Bigging up the Danes

For my sins, from 2013 to 2020 inclusive, I taught Human Physiology to 1st year Pharm tech students. My only qualifications for doing this were a) I have a body b) nobody else wanted to do it. I inherited a bunch of PPT slides, the Learning Outcomes and 30-something students almost all of whom were women. Don't know about the students, but I learned a lot. Human Phys is all about homeostasis - keeping the various systems of the body in trim to quite fine tolerances. You know this: over-heating by even 1 or 2 °C makes you feel like crap. If your blood pressure goes up a little, you're likely to blow an aneurism or have a stroke . . . goes down a little and the blood will rush from your head and you'll collapse to the floor. Your bod keeps to the set-points of tolerance with a complex system of checks & balances = belt & braces = redundancy. My fave hormone Vasopressin squeezes the smooth muscle AND reduces water-loss in the kidneys both effects geeing up the blood pressure.

I put it to you that 9/10 people stopped on the street will have heard of insulin and have some idea about what it does [regulates circulating blood sugar). otoh those same 9/10 will nope out when asked about glucagon. But you absolutely need them both and the receptors to which they bind to effect their magic on each cell of the body. I've shared my discoveries about glucagon several times in The Blob. TIL that, like a lot of proteins /peptides, the hormone glucagon is derived from a rather larger "pro"-peptide which is 180 amino acids in length. After translation this longer protein is enzymatically cleaved into three quite similar peptides, at least two of which are biochemically active: a) glucagon b) GLP-1 = glucagon-like peptide #1 and b) GLP-2. This shows that three copies of the active bit 'were created' in evolutionary time and have subsequently been free to mutate and acquire a wider range of specific functions.

GLUC      ------HSQGTFTSDYSKYLDSRRAQDFVQWLMNT----
GLP1      HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG--
OZEM            HxEGTFTSDVSSYLEGQAAxDFIAWLVRGRG
GLP2      ------HADGSFSDEMNTILDNLAARDFINWLIQTKITD
                *::*:*:.: .. *:.  *::*: **:: 

These peptide hormones are at nothing unless and until they dock with a specific receptor sitting in the membrane of all the cells in the body. GLP1 binds to <surprise!> the GLP1 receptor which starts a cascade of internal reactions to do with glucose metabolism. These reactions may be wide-ranging in different tissues (as with vasopressin == ADH anti-diuretic hormone two paragraphs up). One known effect is the inhibition of glucagon. That will prevent free glucose circulating which means that insulin won't have to work so hard to keep glucose levels at their set point. and that would be good for diabetics. A few years ago boffins looked at the sequence of GLP1 and thought "target". They modified the sequence of GLP1 [see alignment of the amino acids in colour above] to create semaglutide which really binds the GLP1-receptor.

Novo Nordisk the Danish Megapharm which owns the IP on Semaglutide = Ozempic = Wegovy is now the biggest corporation in the EU with a market cap of $500 billion. Ozempic is the company's golden goose and is responsible for pretty much all of Denmark's economic growth during Coronarama. If you'd bought shares in Novo Nordisk  5 years ago you would have had a 5x return on your investment. Ozemic featured on RTE on 4th March b/c World Obesity Day.

Ozempic hopped through all the regulatory hoops as an effective treatment for type-II (late-onset) diabetes because of it's domino effect on the regulation of blood-sugar levels. Later on it was realised that Ozempic was effective in helping ppl with obesity shed a few kilos. It was therefore widely prescribed for that condition. In 2021, the FDA approved this use of semaglutide, under the trade-name Wegovy. 

It turns out that Novo Nordisk, even with outsourcing production to several other facilities, cannot produce enough Ozempic to satisfy the market in diabetes and obesity. Part of the problem is that this drug is being widely prescribed 'off-label' to reasonably healthy people who desire to trim their midriff to look good [and maybe pull their cousin's BFF]? at an up-coming family wedding. That's how markets work: well rich people can obtain a scarce resource - because money - and can insulate their conscience from the effect this choice has on really sick poor people on the other side of the tracks. And social media influencers? They can eat their own brittle!

The Islets of Langerhans

Living on an island gives me a small-small excuse to rabbit on about other islands as I have been doing all week. Argumentative SciFi writer Harlan Ellison wrote a rather challenging short story called "Adrift Just Off the Islets of Langerhans: Latitude 38°54'N, Longitude 77°00'13" W".  In which he pushed the imaginative idea that the Islets were a geographical feature. I'll save you a lot of trouble by noting that Washington DC is located at Latitude 38° 54' N, Longitude 77° 00' 13" W.  There is something romantic-sounding about the Islets of Langerhans, which I first met when studying high-school biology as a teenager. My mentor then - Mr Wilkinson - drew attention to this when we were learning about the pancreas, of which the Islets are an important part.

In the same course he also introduced us to the involucre of bracts, which is are the ring of green leaf-like things supporting the coloured part of daisy Bellis perennis and dandelion Taraxacum officinale flowers and other members of the Compositae Asteraceae. Actually he introduced us to the Involucre of Bracts, which/who might have been an obscure Highland prince like Lord of the Isles, Moncreiffe of that Ilk or the Laird of Glenbogle.  You should know that the inflorescence of Asteraceae is not a single flower with stigma, stamens, petals and sepals but a sweep of tiny separate flowers.  In the daisy there are two sorts: the yellow disc-florets in the middle and the peripheral ray-florets with one enormously exaggerated petal pointing outwards.  Have a close look next time you're making daisy-chains with your daughters.

The Islets are tiny blobs, barely visible to the naked eye (0.1mm-ish or about the size of a human egg) that look a little like warts on the edge of small blood-vessels in the pancreas.  Though they be but little, they are numerous and if all 3 million of them could be scraped into a tea-spoon, they would weigh about 2g.  Each one consists of a number of identical looking cells which have very different functions. As far as we can tell, each cell is specialised for producing one hormone but several different hormones are produced in each islet. You can use a technique called immune-histochemistry to attach different coloured markers to these hormones [L] which are all small proteins. That creates a false colour image - the islets are pinky-beige in real life - which is rather informative. Here [L] insulin has a green fluorescent dye attached while glucagon has a reddish tag.  You can see two things: one is that the insulin producing cells far out-number those making glucagon and also that the glucagon cells are located on the periphery of each islet.

If you're anything like me - expensively but inadequately educated - you have an excuse for never having heard of glucagon but you're reading the wrong blog if 'insulin' is a totally new word to you. In teaching Human Physiology for the last three years, I've learned a lot that I didn't know or about which I was wrong.  The theme in Hum.Phys is homeostasis, maintaining everything - core temperature, acidity, blood-pressure - in equilibrium.  Insulin and glucagon do this for blood-sugar levels: insulin reducing it and glucagon increasing it.  As I tried to explain about haemophilia and Factors VIII and IX, the normal body manages such things with exquisite subtlety 24/7 while pharmaceutical/medical surrogates are bludgeon-crude by comparison. It's like that with insulin therapy for diabetics: they inject far too much in one go and over the next several hours the concentration in the blood trails down to rather too low when the body receives another deluge by needle.

Mais revenons nous a nos îlots: there are two types of diabetes: type I occurring when the pancreas doesn't produce enough insulin; type-II when the pancreas is chuntering along nicely doing its job but the body fails to react appropriately to circulating insulin. It seems likely that type-I diabetes is an autoimmune disease, in which the immune system convinces itself that beta-cells in the Islets of Langerhans are 'foreign' and need to be taken out.  As the beta-cells produce the insulin on which glucose metabolism depends, this is response turns out to be a costly mistake. A lot of auto-immune disease occurs as a consequence of a viral or bacterial infection.  When the pathogenic insults has been beaten up and swept away, the immune cells are still spoiling for a fight and turn on some part of the body with a superficial resemblance to the ex-parrot-parasite. This is the best explanation for Guillain–Barré syndrome's appearance after a bout of the trots from Campylobacter food-poisoning.  It you wake up screaming tonight knowing the identity of the virus that causes type-I diabetes, and you are correct, you can sit back a wait for the Nobel Prize.

Bloody Sugar

No, this is not another rant about the Food Police. Well not directly anyway. It is rather another part in my series of Graphics for HumPhys [prev Calcium balance; blood pressure; mitochondria; temperature]. You may think you can drift off, because this is going to be boring, over-my-head, academic and irrelevant. It may have the other three attributes but it is not irrelevant because, like me, you have a body. Having a, now beginning to fall apart, body is what has sustained my interest in teaching Human Physiology these last 6 years. If you don't make some effort to understanding the vital functions you'll be wrong footed in managing your health. If you're approaching, or over, 50 you'll no longer be able to take continued health for granted.

There is a difference between knowing a thing and knowing the name of a thing; as Dick Feynman's Dad famously instilled into his young son. But in the artificial learning system which is school and college, you have to be up for the Naming of Parts [evocative, deliberately retro, 1971 film of same by Robert Bloomberg] so that the Learning Outcomes [boo hiss] can be assessed. I've told my students that naming of parts in the micro-management of the concentration of glucose will likely come up on exams and so they might concentrate some attention on their notes on the subject. Their notes are few and far between, because my students have mostly not been trained to write things down as an aid to memory. Some of them will concentrate some attention on my [powerpoint] notes on the subject and for some of them staring at the PPTs the night before the exam will work. But there are pages of notes and if they just internalise, as an Executive Summary, the picture at the top of the post.

What does it mean? That two households hormones both alike in dignity, in fair Verona Pancrea, where we lay our scene, act out a delicate pas de deux of homeostatic regulation. Insulin and Glucagon are both made in the pancreas, an organ the size and shape of a flubby parsnip that sits just under your stomach and above the bowel. The pancreas has two main functions a) producing and leaking digestive enzymes into the top of the small intestine b) making a passel o' hormones and leaking them directly into invasive capillaries and thence into the circulatory system. Insulin is made in little clusters of beta beetroot cells while glucagon is manufactured in alpha [male] cells. In the lecture, I may make a quip about me being the alpha male because I am a silverback and almost the only bloke in the room [the sex-ratio in Pharmacy Technicians is 95% female].

In a well regulated bod, insulin and glucagon circulates at just the right complementary concentration, so that every cell [100 trillion of them all demanding service] gets enough insulin to dock with its insulin receptors and allow the uptake of glucose. Without glucose inside the cell, there would be no metabolic activity, without insulin the glucose just stays in the blood where it encourages the growth of pathogenic bacteria, septicaemia, gangrene and an early death. Therefore, it's insulIN to the cell with the glucose. Insulin is a small protein with a half-life of about 4 minutes! The beta cells crank up production of insulin after you eat something because the cells detect the upspike in circulating glucose. Four minutes later half the insulin has gone and within an hour it is all degraded and the cells have scarfed up all the available glucose.

What then? what if you have to run for a bus or sit an exam more than an hour after you ate your porridge? Well we have a word for that and its glucagon. Certain cells, especially in the liver and in muscles, are rather greedy for glucose when it is available. They clag a lot of glucose molecules together in a complex poly-saccharide called glycogen. Glycogen is, like starch its plant equivalent, relatively inert - it just sits there waiting for the call. Demand for glucose is that call: when blood glucose sinks below a threshold, the alpha cells of the pancreas detect the fall and release glucagon. Glucagon triggers the liver cells to give up the ould glycogen and break it down into usable glucose. Therefore glucose is glucaGONE from the cell.  In the picture I show a yellowed crumbly liver on its last legs from cirrhosis because that is going to be more memorable. In your Memory Palace, it's more effective to employ images which are ludicrous, naughty, revolting or unsettling because they are more sticky <eeuuuuuuw>.

Glucagon

Today is World Health Day which has been celebrated every 7th April for more than 20 years.  Each year a different theme is pushed out by the WHO is boost their profile in the media [and to provide focus on needless death and distress].  Previously covered include such problems polio, road safety, food safety [last year], motherhood.  The big global health problems get their own days, some of which have been Blobbed - Malaria + Tuberculosis - but this year's theme is diabetes [prev].

You might think that WHO should concentrate their efforts on the dispossessed of the third world. The map shows that the incidences of diabetes is far higher in the affluent West = Europe and North America, than in tropical Africa. But diabetes is everywhere and demonstrably increasing in frequency. We know that one of the triggers is a generous diet.  Recent research on [half] starved mice suggests that we will live much longer if we go to bed hungry every night.  Those of us who have tried the delights of Food Engineering will ask if it is worth living at all if we can't have bright yellow cake and ad lib pink sausages.

At The Institute, I'm just covering the endocrine system in HumPhysiol 101. The over-arching theme in how the human body ticks is the concept of homeostasis - the maintenance of balance in core body temperature, blood pressure, acid-base balance, calcium levels and everything else.  It should lead to a perpetual sense of wonder that all these things are so finely balanced that we can take them for granted . . . until they go wrong. I've talked recently about haemophilia, where that balance goes out the window. Instead of having just the right amount of factor VIII circulating that they neither haemorrhage from a bump nor suffer thrombosis, heamophiliacs get a huge blurf of Factor VIII once or twice a day which then gets degraded over the next 24 hours. It's crude and hideously expensive.

Diabetes is when the regulation of circulating blood glucose goes wrong.  Everyone knows that the level of glucose is mediated and controlled by the hormone insulin which docks onto receptors in the cell wall of pretty much all cells in the body and allows those cells to suck up enough glucose to carry out the normal metabolic activities which depend on that energy source. Without insulin, there is too much sugar in the blood which, among other bad things, encourages the growth of pathogenic bacteria. To prevent diabetes you need to produce enough insulin but you also need functional receptors. The failure of one of these supply chains causes Type-I diabetes, the other makes for Type-II diabetes. Obviously only one type is treatable by regular injections of insulin. As with Factor VIII, injecting a bucket of insulin every few hours is grossly crude compared to the elegant finely tuned dribble that healthy people maintain year-in year-out.

What's interesting, but obvious if you think about it for 3 seconds, is that there is another system in place for when blood sugar gets too low.  This is controlled by another hormone produced in the pancreas called glucagon. We need to give a bigger press to glucagon because without it we'd be equally as unhealthy as all the diabetics. Let's hear it for the Islets of Langerhans, where both hormones are produced.

Relaxing the pancreas

It's Rag Week at The Institute  . . . except it's not.  Other colleges are getting a mid-term break but we have a policy that classes will go ahead regardless of the fact that 80-100% of the students are off-site.  Some of them are doing traditional Rag Week things - pushing bedsteads about the country or washing car-windscreens for some Good Cause.  Others are just going down to the offy, buying a slab of tinnies and getting hammered.  Having very short classes means that I've had time to prep a bit of teaching material for the medium-term future, so that when things return to normal I'll have something sensible to say about, say, ductless glands.  A key difference in classifying the wobbly bits of human physiology is whether a gland has a duct (tube) through which it delivers its product: these are called exocrine glands.  The bits that seep their stuff directly into the bloodstream (and thus ductless) are called endocrine glands.

The pancreas, a body about the size and shape of a parsnip and found tucked in under the stomach, is both exocrine and endocrine.  The pancreatic ducts empty into the gut and push digestive enzymes like trypsin into the top of the duodenum to make a start breaking down the proteins in the food.  The rest of the organ is taken up with little clusters of cells, evocatively called the Islets of Langerhans, which make a number of hormones.  The most well-know of these is insulin which, with its complement glucagon, regulates the amount of glucose circulating in the bloodstream.  Lack of insulin is the basic cause of diabetes which is getting ever more prevalent in our society.

In the early 1920s insulin was discovered and purified as an alcoholic extract with demonstrable efficacy against diabetes in humans by two young Canadian biochemists Banting and Best.  Fred Banting was born in 1891, qualified as a doctor and joined the Canadian Army Medical Corps where he won a medal for tirelessly helping wounded soldiers at the Battle of Cambrai despite being shot himself.  So he had that in common with Francois Jacob.  After WWI, he returned to medical research, intrigued by what he'd read about a protein supposedly secreted from the pancreas that regulated the levels of blood sugar.  The problem was that all efforts to purify this active principal mobilised the trypsin which digested the protein before it's effectiveness could be measured.  In the Summer of 1921, Banting borrowed some lab space and a research assistant from University of Toronto's Professor of Physiology J.J.R. MacLeod.  MacLeod promptly left for an extended European vacation. The 22 year-old research assistant turned out to be Charles Best, who despite his youth had also done a wartime stint in the Canadian Army.  Between the two of them, they cracked the problem, obtained an alcoholic extract of the insulin, tested it with success on diabetic dogs and later on a diabetic boy.

This was a revolutionary break-through and the Nobel Prize was awarded about as quickly as it was possible to do so in 1923, to . . .  Banting and MacLeod.  Despite the frequent assertions of lazy-arsed 'researchers' in the history of science, it is not true to say that MacLeod's contribution to the project was that of an absentee landlord of the rooms where the experiments were carried out.  On his return from vacation, he was instrumental in improving the quality of the insulin with better extraction and purification procedures, getting Biochemistry Professor James Collip to oversee this aspect of the work.  But the exclusion of young Best from the winners (three is the maximum number of ways a single Prize can be split) struck many people then and since as unfair. It was probably just ageism: Banting, at 32, is still the youngest winner of a Nobel in Physiology & Medicine: maybe it was inconceivable to a committee of Swedish silverbacks that 'a mere boy' of 22 (who could drive a tank!) could have contributed substantively to the discovery. It's quite a neat antidote to the story of non-Nobellist Jocelyn Bell Burnell - exclusion from credit due is not the prerogative only of young women in science.  Like Burnell (N = 21), Best later got a rash (N = 18) of honorary degrees as consolation prizes.  Banting was sufficiently annoyed with the slight to his Effective that he shared his own prize money with him.  That induced a similar gesture from Professor MacLeod who shared his loot with fellow Professor Collip, keeping the money at the correct level in the hierarchy.  The list of exclusions might include Clark Nobel the other potential lab-assistant to Banting - he lost a coin-toss with Best for first dibs in the Banting laboratory.  Other people feel that B&B were pretty well scooped by Romanian physiologist Nicolae Paulescu who had treated diabetic dogs with his pancreatic extracts as early 1916.  But Banting's team were the first to successfully treat human diabetes with insulin.  Everyone seems to like and respect Banting.  He died on 21st February 1941 in a plane-crash en route to war-torn Europe (again!) to test another life-saving invention.

The discovery and purification of insulin started an industry removing the pancreas from every pig that went to slaughter and purifying porcine insulin to medical-grade injectible material.  The pig protein is 88% identical to the human product which was not enough to trigger a "this is foreign" immune response but was sufficiently different that diabetics on that treatment felt a little off when they needed an insulin boost.  Later this abbatoir-based biochemical solution to insulin availability was replaced with genetically modified microbes that grew human insulin in vats.  With the new product diabetics didn't get the tell-tale pre-crisis indications which made management of the disease a little more difficult.

Some years ago, The Beloved persuaded me and the girls to spend a week in the South of France on a Buddhist Retreat for Scientists. It was a little out of my comfort zone (except for the getting up before first light to not-think) but was a pretty wonderful experience.  There were 1000 people on the Retreat but the actual Scientists were very thin on the ground. In that world iridologists, chakra-boffins and crystal-therapists identify their whoo-wah as a branch of science. One of the techniques employed at such events is whole-body relaxation where everyone lies down warm-and-comfy on the floor and listens to somebody quietly, relentlessly, urging you to relax each part of your body in turn starting with the toes.  It's a bit "your toe bone's connected to your foot bone; your foot bone connected to your ankle bone . . ." but before we'd reached the hip there were wholly-relaxed snores in the room.  I was feeling a little dozy myself when I heard " . . . relax your pancreas . . .".  "WTF," I thought, "I'm sure I'm the only person here who could point to his pancreas, let alone relax it".

Throwaway tech

Humours! Since Hippocrates and Galen, doctors have been tuning in to the fluid balance of the human body. Those ancients and 1,000 years of their followers recognised

• Black bile - μέλαινα χολή, melaina chole
• Yellow bile - ξανθη χολή, xanthe chole
• Phlegm - φλέγμα, phlegma
• Blood - αἷμα, haima

From which we derive the words for character traits like Melancholy, Phlegmatic and Sanguine. Nobody now believes that depression is due to the spleen making an excess of black bile but the principle did put doctors onto the idea of checking bodily out-puts. If you have experienced a lot of snotty kids in surgery, you can tell from the colour and smell when an excess of rhinovirus has been superseded by a more threatening bacterial infection. In the Netherlands toilets are designed so that user can easily scrutinize the stool before flushing - which is handy for getting on top of another pinworm infestation. It is a rare visit to your medico that doesn't involve a urine sample.

In the old days, the doctor was likely to dip the tip his [sic in the old days] pinkie in the sample bottle and taste it. We have a mighty set of over-lapping, complementary physiological mechanisms for controlling the amount of circulating glucose. Waste not, want not: glucose is the primary currency for energy in the body and without a source of energy cells are quickly dead. The normal interplay between insulin and glucagon scoops up excess glucose before the kidney gets a chance to dump any. You're likely in trouble with sweet pee [Lathyrus odoratus - not].

You may have noticed that your doctor doesn't do the finger thing! They rather shake one out from their vial of 100x Multistix and dip that instead. That gives a more or less instant read out of Blood, Leucocytes, Nitrite, Specific Gravity, Glucose, Protein, Ketones, Ph , Urobilinogen and Bilirubin. At 43c it really is extraordinary good diagnostic value. Novice clinicians may need to read the manual [above R] - not to be confused with a Pantone colour swatch for matching the curtains with your new dinner-service - but old hands know what key colour change they are looking for. We have Helen Murray Free, and her husband Al, to thank for this now taken-for-granted appropriate technology. 

Helen Murray was born in Pittsburg in 1923 and was all set for an Arts major at college reading English and Latin when Pearl Harbor was bombed and vacancies opened up in blokey science disciplines. Murray switched to Chemistry - if you're smart you can do that - and graduated in 1944 and got a job with Miles Labs in their QC and diagnostics division. But she transferred sideways into the research division run by Al Free and the two of them quickly became a complementary and very effective team. They were tasked to develop new diagnostics for urinary glucose. This was important because there were treatments for diabetes [thank you Banting and Best!], so patients could go forward with hope from a reliable test.

Like a lot of chemical tests, they were looking for a colour change which would light up for glucose and nothing else. Their first products involved soluble pills that could be popped into a urine sample. Clinitest used cupric sulfate, citric acid, sodium hydroxide and carbonate for the fizz. Miles Labs' cornerstone product was Alka-Seltzer so <fizz> was almost required.  But that was wasteful because it needed an extra bottle - the rest of the sample could be used for other diagnostics, sent to a specialist urology lab. Creating another diagnostic test - for Hepatitis A - set the Free lab on a trajectory to make a single product that would do multiple tests at once. Another key conceptual break-through was dry-testing where the active ingredients were migrated to a plastic strip which could be dunked. That saved on the extra bottles and effectively replaced Galen's medieval finger-tip. And the idea could be scaled up to make multiple tests from one product. All sorts of teething problems had to be confronted and solved: separating the various chemical cocktails so they didn't bleed into each other; ensuring stable shelf life. Of all the one-time use plastic products which are available, pee-sticks have arguably the best utility:carbon-footprint ratio.

Helen Murray Free [interview] continued working through six children; co- wrote The Book Urinalysis in Laboratory Practice with Al and retired in 1982 before she turned 60. She then devoted the next few decades to making chemistry understandable and accessible to girls and other groups normally excluded from the Joy of Science. She won the National Medal of Technology & Innovation in 2009. She died in the fullness of her years last Saturday having made a difference.

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