Summary

Plants have co-evolved with animals over hundreds of millions of years and they manipulate animals in many ways, thus enhancing their own survival, e.g. by being more, or less, tasty, or toxic — sugar, tannin, atropine, nicotine, heroin etc. This co-evolutionary process has moulded animal and human biochemistry and behaviour in complex and subtle ways over the course of evolutionary time — hundreds of millions of years.

Alcohol’s roll in, and connection with, nutrition in our ape ancestors goes back 4-5 million years. It has influenced the development of dopamine reward pathways in the brain, multiplying the effects of alcohol on hedonic reward. Cultural factors have woven alcohol into the fabric of human society, perhaps even before larger human settlements in the Neolithic (10,000 years ago), and through all continents and societies over millennia.

The countless ways plant chemicals (nicotine, heroin etc.) affect animals is reviewed and interpreted to illustrate this a ‘co-evolutionary’ perspective.

Introduction

Part 1 of this commentary concentrates on evolution, how plants have been manipulating animals with tasty treats, like sugar, for around 100 million years: plants interact with all animals, both invertebrates and vertebrates, including humans, by producing chemicals that alter their behaviour and physiology — ‘Part 2’ deals with peripheral socio-cultural aspects and how they interact with ‘government’.

Think of caffeine, tannin, nicotine, atropine, the opium poppy, cannabis, and 1000 other things you don’t even know about — these chemicals do not just exist for no reason, they are produced for a purpose and at a metabolic cost to the organism producing them. Alcohol and sugar are the principal examples dealt with here; but various other examples are given to illustrate the glimpses of knowledge that we have about plants’ bio-active products and toxins, and their effects.

A recent book, the follow-on to a conference at the British Academy in Sept 2018, titled ‘Alcohol and Humans: A Long and Social Affair’ [1], was published as I was recensing* this commentary (from a previously posted version — as I often do with the material on my website).

* A term for the process of (critical) revision of texts is ‘recension’.

This book, Alcohol and Humans, has much interesting material, some, like the chapter ‘Hominoid Adaptation to Dietary Ethanol’ [2] that expands on what I have previously touched on. The authors, Hocking & Dunbar, cite Dobzhansky, ‘Nothing in biology makes sense except in the light of evolution’ [3]. That statement by Theodosius Dobzhansky has echoed down the years: Dobzhansky was a major figure and influence in genetics and evolution, his 1937 work ‘Genetics and the Origin of Species’ was influential and has been cited thousands of times. He was awarded the US National Medal of Science in 1964 and the Franklin Medal in 1973 — a towering figure in the field.

The book makes the point — that I think the medical profession might take account off — that the general social and psychological benefits of alcohol in society are deeply embedded and are somewhat greater than is generally appreciated (at least by some elements of the medical profession). A balanced approach for individuals in making decisions about hedonic life choices is preferably based on sound analysis of the facts (of the real medical disadvantages, or harms, of alcohol) and a broad understanding of the place of alcohol in society. Hopefully those reading this commentary will come a little nearer achieving that.

Such an understanding may enable people to balance the views, attitudes, and information that they receive, including that from the medical profession which can sometimes be authoritarian and with a narrow perspective: that may owe something to puritan philosophy.

Definition: Puritanism; the haunting fear that someone somewhere may be happy (H L Menchen, A Mencken Chrestomathy).

I am sure Dobzhansky would endorse the view that not only does nothing in biology makes sense except in the light of evolution, nor do most things in medicine.

Medical matters relating to alcohol, sugar, and obesity are prominent examples of that idea.

Another key part of this ‘big picture’, is the political, cultural, and social dimension, which is discussed in Part 2.

The oldest battle on the planet

The oldest battle on the planet is the battle between plants and animals. Just because plants do not leap up and attack us, that does not mean they are not engaged in an ongoing war to manipulate us, harm us, and protect themselves. They have been producing chemicals (and spikey bits) to combat all the other organisms, with which they compete on the planet, since the beginning of evolution, hundreds of millions of years ago.

Insects first appeared about 400 million years ago, and flowering plants about 150 million years ago. Our primate ape ancestors descended from the trees, and started to walk upright, about 5 million years ago, and permanent human settlements started in the Neolithic about 10,000 years ago. So far, the earliest evidence for the possible production of alcohol by humans extends back 100,000 years.

There are many examples of complex chemicals produced by plants — which modern pharmacology has yet to replicate and synthesise — that have multitudinous effects on the functioning and behaviour of animals. Many are toxic. However, the effects may also be subtle, and compounds produced by plants manipulate the behaviour of animals, to the advantage of one, and sometimes both, parties.

There might be a book about this by now [recension postscript, here is a relevant contribution [1]], but I will give illustrations from my own knowledge to make my point.

Foods: safe or toxic?

It has long been my view that some aspects of medicine are illuminated by considering them with an evolutionary perspective, and that ‘Evolutionary Medicine’ is undervalued. It is a view Dobzhansky surely would have supported [3].

There are many interesting and revealing examples concerning evolution, and how plants influence many aspects and characteristics of animals, including humans — like why we have such large livers.

Why the human liver is large

The human liver is large because we are omnivores. Being able to get nutrition from so many diverse sources, both plant and animal, inevitably exposes us to a greater number of potentially toxic substances. As discussed here, many of these are produced by plants (and animals) to deter predators, or even to kill them. Therefore, to be a successful omnivore requires the evolution of many enzymes, which are in the liver, that can break down these toxins into harmless substances. That requires space and a lot of energy. A big liver.

The liver is ~3% of total body weight, but it consumes around 20% of the oxygen we use; vs brain ~20%, muscles ~20%, ~heart 10%. It is an expensive organ to maintain: it puts many of the enzymes into ‘sleep mode’ when their particular substrates are not present. That is one mechanism by which tolerance to drugs develops. The enzymes needed to metabolise them are switched on (induced) when the body encounters the relevant chemical-drug-toxin which is the substrate for a specific enzyme.

How do we know that the plants we consider safe to eat, really are safe to eat? The answer is we do not know, it is little more than ‘folklore’ — it is entirely possible that, unbeknownst to us, long-term consumption of some may lead to the accumulation of toxins that cause disease. After all, plants that were in the past toxic to primates, we are now able to detoxify with our complex liver enzymes, which have evolved — but only after numerous individuals in the populations were poisoned — so that which was previously toxic, is no longer. That is the ongoing evolutionary arms race. But we do not know at what point in that evolutionary story a plant relates to us now. It would be hubris indeed to assume that we do know.

Fruit flies and alcohol

It was recently discovered that fruit flies preferentially deposit their larvae on fruits which have undergone alcoholic fermentation, which confers protection against parasites [4]. Insect evolutionary adaptions like this probably occurred hundreds of millions of years ago — the insect taxa are around 400 million years old. We might also suppose that this influenced the ‘co-evolution’ of insect olfactory and taste receptors, and receptors in the CNS (which were needed to detect and remember the fruits containing alcohol), and that these adaptions flowed through the genetic tree into early vertebrates, and then mammals. This complex interwoven tapestry of co-evolution that we see now started hundreds of millions of years ago.

These sorts of observations suggest that the dopamine reward pathways in insects, and vertebrates and primates, co-evolved in tandem with these traits that were related to the ebb and flow of the harms and benefits of alcohol — it was natural selection, not chance. Dobzhansky would love it!

The fact that alcohol releases dopamine in the reward pathways is the result of tens of millions of years of evolution.

Colour vision and sugar

Old-world apes are different from other mammals in having three types of retinal colour receptors (trichromacy), not two (dichromacy).

For an outline of the evolution of colour vision in vertebrates and primates, for those that have the time and interest, see: [5-8].

One explanation for the selection pressure that drove the evolution of this trait is that trichromacy enabled better recognition of red-ripe fruit. This has been debated for some time, and recent findings continue to support the theory: observations now suggest that dichromatic individuals (i.e. ‘colour-blind’) are slower to find fruit in the forest, which thus puts them at a disadvantage, for which they compensate by relying more on olfaction [9-11].

As Melin et al. state in their most recent paper:

‘These results provide some of the first behavioural evidence of how wild frugivorous mammals use the chemical properties of food to inform their foraging decisions, and are consistent with recent research reporting that lemurs increase their reliance on olfaction when feeding on fruits whose scent changes with ripeness, and that primates are highly sensitive and attentive to some odorants.’

Wine drinkers may be interested to understand that this selection pressure, for the ability to smell different compounds in fruit of varying degrees of ripeness, was probably a factor that made this ability more pronounced in Homo sapiens (cf. ADH evolution below). Those monkeys that are dichromatic rely more on their sense of smell.

It seems that our ancestors evolved trichromatic colour vision, and the attendant ability to more easily find ripe fruit which contains sugar and odiferous compounds, and alcohol, because finding nutritious ripe fruit was essential for survival [12]. There is a great deal more about this fascinating story, and the evolution of alcohol metabolism in apes versus monkeys, in a book that was published following a recent conference at the British Academy [1].

In short, apes on the forest floor were more likely to encounter over-ripe fermenting fruit, which is typically about 4%, and up to 8% of alcohol [12]; there was ‘selection pressure’ for the more active form of the alcohol metabolising gene, ADH, as discussed below. The monkeys who stayed up in the trees did not develop the ability to metabolise alcohol; they became intoxicated easily if they consumed over ripe fruit, fell out of the trees, and did not survive.

A recent paper consolidates this evidence with a comparative genetic analysis of alcohol dehydrogenase class IV (ADH IV) in various mammals [13]. It also raises other interesting questions.

This persuasively links together fruit, colour vision, olfaction, the ability to metabolise alcohol, and dopamine’s role in reward pathways; it explains how they were selected for in hominids by the evolutionary pressure to ingest calories for survival. They were then passed on to Homo sapiens.

Alcohol: Neolithic brewers started it

The interesting speculation is thus substantially supported that alcohol has moulded the evolution of the animal nervous system (as above) continuing through primate evolution, influencing CNS receptors and brain reward pathways; both sugar and alcohol release dopamine in the CNS reward centres.

A major difference between the monkeys and the apes was that the apes, when they descended to the forest floor approximately 4 million years ago, had a form of the alcohol metabolising enzyme that was 40 times more active. This was likely because they encountered alcoholic fermented fruit on the forest floor and this was another step in the co-evolution of man and alcohol [14].

As Dudley [12] suggested some 15 years ago; ‘behavioral responses to ethanol may have been the target of natural selection for all frugivorous species, including many primates and the hominoid lineages ancestral to modern humans.’

It seems that homo sapiens evolution-generated predilection for alcohol motivated the intensive cultivation of cereals in the early- or pre- Neolithic period (around 10-12,000 years ago). Such cultivation may have been to do with producing alcohol, rather than being just for dietary carbohydrate needs via ‘bread’ production [15]. Indeed, evidence from Mozambique suggests the tantalizing possibility that Sorghum may have been fermented as much as 100,000 years ago [16].

Two strands of evidence indicate that Neolithic cereals may have been used in brewing: first, genetic studies of the already existing human alcohol metabolising genes, especially ADH4, indicate that the 40x more active mutation of the ADH gene spread in the population around then [17]. That coincidence may be explained by the fact that there was selection pressure to metabolise increased quantities of dietary alcohol from fermented cereals, compared to that ingested just by eating natural fermented fruit. Second: the genetics of the yeast S. cerevisiae may also have diversified around 12,000 y ago, and the two oldest strains show evidence of ‘domestication’, i.e. they may have been selected by early Neolithic ‘brewers’ for fermenting grain [15, 18].

When and where was the first Tavern? Could it have been in Göbekli Tepe? Wherever it was, the people who went to it probably would agree with the quotation from Samuel Johnson, the famous 17^th century diarist:

There is nothing which has yet been contrived by man by which so much happiness is produced as by a good tavern.

Weak (1-4%) ‘beer’ is an effective way of sterilizing water of harmful bacteria — the production of ‘small beer’ for this purpose existed when the Egyptian Pyramids were built and continued into 19^th century Europe, after which the more modern 4-5% standard concentration became ubiquitous. A typical ‘allowance’ for workers was a couple of litres per day, which is not a great deal of alcohol: at 2% it would be only 40 mls, just clean water and a few grams of carbohydrate, with the anxiolytic effect of a few mg of ‘valium’.

Rather good popular ‘mass-medication’ of the population! Perhaps it was the first and most successful public health measure ever taken!

The effect of alcohol on reducing anxiety and facilitating social interaction in humans may well be more than mere coincidence. It would have facilitated social interaction in emerging Neolithic permanent communities, which, compared to hunter gatherer societies, would have been more dense concentrations of population. That probably reduced the inevitably increased social anxiety and reduced water-born infections.

It is beyond dispute that alcohol triggers increase dopamine activity in the human brain, which drives the dopamine-dependant reward pathways in the and leads to anticipation and pleasure [19-21]. It also affects various other ion channels and receptors, particularly GABA receptors: its effect on those emulates the antianxiety effect of Valium type drugs (benzodiazepines), as described in this recent update [22].

So, pause a moment before you judge somebody who feels they need a drink before they can go to a party (a common phenomenon — how many friends do you have who go to a social function without having a drink first?). It is probably innate to our evolutionary heritage.

Toxins

Parkinson’s disease

Rotenone is a plant derived toxin used to control both insects and fish. It is produced by several families of plants. Experimental and epidemiological research has shown there is both a possible mechanism, and a clear association, between rotenone exposure and a higher risk of PD [23-25].

As a ‘proof-of-concept’ example this shows that plants do produce substances with long-term toxicity to the human nervous system — even if Rotenone is not causal in human cases of Parkinson’s disease, it illustrates that we simply do not know how much of this substance is produced by different plants in nature, and how much we are ingesting. This is because nobody has ever screamed all edible plants, at all stages of their growth, for concentrations of Rotenone — we simply do not know. There have been no long-term human studies of the degree of toxicity of low-level ingestion.

Lathyrism

Epidemics of Lathyrism have occurred in humans (and animals) caused by quite modest amounts of chickpea-like legumes (Lathyrus sativa) for as long as records have existed. Lathyrism is a late-onset spastic ataxic paraplegia [26-29]. It is quite probable that many other related plants produce similar toxins, perhaps at levels that have so far evaded detection [29-31]. After all, limited toxicological screening of plants has been carried out, so we have inadequate information [32]. It may just be that low or undetected levels of such compounds in these plants accumulate over decades and cause CNS damage.

You might well think that if a plant has been used for 2,000 years that it would be obvious if it was causing a problem.

You would be wrong — spectacularly wrong.

Aristolochia

Here is a recent example of a natural (must be good) age-old Chinese health supplement/treatment: its deadly effects only emerged recently. It is the vine Aristolochia [33, 34].

There is a complex story to this, about which I have written elsewhere. It is fascinating because it involves one of the largest and most beautiful butterflies in the world, the Cairns Bird-wing, native to our area of north Queensland. The caterpillars feed on the [poisonous] Aristolochia vine. The poison they ingest (aristolochic acid) is passed on to the adult butterfly, which is thus protected from attack by birds, who very quickly learn to avoid them. The plant has been used since antiquity in various civilisations across the globe, for its supposed health benefits, being especially popular with the ‘Han’ Chinese.

The toxic effects (renal carcinoma and renal failure) were first recognised and called Balkan endemic nephropathy in 1956, but was not till the 1990s that full recognition of aristolochic acid’s toxicity started to be more widely understood — amazingly, it is still consumed in Taiwan (whose population is predominantly Han Chinese) because a naïve faith in ancient Chinese medicine remains wide-spread. Taiwan has, as a result of this superstitious ignorance (aka ‘folklore’, or ‘ancient wisdom’), the highest incidence of renal failure and urinary-tract cancers in the world [34].

These deaths are all caused by Aristolochia, used for two thousand years, and still causing innumerable deaths. Natural, safe? Nature fights back and cannot be wished away with magical beliefs. So much for ‘ancient wisdom’.

Anti-oestrogen compounds

Some grasses produce anti-oestrogen compounds, but only in their early-spring shoots. That suppress the ovulation of some grazing animals, until the grass has reached a certain stage of maturity. This mutually benefits both the grass and the animals by making sure that the animals do not breed until the grass is fully established in the early growing season, such that it is not over-grazed. This avoids the denudation of the landscape and erosion and lessens the chance of the offspring of the animals starving through lack of food.

Laxatives: ‘Senokot’

Since the ‘information-environment’ that most people are exposed to is so full of execrably poor material, let us have an example related to excretion. Why do you think so many plant-based extracts act to increase the speed of bowel action in mammals, including humans (think of the laxative ‘senokot’, extract of the senna pod). It is sometimes because of a dynamic relationship with the plants eaten, and some plants produce compounds which maximise the chance of the animal excreting their seeds in an advantageous location.

Toxoplasma gondii and car accidents

Toxoplasmosis is caused by the Toxoplasma gondii parasite: rodents infected with toxoplasma show diminished reaction times and a reduced fear-response to predation by felines, including domestic cats. This is caused by a chemical produced by the Toxoplasma parasite that affects the nervous system. Thus, such rodents are more likely to be caught and eaten, and the likelihood of Toxoplasma maintaining itself in the population is increased [35, 36].

Toxoplasma also infects 20-60% of humans, via domestic cats (how many reasons are there for not having cats?): so, here is an example of a profound effect on human physiology and behaviour (reaction times) that has only recently been elucidated [37]. Humans who are RhD-positive seen to be protected against latent toxoplasma-induced impairment of reaction times which, however, affects everyone else, who suffer slowed reactions, and are therefore more likely to have road traffic accidents, and probably other misfortunes as well [36, 38, 39].

This interesting example of host/parasite evolution may explain the otherwise puzzling perpetuation of the Rh blood group variant in the human population, because it causes occasionally fatal haemolytic disease of the newborn [40-42]. Sickle-cell disease and Malaria show a similar inter-relationship.

Summary perspective

This is a fascinating subject that involves an understanding of evolution, chemistry, pharmacology, psychology, sociology, and politics. It doesn’t get more wide-ranging than that. An accumulation of many similar observations to those above illustrates that there are extensive interactions, many unexplored or unknown, between a myriad of compounds produced by plants, and the behaviour and functioning of vertebrates, including humans.

Likewise, these observations suggest that it would be unwise to assume that we yet know enough about the foods we consume to be confident about their long-term effects on our system.

The implications of contemplating health and medicine with an evolutionary perspective are instructive. I learned — after reading Hockings ‘Alcohol and Humans: A Long and Social Affair’ — that I am in the esteemed company of Theodosius Dobzhansky [3] in thinking along these lines.

The reasons we get pleasure from alcohol, both biologically and culturally, emanate from the inextricable way that evolution has woven these threads together over millions and millions of years — alcohol is an inseparable part of the warp and weft of our existence.

The evolutionary perspective on the relationship between the plants we eat, and their effect on us, will continue to produce interesting insights. These effects are both powerful and nuanced, as exemplified by the hundreds of millions of tonnes of sugar that plants have manipulated us into growing, to say nothing of heroin. If you add together all the people essentially earning a living from grapes, sugar, cannabis, heroin, tobacco, etc. I should think you could estimate that half of those of working age on the planet are essentially working for the plants!

It is interesting to understand the metabolic parallels between excess sugar and excess alcohol, and their similar ill-effect on health. There is not space to detail those here, but to learn more, read Lustig’s summary [43-45], and read Part 2.

Obesity in the Western world is a prominent and expensive health problem — the plants are winning!

I have tried to weave together a number of disparate threads having to do with evolution, and link these ‘drugs’, eating, metabolism, and health, in such a way as to increase understanding of the big picture of what influences us to eat as we do, and how the category ‘food’ is not as clear-cut as many imagine, and how easily ‘food’ can cause harm.