Pitohui ptui ptui

It's been a while since I had a piece on poison. Prevlier: Sarin - Ricin -  Botox - jellyfish - scorpionfish - diphtheria - mushrooms - so I was delighted to find out that the jungles of New Guinea host one of the few toxic birds we know about. How do we know they are toxic? Because Jack Dumbacher and museum curators experienced a tingly numbness in their fingers after handling the skins of Pitohui dichrous but not other species from the same region in their Dead Zoo. It transpires that the skin of these birds is loaded with batrachotoxin BTX, a steroidal alkaloid which had previously been isolated from the skin of frogs. Holly Grimes, while a student at Western Oregon University helpfully highlighted the characteristic steroid rings of the molecule [R]. Same core structure as testosterone and cholesterol. BTX is a neurotoxin that wedges into sodium channels in neurons making them permanently leaky. As nervous conduction depends on a delicate dance of sodium, potassium and calcium ions across the cell membrane this is severely and often fatally damaging. The LD₅₀, injected subcutaneously into mice, is as low as 2µg/kg making it between botox and ricin in the the toxicity stakes.

Whoa, that's weird because it appears to be an example of convergent evolution where the same solution to a problem [don't try to eat me or you'll regret it] appears in totally unrelated groups of organisms. They don't look a bit alike [L] do they? And it's not just the feathers. The classic example of molecular convergence was Allan Wilson's finding that the digestive enzyme lysozyme was evolving faster in langurs Semnopithecus entellus than other primates and coming to resemble lysozymes from fore-gut fermenters like cows Bos taurus. Langurs spend their whole life chewing leaves and got better at digesting the mash when they acquired some key, cow-like, mutations.

But it turns out that neither the pitohuis nor the golden tree frogs Phyllobates terribilis,  are doing the heavy biochemical lifting in the toxin department. The frogs of the world are taking a pounding from the mills of evolution recently and  Phyllobates terribilis, are among the many amphibian species on the IUCN red list. Like with White Nose Syndrome in New World bats, the immediate cause of mass frog extinctions may be the spread of a damaging fungus Batrachochytrium dendrobatidis, but climate change and habitat destruction are not helping. Ph. terribilis was not the first frog from which batrachotoxins were isolated, but it turned out to be the mother-lode, with some individual frogs containing 1 mg of the stuff. No matter how desirable the research outcome, you can't gather up handfuls of tropical frogs for destructive distillation of BTX, especially when they are endangered, so a captive breeding plan was implemented in toxicology labs. Farmed frogs had no toxin! That's when it was realised that the production of BTX is probably carried out by Melyrid beetles of the genus Choresine spp. The frogs eat the beetles and sequester the toxin in vesicles in certain cells of their epidermis for toxic recycling. It seems that the frogs have evolved a novel form of sodium channel that is immune to the effects of the poison. It is likely that the birds have achieved a similar feat. Presumably the beetles obtain the steroid building blocks from the plant stanol esters in their diet. Next question: Is there convergent evolution in the BTX-resistant sodium channels of Pitohuis and tree frogs? I think I feel an undergraduate research project coming on!

Making money from sheep

Yesterday I was writing about the easiest and most enjoyable $1,000 I earned in the 1980s. My career has not been a stable, steady progression accumulating promotion and pension contributions so that I can retire in a few years time and start going on cultural cruises round the Mediterranean like my folks.  It has rather been a succession of short-term contacts (two of six weeks duration) and part-time contracts (2012 down to one day a week) and the occasional purchase of Lotto tickets. We've been on the farm for 20 years now, which was the manifestation of our fantasy of self-help (Samuel Smiles) and self-sufficiency (John Seymour). We never intended to make a fortune from 7 hectares on the side of a mountain but we raised two upright and independent girls there which was reward enough. When Dau.I and Dau.II were small we had chickens - as eggs for tea and as consumers of kitchen scraps. And we've always had sheep - mainly to mow the fields. Sheep are hardship. They are frisky when you want to catch them; dilatory when you want to move them; and they die for no apparent reason. The very first ewe we had died [heart-attack] under the shearers clippers and left two orphan lambs to be raised by the girls. And one of our sheep may well have destroyed my thumbs.

Well, even as I was posting about earning money from pushing my quill pen across the parchment, The Beloved was yesterday making some money at the Mart by selling three cast ewes [Old breeding ewes which are sold off hill farms to lower ground farmers who take one more crop of lambs off them] and is now expecting a cheque for €250! T'buggers took a lot of time to round up and load into the neighbour's trailer and he remarked that it was easier to manage 300 sheep than 3 and that you're at nothing trying to herd a singleton. But at least we got them off the farm on four legs. Indeed we haven't have any death on the farm this year which is a better than average record for us. In the old days, the sheep would die and I'd dig a hole and bury the carcass. If the poor creature was a lamb, the girls would attend with flowers and then we've move on. Then in 2001 came the foot and mouth epidemic and the government got a lot more bureaucratic about the economics of death in sheep. It also became apparent that one herd of sheep had been claiming EU subsidies for several farmers on the same mountain. The inspector would visit one farm, count the sheep, sign the form and go into town for lunch; the sheep would be run over the hill to be counted again in the afternoon. It was like the famous story of the father of the Marx Brothers appearing as an extra in Monkey Business both on the ship and on the quayside waving goodbye to himself.

Thereafter, like cattle before them, every sheep had to have a unique ear-tag and each tag had to be accounted for at the Dept Agriculture. If a sheep had the misfortune to die on site, then we'd have to call the fallen animal guy who would take away the carcass for 'rendering'. You can't send dead animals to the factory for slaughter because they are already dead and the meat inspectors can hardly be expected to sign off on those chops being safe to eat. The fallen animal guy is running a business and charges €35 to give you a docket that can later be reconciled with your herd register. The maths therefore indicate that we are another €100 ahead because we didn't have to call out Disposal. Win!

We've also made a little money on mutton; selling the meat from our organic unmedicated ram lambs. But that only goes to a) friends-and-relations who b) have freezer enough to take at least half a lamb butchered into chunks. That is a limited market and our freezer is still full of chops and scrag-end because half of our small household is vegetarian. We have been careful about the process, there is a butcher on the far side of the mountain who will take small batches of lambs in the evening; put them out to grass overnight; and slaughter them in the morning. Any journey is a trailer is super-stressful for livestock and a surge of adrenalin from a hyped-up sympathetic nervous system does the meat quality no favours. Against that is the many many bags, at €8.50 each, of sheep muesli [mmmm good] that get loaded into the back of my car at the feed-store and lurried into the sheep during the winter,

Word-a-day notes that it is Peter Singer's birthday today with his quote "Animal factories are one more sign of the extent to which our technological capacities have advanced faster than our ethics." Quite so. Singer coined the phrase Animal Liberation in 1973. And more recently has asserted The abuse of animals won’t stop until we stop eating meat.  Nobody with the least sensitivity would deny that industrial slaughter houses give the bum's rush to the animals that most of us finish up eating. I'm under no illusions that the chute our ram-lambs go up on their final trip is a bed of roses - it's just better than the other options. Temple "Think Like A Cow" Grandin has made a huge contribution in making abattoirs more efficient by making them more humane. 'better than the other options' is me trying not to be all black&white over the ethics. Before you get too dogmatic on either side, you might read Simon Fairlie's book Meat: A Benign Extravagance [Amazon £8.00+] which puts the case that meat can be incorporated into a holistic sustainable agriculture. Pigs raised on kitchen waste and weeds is perhaps the best option. Fairlie scythes and has been interviewed by Time. We've met Peter Singer before on the ethics of conscience. and experimental psychology.

Making money from science

Up until about 1953, science could be considered a past-time for gentleman. Of course there were women in science, and of course there were bitter rivalries - think Liebnitz vs Newton on The Calculus - but the pace was less frenetic and there was space for other things. There is a famous (so famous I can find no reference to it aNNywhere on the interweb) anecdote about Ernest Rutherford dropping back to his office after hours and seeing a young researcher still working in the lab: "Go out and play a game of tennis, young man" he ordered. While I was writing, but before I posted, one two recent pieces on the scientific literature, two separate people sent me a link to a long essay in the Guardian Is the staggeringly profitable business of scientific publishing bad for science? which suggests that something was rotten in the state of science. That essay is worth reading as a history of the transition from science as a leisurely pursuit by chaps who had a job for life (or lived on their estates polishing a really massive telescope) to today when life in science is a more relentless and unforgiving mill driven by money and published results. The key figure in the transition was a serial entrepreneur called Robert Maxwell who recognised, in a post-WWII devastated Europe, that a scientific journal was a licence to print money. His publishing empire Pergamon Press wittily adopted a head of Athena Goddess of Wisdom [R above] taken from a coin discovered in Asia Minor. Wisdom makes money, geddit?

The business model is a "triple pay": the government funds the research that needs to be published; they also pay the salaries of those who validate those results through peer-review and then they pay the subscriptions to make the journals available in academic libraries. Somewhere in the middle of this Elsevier, Springer and Wiley-Blackwell are charging whatever they like to put the peer-approved scientific papers into coherent bundles and ship them to the World's libraries.  It is a terrible wasteful business because nearly half of all the papers published are not cited at all. Thus a mammoth publication like the Journal of Biological Chemistry might take up 2 meters of shelving for the 24 volumes published each year and some volumes in a given library may never be taken down to be read. Most of the 50,000 pages just serve as a fire-hazard and would be more useful as a nest for mice.

The thing about this business model is that the humble workers at the coal-face of science get nothing at all financially for creating the literature upon which the whole edifice floats. Indeed, they are usually required to pay a fee or page-charges for the privilege of publishing. For a brief period in the mid-1980s I bucked this trend and in one year period made an additional month's salary - about $1,000 all told - for writing two papers explaining my science to a general audience. I thought I would soon be able to retire on my money and polish my telescope forever but I never got a seat on the gravy-train again, because my subsequent research didn't involve kittens.

I spent the 1980s tooling around the Atlantic looking at domestic cats, noting their colours, calculating gene frequencies and testing hypotheses to account for the differences among populations. The cats of St Pierre et Miquelon, for example, look far more like the cats of Bordeaux than they resemble the cats of nearby St John's Newfoundland. My PhD thesis analysed the cat gene frequencies of New England, Québec and the Canadian Maritime Provinces and used these data as a test of the historical migration hypothesis. That theory hinged on the primacy of founder effect - the first cats to step ashore in a previously cat-free continent got their genes firstest with the mostest and established the gene frequency profile for the rest of time. Hence the observation about SP&M and its mothership at the mouth of the Gironde. The story was a bit woollier but the cats of New Amsterdam York seemed to have a Netherlandish signature different from those of Connecticut or Massachusetts. I worked long and hard on the data and their analysis and wrote up a dry summary of the key findings from my thesis for the Journal of Biogeography. It has been cited 10 times, achieving a certain minimal - but way above average - utility for the progress of science. By the time the paper was published I was working in Newcastle upon Tyne in NE England.

Sometime in 1986 I got a letter from a popular science glossy called Natural History offering to pay me $750 if I would write 3,500 words about my research in cats.  One of the researchers at NatHist had read my paper in J.Biogeography!  I was flattered to get the call because that was where Stephen J Gould [multibloboprevs] published his monthly column This View of Life, the universe and whatever was floating his boat that week. I had an e-mail address back then, but such things were an academic rarity and the editor at Natural History definitely didn't. The WWW wasn't released until 1991 and Mark Zuckerberg was still in diapers. Accordingly we communicated by transatlantic telephone and FedEx. I wrote my 3,500 words; a super-qualified copy-editor blue-pencilled it and took it apart; reassembled it in a much more direct and engaging form . . . and sent it back to me. I corrected the editor's science and sent it back to her.
They got some stock photos of cats on docksides [less creepy / threatening than the cats on Aoshima Island L] and kittens-in-baskets tortoiseshell cats and drew some swoopy maps showing emigrants from France to the St Lawrence and Spain to Mexico. I objected to their title Pussy cat pussy cat where have you been? because it seemed to trivialise the science but they won that argument. When it was finally published they sent me a cheque for a little more than $750 because I'd incurred FedEx charges. I was delighted.

A few weeks later I had an enquiry from Endeavour, who asked if I'd like to write something similar for them for £200. Less money gave me more editorial control and I chose the title Cats from history and history from cats. Endeavour was then owned by Pergamon Press, Robert Maxwell's going-exponential academic publishing house. It was an exception to the triple-pay business model in that they gave their authors a small slice of the pie.  My research paper in J.Biogeog. or these two secondary sources was picked up and reported by Forskning och Framsteg in Sweden and Scienza e Tecnica in Italy but I didn't get any money for those articles . . . because I didn't write them!

Isola Ferdindandea

x marks the spot, midway between Sicily and Pantellaria, of a submarine volcano called Empedocles. In July 1831 it gave a sulphurous burp and then blurfed its lunch above the waves.  On the 1st August that year, as soon as it was cool enough not to melt boot-heels, Captain Senhouse of HMS Vincent put a party ashore to claim it for His Britannic Majesty.  Senhouse named it Graham Island after his naval boss. The Italians called it Isola Ferdinandea or, more recently, L’isola che non c’è - the Island that Isn't. La francophonie knows this non-existent island as île Julia. It is non-existent because, having caused a running diplomatic incident and been a tourist hub for six months, the heap of cinders sank beneath the waves again. The rise is now 6-8m below the surface (all the time, the Mediterranean has virtually no tides) and known as Graham Bank or Bar. Several other names have been proposed. It seems unliklely that any country other than Italy would lay claim to it if it re-appears anytime soon. It would soon be full of African refugees like Lampedusa and nobody wants to take responsibility for them.
In 1831, au contraire, it was 60m above the surface as seen in the images [L from amusing planet] by French geologist Constant Prévost. That was its most spectacular and best recorded appearance, although it bobbed up again in 1863 and in 2000 and 2002 showed signs of activity that might have presaged another showing . . . which did not materialise. It is rather like the dynamic ups and downs manifested in the Vestmannaeyjar off the South coast of Iceland. Empedocles and other well known volcanoes in the region (Stromboli, Etna, Vesuvius and indeed Volcano] are a consequence of the African tectonic plate crashing into Southern Europe and subducting. This Restless Earth!

Lots of other islands on The Blob.

When lysosomes go bad

Back in the 1950s, Christian de Duve was trying to measure the activity of the enzyme acid phosphatase in the liver. His results were not as reproducible as he needed and he realised that a major variable was whether he ground up the gob of cells in a pestle and mortar or put them in a blender. He parked the enzyme assay to solve this sample preparation problem and discovered lysosomes: small membrane-bound organelles that are brimful of enzymes. Blending burst open the lysosomes; grinding kept them intact.  The discovery of lysosomes and the itemisation of their enzyme repertoire explained a number of degenerative childhood diseases, including Morquio Syndrome and Tay-Sachs Disease.

This last academic year I set my 1st Year Pharmacy Technician PT students a research task. This is really quite unprecedented because, even in final 4th year, only a subset of our students are able to carry out a research project with literature review. The PT1 research task was more of a literature review but each one was requested and required to find out about a particular lysosome storage disorder. They did really well and at the end of the year I told our external examiner that I'd be giving more such tasks in future. Our students are often bad at recalling information in the May exams, so why not have them work to discover something in October and January. I'll bet they'll retain that hard-won auto-didactic information longer.

I am, therefore, a bit primed for lysosomes and lysosome storage disorders or LSDs, so was delighted to find a fine supplement on LSDs in Nature from last September. The information appears to be outside the Nature paywall, so you can read a helluva lot about LSDs, their tragic effects, the robust advocacy of parents, the beginnings of therapeutic success and the economics of rare diseases. I'm not going to give you a synopsis but rather focus on a couple of interesting nuggets.

There are about 50 known and named defects in the inventory of the lysosome. The inventory consists of enzymes which break-down worn-out components of the cell. Because some poor wee mite presents with a really weird set of symptoms, doctors and genomic researchers have been able to reveal the existence of a normally present enzyme which is banjaxed in that child. You don't have to know the molecular basis of a disease to perform a diagnosis and implement a protocol for reducing its incidence  - Waren Tay first noted a characteristic symptom of Tay-Sachs  in the 1880s - but it sure helps. The protocol that worked for Tay-Sachs was no therapy but a battery of methods for preventing the birth of kids with the lesion. Knowing the molecular fundamentals is key to developing a therapy.

A nice infographic in the Nature LSD supplement bins potential therapies (oh oh a list, I feel an exam question coming on):

• gene replacement therapy
• This is the Holy Grail. genes make enzymes, so if you can sort out the genetic defect you can make as much enzyme as you need. The gene is buried in the nucleus of the 100 trillion  cells we each possess, split into exons and we know only a little about how and when and where it is switched on. Delivery and implementation are both huge problems currently.
• enzyme replacement therapy ERT
• This is the current cutting edge. Lots of pharma companies, big and wannabe big, are developing molecules that can be taken by patients and get delivered to cells, absorbed by them and thereafter popped into the lysosomes and get going on the enzymatic breakdown and recycling process. There are 100 trillion cells in there, each with 50 -1000 lysosomes which are constantly being turned-over. It strikes me as being amazingly confident that a company would embark on such a mighty distribution problem. It's a lot harder than that faced by Amazon or FedEx!
• enzyme refolding therapy by chaperones
• for some of the 50+ LSDs, the gene is there and the enzyme is almost there but it just comes off the assembly-line a bit bent out of shape. Broken and defective proteins get tagged for recycling and delivered, with some irony, to the lysosome . . . but to the loading dock rather than the executive entrance. Chaperones aka Heat Shock Proteins HSPs are tasked to primp up some normal enzymes (only a minority of proteins fold spontaneously as they come out of the ribosome). Entrepreneurs are asking if they can make or modify a chaperone to push  a defective lysosomal enzyme into shape.
• substrate reduction therapy SRT
• Gaucher's Disease GD, one of the commoner LSDs is caused by the accumulation of glucocerebroside aka glucosylceramide aka sphingolipid in cells because glucocerebrosidease, the enzyme that breaks it down, is defective or missing. We need sphingolipid and quite a lot of it, but like many good things (carrots, alcohol, cream-cakes) too much is toxic. If we could limit the amount of sphingolipids produced then the lysosome wouldn't get overwhelmed. That's the idea aNNyway.

Okay exam time! what is the meaning of these three-letter acronyms TLA: ERT, HSP, LSD, SRT ?

Hard enough? Just one more point. The problem with developing novel molecular therapies is that, with the idea, the experiments, the false leads, the dead ends, the replications, the validation, the clinical trials phases I, II and III, the licencing . . . it costs the bones of $1 billion to bring a new drug to market. All new drugs are developed on a For Profit basis and a great many entrepreneurs /  capitalists have taken a risk on the venture: they want a return on their investment, so the costs and the profit must be amortised over the market so that the debt can be paid off before the patent runs out - between 5 and 10 years. Some markets are cash cows: overweight, un-young, insured people will benefit a little from statins on prescription and there are LOT of punters in that category. So the cost per dose is small enough. But take a LSD like Niemann-Pick type C brought on by a defect in the NPC1 or NCP2 gene. That only occurs in 7 births in a million. That's about 30 cases in the USA and another 75 in the EU . . . and that's your market! Everyone avoids thinking about poor black babies with a broken NCP1: they couldn't afford the drugs no matter how cheap.

There is tantalisingly good news for these orphan diseases which nobody will own. It turns out that both Gaucher's Disease an LSD and Parkinson's have a genome wide association with having a mutated GBA1 gene. Parkinson's is about 600x more common in over 65s than Gaucher's is in under 1s. Nobody has found the mechanistic common ground on that association . . . yet. But if Gaucher's is a sort of early onset Parkinson's, like chicken pox is the childhood version of shingles, then the bigger market might encourage creative science that might have positive fall-out for Gaucher-mites.

Sunday outdoors 020717

Gerrout off yer sofa Bob. into the fresh air.
YouTuBe was briefly ProudToBe:

• Fishin' and mountain bikin' in the Rocky Mountains
• Slack-lining meets base-jumping - I can't bear to warch
• Lofoten Islands
• Transhumance: shifting your stock to Summer pasture 
• Les moutons de la Gascogne [French]
• In Patagonia too
• Harder in Iran
• You can sing it: chanson la transhumance
• Hegoak = wings. Jonathan Livingston Seagull for Basques.
• Feet in the clouds [prev book review] Askwith talks about fell-running
• running against the clock: BobGrahaming in English Lakes. 
• [note Billy Bland ran the 42 peak 106km Bob Graham round in less than 14 hrs in 1982]
• The [inevitable] Nazi view
• More fell running better production values
• But move over blokes: Nicky Spink aged 48 ran a double Bob Graham in 45.5 hours last year. There's a film whc might be called A Life in Two Days Of . . .
• Lumberjack reveals things inside trees
• Medemblik Stoommachinemuseum has a steam-driven plank-cutter.

Saturday Arts Block 01Jul17

O Canada! It is the 150th Anniversary of the foundation of the Dominion of Canada. I wrote about the Canadian flag 4 years ago. [Part of] Canada is part of la francophonie - sing it!  More party propaganda.

There has been a movement for the last several years which leaves books in public places so that they can travel further. Emma Watson, a person in her own right, has been leaving signed copies of Margaret Attwood's La servante écarlate around Paris. With the majority of my readers tuning in from France, some of you know somebody who knows somebody who has picked one up. via Metafilter which elicits this plaintive comment "Damn it, Emma! Stop making me love you so much. You're too young for me."

Young Emma is freeing The Word up.  As a counter point, a friend of mine has just landed a job at the Higher Education Authority HEA here in Ireland. He thought to check up on The Blob (on company time tsk tsk!) and found we are flagged as "prohibits access to websites categorised as Adult/Sexually explicit."  Sounds exciting, I should  surely be getting more page-views.

The late lamented Alan Rickman asserts My mistress' eyes are nothing like the sun.

Yesterday was the 123rd anniversary for the opening of London's Tower Bridge. That's the Gothic one with the bascule opening which was decorated with Onion Rings in 2012 [see R]:
In 1952, before Rotterdam became Europe's largest port, there was a lot of traffic under the bridge and ships had priority over road-vehicles. In December of that year a #78 bus was trundling across when the bridge started opening. The driver Albert Gunter floored the accelerator to clear a 1m gap landing 2m down with a clunk. There were no serious injuries and Gunter was given £10 for pluckiness. This chap in Bruinisse NL didn't have sufficient momentum for his jump. This guy from Palm Beach FL made it; as did a 3m long bratwurst, in Chicago.

According to Quartz everyone - Left Right Goopi Loopi Nazi - is into Ashwagandha Withania somnifera nowadays. Tonifying their immune system; curing cancer; benefitting their adrenals; de-stressing and curing hiccups. Ashwa-gandha means horse-smelling in Sanskrit, so maybe it will help you decide on the winner in the 2.30 at Punchestown. Goop booboprev.