Bugging the blood pressure

In between Blobs, I teach science in The Institute: a shadowy college of further education in the Irish Midlands with links to Opus Dei and the Illuminati. It's coming up for five (5!) years now but the one course that has been mine through all that time is Human Physiology. My only qualification in this area is that I have a body, some curiosity and a preference for making sense of the world. Everything you need to know about Human Physiology is homeostasis:t he remarkable, and energetically costly, maintenance of things in equilibrium at a set point. Our core body temperature holds at 37^oC +/- 1 degree through a remarkable range of external conditions: bouncing starkers from a sauna to a snowbank does Finns no harm at all and the thermometer popped up a Finnish rectum stays steady at 37 throughout. The remarkable properties of dissolved carbon dioxide and the bicarbonate ion maintain the blood pH at a constant level of acidity. Circulating glucose, circulating sodium, circulating calcium are some of the substances whose set-point maintenance we understand well.

One definition or explanation of senility (the process of growing old, not necessarily associated with dementia or dribbling) is the breakdown of these precise regulatory mechanisms, so that the swings about the set-point are less subtle. Hand-tremor is a good example of this: when you young chaps hold a pint steady at the end of your arm, about 30 different muscles are acting against each other to stop the booze slopping down your shirt. This handy life skill, which you take for granted, is a bit of an ask for Pat the Salt my 92 y.o. father in law. One muscle will contract and its oppo will over-react, so his hands are less steady than they were when he was your age.

Now think about blood pressure; that has to be maintained in a wide variety of conditions. Asleep, your heart has it easy: pumping blood on the flat. When you stand up, immediately, your heart and arteries have to up their game for some metaphorical fell-running, the system is now being asked to pump blood up a 1.5m to 1.8m hill between ankles and head. Me, I now have to be careful springing out of bed in the night. Unless I meet the problem halfway by sitting on the edge of the bed for a moment, I am likely to feel a touch of faintness, a prelude to crashing to the ground in a heap

Obviously, the problem of normal blood pressure maintenance features largely in my Human Physiology course. That way my colleague, a real pharmacist, teaching Drug Actions and Uses can look at all the interventions that are possible when blood-pressure goes too high. BP is a regular cash cow for MegaPharm Inc. I'll get round to some of these drugs and how they work later - it's a fascinating insight into how scientific research works. Ignore the drugs and abnormally high blood pressure: that's a very modern problem. Let us rather look at how BP was kept UP in normal life for the super-thin, marathon-running, hunter-gatherer who came down from the trees and started walking upright 4 million years ago. Those chaps, and we are their descendants, were designed to keep blood pumping uphill to the head, without that you can't make decisions while running down a wildebeest.

There are two ways to increase pressure in a closed system: you can make the volume smaller or you can add more fluid . . . or both. And you can also increase cardiac output: make the ticker beat more frequently or with more force. Making the system smaller is largely about peripheral vaso-constriction, your small arteries are all surrounded by rings of muscle, contract these and blood pressure will increase. A nifty way of increasing the volume is to have the kidneys retain Na = sodium. These sodium ions suck water back from the kidney tubules to stop the salt from coming out of solution and forming crystals. That's so elegant a working solution! Sodium is maintained in equilibrium in the blood because we need it for muscle contraction and nerve signalling, using it to attract water is a secondary feature. Everything is interlinked, sometime in quite unexpected ways.

Hot Press, we had it all wrong. Or at least our understanding of sodium balance and blood-pressure as a physico-chemical problem to do with hydrostatics was laughably simplistic. Actually it's all in the microbiome innit? I've had multiple occasions to write about the intestinal flora / microbiome - the 2kg / 100 trillion cell / 10,000 species menagerie that we tote around in our guts . . . with out-stations up the nose, down the uterus, in yer armpit and all over our skin. It seems that, although salt intake is very closely related to blood-pressure (and this is why we are begged to use less salt in our food) some people don't seem to respond to dietary salt in that way. A group from Charité-Universitätsmedizin Berlin wondered whether the connexion between high salt diet and high blood pressure might have a microbial dimension.  The News & Views about the study from Nature 30 Nov 2017 [paywalled] is by David Relman a leading light in microbiome studies. Apparently the excess sodium leaks across the intestinal epithelium and inhibits the growth of one species of the normal flora of mice called Lactobacillus murinus. Apart from being rather sensitive to salt, these Lactobacilli metabolise a dietary amino acid tryptophan into indole. Indole leaks back across the epithelium and prevents the development of a class of key immuno-inflammation white blood cells called T_H17 lymphocytes. These lads have a tendency to blurf out a pro-inflammatory cytokine called IL17 (hence the name of the cell). IL17 is a small molecule that promotes inflammation which is an essential part of fighting off infections and pathogens and one of its effects is to  annoy the inside of arteries so they swell up . . . which increases blood pressure. You will have gotten lost on the roller-coaster of consequences, so here it is in tabular form:

Input	Output	Cell	Cytokine	Effect	Conseq.
Salt	Indole	TH17	IL17	Inflam	BP
up	down	up	up	up	up
down	up	down	down	down	down

Who designed such a Heath Robinson brown-paper and string system? Mrs and Mrs Evolution, that's who. It worked fine when we were all hunting about the Serengeti. Salt was in desperate short supply back then - there were fights at the salt-licks because everyone needed enough sodium to service their muscles and nerves. Now otoh it snows salt, so it's no wonder that the carefully crafted regulatory system are thrown all ahoo.

Covid Comms

We've been running the Wexford Science Café WSC for nearly 6 years now. The idea was that STEM-folks in the Sunny South East would have the equivalent of a Book Club, a Choir, or a Men's Shed - a place to gather with like-minded adults to chat about about science. For those who have made the effort - it can be all to easy to stay indoors on the 3rd Tuesday of February if it's dark with a whippy wind and the roads are a litter of fallen branches - it has been rewarding. Then again, there are more people who came once only than those who stayed to learn the handshake and the secret sign. We've covered a few bases because the community is diverse in its interests and expertise:  Air-quality and asthma; Allometry; Back-garden astronomy; Bacteria in food; Cider; Compost toilets; Diabetes & Alzheimers; Diets; Erwin Schrodinger; Galena; Generic meds; Gravity waves; Greenland ice melt; Gut Microbiome;  March for Science; Neuroscience of torture; Oroville dam; Pheromones; Radon; Science book-swap; Soil microbiome; Stephen J Gould’s spandrels; Thomas Kuhn’s paradigms; Toxicity from botox to beer; Urination once again; Water quality; Wolbachia and tropical diseases; Zombies;

The theme or topic for each night is part of the attraction but the networking and the sense of belonging is at least equal in importance. Last year [2019] we tag-teamed with the Wexford Science Festival WSF which had been launched with some razz-ma-tazz the previous [2018] year. That was a success because their publicity machine was better funded than ours and we swept a handful of new STEM faces into our orbit. Our mutual admiration and common ground made us promise to do the same again in 2020. Then Coronarama swept out of Wuhan [L market-watch] as a pestilence and a great disruptor of all social events; perhaps especially those which habitually met in a pub!

Well, whatevs, we are meeting tonight for a discussion about Coronarama. Far too many people pretend to know everything about: Corona Viruses; SARS-CoV-2 itself; Covid-19; epidemiology; statistics; zoonoses; masks; mink! long-covid; asymptomatic covid; my dead neighbour; PCR testing; R-numbers; vaccines; the Economy; care homes; Sweden and intubation. But when the usual suspects are wheeled out for a sound-byte by the media there is far too much hubris and not enough humility. I am working on a hypothesis that the usual suspects are overwhelmingly male . . . because they are so goddamn certain; which means that whatever news requires a response can be explained and finished with in 200 words or 90 seconds whichever is shorter. Accordingly tonight we are digging with the pink foot and hoping for a more measured discussion about how scientists communicate their findings and how they could do better in explaining things to Jo Public. The gig is hosted by podcaster Dr Megan Hanlon and Cliona O'Farrelly, the Chair of Comparative Immunology at TCD.

Megan's channel is called Unravelling Science, where she is currently on a podcast jag interviewing successful scientists about where they came from, where their inspiration came from, what they do and what can they say to encourage early-stage scientists that it is worth the candle. I like the interview genre very much, it conveys the Passion for Science in a way that any number of dry, passive voice, peer-reviewed formal scientific papers manifestly fail to do. The irony is that the only thing which counts in scientific progress [= promotion] is peer-reviewed papers while the only thing that will recruit the next generation is the passion and engagement of mentors and teachers. Strength along these two unrelated axes rarely meets in one person.

Y'all come along down; you need not leave your sofa but you do have to book one of the 100 seats in the virtual Wexford Science Café. Looking forward!

Lighter by 3g and €150

Let nobody tell you that sad-sack Bob has no social life. I was up in Dublin for two days this week meeting people and doing the Orthodontic (it takes two to) Tango.

The main social event celebrated the elevation to Full Professor of one of the short handful of graduate students whom I've helped over the line to get a PhD. It's good to mark these transitions: getting there is what motivates a lot of scientists. External validation with a bigger office, more money, better students will keep you trundling along the tracks when you have an attack of impostor syndrome. If you don't have an occasional attack of impostor syndrome you are probably, like Byron, mad, bad and dangerous to know; prone to bullying, plagiarising your post-doc's data and nicking milk from the communal fridge. [aside check out Colm Tóibin's MBD2K book]. As we were wetting the [40 y.o] baby's head with a bottle of Moët, the two established Full Profs confessed to impostor syndrome: so they are probably okay to invite to dinner and trust with the mental health, happiness and career progression of a succession of young scientists. And so many of those youngsters are brilliant: motivated, dexterous, creative, crap-detectors. What few of them realise at the time is that their PhD is not about the results, or even the papers, it is about polishing your capacity to critically evaluate data: you own and other people's

I reflected on how content was I to be winding up my [Chairless] lifetime in science working in The Institute. Because my ambition genes were shot off in the war, and because there is effectively no path for progression in the InstTech sector; I can concentrate on the welfare and education of the students rather than having to boast my corner at faculty meetings. The following day, I was in the office of another flying genius, sorting out a possible research project for one of my students. This young chap had sent me an unsolicited e-mail asking if it was possible to do a final year research project on epilepsy. I've just taken delivery of a very nice project showing that the collective gut microbiome has the enzymes to make neurotransmitters. Now bacteria are bears of very little brain and are presumably using NTs for a weirdly unknown purpose of their own, but if these small molecules are taken up by the intestinal epithelium and into the circulatory system, then maybe that's the mechanism by which out gut flora influences our happiness and mental health [as well as out line-manager, that is]. I googled "epilepsy microbiome" and up popped an exact contemporary of the previous night's head-wetter. On Friday afternoon we had a really productive discussion and have roughed out a Heads of Agreement that will see my student getting Tenure at Harvard in about 15 years time.

In between those events I was back in the dentist's chair of the wholly competent surgical orthodontist who removed three of my impacted wisdom teeth in August 2017. Me and Bill the Dentist (he of the peach coloured dental chair) agreed that, for my upper left premolar, it was time to die. The labial face of this hard-working servant had failed and been replaced; the lingual face had collapsed afterwards; the remains had been cleared off and 2 titanium steel pins inserted in the stump as scaffolding for a crown of white plastic. That shaky edifice had bitten the dust over Christmas. Around about 1350hrs Friday, after 2 paracetamols and a local lidocaine, the orthodontist put her knee on my chest, one hand on my forehead and wrastled the stump of my P² out of my head. It cost €220, of which €70 [removal of dental root] could be offset against my health insurance, hence my laconic txt to the family Lighter by 3g and €150.

Dau.II the Quant wasn't having any of that. What do you mean 3g as the weight of a tooth root? A cc of water is 1g, that tooth is surely less volume than 1cc. Does a tooth float? No? but it is not 3x denser than water, is it? errr quite so, that young woman doesn't need to go to graduate school to hone her crap-detector.

aspartame makes you fat

Nearly two years ago towards to Birth of the Blob, I wrote a comment on a poorly nuanced RTE report about the association between diabetes and 7up (and other sweetened soft drinks).  If true it needed to be stated in a less hysterical fashion to convince me.  One of the factors that tuned my skepticism antenna was the fact that diet coke appeared to make you even fatter than regular sugar-loaded soft-drinks.  Although, when the increase in diabetes was properly contexted by BMI, the apparent association disappeared.  Turns out I was quite possibly >!gasp!< wrong . . . to think that aspartame and saccharine were irrelevant to the obesity epidemic.

It's all in the microbiome, stupid: the 10,000 species of bacteria that we all tote around with us, mostly in the large intestine.  On 18th September last year, there was a nutrition report which laid out some pretty convincing evidence that drinks loaded with artificial sweeteners, far from being a solution to our increasing girth might actually be making things worse.  Check out the work of Eran Elinav from the Weizmann Institute in Israel. Elinav at the movies!  One of the early (that's as long ago as 2006!) studies searched for twins, identical and fraternal, who differed primarily in trouser size. They took twin-paired samples from the twins' intestinal flora and introduced them into germ-free (caesarian-sectioned, brought up in a bubble eating gamma-irradiated mouse-chow) genetically identical mice.  The mice receiving the 'obese' bacteria reliably ballooned out, while their cousins who received slim bacteria gained weight at half the rate.  Why is this important?  Because we have in the last 100 years developed an epidemic of "metabolic disease" - a syndrome involving the woes of Western society: obesity, diabetes, fatty liver, high blood pressure and heart disease.

They have now done similar controlled experiments with mice getting artificial sweeteners in the water and mice getting glucose.  The mice taking saccharine.etc. rapidly developed glucose intolerance.  If you experience the following symptoms and are not recovering from a night on the batter, you might consider seeing your diabetologist:  Feeling very thirsty; Dry mouth; Extreme tiredness Blurred vision; Drowsiness; Frequent need to urinate; Loss of muscle mass.  Glucose intolerance essentially means that glucose doesn't get cleared from the blood circulation quickly after food intake but hangs around rather than getting converted into glycogen for future use. Apart from anything else, glucose is a universal currency and you are much more likely to develop septicaemia if you are hyperglycaemic - peripheral gangrene, anyone?  Convincingly, this glucose intolerance evaporated when the mice had their intestinal flora eliminated with a short course of broad-spectrum antibiotics.

Perhaps the most important factor that has developed from Elinav's huge sampling of people, their lifestyle, their circulating glucose levels and their microbiome and cross-referencing of these different threads (or tsunamis - we're talking terabytes of information, here) of data is that Folks are Different. The Atkins diet may work a charm for that lady you met at the water-cooler . . . and her sister; but will do nothing at all for you because your bacteria are not her bacteria. When I was working in St. Vincent's Hospital a dozen years ago, we were just beginning to talk seriously about personalised medicine: only 50% of people with chronic Hepatitis C Virus infection will respond to interferon-α therapy, and it costs €12,000+ a year, so we'd dearly like to know who will respond: not least because the side-effects of interferon are almost as bad as the disease.  Now we are clearly talking about personalised intestinal bacteria.  There are people out there, whom I've never met who have something in common: they have essentially the same bugs as me and therefore the same pitch of glucose intolerance, possibly similar food preferences, the same sort of winter sniffles.

As this intestinal flora changes radically and within a couple of days when we have a change in diet, it is not beyond belief that the bugs inside are telling us what to eat. That, frankly, seems a little invasive.

Tweaking the microbiome

Only connect!

We could weather a lot of the crap that dumps on us through life if only we weren't already compromised in some quite distinct way. Being caught outside in a deluge is okay if you've packed an umbrella; you don't get Guillain-Barré syndrome unless you've been struck by Campylobacter or HPV vaccine AND you have a genetic pre-disposition. Did someone say vaccination? Seems that for some people, 'flu vaccine can trigger narcolepsy. I've had a lot to say about the microbes of our guts and how they affect our health and happiness. Why just the other day I reported that some people will gee up their immune system to an annoying intolerance of gluten IF their immune-system is programmed to react in that way to the natural (and almost always benign) zoo of bacteria in their guts. At the end of that essay, I suggested that it was diffcult to precisely promote the death of baceria known to be harmful, but that you might be able to preferentially feed 'good' bacteria.

Two days later, because the internet loves me very much, up popped a story about that very matter. It was doubly interesting ecaue I've got a final year project student who is looking at the genetic make-up of viruses which infect Listeria monocytogenes she is also looking at the mechanisms that Listeria uses to control the depredations of, and limit the damage caused by, these infectious particles.

A group of microbiomologists from San Diego [press release / exec summ] led by Lance Boling [L above] in the lab of Forest Rohwer [R above] have coursed over the literature to identify 100+ foods and food products that are claimed to be specific for affecting the microbial community in the gut. Among these foods are Stevia, a key ingredient in Gwyneth Paltrow's woo-wah fashion-accessory 'foods' or Goops as she prefers to market it. Other tested foods include citric acid, caffein, capsaicin, cabbage, cinnamon, clove - and that's just the Cs.
They have then tested these compounds to see
a) whether they killed such bacterial star players down there as Bacteroides thetaiotaomicron [prev] Enterococcus faecalis, Staphylococcus aureus and Pseudomonas aeruginosa.
b) whether the bacteria grew better "yumm: send more cottage cheese"
c) whether and how they affected the viruses that they deduced from sequence analysis infected the bacteria.

One of the key metrics used by Team San Diego  to count the cases of the change from lysogeny to the lytic phase of the viral life-cycle. Lysogeny is when the virus genetic material is physically incorporated into the bacterial genome where it lies dormant; getting replicated passively every time the bacterial host divides. This can go on forever . . . until something induces the virus to excise from genome, actively assemble dozens of whole viral particles and burst out of the bacterial host to infect dozens of other bacteria. That 'something' trigger might be a sense that the bacterial host is in trouble and like to die. The virus would be better off if it sent a great many descendants out to try their luck in the cruel world than passively wait for the end with and in the current home. This make copies and scatter is called the lytic phase, because it involves the lysis of the bacteria.

The original paper, replete with data and informative graphs is freely available, so you may go and mine the horse's mouth for things that you may like to include in your new rich and varied and pre-biotic diet. You may bet that there will be some problems with replication - another strain of Bacteroides thetaiotaomicron might have a subtly different genetic make-up but this is grist to my mill of reflection on the relationship among diet, microbiome and health. It's in the detail: Arctostaphylos uva-ursi [bear-berry] will cause massive virus induction in Bacteroides thetaiotaomicron but tends to prevent this bacteriocidal phenomenon in Enterococcus faecalis and Staphylococcus aureus. If one food product doesn't do much then there is always the possibility of synergy on the plate: a salad of chicory, clove and cashew may turn out to be just the thing for duffing up Clostridium difficile.

Multitudes down there

I have finished Ed Yong's I Contain Multitudes, his book about the intestinal microbial flora. It's gallop and has a number of interesting stories about how unexpectedly nifty are the interactions that have been driven into nature by evolution. For many of us in Europe, such stories negate the idea of a deity.  Darwin and many others have objected to the cruelty: I cannot persuade myself that a beneficent and omnipotent God would have designedly created parasitic wasps with the express intention of their feeding within the living bodies of Caterpillars. But for me it's the complexity: surely if Your Omnipotence wanted to creates something nifty from scratch you'd be a bit more streamlined and efficient.

Dr Yong's thesis is that "the world we see is profoundly influenced by the world we can't see". My Food & Ferm microbiologists can see microbes, because they can do a Gram stain and use a microscope. But not all microbes; because the vast majority won't grow happily, or at all, on a Petri dish in a laboratory incubator. In one of our series of experiments, I brought in a jar full of soil and they isolated different bacteria fom the jar but we had no confidence that the colonies of dividing cells observed a couple of days later were major players in the ecosystem of that spoonful of soil.

As a modern multimedia publisher, Yong wrote a book but teamed up with a film company TangleBank Studios to make a series of <wow> short films based on the book. I don't know about you but I'm spoiled for reading my the presence of youtube which is effortless in its digestibility. It took me weeks of snatched snippets and rare whole chapters to plough though the book: my brain fighting for consciousness with the requirements to process dinner. Talking of dinner, I Contain Multitudes, is pretty comprehensive in its rejection of oral probiotics as aids to a healthy gut and hence to health & happiness. It is more or less inconceivable that pot or two of Actimel containing a single [purity ensured to get licenced] strain of a single species of Lactobacillus is going to be able, on its own, to do enough. On the other hand a far more complex mix is used in FMT as effective treatment for Clostridium difficile aka Cdiff. But that is definitely not reproducible from treatment to treatment and is administered per anum. No sane person is going to try a fecal microbial transplant by mouth: leave that to dogs . . . and indeed to rabbits.

It is more elegant to eat bacteria-food than bacteria themselves. Most living bacteria get blitzed by the concentrated hydrochloric acid in the stomach but complex sugars can come through intact. This is one of the peculiarities of breast-milk. There are a bunch of indigestible sugars secreted into the milk that do no direct good to the nursing infant but seem to tilt the balance of power in the intestinal flora; giving a bit of a leg-up to some species, so that they can more effectively exclude the black hats.
https://www.metafilter.com/161203/Breast-Feeding-the-Microbiome

If we're talking about babies we're talking about birth. Yong went to NYU and innerviewed Maria Gloria Dominguez-Bello: the Go-To for thoughts about what she calls vaginal yoghurt and its importance in establishing a functional microbiome in a newborn when s/he is delivered. It is called labour for good reason because a lot of work is going on down there to extrude an enormous 'uman 'ead (and the smaller trailing tadpole of shoulders and feeble diminutive legs) through a smaller hole in the pelvic floor. All that oxytocin squeeeze forces the yoghurt . . . good bacteria . . . vaginal microbial community into every orifice, fold and crevice of the baby's body. There are definite and reproducible differences in the gut flora of kids delivered vaginally or by C-section but these diffs regress to the mean over the next sveral weeks. The jury is out on whether there are long-term effects on the health {obesity? diabetes? asthma?) of the two cohorts.
Too much in Ed Yong's book to cover here. Get it out of the library - I did.

It's your gut talking

Back in college, when I was studying genetics before molecular biology had really taken off, we had to do something to fill the curriculum for two years. One of the topics was testing for potential carcinogens in the environment.  We knew that one of the causes of cancer was mutations in the genes which stop cells growing when they are crowded up against each out. Without these genes you had uncontrolled growth of cells, which is a pretty good definition of cancer. The way we tested the mutagenicity of stuff [R. Ames Test] was to spread out a 0.1ml drop of concentrated bacteria on a petri dish that contained insufficient nutrients for them to grow. If they did grow, then you could suppose that a mutation had occurred which allowed them to make whatever was missing from the medium. This might occur spontaneously, and with 10 million bacteria in the drop, one of them changing was not impossible; so you needed to run a controlled experiment a) plating out the bacteria on the nutrient-deficient petri-dish and b) plating out the bacteria and a potential mutagen on the nobbled petri-dish. Count the colonies on each plate and do a statistical test and you knew what was mutating bacterial DNA and so what was likely to mutate human DNA . . . and cause cancer. It was a method dreamed up by Bruce Ames at U.Cal Berkeley.

Actually, the Ames Test had an additional layer of complexity.  It acknowledged that the liver is the metabolic kitchen of the mammalian body.  Loaded with enzymes to cleave this and add that and detoxify the other, the liver will process pretty much any chemical and reduce it to its component parts or at least change it into something different. It could be that some perfectly innocuous additive to Purina Cat Chow was converted into a potent toxin by the cat's liver and it goes blind and dies. So there was a third option in the full Ames test: c) plating out the bacteria and a potential mutagen and an extract of rat liver on the nobbled petri-dish.  One of the most startling events of my undergraduate career was adding a drop of own brand Quinnsworth Lemon-Lime shampoo to the Ames test and two days later seeing a constellation of bacterial colonies scattered across the petri dish. That shampoo was a fluorescent lime-green in colour that shouted mutagen quite loudly - that was why we tested it. That was just great - we were doing real science - nobody had done that experiment before and they probably should have done. My other triumph was working through a bomb-scare to see polytene chromosomes.

This all came rushing back to me because of the Nature Supplement on Liver Cancer which I have been reading like a really gripping novel.  One of the essays in that compendium is an investigation of the role of the intestinal flora in the cause and cure of liver cancer. That might seem a bit of a long shot, until it's pointed out that everything we eat is taken from the gut up the hepatic portal vein direct to the liver. There are 100 trillion bacteria in your gut of maybe 10,000 different species each containing up to 6000 different genes.  That's 60 million potential enzymes for converting harmless substance A into toxic substance B.  There is evidence for this quite out-there hypothesis in that rats which are treated with oral antibiotics are less likely to get liver-cancer than reg'lar rats.

Given that observation, any trained scientist will be down in the guts looking for likely suspects for a mechanistic explanation: which chemical A is being converted to which chemical B that is known to be carcinogenic? The accusing finger is currently pointing at deoxycholic acid DCA a "secondary bile salt" not a million miles, chemically, from cholesterol [see R]. The story is that the liver manufactures bile-salts which are stored in the gall-bladder and secreted into the duodenum to help absorb fats.  Having done that, the fat is unloaded in the liver and the bile salt is recycled through the gall-bladder. We've met a bile-duct before, getting unblocked.  Some of the normal constituents of the intestinome (the gut flora) convert the 'good' bile-acids into DCA which is not only not good, it is positively toxic not only to humans but also to cohorts of other bacteria. It is likely that the DCA-making bacteria benefit from the conversion by creating a bit of lebensraum for themselves by laying a little light holocaust on their neighbours.

That's a story you can tell to Joe Public, untrained in science, as an internally consistent and coherent explanation of what might be actually happening at the interface between the microbiome and the hard-working liver. It's therefore good enough to write a grant application to pull in a $million$ and start investigating how you might be able to put a spanner in the DCA production works.  One idea, for example, would be to genetically engineer some street-cleaning bacteria that hoover up DCA and convert it back to bile-acid. That way you leave the intestinome intact and just tweak it to your bidding.  Broad-spectrum oral antibiotics really do damage to the delicate balance 'down there' and should only be used as a last resort. FMT fecal-microbiota transplant is one way of delivering bacteria to the dark places to do good works.

Boiling Bill Bryson

I am a fan of Bill Bryson.  his Lost Continent was the funniest book I ever read on the recommendation of rec.arts.books - which was part of Usenet; which was social media before the World Wide Web turned the internet into something altogether bigger and uglier. In November last year, I saw that an audiobook of him reading his own The Body; a guide for occupants was available on Borrowbox . . . but not until 30 Dec 2o2o. So I reserved it. The very next day, last of 2o2o, I was on a road trip to Cork and picked up a big box of Seville oranges. While the kettle was boiling, I took advantage of Dau.II's unlimited WiFi to download Bill's Body to my smartphone. Such an inconsequential act would have taken many minutes over our rural "broad"band, even assuming our bandwidth neighbour wasn't on a Netflix jag.

The next morning was the First of 2021 and I reckoned that the oranges were not going to marmalade themselves. Accordingly, like Leap Day 2020, I cherry-picked as many oranges are would fit into my tallest and most capacious saucepan and set it to boil-then-simmer for 3 hours. I could / should have halved the fruit before packing and cooking them but forgot to do that . . . because I R old, forgetful and can't read my own notes. This is the easiest part of the Marmalade Protocols because it is perfectly possible to let the fruit simmer and multitask about the house: emptying the grate; counting the sheep; making tea; making water; gathering Winter fuuuelll. Note to self: I went at it again on 2nd Jan because we had sugar and jam-jars sufficient unto the task. This time with hemispherical fruit - this allows only about 10% extra packing. 

But this is just the lull before a storm of pain as the fruit are eviscerated with a sharp knife and a scooping tablespoon. It's quicker and more fuel efficient to do this hot, but begod ye need asbestos fingers. That yielded 4-and-a-tad pints [~2.3 lt] of pulp which will take 4kg of sugar by past experience. The skins were rough-minced with m' trusty Spong mincer and cast thereto.  Actually those quantities are about twice as much as can be conveniently handled with my ⌀ 40cm jam-pan; so I split the task into two batches. The second batch was cooked a little longer than ideal and so will support a standing spoon as well as being darker in colour. By tea-time I had 17 pots of marmalade: sealed, labelled and ready for the Armageddon bunker.  By tea-time the following day I had another 17 pots full of the warm south. Outlay in cash makes it about 75c /pot for quality [organic] 3 ingredient [water sugar orange] calories. And I still have 6-7kg fruit à la peau.

It certainly helped the yaroo pain to have Bill Bryson burbling along in the background about dermis and the microbiome. But I'd much prefer to be meithealling the marmalade like last year; although that is unconscionable under Coronarama Rules. The day's work really hadn't made much dent in the box of fruit, so I anticipate cooking through the current lock-down until I run out of jam-jars. Then I will freeze any remaining oranges until the jar-fairy delivers more. On the way down to Cork, Dau.II and I were speculating about whether the process of freezing might actually generate the better product - because the cells of the oranges get bursted by the formation of ice within. A bit like bletting?

sleep early and often

The Wexford Science Café meets on the third Tuesday of every month . . . except when it doesn't. It has been lurching running for more than 4 years now and we've covered:
Stephen J Gould’s spandrels; Galena; Thomas Kuhn’s paradigms; Organic soil microbiome; Composting toilets; Water quality; Bacteria in food prep; Urination once again; Toxicity from botox to beer; Air-quality and asthma; Gravity waves; Neuroscience of torture; Greenland ice melt; Cider making; Zombies; Wolbachia and tropical diseases; Radon; Diabetes & Alzheimers; Marketing generic meds; Oroville dam crisis; March for Science; Allometry; Science book-swap; Erwin Schrodinger; Pheromones; Back-garden astronomy. 
All interesting and showing the reach of science and the collective interests of the WSC participants. I am quite religious about turning up even if it means driving nearly a hour from home to get there: It is one of the few social engagements I have outside of work and nuclear family so is important for my mental health.

Last Tuesday we heard that getting a good night's sleep is also vital for your mental health. One of our reg'lar participants in the WSC Happy Family is Mr Pill the Pharmacist, who has recently become a Daaaad and two years into the gig is still laboring under a sleep deficit as the wean frequently neglects to snooze the night through. If he was a Kiwi, he'd have an instructional video. What the child's father has noticed is that he can be unaccountably ratty at work - amazed at the stupidity of his customers; furious when things go wrong; narky with his colleagues. Then he put two and two together to realise that his anger descended when he'd endured a really wretched night.  He also floated a hypothesis, as yet unquantified, that most of the kids who present a script for ADHD medication are no way ADHD: they are just sleep deprived. When a family comes to the doctor's surgery with €60 and a troublesome restless teenager, it is impossible for everyone if they come out with only a suggestion that a good night's sleep is required . . . and why not lock up the youngster's phone before bedtime? They'd rather dose the trouble away . . . and then get really indignant when Young Jimmy scores a few Es at the weekend.

The hook on which our discussions about sleep were hoist was the book by Matthew Walker, British author of Why We Sleep and Prof of Neuroscience at UC Berkeley. It is Walker's contention that sleep hygiene is at the root of many woes: mental and physical health; success at work; success "ín bed"; that car crash; that slice of chocolate cake. The book was a surprise runaway best-seller in 2017, so must have rung a few bells (or jangled a few chains) with the reading public. Which is a rather diminished cohort because book-reading is soooo yesterday and pushed to the back of the closet as everyone embraces screens. I've written about the negative impact of the [blue] light used to make screens work. Dau.II pointed out that device content is designed to be seductive if not  addictive. What are we like? The evidence of the damaging effects of sleep deprivation is piling up while we're swiping just one more tweet long after after midnight.

The sleepy discussion at WSC led on the work of Annie Curtis and her Clock Lab, now at RCSI in Dublin. She is finding that disruptions to another cycle can have serious health consequences. Lots of things go round and round and up and down for us on a daily basis - core body temperature; sleep-wake; the bowels. Curtis has put together large datasets [like half a million middle-aged Brits] showing that other aspects of well-being and equanimity fluctuate on an annual basis. You're more likely to have a fatal heart-attack in the Winter; surrogate cardio markers also tip up as the days get shorter: we get fatter and our blood-pressure goes up significantly, for starters. And another large cohort study showed that clinical depression descends on many women in Winter. The underlying basis of these adverse events is the molecular clock which is ticking in us all: cranking up the immune system at certain times of the year (perhaps because that's when the pathogens are abroad??) with unexpected side-effects in other systems of the body. Those epidemiological studies are paralleled by lab-based studies in which the undulating concentration key molecular immune markers are tracked across time. What's not to love about someone who can use a quote from Wm. Shagsper as the title of one of her papers.

“Sleep that knits up the raveled sleave of care,

The death of each day's life, sore labor's bath,

Balm of hurt minds, great nature's second course,

Chief nourisher in life's feast.”

Night-caps off!
More Women in Science.

Sweeter sweetener

Tuning into MetaFilter last week, I was brought to realise that "no added sugar" is not the same as green grow the rushes O "natural". The worried well asking about the safety status of food is A Thing on MeFi: {I left the chicken out on the counter last night | this cheese is beyond its sell-by | the dog ate only half the salmon}. . . should I ate it. The hive-mind (top heavy with USians) tends to be more leery about risk and less concerned about food-waste than, say, me. This Spring, a neighbour cleared out their dodgy freezer before going foreign for a while and I got a gallimaufry of frozen convenience food. I ate the last two salt and chili chicken burgers 7 days ago and they stayed down. Now I could have left these horrors out for the magpies but I reckoned that as Top Level Carnivore TLC hereabouts, I took precedence. All that remains is 3 loaves of beige sliced gluten-free "bread".

Concerning the Del Monte bb 11Apr20 canned peaches, I was sure they'd not deliver any coliforms let alone botulismus, and was about to give [FFS] appro. But others before me had twigged the “No Sugar Added” and balked: "ya wanna to be careful about old sucralose it tastes glaaark". What a difference an "al" makes as the spot the difference picture [R] reveals: top is the natural disaccharide white granulated sucrose the bottom is 1,6-Dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactose or sucralose. I've flagged the chlorine atoms which replace the -OH groups in three places.

This adulteration has two effects
a) it over-stimulates the taste receptors on the tongue making sucralose about 500x sweeter than sucrose
b) it bamboozles sucrase the enzyme which normally breaks sucrose into its constituent fructose and glucose. This allows sucralose to pass through the digestive tract unmetabolised and so taking its calories away unused. 
There are hints and assertions that sucralose fails to satisfy something in the brain and leads to a craving for other calorie rich foods. Maybe like aspartame affecting the microbiome.

Sucralose was discovered in the lab of Les Hough at Queen Elizabeth College, London in 1976 as part of a project sponsored by Tate & Lyle the sugar megacorp. T&L had access to hella quantities of sugar which was sold retail at €1/kg. They wanted to know if value could be added to the raw material so it could be sold higher up the economic ladder; not necessarily as food. Riaz Khan, a previous student of Hough's, was working for T&L. He phoned his old boss to ask for a sample of a chlorinated sugar. Hough was busy so handed the phone to Shashikant Phadnis, a younger more available research chemist. Khan said he wanted to test the compound which the lab had just purified. Phadnis heard this as taste the white powder and - the thought being the deed - dipped a small spatula into the powder and applied it to his tongue; finding a tiny amount to be  super sweet. By the time Hough returned to the lab, Phadnis had taste-tested all the vials in the lab finding many of them sweet and some sweeter than others! The first compound was thereafter called serendipitose. Don't do this at home kids . . . only in the lab.

Patent number: 4435440 "A method of sweetening a substance comprises incorporating therein a mono- or poly- chloro, mono- or poly- deoxy sucrose derivative having chlorine atoms . . ." is held by Leslie Hough, Shashikant P. Phadnis, Riaz A. Khan, Michael R. Jenner [Khan's boss] but vested in Tate and Lyle. Sucralose is marketed as Splenda.

YMMV but this reminds me of "I said take care of him not f*ing TAKE CARE OF HIM!"

Down in the dark

Classes started at The Institute on the 11th September and the next day I gave my Pharm Tech the How much do you know? Human Physiology Prequiz. As in previous years only a third of ordinary adults know their guts well enough to correctly order the different sections: Appendix - Colon - Duodenum – Esophagus – Stomach. Of course you can get through your whole life, and be a nett contributor to human health and happiness, without being able to name different parts of your body. But my data suggests that most people have a) no idea how the digestive system works [that's okay] b) no idea how it might work better [less okay if the goal is health and happiness]. This ignorance is appreciated beyond the confines of The Blob: it is explicit in the sub-title Giulia Enders book Gut: The Inside Story of Our Body's Most Underrated Organ; [Darm mit Charme. Alles über ein unterschätztes Organ] which I have finished reading.

I'm a professional biologist, so I can't remember a time when I didn't know the basic arrangement of my internal wobbly-bits [diagram R]. Nevertheless, I'm continually learning new stuff, most recently about the importance of the intestinal flora. The Blob records microbiome 26 times apart from this mention and flora 62 times; and rarely as a girl's name. I reckon I'll have more to say on our intestinal co-workers in the future.

On farts. One phrase I've never used before is sphincter ani internus SAI - because I'd never heard of it until Giulia Enders kicked off her book with a discussion of its value. Those of us who maintain some semblance of bowel continence are aware of the sphincter ani externus known to his pals as sphincter ani. When we grow up enough to stop having a accident downstairs we have achieved conscious control of when to open [rarely] and close [mostly] this little ring of smooth muscle. Actually it opens rather more often than when we are sitting at stool because the active microbial flora is producing quite a lot of gas methane and carbon dioxide mainly with a touch of hydrogen sulphide if we've been eating eggs or cabbage. The SAI is a sampler gate-keeper and every so often opens up to allow a sample of gut contents into the ante-chamber of outside. IF that sample is a bubble of gas ANDIF we are not having tea with Great Aunt Gwendoline THEN we can let rip; ELSE NOT. If the sample is more substantive we need to find a toilet - OR the woods IF a bear. It is not only 12 y.o. boys who find a darn good fart to be immensely satisfying. Or dangerous: methane fart deflagration; not the same as a BLEVE. Are you still a 12 y.o?

On sitting at stool. As we get older all the subtle, intricate, multiply-redundant systems of human physiology start to become more erratic: blood-pressure more variable; blood-sugar less reliable; brain function sketchy; bowels sluggish. In Ireland we have adopted a standard toilet which makes it much less easy to have a good crap; compared to all them foreign johnnies who squat to defecate. Squatting puts all the poo-ducks in a row making evacuation of the rectum a bit easier. You can do it sitting on a throne that is 450mm higher than your heels but you are making it more difficult for the poor old bowel. Ironically, as having a good shit become more difficult with age, some dogoodnik carers will actually raise the height of the seat to make it easier for dear old dad to get up and down to it with his enfeebled leg muscles and degenerate sense of balance.

<over-sharing alert>I have taken this Giulia Enders analysis on board and am experimenting with a little step (330 x 330 x 80 mm & made from a square of polystyrene: previously the lid of a biological-sample cool box) to raise my feet and make the experience more squatty.</over-sharing>. There are probably 1,000s of elderly British and Irish folk who are forking out for Movicol or Senokot.; when foot-shelf 10 or 15cm high in front of the jacks might do the trick.

Here's a TED Giulia Enders preview or an exec summary.

Other women in science.

The Heather Blazing

Up and down the Blackstairs, as part of the covid-lockdown we have been requested and required to not set the uplands on fire at this time. But some fuckwits hill-farmers persist in exercising their Rights of Ancient Days to burn off the thatch and promote the growth of fresh green shoots for their sheep to graze. A series of incidents made the news last week in Wicklow [400 hectares in one case] because it needed a helicopter to dump water on the blaze to bring it under control. We've had one spill of rain here since the shut-in started a month+ ago which makes it a grand bone-dry time to walk in the hills - although nobody is allowed to. In Ireland you may only burn uncultivated land for six months - 1st Sep to 28 Feb - each year. tbh, I have as little - or as much - care about the wildlife and property destruction in Wicklow as I do about ditto in Australia this past January. But on Thursday night, the arsonists got rather more up close and personal with Castle Bob. As I was composing myself for bed at 2215 I looked out into the darkened yard - in case zombies - and was confronted with

on the hill of Cullentra on the other side of our valley. Which was a bit concerning because one of our kindest and most civilised neighbours lives at the very edge of the forest underneath that same ridge. Such a blaze looks like nothing at all on a camera; it's like the spectacular full moon subtends a half-a-degree angle on your retina so looks utterlty inconsequential when you snap it with your smartphone. Hold a c€nt [remember them?] at arm's length: that's how big the moon is. But Bob's the Scientist! he can triangulate to estimate the extent of the picture I captured at 2240 that night. I stood back in the bedroom upstairs at home until the window framed the flames and could thereby calculate the angle subtended. The 16-04-20 Cullentra blaze is 1500m long! Our farmer's meitheal has been put on high alert because if our hill gets any significant fire-damage we'll lose our hand-out for doing the right thing by the ecosystem.

There's a 42 page Code of Practice produced by the Dept Agriculture which summarises the legislation on the matter

• Wildlife Act, 1976
• Wildlife (Amendment) Act, 2000
• Birds and Habitats Directive
• Air Pollution Act, 1987
• The Safety, Health and Welfare at Work Act, 2005 and Safety, Health and Welfare at Work (General Application) Regulations, 2007
• Forestry Act, 1946
• Waste Management Act, 1996
• Waste Management Act, 2008
• SI No. 286 of 2009 – Waste Management Regulations
• Fire Services Act, 1981
• Fire Services Act, 2003
• Criminal Damages Act, 1991

Few enough of the farmers I know went to college and several of them left school at 14, so a 42 page Code of Practice is not something they'd happily read with care and attention. Any more than they'd read the instructions that came with their chain-saw or PTO at the back of their new tractor. Farmers I know are amazing for getting things done rather than, like me, piffling around thinking of the most efficient way of doing it. But really, the names of the laws and regulations gives an executive summary of the issues. As well as the farmers' right to burn the heather to get a better living from their hills . . .

• birds and solitary bees have a right to an unblacked nest and fried eggs
• the mineral content of the soil is not going to come back when it is plumed up in the sky on its way to the next county
• the soil microbiome, on which the whole edifice is built, doesn't tolerate even transitory spikes in temperature
• the people down-wind don't want your particulate matter in their lungs
• whether or not they have asthma or COPD
• the A&E of your local hospital has a right to be unburdened with your 3rd degree burns when the wind veers 
• your local fire service has a right to play games of cards waiting for an accidental emergency
• your abutting neighbours, including Coillte, have a right to grow trees - yes even Sitka spruce Picea sitchensis

The Blob-title is a conscious hat-tip to Colm Tóibín's brilliant novel The Heather Blazing. That is a history of this our bold republic illuminated by the life of a fictional Enniscorthy man who makes good as he grows up with and within the state. Enniscorthy is where Tóibín was born and where we do our shopping, but the book, its loves and losses is bigger than local. You must order it up as soon as the library service resumes.

Bacteroides thetaiotaomicron

I reckon that for most of us the microbe we associate with "human intestinal flora" is Escherichia coli. We'd be quantitatively wrong though, because E. coli and its near relatives the enterobacteriaceae together make up less that 0.5% of the microbiome.  Like Escherichia and  Neisseria gonorrhoeae, "hard to spell, easy to catch", Bacteroides thetaiotaomicron looks like a mouthful but actually breaks down easily: theta-iota-omicron.  I think that's a great name, like a college fraternity, but I know of no other species named after a clatter of Greek letters. Rather than being a homage to someone called Thio, the name was first recorded more than 100 years ago by Arcangelo Distaso, a microbiologist at the Institut Pasteur in Paris, in a 1912 paper "Sur le putréfaction de la paroi instestinale de l'homme".

We should really all pay more attention to B. thetaiotaomicron because it is a major component of our gut bacteria and performs a vital task for any of us who eat either plants or fungi, which is all of us except for some extreme Masai and Inuit who eat only meat.  B.thio has a genome coding for 4,800 proteins, so it's a little more biochemically capable than E.coli but it is particularly rich in enzymes that can process the complex polysaccharides that are a major component of plant and fungal cell walls. That makes more digestible sugars available for us and presumably reduces the bulk of the stool. The presence of these bacteria is therefore really important for the weaning transition when we take infants off the breast [or more likely off formula milk in Ireland] and start to shovel rice- and wheat-based pap into their gaping maws. Without B.thio there will be colic, sleep deprivation, ill-temper, battery and divorce. A recent paper in Nature, suggests that Bacteroides spp. may have gotten a toe-hold in the human gut when we started to incorporate a lot of yeast [bread and beer] in the diet.

Because it is there, B.thio is an 'opportunistic pathogen', it can be responsible for what Distaso was studying in his 1912 paper which can be translated as "pathogenesis of the human gut wall".  This is particularly so in cases where abdominal wounds and peritonitis have made a hole in the gut wall. It's a problem because B.thio is resistant to many of the antibiotics: because of its biochemical toolbox, it just sees antibiotics as more food. But its normal function and normal interaction with the cells of the intestinal epithelium shines a light on the complexity and subtlety of our relationship with the bugs inside. B.thio for example secretes metabolites that encourage the development of vascularisation of the epithelium, so that the goodies created by its digestive enzyme scan be more effectively carried away to the liver.  It also seems to play a role in the development of the mucosal surface which is a key physico-chemical barrier keeping potential pathogens at bay. So little known, so much to learn.

mouldy ouldy

Q. What's worse than biting into an apple and seeing a maggot?
A. Biting into an apple and seeing half a maggot!
And face it, neither is as bad as having electrodes applied to your testicles. I think we are a good deal too fussy when it comes to rejecting food. While I still have a functioning immune system, I'm going to get as much as possible out of the food we buy or grow. Throwing a mouldy orange in the compost bin betrays a cock-up on the catering front. But I guess when the choice is buying No apples or Six apples (and a dinky polystyrene tray) then over-catering is not entirely the fault of the consumer. tbh, I wouldn't eat a lot of fruit and I have never consumed a smoothie [because I have (most of) my own teeth] so I suspect that the appearance of oranges and apples is part of a plan to get me to eat nearly 5-a-day.  Can't I just eat caldo verde five times a day? I made a big pot of this Portuguese ambrosia when spring cabbage was on 49c special last week and ate it four days running. My microbiome delivered a huge thumbs up and I felt mighty.

Mais revenons nous a nos pommes. What do you do with a bruised apple? If I'm at home I'll probably cut out the squidgy portion and eat the rest but if the bruise is sustained between home and work, I might just eat the whole thing shkin-and-all. Fresh bruise is less likely to be furry. And if you can't actually see the fungal mycelia, it's reasonable to assume what there will be too little to count. Microbiologists will look shocked at this and talk about aflatoxin and or mycotoxins but to a hammer everything looks like a nail and I think the odds are in my favour that I'll more like sustain injury in my car (slamming digit in the door is not unknown) than that I'll get sick from what I eat. My long term personal experience of eating re-heated rice is set against the occasional horrow story from the path lab.

I use that experience and common sense: salami and cheese routinely acquire a white schimmel and I've decided that it's delusional to scrape off the white stuff when there will be at least as much left invisible just below the scraped surface. I wouldn't treat mouldy chicken or hamburger in the same way - it just doesn't seem right. And chicken doesn't last long in the fridge: chicken soup is always a welcome change from caldo verde.

Dau.I sent us this diagram from an unattributed but seemingly authoritative source which leaned heavily on discard for pretty much every sort of fungal contamination. A key factor seems to be moisture content: hardy fungu that can make a living under dry harsh conditions are more likely to be 'good'. There is no way I'm going to 'discard' a whole pot of jam because it's got a little white orbblue cushion on the top surface. If I'm feeling twitchy, I have been know to boil the old pot up (having flicked out the manifest colony) and then start ploughing through it. Likewise, if I'm home alone, I'm more likely to put mouldy soft fruit in the saucepan than in the compost bin. I must admit that I am a little bemused / concerned about mayonaisse - how does that stuff remain good-to-go weeks after opening.

Elegant against Zika

I'm on a bit of a microbe jag this month and there's more to come. There are two aspects which interest me

1. the diversity of the invisible microbiome and its interactions with the nearby bigger-than-a-breadbox world. The technology (Next Generation Sequencing NGS) for documenting this has only developed in the last 10 years. Before than we really hadn't a clue because most microbes cannot be grown on a Petri dish, so we could not characterise, name and catalogue them.
2. precision use of particular microbes to carry out beneficial tasks instead of a blood-bath kill them all approach which takes out a lot of innocent bystanders. Like Eleftheria terrae's novel antibiotic; or Monsanto's plant-growth promoting bacteria trials.

Wolbachia pipientis is a member of the Rickettsiae a subset of the alpha-proteobacteria. We've met Rickettsia before as the agent of typhus on emigrant ships and as the probable ancestor of mitochondria. They have really small genomes, and Wolbachia is no exception: managing quite nicely with only about 800 genes on a chromosome about a third the length of E. coli's. One of the consequences of a small genome is that Wolbachia needs a bit of molly-coddling.  It wouldn't survive for months in a cold pasture like Mycobacterium tuberculosis, for example. Contrariwise, it can only grow and multiply in the the cosy environment inside eukaryotic cells. See [R] a Drosophila embryo filled, like a cake with currants, with Wolbachia false-stained in blue. W. pipientis has a preference for arthropods so you don't need to worry about catching a dose yourself. In particular it seems to zero in on the reproductive organs of flies, beetles and spiders. There it has a variety of bizarro effects on the behaviour and capability of the flies:

1. selective killing of males
2. a switch to parthenogenesis (reproduction in the absence of males)
3. feminisation of males
4. restrictive incompatability: Wolbachia infected males cannot mate successfully with uninfected females

If you're going to use Wolbachia as an agricultural or medical intervention you want to be double-plus sure you know which of these scenarios will play out with the particular strain of Wolbachia, the particular insect species and the particulars of the environmental conditions that pertain. Get it wrong and you may reap a whirlwind: turning all the males into blood-sucking females for example.. It may work fine in the lab but eventually you have to carry out a field trial and that will have a more complex system of interaction terms than you can begin to model in a laboratory or as a computer simulation.

In the free back-issues of Nature I picked up in Dublin earlier in the month, there was an article which describes a new proposal to control the spread of Zika. Published in May, it was unaware of the cases of Zika more recently reported in Florida. The Center for Disease Control CDC in Atlanta, Georgia cannot help but get more engaged when the threat is only one state line and 500km away. ANNyway, a biotech startup called MosquitoMate is proposing to infect male Asian tiger mosquitoes Aedes aegypti with a strain of Wolbachia pipientis that will ensure their sterility. When these doctored males mate in the wild with incompatible females, the eggs fail to develop properly like in case 4 above. The descendantless males will be in competition with wild-type males so the company or their customers are going to have to release containers-full of the infected males to make a difference in the reproduction of this species of mosquito. Aedes aegypti is not the only vector of Zika virus, so I guess the argument is that any intervention that reduces transmission of the latest virus should be considered. Field trials by the company with a different mosquito species have been claimed to reduce the population of the flies by 70%. The reservoir of 30% mean that the protocol is set to keep on giving value to the shareholders. If the customers (state health boards, the UN, whoever) don't keep on throwing out doctored flies, everyone is back to the status quo ante except for being several million dollars poorer. It won't be like fatal hammer given to screwworm in Libya in 1990.

Bugging the uterus

I grew up as a geneticist and evolutionary biologist,  at the top of my modest game when analysing DNA sequences on a computer. I was safe there, although a disaster in the lab. Then about 15 years ago I got a billet in a comparative immunology lab on the theory that my expertise could bring a needed new dimension to their research.  It was hard for everyone because geneticists go all weak at the knees with B-cells, T-cells and dendritic cells and affect to be unable to understand the difference between CD4 and CD8 and the other proteins which coat the surface of these immune cells. Immunologists, on the other hand, have a model where CD4 and CD8, and the other proteins poking out of the membranes of cells, are just there without ever reflecting that they are there because of the DNA in the cell's nucleus.

I have a long-standing interest in microbiomes: the invisible freight of bacteria on which a lot of our health and happiness depends. The intestinal flora is one such ecosystem which you should cherish with kale and strawberries straight from the field. If you wage war down there with oral antibiotics for an earache, then you can get yourself in serious trouble with Clostridium difficile or worse.

Now here comes an interesting study of the uterine microbiome which gives a clue about two of the great immunological mysteries of mammalian reproduction.  The first is the miracle of bearing young at all.  Birds get their eggs fertilised and then unload them in a convenient hard-shelled package where they continue their development until hatching.  Mammals otoh hold these ever growing cluster of 'foreign' cells inside.  Immunity is all about recognising the difference between self and non-self.  The embryo may have half its genes in common with its mum but the other half is clearly foreign, yet women tolerate this interior growth for nearly 40 weeks.  If it was a tumour (which is much closer genetically than a fetus), the mother would be f**ked.  Lots of people have theories about how this tolerance is achieved but we're still short of data and evidence to clear up the conundrum.

The other mystery was mostly in my head and hinged on a false premise. If the uterus is effectively sterile and delivery is such a one-way ticket, then how come so many cows get endometritis [inflammation of the uterine lining] immediately after birth.  This is a major cause of bovine infertility and so economic loss to the dairy industry.  I was wrong about the sterile uterus.  Like every other warm wet place about us, bacteria like to set up home there. Endometritis occurs when the balance among the uterine flora changes with the disruption - physical and hormonal - of delivery.

It turns out that the uterine flora is more similar to that in the oral cavity than the wild bunch in the vagina next door.  I've shown that oral, fecal and vaginal bacteria are as different from each other, despite being in the same person, as the ecosystems of the Serengeti and a Rwandan jungle are different despite being on the same continent.  For a long time we couldn't get a handle on the microbial diversity in real ecosystems because swab we might but most bacteria have never been grown on a Petri dish and were effectively uncharacterisable because of this. Non-culturable bacteria are no longer invisible because of next generation sequencing NGS.  This allows researchers to pick up a mess of potage, give it a good whizz in a Moulinex blender and then sequence all the DNA. In particular they tend to pick out all the 16S RNAs which will tell them what sort of bacteria were present in the sample before they were turned into soup.  We have, for example,  the complete sequence of Neisseria meningitidis, which can be grown in the lab. If they pull out similar but not identical 16S RNA they can surmise that Neisseria unknowniditis is present. And the researchers can even get a quantitative estimate of what's present.

The paper gives a really interesting insight into the complexity of microbial interactions.  Several adverse conditions including premature birth depend on (are caused by) the presence of more than one species of microbe: it's the interactions, stupid. But normal full-term pregnancy seems to be mediated by the bacterial flora of the uterus as well. The solution to the mystery of pregnancy may well lie with our beneficial bacteria.

New weapon against MRSA

We have squandered out patrimony, consumed our seed corn 

and laid waste the gardens of our delight. 

[don't google that, I just made it up] In the 20thC, science, aided by The Gods of Serendip and St Loads of Money, discovered a range of chemicals that would kill, or inhibit the growth of, harmful bacteria. In 1925 my 9 y.o. father almost died when he was made to go for a winter swim and caught pneumonia. His mother sat, beside herself with anxiety, with him until the fever broke. Exactly 70 years later, 2 y.o. Dau.II caught Christmas pneumonia and spent 2 days in hospital getting rehydrated and antibioticked. The antibiotics made all the difference. So what have we done with these miracle drugs that have seen off child-killers like diphtheria, scarlet fever, meningitis, tetanus, septicaemia, and pertussis, and young adult 'issues' [and discharges] like syphilis, gonorrhoea, and chlamydia. You can see from the links how much this has engaged and enraged The Blob. And what have we done with these miracle drugs? Why, we've sold them to farmers to inject their sheep and to chicken factories as growth promoters. V e r y   s l o w   h a n d   c l a p.

Because bacteria are more numerous than sand on a beach and have a huge collective ability to develop resistance to antibiotics and spread that ability around. Big Pharma argues that there is no market in developing novel antibiotics because it will cost €1 billion and 10 years in testing and licensing and it will be difficult to recoup that money in the few remaining years of patent protection. Somehow that argument does not prevent them developing clever-sexy novel therapies for minority inherited disorders and selling them to the insurance companies of grateful parents for $150,000 a year. Another issue with scaling up the production of natural antibiotics is that only a tiny fraction of bacteria Out There can be grown under controlled conditions in the laboratory and ultimately in a production vat. We just don't know enough about their particular and peculiar dietary requirements.

Accordingly, it is left to academic scientists to dream up new ways of approaching the problem and trying to persuade their governments to take a punt in blue skies research. Two years ago I gave tribs to a couple of scientists who discovered teixobactin the first distinctively different antibiotic in 30 years. What Kim Lewis and Slava Epstein figured was that in a handful of soil there are 10,000 species of bacteria fighting over limited resources in a brutal take-no-prisoners war. Some of the the successful microbes will have produced chemicals that were toxic to rivals. They developed a brilliant, high-throughput, iChip that would identify those bacteria that were thus weaponized.

It's a model for the future development of novel antibiotic therapies. Now Sean Brady [R] and his crew from the Laboratory of Genetically Encoded Small Molecules, Rockefeller University, NY, NY, have done something similar to launch malacidin into the war against MRSA and related diseases. This is so important that Nature Microbiology is exposing the paper beyond its pay-wall. Brady's lab is also working in parallel characterising the bacteria of the human microbiome to better understand the environment in which his novel therapeutics are going to have to work.

I think it's fair to say that Lewis and Epstein were on a massive fishing expedition when they isolated Eleftheria terrae from their multiple soil samples. Sean Brady's project was much more hypothesis driven. Previously identified interferers in cell-wall building were small peptides that were dependent on calcium for their action. Sequence analysis had shown that many of these Ca-dependent peptides contained a Asp-X-Asp-Gly motif: supposed to be were the calcium ions bound to the functional molecule. They were able to tailor their pipeline to reject microbial products that didn't contain that short sequence and enrich those that did. By gathering 2,000 soil samples, each containing 1000s of bacterial species from all over the world Rockfeller is now warehousing one of the largest bacterial collections on the planet. Much good it may do them because most of them won't grow can't grow on a Petri dish in the lab. Whatever about a whole new world of potentially therapeutic bacteria, I've been battered with a whole new world of acronyms in trying to read their paper. AD, BGC, eDBA, eSNaPD, NP, NPST, NRPS, pTARa.

Malacidin [nothing to do with Mal=bad or Malus=apple, it is an acronym: metagenomic acidic lipopeptide antibiotic-cidin] works by interfering in the construction of the thick cell-wall which is an essential building block of Gram-positive bacteria. The diagram details where the targets of three different antibiotics, daptomycin, friulimicin and malacidin, each find a different way to interfere with bacterial cell-wall building.

Bacteria can double their numbers in less than an hour under optimum growth conditions, and that requires twice as much cell-wall. So none of those antibiotics will work against thin cell wall Gram-negatives: these include Bordatella petussis, Campylobacter jejuni, Chlamydia trachomatis,  Escherichia coli,  Neisseria gonorrhoeae, Neisseria meningitidis, Salmonella typhi, Treponema pallidum, Vibrio cholerae, etc. etc. However, it seems to be able to knock MRSA on the head and that is what is making the headlines.

On Edge again

A palomino sent me and El Asturiano a link to the 2016 Edge Question. I started having rant to myself about The Edge without really knowing what was shaking my equanimity. The contributors attempting to answer the 2016 question are the Usual Suspects: friends of John Brockman, the Great Facilitator.  Many of them were asked their opinion in 2015, 2014 and back to beginning of Edge time BET. Then I started to sound oddly and grumpily familiar and it dawned on me that I'd written a whole critique of the 2016 Question and the Cult of the Celebrity-Pundit back in January. Before that realisation, however, I'd followed the link and read what Freeman Dyson [prev] and Matt Ridley had to say on the matter-in-2016-Question.

Matt Ridley wrote about the connexion between lack of intestinal worms and the rise-and-rise of allergies in the Western World.  I found myself nodding about that, not least because I've recently recognised that others have recognised the association myself.  Nina Jablonski says something similar although her piece is about the relationship between the intestinal flora and obesity and other health issues. The microbiome is the new black.

Dyson, who is always good copy and full of sense [chekkitout youtube], had a rather interesting comment about the Dragonfly telescopic array which is super-efficient, because intrinsically cheap, at finding dim objects in the depths of space.  They are better at this mundane task than fat (foundation and government supported) super-big telescopes and cost a fraction of the price.  It is a great example of appropriate technology producing a neat solution rather than getting suckered into the idea that, as more is better, so more money is better. One of the criteria of success in science, as defined by bean-counters who believe all that matters must be measured, is the amount of external funding acquired by your researchers, departments or institutes.  As with American elections, there is a frighteningly good connexion between investment and result. Nevertheless it is a crude surrogate for actual scientific progress - difficult as that is to a) define and b) quantify. Dyson recommends that a third of all money allocated to funding research should be ear-marked for modest mom-and-pop research projects by comparative unknowns. As Aled Edwards has identified, much [far too much] of scientific research follows safe well trodden paths rather than veering sharp left into jungle to make radically new discoveries. If most of these cheap left-field research ideas come to nothing, then not much is lost. Most Big Science projects come to not-very-much themselves and they beggar the tax-payer. Back in my Jan EdgeQ critique, I cited Judith Rich Harris's essay for pointing out that most published research is useless, boring, or wrong.

Dyson's suggestion made me think about the whole goddam, smug edifice - The Edge; it's 2016 Question, and indeed science itself. Scientific, medical and agricultural 'progress' has been instrumental in creating 5 billion more people than can be sustained on our small blue dot. That's the excess since 1916 when there were less than 2 billion living people on the planet. Their demand for:

• bright plastic buckets; 
• throw-away containers with barcodes
• huge homes in absurdly inclement regions like winter New England;
• a helluva lot of uncomfortable shoes in closets 
• a private automobile and dirt-cheap fuel to make it go; 
• a server in Finland next to a hydro-electric plant to store 100,000 crap photos of kittens doing antic things in bathtubs

has buggered the planet.  The creators of the small grey cinder we won't be able to inhabit don't seem to be mobilising 'science' to sort out the ramified problems engendered by technology.  Let us, accordingly, not ask, the undoubted;y brilliant, Steven Pinker, Martin Rees, Paul Bloom et al. what they think again. Let us rather ask an articulate teenager what she thinks we should do and give that a go.  We can't finish up in a worse place.