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Tuesday, August 14, 2012

Are human brains especially fragile?


As many as a quarter of people will experience mental illness at some point in their life (over a third in any given year with more expansive definitions). At least 5% of the population suffer from lifelong brain-based disorders, including intellectual disability, autism spectrum disorders, schizophrenia, epilepsy and many others. Many of these conditions dramatically increase mortality rates and reduce fecundity (number of offspring), impacting heavily on evolutionary fitness.

Faced with these numbers, we have to ask the question: are human brains especially fragile? Are we different from other species in this regard? Is the brain different from other organs? As all of the disorders listed above are highly heritable, these questions can be framed from a genetic perspective: is there something about the genetic program of human brain development that makes it especially sensitive to the effects of mutations?     

I have written lately about the robustness of neural development – how, despite being buffeted by environmental insults, intrinsic noise on a molecular level and a load of genetic mutations that we all carry, most of the time the outcome is within a species-typical range. In particular, the molecular programs of neural development are inherently robust to the challenge of mutations with very small effect on protein levels or function, even the cumulative effects of many such mutations (at least, that is what I have argued). The flipside is that development could be vulnerable to mutations in a set of specific genes (especially ones encoding proteins with many molecular interactions) when the mutations have a large effect at the protein level.

That fits generally with what we know about robustness in complex systems, especially so-called small-world networks, which are resistant to error of most components but vulnerable to attack on highly interconnected nodes. But here’s the rub: the number of such genes seems too high. Geneticists are finding that mutations in any of a very large number of genes (many hundreds) could underlie conditions such as autism and intellectual disability. In addition, many of these mutations arise de novo in the germline of unaffected parents (who are not carriers of the responsible mutation) and thus have dominant effects – mutation of just one copy of a gene or chromosomal locus is sufficient to cause a disorder. This is not what is predicted, necessarily, from consideration of robustness of complex systems and the way it evolves. Why are so many different genes sensitive to dosage (the number of copies of the gene) in neural development?

The first thing to assess is whether this situation is actually unusual. It seems like it is, but maybe heart development or eye development are just as sensitive. (Certainly there are lots of genetic conditions affecting these systems too, though I don’t know of any studies comparing the genetic architecture of defects across systems). Those are organs where defects are often picked up, but you could imagine subtle defects in other systems which would go unnoticed. Maybe we just have a huge ascertainment bias in picking up mutations that affect the nervous system. After all, we are a highly social species and finely adapted to analyse each other’s behaviour. I might not know if your liver is functioning completely normally but might readily be able to detect quite subtle differences in your sociability or threat sensitivity or reality testing or any other of the myriad cognitive faculties affecting human behaviour.

As for whether this situation is unique to humans, it is very hard to tell. Having analysed dozens of lines of mutant mice for nervous system defects, I can tell you it is not that easy to detect subtle differences in anatomy or function. Many mutants that one might expect to show a strong effect (based on the biochemical function and expression pattern of the encoded protein) seem annoyingly normal. However, in many cases, more subtle probing of nervous system function with sophisticated behavioural tasks or electrophysiological measures does reveal a phenotypic difference, so perhaps we are simply not well attuned to the niceties of rodent behaviour.

That kind of ascertainment bias seems to me like it could be an important part of the explanation for this puzzle – it’s not that human brains are more sensitive, it’s that we are better at detecting subtle differences in outcome for human brains than for other systems or other animals. That’s just an intuition, however.

So, just to follow a line of thought, let’s assume it is true that human brain development and/or function is actually more sensitive to mutations (including loss of just one copy of any of a large number of genes) than development or function of other systems. How could such a situation arise?

Well, most obviously, it could simply be that more genes are involved in building a brain than in building a heart or a liver. This is certainly true. At least 85% of all genes are expressed in the brain, far higher than any other organ, and many are expressed during embryonic and fetal brain development in highly dynamic and complex ways not captured by some genomic technologies (such as microarrays). So, maybe there are just more bits to break. The counter-argument is that natural systems with more components tend to be more robust to loss of any one component as more redundancy and flexibility gets built into the system. Robustness may come for free with increasing complexity.

To really understand this, we have to approach it from an evolutionary angle, though – how did this system evolve? Wouldn’t there have been selective pressure against this kind of genetic vulnerability? Well, possibly, though robustness may more typically evolve due to pressure to buffer environmental variation and/or intrinsic noise in the system – robustness to mutations may be a beneficial side-effect as opposed to the thing that was directly selected for. (After all, natural selection lacks foresight – it can only act on the current generation, with no knowledge of the future usefulness of new variations).    

Still, imagine a mutation arises that increases vulnerability to subsequent mutations. Given a high enough rate of such new mutations, the original mutation may well eventually be selected against; i.e., it would not rise to a high frequency in the population. Unless, that is, it conferred a benefit that was greater than the burden of increased vulnerability. That may in fact be exactly what happened. Perhaps the mutations (likely many) that gave rise to our larger and more complex brains gave such an immediate and powerful evolutionary advantage that positive selection rapidly fixed them in the population, potential vulnerability be damned.

This would be like upgrading your electronic devices to a new operating system, even though you know there are bugs and will be occasional crashes – it’s usually so much more powerful that it’s worth it. The selective pressures of the cognitive niche, which early humans started to carve out for themselves, may have pushed ever harder for increasing brain complexity, despite the consequences. 

Increased size and complexity may also be intimately tied to another feature of human brain development – early birth and prolonged maturation. Early birth, while the brain is more immature than that of other species, was probably necessitated by the growth of the brain and the size limits of the birth canal. One effect of this is that the human brain is more exposed to experience during periods of early plasticity, providing the opportunity to refine neural circuitry through learning. Indeed, human brain maturation continues for decades, with the evolutionarily newest additions, such as prefrontal cortex, maturing latest.

This brings obvious advantages, especially providing greater opportunities for an amplifying interplay between genetic and cultural evolution. But it has a downside, in that the brain is vulnerable during these periods to insults, such as extreme neglect, stress or abuse. Perhaps selection for early birth and prolonged maturation also made the human brain more sensitive to the effects of genetic mutations, some of which may only become apparent as maturation proceeds.    

For now, it is hard to tell whether human brains are really especially fragile or whether we are just very good at detecting subtle differences. If they are fragile, one can certainly imagine this as a tolerated cost of the vastly increased complexity and prolonged development of the human brain.

12 comments:

  1. Kevin, fascinating! This picture exhibits my individual point of view on the unique evolution of the human brain (especially, hominin brain expansion and the vulnerability of human brain development) and is made with the clear intention to be a work of CEREBRART.
    http://cerebrart.blogspot.de/

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  2. Thanks for this great post.

    In my upcoming popular science book about consciousness, THE RAVENOUS BRAIN (coming out in a couple of weeks), I make basically the same point in the final chapters, that the price we pay for such a powerful large brain, which is fantastic at finding innovations to help us survive, is that, like any exceptionally complex machine, it is more liable to malfunction. This is both true neurologically (where we are particularly susceptible to concussion, for instance) and psychiatrically. You can see a bit more about the book here http://www.danielbor.com/the-ravenous-brain/

    (or on Amazon).

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  3. Could the reverse not be argued - that the brain is especially resilient - i.e. genetic mutations affecting other bodily systems affect the viability of the organism and so have terminal effects

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    1. This is an interesting possibility - that the ascertainment bias goes the opposite way - that we see more mutations affecting brain development because they are tolerated better.

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  4. I think I agree with Prof Laws...
    Maybe our genetic fitness to breed is contained in the genes that affect our physical integrity, rather than in our brain genes. This may be due to:
    a)having many genes for brain development mean their influence must overlap & protect mean brain integrity;
    b)the fact that we give birth to quite immature young/brains, which allows for early compensatory plasticity to overcome any genetic problems before maturity
    c)we have some backup for many systems by having 2 hemispheres,
    d) the fact that most brain-directed mutations are de novo & not passed on.
    This also means that we should not "worry" as a species about reproduction by individuals whose brains seem "unfit" for their own survival, since their offspring's genes will be OK. However, it's a bit difficult to decide who looks after the "fit" offspring of those enthusiastically copulating behind the couch at facilities for the severely intellectually impaired!

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  7. Gah! Lost my first post thanks to google accounts.
    Anyhew; First of all I think ascertainment bias does have a role here.

    Secondly, you say that network robustness theory is kind of at odds with the observation that so many single gene mutations have pronounced effects. I don't really think there is a paradox here; I think we have to have a closer look at the networks.

    We could look at a single, huge network of components involved in neurodevelopment, and pretend that this would tell us how robust the system is, but, of-course, that network doesn't exist in real terms. As you said above, the components of a network are constantly in flux, as are the connections between them, as you move from cell A to cell B, from time X to time Y. So if we look at, say, a developmental process in a specific place, there will be times and places where the network is relatively large/robust/redundant etc.. punctuated by periods where the network is less robust. Shuffling, expansion, contraction etc.. Context will determine when a gene/protein/element occupies a peripheral, and bufferable position in the network or a more vulnerable, possibly central position, in a smaller and less well laced network. I think what I'm trying to say is we can take network robustness to be something that exists, but we must carefully consider the shape of the real networks. Our view of network architecture and robustness, maps to the more exhaustive work on very old single celled organisms.

    It's pretty difficult to conceptualise the actual process of evolving network robustness (in humans). Like you said, it's likely to be something that comes packaged with complexity. That said its also difficult to imagine how real time network complexity and massiveness can be maintained along with organismal/developmental complexity (I'm having difficulty thinking of a way to articulate what I really mean here). Lets talk about human brain evolution, and specifically look at the genes that have had a selective push to contribute to adaptive complexity/size/function etc in specific parts of the modern human brain. The networks around those genes, I would think, are going to be small and diffuse (those networks that exist in the context of their novel function). Consolidation and "repopulation" of those networks in such a way as to maintain the initial adaptive function seems like a very tall order for selection operating on a tens of thousands of years time-scale, especially given our drifty history. So I think that the drive for developmental complexity in the brain has left a 4D network that is also more complex, but one which is more leafy and less webby at it's extremes. I think that that is likely to be a defining feature of complex organisms that have undergone fast evolution in complex organs.

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  8. I definitely agree that it is definitely fragile. So many people deal with mental issues. It seems like it is more and more. So much research has to be done here. click here

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