Thursday, 15 December 2016

Human 'Mouse Utopia' due to mutation accumulation - a summary

A microcosm of what went wrong with the industrial revolution: Calhoun’s Mouse Utopia experiment

Bruce G Charlton

Note: for convenience in referencing - this essay is cross-posted in a dedicated blog:

The so-called ‘Mouse Utopia’ experiment was conducted from 1968 by John B Calhoun

Four healthy breeding pairs of mice were allowed to reproduce freely in a 'utopian' environment with ample food and water, no predators, no disease, comfortable temperature – a near as possible ideal conditions and space. What happened was described by the author in terms of five phases: establishment, exponential growth, growth slowing, breeding ceases and population stagnant, population decline and extinction:

Phase A - 104 days - establishment of the mice in their new environment, then the first litters were born.

Phase B - up to day 315 - exponential population growth doubling every 55 days.

Phase C - from day 315-560 population growth abruptly slowed to a doubling time of 145 days.

Phase D - days 560-920; population stagnant with births just matching deaths. Emergence of many pathological behaviours.

Terminal Phase E - population declining to zero. The last conception was about day 920, after which there were no more births, all females were menopausal, the colony aged and all of them died.

To summarise – when four breeding pairs of mice were allowed to reproduce under ideal ‘utopian’ conditions, the colony entirely ceased to breed after three years, and then went extinct.

Interpreting the demise of Mouse Utopia

The main fact about Mouse Utopia, was that despite everything possible being done to create ideal biological conditions; the mouse colony rapidly declined and became entirely extinct. This was a very surprising outcome, biologically; and implies that some very major factor about the basic requirements or behaviour of the mice was neglected.

The Mouse Utopia experiment is usually interpreted in terms of social stresses related to 'over-population'; that crowding generated pathological behaviours and a loss of the will to reproduce. But this seems, very obviously – I would have thought – an incorrect explanation; because 1. The mouse population never actually became crowded, 2. The suppression of breeding happened very quickly, and never recovered even after the population declined rapidly and crowding was reduced, and 3. the population rapidly became extinct.

Michael A Woodley suggests that what was going on was much more likely to be mutation accumulation; with deleterious (but not-individually-fatal) mutated genes incrementally accumulating with each generation and generating a wide range of increasingly maladaptive behavioural pathologies; this process rapidly overwhelming and destroying the population before any beneficial mutations could emerge to 'save' the colony from extinction.

So the bizarre behaviours seen especially in Phase D - such as the male 'beautiful ones' who appeared to be healthy and spent all their time self-grooming, but were actually inert, unresponsive, unintelligent and uninterested in reproduction - were plausibly maladaptive outcomes of a population sinking under the weight of mutations.

Why mutation accumulation?

The reason why mouse utopia might produce so rapid and extreme a mutation accumulation is that wild mice naturally suffer very high mortality rates from predation. Because wild mice are so short-lived, mice are not 'built to last' and have the reputation of being unusually-prone to produce new deleterious mutations (and are therefore extremely prone to cancer, and susceptible to carcinogens - which is why mice are used to test for carcinogens).

Thus mutation selection balance is in operation among wild mice, with very high mortality rates continually weeding-out the high rate of spontaneously-occurring new mutations (especially among males) - with typically only a small and relatively mutation-free proportion of the (large numbers of) offspring surviving to reproduce; and a minority of the most active and healthy (mutation free) males siring the bulk of each generation. Something similar is routinely done among laboratory mice - which are selectively bred using only the healthiest specimens - the sick and unfit mice being eliminated (usually killed, but at any rate not bred-from) with each generation.

However, in Mouse Utopia, there is no predation, and no artificial selection, and all the other causes of mortality (eg. starvation, disease, violence from other mice) are reduced to a minimum - so the frequent mutations just accumulate, rapidly, generation upon generation - randomly producing all sorts of pathological (maladaptive) behaviours.

The danger of mutational meltdown

Extinction due to relaxed selection leading to rapid mutation accumulation is called ‘mutational meltdown’.

It happens because, in addition to the problem of mutation accumulation by relaxation of selection, when a population has begun shrinking, there is an increasing danger of extinction due to a positive feedback cycle. Deleterious mutations accumulate so rapidly that they overwhelm a population before it can evolve an escape – as the population shrinks so it becomes less and less likely to ‘randomly’ generate a compensatory beneficial mutation that might recue it from extinction.

Mutational meltdown was first described as a threat for small populations of asexual organisms; later the phenomenon was described in sexual organisms, and then fond to occur in large populations. Therefore, mutational meltdown has gone from being a specific case to probably a universal possibility. And thus a possibility in humans.

The unusual twist with modern humans is that native populations in developed countries have begun falling (rapidly) over the past several decades apparently due to chosen sub-replacement fertility, and probably before mutation accumulation had reached a level sufficient biologically to suppress fertility.

In other words psychological factors have anticipated biological factors - and presumably both psychological and biological population decline will combine to increase the degree of reduced fitness resulting from mutation accumulation.

This will probably have increased the risk of mutational meltdown, and of extinction.

Modern England as Mouse Utopia?

If we look at the Mouse Utopia experiment and try to fit the history of modern England into it

There could be an inflection point in 1921 when English population growth suddenly slowed - somewhat like the transition from Phase B to C in the mouse utopia graph (page 83)

Then the plateau Phase D - where births just replace deaths - was reached in the 1970s

Which perhaps means the next phase would be the Terminal Phase E (among the native population - disregarding immigrants) with fewer births than deaths dwindling to zero live, births and escalating median age, until eventually ‘all’ women are aged beyond the menopause at which point extinction (of the native population) is inevitable.

Well, this isn't really comparing like with like! - and the whole picture is muddied by increasing medical capability and cossetting, which has radically reduced deaths from infectious disease (the main cause of mortality); and keeps infants and the elderly alive in circumstances which would previously have been fatal - but maybe gives us clues of what to look-out-for; assuming that the demise of Mouse Utopia was indeed substantially due to mutation accumulation.

Possible timescale for human extinction

If humans are recapitulating mouse utopia, what might be the approximate timescale for extinction?

As far as I can gather, mice are fully ready to reproduce at about 4 months, so the average generation time is probably about 5 months which is about 150 days.

So, starting with 104 days as zero - when reproduction in Mouse Utopia began; we can convert the above timings into mouse generations

Phase B exponential growth doubling every 55 days lasted 201 days, = 1.3 mouse generations.

Phase C exponential growth doubling every 145 days lasted a further 245 days = 1.6 mouse generations.

So population growth phase in utopian conditions lasted only 3 mouse generations.

Phase D of population stagnation phase lasted a further 360 days = 2.4 mouse generations

Therefore, Terminal Phase E the last conception (and de facto inevitable extinction) was 816 days after breeding commenced = 5.4 mouse generations.

Human generations are conventionally 25 years, although these have slowed to about 30 years in Western countries in the past several decades - but let us therefore give two values - one for 25 year, and the other for 30 year human generations.

If we start at 1850 as the date when the Industrial Revolution seems to have become certainly established and child mortality rates began to drop rapidly (from more than 60 percent to about 1 percent), and start counting generations from that point, and if humans were made like mice (which they are not!)...

We would then predict that human population growth phase (B & C) would last three generations up to 1925-1940

And the stagnation phase (D) for another 2.4 generations - with 5.4 human generations taking us up to 1985-2012.

Well, clearly English people did not stop conceiving four years ago, because babies are still being born to native English - albeit not at a high rate!

I have guesstimated above that the English situation was that the slower growth Phase C began in about 1920 (not about 1880) and the plateau phase began in about 1970) not 1930-ish

So maybe England is lagged about 40 years (or about 1.5 generations) behind Mouse Utopia , because 1. we are not mice, and 2. our mouse utopia emerged only incrementally – moving from the upper to the lower classes; and was probably not complete until about 1950.

So we do not need to worry about mutational meltdown and de facto extinction (i.e. the final English child of English-descended parents being conceived) for, oh, another thirty or forty years!...

Longevity versus fitness

In the late phases of the mouse utopia experiment the birth rate dwindled to zero - but there was a plateau phase when the population numbers remained approximately static because the fewer mice were being born but more mice were living to an extreme old age – a lifespan of four years and longer, which is considerably older than mice would expect to live in the wild.

Yet these mice were grossly abnormal, indeed pathological, in their behaviour. - in particular suffering what might be termed psychiatric abnormalities that impaired social interaction (and reproduction) including a strange narcissism in some male mice (the 'beautiful ones') which looked like superb physical specimens but did not mate.

So we find on the one hand a combination of evidence of cumulative disease, initially manifested in the realm of behaviour - yet on the other hand an ageing population with some animals having a very long life span.

My interpretation is that an increasing average lifespan cannot be interpreted as improving fitness - indeed increasing lifespan is compatible with a severe reduction in functional behaviour; especially when functionality is defined 'biologically' in terms of reproductive success (having sufficient viable offspring to maintain population numbers, and potentially amplify the population when conditions permit).

In Britain in recent decades there has been a large increase in average lifespan (among the native population), including several-fold increases in the length of survival of many groups of ill people. For example, elderly people with moderate to severe dementia may now live for many years, whereas thirty or forty years ago such a diagnosis was regarded as being rapidly fatal within months and less than two years. (And taking into account that modern English average life expectancy is about 80 years – an age at which about 20 percent of people have measurable dementia).

There is no doubt that modern people have been, and are being, misled by the increase in lifespan - and superficial appearances of youthfulness - into assuming that population health is improving; when in biological terms what matters is the ability to survive and reproduce under given conditions. Only if modern people - in particular those of reproductive and productive age - were put into the same kind of harsh, high mortality-rate environment that people of the past lived-in, would we know whether they really do have better functionality.

For example, in hunter gatherer societies those who lack mobility will, sooner or later, necessarily be left to die. In agricultural societies, the struggle for survival was extremely severe and the shortage of food, poor housing, and high prevalence of severe infectious diseases meant that the mortality rate among the elderly was much higher.

But modern societies shelter pretty much everybody from exposure to extreme heat or cold, dehydration, starvation, epidemic infectious disease and violence; plus there are several life-extending treatments of chronic medical conditions (such as high blood pressure) which would soon cripple or kill without continued medication and management.

Therefore, many people of much-reduced functionality who would been unable to survive in historical societies, are currently kept alive for many extra decades in modern societies - with all appearances of reasonably good health... except for behavioural pathologies and sub-fertility.

My point is that modern people may be much less biologically fit than they think they are; and that if societal conditions reverted towards those of historical agrarian societies, or hunter gatherer conditions, their low fitness and inability to survive would become very obvious.

Perhaps the increasingly elderly individuals of the terminal phase of mouse utopia may have congratulated themselves on the success of the experiment, and that mice had attained a more comfortable and compassionate level of social organization than in any previous society.

And then they died out; every last one of them.

Nonetheless, I draw the following lessons.

1. Assuming the decline and extinction of mouse utopia was due to mutation accumulation leading to mutational meltdown - then it happened very quickly indeed: only 5.4 mouse generations to the final conception, with half of that being stagnation.

2. The decline in rate of population increase after only 1.3m mouse generations suggests that the effect of relaxed natural selection and mutation accumulation leads to genetic damage immediately, in the very first generation.

3. Although humans (maturing over 14 years and with a natural life expectancy about 70 years) are built to last longer than mice (maturing over 4 months and living about 2 years) - this may mean that humans are actually more vulnerable to mutation accumulation - because we have a more prolonged and multi-phasic development and depend on extremely-complex brains supporting extremely complex behaviours; which depend on many genes to create and to sustain. Complex social and sexual adaptations are, in other words, large mutational targets – susceptible to damage from many mutations.

4. In mouse utopia, the mouse environment, shelter, food, hygiene etc were all managed by humans - and did not depend on the mice doing anything much for themselves except eat, sleep, fight, groom and reproduce (until they altogether lost interest in sex) - but humans depend on other humans for survival. But when the human population is damaged from mutation accumulation, there will be no external experimenters to ‘look after’ the increasingly-dysfunctional humans – and this will tend to destroy the 'utopian' environment. In other words, there will be a combination of an increasingly dependent population with a reducingly-capable population.

If this destruction is severe enough and comes early enough- then mutational meltdown will be avoided; because harsher natural selection (from the less capable ‘caring’ population) will purge the mutationally-loaded population to prevent it from breeding (and worsening the problem). But if there is a generational lag - and utopia is maintained for sufficiently long that further mutational damage to younger generations continues to accumulate rapidly - then this will hasten the meltdown and extinction; because by the time utopia comes to an end, the younger generations will be unfit to survive the harsher conditions which are the best they can themselves manage.

That is, the younger generations will become too unfit even to care for themselves at a bare minimum level while also being able to reproduce with genetically-viable offspring, and to raise them to independence – at which point extinction is inevitable. The ‘plateau’ phase is when a generation is born that can just-about keep itself alive and functioning, but not able raise any of its (even less-fit) offspring. Eventually, a generation is born that is not even capable to sustaining itself, and the die-off will then be very rapid.

What signs should we look for in monitoring mutation accumulation?

The first signs of mutation accumulation would probably be de-differentiation/ loss of adaptations - especially in social and sexual functioning. These would affect general intelligence 'g' (because g is a fitness measure), and adaptive social and sexual functioning (because these are subtle/ advanced adaptations which are damaged by even slight illness, intoxication, and functional or structural brain impairments).

I think evidence consistent with both lowered intelligence and also impaired adaptive social functioning can be observed in the report of Mouse Utopia. The reduced fertility in Mouse Utopia is perhaps also related to impaired drive/ motivation - as well as ineffective drive/ motivation (due to loss of functional adaptations).

I general, I think loss of adaptive functionality is what should be looked-for with mutation accumulation (i.e. adaptive behaviours knocked-out or damaged or distorted) as the first and most sensitive changes; rather than weird new behaviours. Specifically:

1. The social domain - first subtle, then gross impairments of adaptive social interactions

2. The sexual domain - first subtle, then gross impairments of adaptive sexual interactions

...bearing in mind that 'adaptive' means tending to enhance reproductive success.

I suggest social and sexual functioning, since these are the areas which I think are the most sensitive to brain impairments; at least that seems to be the situation in neurological and psychiatric disease.

My observation has been that when there is almost any significant degree of neurological or psychiatric disease, even the slightest; social and sexual domain functioning can usually be detected as having been impaired, by those who best knew the patient before he suffered illness.

Psychiatric aspects of Mouse Utopia

In The Narrow Roads of Gene Land Volume 2, the great evolutionary theorist WD Hamilton partially described that world in a chapter entitled The Hospitals are coming, and that is perhaps a good starting point - the idea that everyone will be damaged and most will be sick, in one way or another; so that life will resemble a hospital in which (some of) the less-sick (or the damaged but not-yet sick) tend the more-sick, as best they may - in intervals between doing whatever it takes to stay alive.

This is not by any means an unusual or unprecedented situation for humans through much of the history of the species. For much of the time, Malthusian mechanisms have been in force, and populations have been limited by various combinations of starvation and infectious disease. Infections - in particular - have sometimes been endemic at a high prevalence, so that the majority or even all of the population might be suffering from, be affected by, some chronic parasitic disease (malaria and bilharzia are examples) - but at a relatively low degree of severity.

And with respect to the Mouse Utopia society being a Hospital, it is important to recognize that much of the pathology will be psychiatric rather than physical - this can be seen from the fact that the problems of the original Mouse Utopia were most behavioural rather than physical; and it follows from the fact that the highly complex human brain is exceptionally sensitive to random mutational damage.

Intelligence is probably damaged by mutation accumulation in an incremental and quantitative fashion - the more mutations, the more the lowering of intelligence. Therefore, decline of intelligence as mutations accumulate is likely to be relative smooth (rather than step-like). But intelligence is 'general' intelligence, and is unusual in being a general attribute of cognitive function – probably sustained by small effects of a large number of individual genes. By contrast, most psychological functions are specific; and genetic damage is likely to be more qualitative and either step-like, or all-or-nothing.

What I think would happen, is that accumulating mutation damage would most likely show-up as varieties of specific brain functional damage leading to a wide range of specific behavioural impairments of a social and sexual type (differing between individuals due to random mutations striking unpredictably at a wide range of individual genes) - in a context of progressively declining intelligence.

The kind of damage I am talking about represents a decline in ‘fitness’ – ie. a decline in the functional adaptation of the human organism to its environment (its sexual, social and surrounding environment): a loss of effective functionality. This represents a decline in absolute fitness, but not just relative fitness. It is a also a decline in group fitness - ultimately in species fitness.

If fitness is measured in terms of the capacity to raise sufficient viable offspring in a given environment; then the sexual and social changes induced by mutation accumulation will be such as to reduce the probability of doing this: partly by damage causing reduced brain processing speed and efficiency (detectable as reduced intelligence) and partly by damage causing specific functional impairments (detectable as sexual and social pathologies).

These impairments would presumably include a decline in motivation – reduced motivation to engage in effective reproductive behaviours, reduced interest in sex liable to lead to reproduction, reduced motivation to procreate, to care for and rear children etc. There is certainly abundant evidence of such changes in modern developed societies, such as England.

In sum, in a broad-brush interpretation of the evidence, it looks very much as if England specifically, and all other developed nations to a greater or lesser extent, are recapitulating the Phases of Mouse Utopia – leading towards extinction, or something close to it.


Acknowledgements: It was Michael A Woodley of Menie who informed me of the Mouse Utopia experiment, and made the interpretation of its outcome in terms of mutation accumulation.


Bluenose313 said...

My gosh this is a terrifying prospect! I have long seen the slow decline of modern western civilization around us as a repeat of the Roman fall, but this goes far beyond that. As a hypothesis, the idea that we are mirroring the 'Mouse Utopia' is entirely conceivable. Reading this, it all makes dismal sense. I can only hope it is wrong, else we could be looking at an imminent biblical apocalypse.

Regardless, it is a damning statement of modern affairs that this is the first time I have heard of this possibility. Something so potentially disastrous and imminent should be a priority to us! At the very least it should be thoroughly researched as a possible outcome of the removal of natural selection.

But then, what can one expect regarding a subject such as this? It will either be hidden to prevent a panic, or avoided through apathy and intentional self deception.

Edward said...

Look sex-specific reproductive behaviours are driven by sex specific neurological modules.
Men should have more on the parietal lobe, women should have more on the cerebellum, as the process of procreation required solving very different problems for the male and the female.

But, in our modern society, to even get as far as the procreation stage requires solving some rather different problems. Problems we were not evolutionarily equipped for, like learning be doctors and lawyers and engineers and teachers and life coaches and motivational speakers and so on.
What if the best lawyers and engineers are the men with rather more on the cerebellum and rather less on the parietal lobe? Good at engineering, not so good at hooking up regularly. Selective social pressure works against those who express the most normal sexual dimorphism, and maybe even selects for those with cross-sex traits. You've got your religion to thank for forcing people to mate the right way round, despite what they might prefer to be doing.
Eventually you get this
where there is no longer much neurological difference between male and female at all, so what's the point of carrying on. Maybe we'd all just rather design new computers chips or write long books about gender theory all day.

gwern said...

This thesis doesn't make all that much sense to me. In asexual organisms and inbred lineages experimentally, they don't fall apart after just 2-3 generations; how can mutation load possibly be *that* fast in mice? Likewise, the assumption that there is no purging seems to be implausible - in all the Calhoun accounts I've looked at, like or he mentioned very high pregnancy losses, sometimes extraordinary levels of infant mortality, and difficulty of young mice making their way against all the older mice, but nevertheless large numbers of pups in the middle of the arc, all of which is the opposite of what one would expect from a no-selection scenario leading to almost instantaneous mutational meltdown. (Given the highly inbred nature of starting with just a few pairs, even recessive variants would exposed to a lot of selection.) If normal mice strains can melt down so fast, how do commercial breeders of all those endless varieties of transgenic and bred mice strains, who keep their mice in very similar conditions, avoid mutational meltdown? Given Calhoun's admission that they didn't keep the habitats all that clean, the steadiness of some of the earlier experiments, and the lack of discussion of infectious diseases, it looks to me like a more plausible explanation is that the Universe 25 experiment resulted in some epidemics exacerbated by lack of genetic diversity.

Bruce Charlton said...

@gwern - An epidemic of some undetected kind is a reasonable alternative hypothesis for investigation; because epidemics may be very difficult/ impossible to detect and could caus extinction.

I think it is an error to rule-out mutation accumulation as a major factor when the scale and importance of the phenomenon is simply not a part of mainstream biology - therefore a sense of implausablility is not based on genuine knowledge but only on unfamiliarity.

If you start to consider the multiple ways in which mutation accumulation would be expected to show-itself - with multiple functional problems in multiple systems and many individuals showing unique behavioural/ sexual dysfunction - you may come to agree that it is the kind of thing which is not likely to be noticed unless you are specifically looking for it.

Mutation accumulation may be happening in many situations and frequently - and yet be unnoticed; until there is a theory and reason to start noticing.

gwern said...

(To expand a little bit: when I say epidemic, I'm thinking less of something like bubonic plague where everyone drops dead oozing pus and more subtler things like syphilis or toxoplasma, which demonstrate that infections can cause broad behavioral changes and sterility, which in such a dense confined population would not need to evolve less virulence.)

Epidemics at least might be easier to check: you can simply introduce one of the last functioning mice into a different stable population to see if it's an infectious carrier (if high mutation load, it should simply fail to reproduce; if epidemic, there'd be a good chance of an immediate drop in the second population followed by recovery due to selection+greater diversity), or look for biomarkers of infection. Even now mutation load in mice would be challenging to detect, I think, because there are always so many de novo mutations.

Bruce Charlton said...

@gwren - Yes indeed. Good idea.

(I used to be a lecturer in epidemiology, so I studied infections a fair bit.)

I should clarify, however, that I had proposed mutation accumulation as a plausible cause of rapidly declining human intelligence (first apprent from slowing reaction times, now confirmed in several other types of study) before I ever heard of mouse utopia.

And although it was mouse utopia that gave Michael Woodley the idea of a mutational meltdown scenario - the Calhoun experiment is not of course intended to be 'evidence' of mutation accumulation (since the theory was not tested for at the time); rather mutation accumulation is proposed as a mechanism of what happened in MU, and the specific details are interpretetd as illustrations of what could happen in a mutation accumulation scenario.

My particular emphasis is on social and sexual dysfunction as early stages, as a consequence of my background in psychiatry and neurology.