Brexit and Homo.semi-sapiens

I have been meaning to write on this topic for a very long time. As a teacher, a biologist and a computer scientist the process we call reasoning is always to the fore, whether delivering a biology module on ethology, discussing  fuzzy logic and AI or marking scripts and wondering what on earth is passing for ‘reasoning’ in the minds of my students. The recent ‘Brexit’ referendum brought it all together for me … just how does homo-semi-sapiens reason?

Artificial Intelligence or AI has had spectacular gains over the past decade or so. It started with IBM’s ‘Deep-Blue’ defeat of Gary Kasparov at chess in 1996 before retiring in 1997 after winning a controversial rematch. 20 years later Google’s computer beat the current world champion at GO! The latter board game was levels of magnitude less ‘logical’ and predictable than chess and regarded as more intuitive and complex. So much for board games. I struggle to play either so would stand no chance against a computer’s intelligence.

Next up in the real world the BBC recently reported a US AI defence system successfully outplayed incoming attack jet fighters by basically outfighting them with its own interceptors. So much for war then. I am not able to fly a jet, real or virtual, and I know little of strategic war routines having not been trained in the military so I must defer to the computers once again.

The question for me is not how smart is AI and how smart can be the very smartest humans but ‘just how dumb are humans, really?’

If we take our mammal cousins, the field mice, and look at their ‘thinking’ in the context of the life choices they have on rising in the morning. They have very little body mass and so have little  food reserve. They cannot go without food for very long so each day they look for food. But they also need to reproduce for the species to survive and to do this they must look for a mate rather than forage for food. This is risky as they may, find a mate and then starve or fail to find a mate and starve.

How do they make this life and death choice?  Well, very detailed study showed that they use a very simple algorithm which is ‘I ate well yesterday so I can look for a mate today’. That’s it!

This simple algorithmic approach to reasoning is widespread in the animal kingdom and are inferred from observed behaviours. This is why it belongs to the field known as ethology which is the study of animal behaviour. These algorithms are known to the higher primate homo-sapiens and we call them ‘rules of thumb’. Rules of thumb abound today, after all if you want to improve something then measure it.  So here then is building block No1 in human reasoning

Reasoning method Number 2 was explained to me on BBC Radio 4 many years ago when a politician was describing ‘thematic reasoning’ which at the time was new to me and a revelation. Essentially things, issues, people, whatever, are ascribed a virtue, that is ‘good’ or ‘bad’. To whit an often repeated 1990’s experiment is to ask the general public which of the following processes were most responsible for global warming: electricity generated by coal fired stations, oil fired, gas fired or nuclear powered?  Invariably the order was, worst=nuclear, best=gas.

It’s simple to understand their mistake. Global warming = a v bad thing; nuclear power = a bad thing ( this is 1990s post Chernobyl), bad begets bad so the conclusions are linked by theme. Apparently according to my radiophonic mentor all politicians understand this and are taught it at politician school which explains a lot...see referendum debates, invasion of Iraq etc etc.

Finally we have reasoning Number 3. It’s called magic. James George Frazer’s famous book ‘The Golden Bough; a study in magic and religion’ in the late nineteenth century does it for me. To cut a long story short, belief systems developed that introduced new ways of reasoning. They were/are characterised by rituals and symbols and embodied principles. The latter include an association inferring cause and effect, eg the Rooster crows just before sunrise ergo the sun’s rise is caused by the Rooster's crow. This is broadly called sympathetic magic the other main type is contact based and is called contagion. So for example the baptising of a baby with holy water is an example of contagious magic replete with symbolism and iconography.

So far so bad for homo-semi-sapiens. What about higher levels of reason? The kind of thing you get from education.

Take for example conditional statements, ‘if I do this, that will happen’. Every teacher knows by experience that students can have their minds trained so as to make correct conclusions using the conditional so long as they are given the initial knowledge conditions and the rules of the game. This is certainly the start of logical thought and in itself an educational achievement but ask also the same teachers (and setters of exams) what success they will have with double conditions. Eg, ‘ if this occurs then that will occur and then the other will occur as a result’...the nested ‘if’ of computing.  Most students cannot do this.

Putting it all together, Homo-semi-sapiens in a developed society will have access to ‘rules of thumb’, thematic constructs, magical thinking and one step conditions.

The famous thinker Scott Adam’s seminal 20th century work ‘Dilbert: Thriving on Stupidity in the 21st Century’ describes this beautifully and is still elaborating his ideas today in his latest comic strips where engineer Wally is nominated for a Nobel prize for his AI humanoid; aka a block of wood.

Homo-semi-sapiens is on the march today aided by the connectivity of social media which allows for self-referencing and reinforcement.  Authority is challenged as never before as ‘priest classes’ lose their grip unable to explain to their audience what is in effect  unexplainable and resorting to using reason that is in common use (as described above).

It is ironic that we debate the capabilities of AI systems when the ‘I’ systems in general use are so primitive. Maybe if we wish to produce realistic AI systems we should start with our own protocols.

Am I being patronising to semi-sapiens? Maybe once I could have been intimidated into being less scornful. However the Brexit referendum has removed all such inhibitions.

Ions and Mitochondria: repair or die

A restored classic car may look and run well but it’s not fresh off the production line. It will have been repaired  umpteen times, and it is not about to be thrashed around the track … except maybe on special occasions. Such is the nature of the rejuvenated.

This analogy serves well enough to illustrate the current thinking in the pursuit of longevity and the preservation of youth.  From the cosmetic (a respray), the physiological fitness plan (new suspension and bearings) to the subcellular diet-related (an engine overhaul), all cases of  ‘rejuvenation’  are synonyms for repair.  I am interested in repairing biochemical engines, which in the case of aging organisms means mitochondria.

To get started I need to set out some ground rules regarding my picture of mitochondria. A picture I have set out in previous posts. To me they are tiny electronic devices. They can conduct electrons and physically separate charges to create potential differences measured in volts.  Their membranes have low dielectric constants and large surface areas so can store charge as does a capacitor and like capacitors they leak a little charge too. Finally, they can (controllably) collapse their charge-gradient and transform that energy into chemical form … or else they can be ‘shorted out’  releasing their energy as heat.

Or, in biochemical jargon:  the process of oxidative phosphorylation and electron transport  generates a membrane potential and a proton gradient, the energy of which is used to synthesise ATP unless it is ‘uncoupled’ by something that makes the inner membrane permeable to positive ions.

My ‘electronic’ mitochondria reduce biochemical complexities to simpler axioms which include making sure that voltage and capacitance remain high and charge leakage remains low.  

To do this we must:

1. Keep the processes that separate charge going flat out.
2. Maintain the dielectric integrity of the membranes.
3. Maintain the surface area of the mitochondria and hence its capacitance
4. Stop leaks.

It has been known for a long time that stimulating the mitochondria by feeding them their favorite food 1 (acetyl units) and transporting them using a the so-called carnitine shunt using the food supplement acyl-carnitine peps up the activity of the electron transport chain. Ditto foods like malic acid and citric acid speed up the citric acid cycle. Such supplements address the first point in the list above but all will be wasted if the other points are not. ‘Revving up in neutral’ will generate heat but not a lot of action.

As we age mitochondria change,  a proportion of them become larger with fewer christae 2, They leak proteins more easily 3,4 and eventually depolarise completely leaking the fatal Cytochrome C which leads ultimately to cell death. I also proposed that larger mitochondria are an adaptive response to reduce capacitance in order to maintain  the threshold membrane potential for ATP synthesis. But what to do about this?

In a previous blog I referred to my work showing that Cytochrome C leakage was reduced in rats fed a diet high in cholesterol.4 Cholesterol rich membranes also have a higher dielectric constant than cholesterol depleted membranes. This is a start, a repair of sorts but what we really need is something to:

a) purge from the cell inefficient and downright dangerous larger mitochondria struggling to maintain their membrane potential against a backdrop of increasing leakiness.

b) plug the leaks.

When the Cats come out.

Metal cations are positively charged metal atoms and cells use different ion gradients to power various energetic processes such as nervous conduction (Sodium and Potassium (Na+, K+), kidney function (Na+, K+ and H+), mitochondrial energy production (Proton H+) and muscle contraction (Calcium Ca++).

But what about the physiological effects of other cations, cations not normally present in high quantities in the food we eat?  Specifically  I mean very small cations that can, could, or do interfere with the ions above by virtue of their small radius and ability to get into cells and bind to membranes.  That is cations small enough and rare enough to be ‘mistaken’ for the usual suspects.

My short list comprises: Lithium, Beryllium, Boron, Aluminium and Germanium ( Li+ Be++, B+++, Al+++, Ge++) on the basis of their ionic radii shown in the Periodic Table5.

Yes, all are poisonous (very)  all are very small and they all affect mitochondria causing them to enlarge and uncouple. Germanium induces mitochondrially mediated apoptosis6; aluminium caused an increase in mitochondrial free radical (ROS) production7; beryllium uncouples and cause them to swell.

Two of them though, in low doses, bizarrely increased the lifespan of short lived organisms8,9. These are Lithium and Boron, now that is interesting. Lithium increased the autophagy ( absorption) of enlarged dysfunctional mitochondria and another author10 speculated that ion channels were blocked by the unusual ion helping to reduce charge leakage and maintain membrane potential when he found enhanced mitochondrial activity in human brain tissue.

Boron also decreased the size of the mitochondrial population making them more elliptical. The experimental animals were: C elegans (a nematode worm) and Drosophila (a fruit fly).

I am intrigued. Plugging leaks and culling the weak would be close to top of my list of repairs to mitochondria. A lot more pieces of the jigsaw need to be found but in the meantime what food would benefit me most according to the repair schedule set out in this blog.

I would get my dietary cholesterol or its precursor squalene from foods naturally rich in it such as oily fish, seafood and olive oil.  Of foods with a high lithium content, pistachio nuts are prominent and for boron, walnuts and dark greens like kale. For a boost in activity I would make sure I got my fructose, malic acid or citric acid from fresh fruit. Ok that looks quite a lot like the perfect Mediterranean diet...I wonder why they live so long and have such low rates of dementia?

1)Ann N Y Acad Sci. 2004 Nov;1033:108-16.Delaying the mitochondrial decay of aging with acetylcarnitine. Ames BN1, Liu J.

2) Antioxid Redox Signal. 2010 Feb 15; 12(4): 503–535. Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of AgingAlexei Terman,1 Tino Kurz,2 Marian Navratil,3 Edgar A. Arriaga,3 and Ulf T. Brunk2

3) AGE-DEPENDENT RELEASE OF MATRIX PROTEINS FROM RAT-LIVER MITOCHONDRIA

Author(s): SPENCER, JA; HORTON, AA  EXPERIMENTAL GERONTOLOGY  Volume: 13   Issue: 3-4   Pages: 227-&   DOI: 10.1016/0531-5565(78)90016-5  Published: 1978

4) Differential Effect of Digitonin on Liver Mitochondria from Old and Mature Rat  Spencer, John A.; Horton, Alan A. BIOCHEMICAL SOCIETY TRANSACTIONS  Volume: 7   Pages: 673-675   DOI: 10.1042/bst0070673   Part: 4   Published:AUG 1979

5) http://ch301.cm.utexas.edu/section2.php?target=atomic/bonding/ionic-radii.html

6) Neurosci Lett. 2006 Feb 27;395(1):18-22. Epub 2005 Nov 9.Cochlear damage due to germanium-induced mitochondrial dysfunction in guinea pigs.Yamasoba T1, Goto Y, Komaki H, Mimaki M, Sudo A, Suzuki M.

7) Aluminum induces neurotoxicity by altering mitochondria of brain cells

Thursday, January 30, 2014 by: Thomas Henry

Tags: aluminum, neurotoxicity, neuron mitochondria

8) Effects of lithium on age-related decline in mitochondrial turnover and function in Caenorhabditis elegans. Tam ZY1, Gruber J2, Ng LF3, Halliwell B3, Gunawan R4.

9) Biull Eksp Biol Med. 1990 May;109(5):492-4.[Morphometric characteristics of hepatocyte mitochondria during internal administration of boron-containing water].Korolev IuN, Panova LN, Zhukotskiĭ AV, Butusova NN, Kogan EM.

10) Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissueMaurer IC1, Schippel P, Volz HP.J Gerontol A Biol Sci Med Sci. 2014 Jul;69(7):810-20. doi: 10.1093/gerona/glt210. Epub 2014 Jan 7

Sweet enough?

When is sweet not sweet?

Poor old Mars PLC, their range of Dolmio sources have been the focus of attention since they warned their customers that they were for occasional consumption only. On their website all the ingredients are clearly presented and they are not dissimilar to rival products in this large sector of the food industry.

They were criticised for the fat, salt and sugar content of their range but to be honest these figures would not be any different from a home ‘prepared from scratch’ version. For example the average sugar content was 4.2g per 100g of sauce. That’s only a teaspoon in a very large dollop of sauce (fresh tomatoes would match that)... there was 5g of fat and 0.8g of salt or  other words less than a teaspoon of olive oil and a pinch of salt. So why the warning?  

There is however something common to nearly all mass produced,  thickened, sweetish liquid products from yoghurt drinks to soups and sauces.

The story goes way back to the late 1950’s when the food industry in the US was converting its excess cereals to new products which were proving very popular with the prepared food industry. These were the product of breaking down starch into smaller molecules by a process called hydrolysis. These products are called hydrolysates and in descending order of complexity and thickening power are: partially hydrolysed starch/modified starch; glucose syrups; oligosaccharides/maltodextrins. All are made from glucose molecules and the products get sweeter as they get simpler and more like glucose. They are used extensively to thicken and sweeten food products.

Clearly these products are sugar-like and the challenge was and is to say how glucose-like they are if only for the purposes of labelling but more importantly for concerns on the effects of  excess consumption of sugar.

Work carried out in the early 1960’s1 showed clearly that the real-life absorption of glucose in the intestine derived from these products was very rapid indeed, often exceeding that of pure glucose and greater than that of sugar (sucrose). Moreover the products which were first broken down to maltose (glucose-glucose) was  itself used as a fuel by the intestines’ cellsl to power the process of absorption. This was a very important finding and one which is well understood by the food industry and overlooked by its lablling.

GI ( glycemic index) v the modern food label.

One classification of the rate of uptake of glucose from foods is the glycemic index(GI). This index measures how much and how quickly glucose enters the bloodstream after eating a particular food. The reference point is glucose itself and other foods are rated against this. It is therefore not surprising to find that maltodextrins which are small molecules having 3 to 20 glucose molecules in them have high GI indices and the sugars in a complex food like sweet dates have a relatively low GI. Unfortunately the GI rating is full of counterintuitive anomalies; fructose, a simple sugar, has a low GI and potatoes (quite clearly ‘complex’) can have very high GI’s. GI is actually useful for measuring glucose availability but is steadily dropping from labelling for the confusing reasons above.  Instead we have standardised and now familiar analyses which read  ‘carbohydrates of which sugars’.

Here ‘sugars’ are glucose, maltose, lactose and sucrose. What we call ‘sugar’ is sucrose alone. Carbohydrates would include partially hydrolysed starch, corn syrups and maltodextrins as well as the whole starches from flours.

The point I am making is that in terms of the sugar-equivalent effects the label under estimates the bio-available  ‘sugariness’. This means a thick soup or drinking yogurt may have a lot more sugar-equivalents in it via maltodextrins and the like than is obvious from looking at the ‘sugars’ content.

To go full circle to the first paragraph you don’t have to be sweet to be sugary! This may be why manufacturers are getting twitchy about the healthiness of their soups and sauces. It also explains why ‘home made’ may have the same labeled amounts of sugars as the manufactured stuff but be nowhere near as potentially taxing on your insulin response to sugar uptake.

1. THE ABSORPTION OF SUCROSE, MALTOSE AND HIGHER OLIGOSACCHARIDES FROM THE ISOLATED RAT SMALL INTESTINE BY E. B. CHAIN, K. R. L. MANSFORD AND F. POCCHIARI.

J. Physiol. (1960), 154, pp. 39-51 Printed in Great Britain

Why Sugar is more fattening than Fat

The problem with sugar.

The current consumption of sugar in such huge quantities is truly a dietary phenomenon. ‘Sugar’ is most often taken dissolved in a drink. In this form sugars such as sucrose ( a combination of glucose and fructose), lactose ( a combination of glucose and galactose) or simple glucose and fructose are gulped down in unprecedented amounts as fruit juices, ‘smoothies’, energy drinks or skinny-lattes. And they are drunk in volumes that would have astonished those accustomed to a tea cup.

Few sedentary workers care or know that a regular* ‘skinny latte’ contains as much sugar as a macho ‘five teaspoons luv’ mug of ‘builder's’ tea’ or that healthy pot of fruit yogurt for lunch can match that amount of sugar with ease...just don’t wash it all down with a smoothie (34g = 7 teaspoons of sugar in 250ml). No question about it, sugar consumption around the world is a phenomenon worthy of our attention. Sugar-sweet has gone from being a luxury borne of honey (glucose and fructose) to mega-tonne cheap and cheerful cereal-syrup ( also glucose and fructose).

*a ‘cup of tea’ is approx 150ml a regular latte is 300ml

Other modern diet-related phenomena include: global epidemics of Type 2 diabetes and obesity boasting staggering statistics such as nearly 1 in 10 of the world being diabetic and over 50% overweight. By any standards that’s impressive.

Is there a link between sugar, diabetes and obesity? Yes of course there is, obviously. Do we have a cause and effect relationship or a just a correlation? The biochemistry of sugar metabolism is well known, it’s standard undergraduate fare. So below is just that, in an easy to swallow soluble form.

The problem with being well fed

Let’s start with a few basic rules. Firstly assume we are animals in what is known as ‘the well fed state’. That is to say that at most times of the day we have had sufficient food to make sure that our ‘ready to access’ stores of food are full or nearly so. By this we actually mean our stores of glycogen in the muscles and liver are full. Glycogen in turn is a polymer (multiple) of glucose molecules and is readily converted to back to simple glucose when we need it in a hurry when exercising for example.  We can store upto 2kg of this stuff even so it’s fair to say a typical modern worker qualifies as well fed with full or nearly full stores.

Secondly let’s get our sugars straight. Glucose is our ‘main man’ its alter egos (isomers) fructose and galactose (respectively from fruit and milk) are, once digested and absorbed, very rapidly converted into glucose. So when we have ‘various sugars’ on a label these are sucrose, lactose, maltodextrin (oligosaccharides), glucose, galactose and fructose but thanks to our speedy biochemistry for all practical purposes we are talking glucose. In this respect food labelling is not misleading or being too vague when it says ‘carbohydrates of which sugars’. ‘Sugars’ is sugar is pretty much actually glucose.

Thirdly, glucose levels in the blood are tightly regulated by the hormone Insulin. Glucose’s Goldilocks zone is 4-7 mmol/litre of blood, or in simple terms 1 teaspoon of sugar for all the blood in the body…. too much and glucose is rushed out of the blood urged on by a surge of Insulin-mediated action into a safe haven. This haven are the aforementioned glycogen stores … unless of course they are full because we are well fed and currently inactive. So here our story begins.

The sugar stores are full:

Sugars shunted out of the bloodstream enter cells, be they liver cells, muscle cells or adipose (fat) cells. Here they are broken down by an ancient biochemical process called Glycolysis. It forms the basis of anaerobic respiration, otherwise called fermentation. Glycolysis ( literally the splitting of sugars)is fast, requires no oxygen and it makes enough energy to keep a simple cell alive and even reproducing.

However by an accident of history the waste product of glycolysis just happened to be the food of choice for a bacterium-like creature which came to live within all of our cells and that was what is now the mitochondrion, complete with its own biochemistry and the ability to turn the end products of glycolysis into carbon dioxide and water with the use of oxygen.  

The modern cell thus has the ability to metabolise sugars completely into carbon dioxide and water so long as has a good supply of oxygen. This process we call oxidative respiration and it supplies enough energy for cells not only to live and divide but to specialise into nerves, brains and muscles.  

The key point here is to appreciate that energy production in the modern cell required the fusion of two biochemistries, that of the host cell ( glycolysis) and that of its mitochondrial guests. Together they made enough energy to make us.

We have enough energy already:

Mitochondria are great accountants. When a cell has enough energy for its needs they back off production and vice versa. Mitochondria are not immortal they age inside the cell, their capacity to produce more energy on demand drops with age and they are inclined to tick over producing just the required energy to keep a cell going and little more, even when demanded. It’s like being sedentary all the time when you are older. They won't be rushed or forced into action by  the supply side and only by demand on only then if they are up to it.

Imagine then that you have stopped growing and started to age ( c 25 yrs old), have a sedentary lifestyle ( ie you are inactive for most of the day..say typing at a computer as I am now), are well fed ( ie not in a starved or semi-starved state) and you drink that skinny-latte or that smoothie right now. The sugar races into your blood stream, quick as a flash insulin responds to keep the glucose under control, the glycogen stores are full, quick...push the sugar into the cells, whoosh glycolysis swings into action...uh oh the mitochondria are on a go slow. There is enough energy in the cell already, no real demand for more, what now?

The ‘what now’ is really simple. The end products of glycolysis cannot be allowed to accumulate in a cells they will poison it. Fortunately this problem has a work around. The products can be made safe by joining them together to form a large molecule and stored in the form we know as fat. Storage depots include fatty muscles, fatty livers and of course the specialized fat cells themselves.

Oops. This means that pick your food right ( dissolved sugar is best), pick a good time of day ( a few more hours at the desk or in front of the TV beckons) make sure you have had breakfast lunch or supper so that you are not semi-starved and almost every sugar molecule you take in should convert straight to fat having of course just given your tired old insulin response system a fright and a good work out.

That’s why you get fat and have diabetes.

PS Don’t bother to go to the gym later on, you’ve missed your chance, that fat molecule is snugly tucked away.