaj samurbanoj en Bjalistoko estis ĉiam ĉe alies gorĝon anstataŭ festi la riĉecon de multkulturaj ebleco. Zamenhof naive kalkulata , ke homoj estis malagrabla ĉar ili ne povis paroli la saman lingvon. Dum 5 minutoj en la kompanio de ia hazarda duono de la loĝantaro estus rakontis al li , ke homoj estas malagrabla ĉar ili estas bastardoj . Tamen , li elspezis ĉiun rezervaj momento de sia laboro kiel sukcesa okulo - doktoro konstrui sia nova Internacia Lingvo , kiu aperis por esti nomata Esperanto - kio signifas plenan de espero en tiu lingvo. Li kaj lia edzino Klara havis tri filojn de Adam , Sofia kaj Lidia . Zamenhof mortis en 1917 , sed liaj filoj estis forkoformajn en la holokaŭsto kaj pereis tie kune kun la tuta kulturo kiu estis nutrata de Zamenhof kaj lia internaciisma sonĝoj. Esperanto estas ankoraŭ ĉirkaŭ , apenaŭ vivas kaj komplete malsukcesis atingi siajn esperplena celoj. Duoble tiom da homoj (560,000) parolas Kimra por komenci. Pardonu Leyzer , bela provo, sed neniu cigaron.

One Cycle

The sing-song yesterday was less excruciating than it might have been.  The scientists all (not all of them mind, but a good couple of dozen) got up and sang together - old and young, students and faculty, admin and technicians.  Regular readers (привет постоянные читатели) will know how important I believe this to be. Then we ceded the mike to the Engineers, the Central Admin, Grade VI and Above, the semi-professional contralto, Father Trendy, and an immensely tall chap with a fine tenor voice.  A lot of folk had donated cakes and cookies, catering supplied warm tea and we all staked up €5 for a poor local wean in hospital.  My HoD was sitting beside me and remarked how much he enjoyed this tradition - one of the few times in the year when the whole family of The Institute got together.  He was only a little deflated when I pointed out that the cleaners were all sitting at that table, the secretaries there, the physicists over there, the biology graduate students next to the buffet (proper place for post-grads) and the Engineers all together as well.  But it is ever thus the world over. There is nevertheless a sense of family about the place - you may not like everyone but you still know them and feel a common sense of loyalty.

After a quick trip back to the office to mark more lab-books we were called back to the canteen for the Retiree's Dinner.  This is free-in and catered by catering. There was turkey&ham or goat's cheese quiche followed by cheesecake or Xmas pud, which I manfully tamped down on top of the scones, short-bread and Dundee cake of the morning.  I asked where were all these Retirees on whose back I had just fed. I had hardly closed my gob on this question when the President stepped up to the mike. She commented on the fact that we are Institute of 2014. I've been quite negative about this piece of unscientific silliness. The Pres claimed that, when the data was being gathered, students from The Institute were asked what was the least good thing about their place of education.  Our lads apparently said "leaving the place when we're done".  If that's even partly true, that indicates that we're doing something right.

Mais revenons a nos retraités.  Anyone who has served their time and retired in the previous year was given an eulogy by their Line-Boss, and a gift from the President as well as a slap-up feed.  It's a Good Thing to say out loud what people may have written on the going-away card earlier in the year.  The recognition and appreciation counts for a lot - offsets the sense of being financially undervalued.  I could well believe the old chaps when they affirmed that it had been the best years of their lives.  It's been my best year this decade: I've now completed one academic cycle.  It's hard to credit what a difference 11 months and 600 contact hours with students of such a wide range of ages and abilities (not to mention 200,000 words on The Blob!) has made to me.  I hope I've made a small-small difference to some of the students . . . и вам уважаемые читатели.

All over bar the singing

Today - the end of term.  Busy day yesterday - marking the exam I set the day before, invigilating another exam, a journal club in the middle of the day, and a good few cups of tea.  I still have a couple of hours marking ahead of me today but I signed up to sing a couple of Christmas carols "Xmas novelty songs" with the other scientists, so I'll be roaring out the chorus mid-morning.  Chorus of what? I hear you say?  "Grandma go run over by a reindeer".  This is a loathsome confection: secular, cynical and condoning avarice.  I don't know where our HoD sourced it but none of the rest of the "choir" had heard it or even heard of it.  If you have a bucket handy you can see-and-hear it now.

But trained researcher me can now reveal the back-story.  The song was written by Randy Brooks for his pal Elmo Shropshire - a C&W singer - and released for the Christmas market in 1979. Elmo has a degree in veterinary medicine and goes on stage as Dr Elmo. He looks uncannily like the seepy compere at the end of Little Miss Sunshine. He recorded the song with his then wife as Elmo & Patsy and invested $40,000 of his own money in studio production.  Over the next few holiday seasons (no youtube back then), the ditty went viral and Elmo recouped his investment many times over.  $million$ are mentioned.  He and other creative people are wrangling with Sony over the carcass of the song that should have died - there are royalties from ringtones and downloads.  This serves as a metaphor of all that's wrong with Christmas.

Christmas is fine, it's good even, if you cherry-pick from what's available rather than feeling obliged to take the whole sorry 21st Century farrago on board..  A little saturated animal fat, especially if it is well roasted into potatoes, never harmed anyone; small gifts to small children are probably a Good Thing; a couple of glasses of wine is said to be great for the circulation.  I also think the whole event should hug The Solstice rather than start to extend its grasping hands right after Hallowe'en..  There I've spoken.  Now I have to go sing.

1339

Christmas time is here, by golly,
Disapproval would be folly,
Deck the halls with hunks of holly,
Fill the cup and don't say "when." 

Well it's NOT here yet, it's nearly two weeks away, but nevertheless I'm sure you're getting antsy about what to buy for that tiresome and rowdy nephew who, last year, knocked your favorite coffee-cup off the table and broke it. I could suggest a folksy remedy for disguising ritalin as smarties and Tom Lehrer has his own solution:

Relations, sparing no expense'll
Send some useless old utensil,
Or a matching pen and pencil.
"just the thing I need! how nice!"

Here's an idea that will go with young Bucko's attention span limitations but keep him quiet in a corner until the brother ("phew!") takes his family back home.  It's a book, it's chock-full of data, it makes you think, indeed some pages make you stop in your tracks and it costs £5 delivered. I lashed out and bought 5 copies - one for each of the families I know which have extremely well-behaved, savvy and symmetrical teenage and sub-teenage boys.  But it will work for girls also.

Today I got an e-mail from that nice chap in Amazon who sold the package to me: "did '1,339 QI Facts To Make Your Jaw Drop' meet your expectations?".  Well yessir! it surely did.  You could get sniffy and call it knowledge for the tweeting generation but it still lives up to the QI mission statement to be quite interesting. Sampler here at TYWKIWDBI.

How does that work though?  It's 350 pages long, bound with a sort of hard-cover, it's been researched and written by the QI team, published by Faber, typeset by Palidrome, printed by CPI in Croydon, trucked to Amazon in Fife, unpacked, warehoused, discovered by an amazonadrone, packed up and posted, air-freighted to Ireland, unbundled in Port Laois, trucked to our Post Office and driven up our buckety land by Paddy the Post. Jings! If I wanted to post the thing back to England it would cost €5 for the stamp! Part of it is economies of scale.  And Amazon doesn't just sell books.

Bingle Jells!