Unlike in many other animals, injured nerve fibres in the mammalian central nervous system do not regenerate – at least not spontaneously. A lot of research has gone in to finding ways to coax them to do so, unfortunately with only modest success. The main problem is that there are many reasons why central nerve fibres don’t regenerate after an injury – tackling them singly is not sufficient. A new study takes a combined approach to hit two distinct molecular pathways in injured nerves and achieves substantial regrowth in an animal model.

Many lower vertebrates, like frogs and salamanders, for example, can regrow damaged nerves quite readily. And even in mammals, nerves in the periphery will regenerate and reconnect, given enough time. But nerve fibres in the brain and spinal cord do not regenerate after an injury. Researchers trying to solve this problem focused initially on figuring out what is different about the environment in the central versus the peripheral nervous system in mammals.

It was discovered early on that the myelin – the fatty sheath of insulation surrounding nerve fibres – in the central nervous system is different from that in the periphery. In particular, it inhibits nerve growth. A number of groups have tried to figure out what components of central myelin are responsible for this activity. Myelin is composed of a large number of proteins, as well as lipid membranes. One of these, subsequently named Nogo, was discovered to block nerve growth. This discovery prompted understandable excitement, especially because an antibody that binds that protein was found to promote regrowth of injured spinal nerves in the rat. (It even prompted a film, Extreme Measures, with Gene Hackman and Hugh Grant – an under-rated thriller with some surprisingly accurate science and some very serious medical malfeasance).

Unfortunately, the regrowth in rats that is promoted by blocking the Nogo protein is very limited. Similarly, mice that are mutant for this protein or its receptor show very minor regeneration. What is observed in some cases is extra sprouting of uninjured axons downstream of the spinal injury site. This can lead to some minor recovery of function but it’s really remodelling, rather than regeneration.

But it does suggest an answer to the question: why would we have evolved a system that seems actively harmful, that prevents regeneration after an injury? Well, first, the selective pressure in mammals to be able to regenerate damaged nerves is probably not very great, simply because injured animals would not typically get the chance to regenerate in the wild. And second, it suggests that the function of proteins like Nogo may not be to prevent regeneration but to prevent sprouting of nerve fibres after they have already made their appropriate connections. A lot of effort goes in to wiring the nervous system, with exquisite specificity – once that wiring pattern is established, it probably pays to actively keep it that way.

There are a number of reasons why blocking the Nogo protein does not allow nerves to fully regenerate. First, it is not the only protein in myelin that blocks growth – there are many others. Second, the injury itself can give rise to scarring and inflammation that generates a secondary barrier. And third, neurons in the mature nervous system may simply not be inclined to grow. (Not only that – the distances they may have to travel in the fully grown adult may be orders of magnitude longer than those required to wire the nervous system up during development. There are nerves in an adult human that are almost a metre long but these connections were first formed in the embryo when the distance was measured in millimetres.)

This last problem has been addressed more recently, by researchers asking if there is something in the neurons themselves that changes over time – after all, neurons in the developing nervous system grow like crazy. That propensity for growth seems to be dampened down in the adult nervous system – again, once the nervous system is wired up, it is important to restrict further growth.

Researchers have therefore looked for biochemical differences between young (developing) neurons and mature neurons that have already formed connections. The hope is that if we understand the molecular pathways that differ we might be able to target them to “rejuvenate” damaged neurons, restoring their internal urge to grow. The lab of Zhigang He at Harvard Medical School has been one of the leaders in this area and has previously found that targeting either of two biochemical pathways allowed some modest regeneration of injured neurons. (They study the optic nerve as a more accessible model of central nerve regrowth than the spinal cord).

In a new study recently published in Nature, they show that simultaneously blocking both these proteins leads to remarkably impressive regrowth – far greater than simply an additive effect of blocking the two proteins alone. The two proteins are called PTEN and SOCS3 – they are both intracellular regulators of cell growth, including the ability to respond to extracellular growth factors. The authors used a genetic approach to delete these genes two weeks prior to an injury and found that regrowth was hugely promoted. That is obviously not a very medically useful approach however – more important is to show that deleting them after the injury can permit regeneration and indeed, this is what they found. Presumably, neurons in this “grow, grow, grow!” state are either insensitive to the inhibitory factors in myelin or the instructions for growth can override these factors.

They went on to characterise the changes that occur in the neurons when these genes are deleted and observed that many other proteins associated with active growth states are upregulated, including ones that get repressed in response to the injury itself. The hope now is that drugs may be developed to target the PTEN and SOCS3 pathways in human patients, especially those with devastating spinal cord injuries, to encourage damaged nerves to regrow. As with all such discoveries, translation to the clinic will be a difficult and lengthy process, likely to take years and there is no guarantee of success. But compared to previous benchmarks of regeneration in animal models, this study shows what looks like real progress.

Sun F, Park KK, Belin S, Wang D, Lu T, Chen G, Zhang K, Yeung C, Feng G, Yankner BA, & He Z (2011). Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature, 480 (7377), 372-5 PMID: 22056987

That this discovery was made using classical “cytogenetic” techniques (physically looking at the chromosomes down a microscope) and in a single family is somehow pleasing in an age where massive molecular population-based studies are in vogue. (A win for “small” science).

The discovery of the DISC1 translocation clearly showed that disruption of a single gene could lead to psychiatric disorders like schizophrenia. This was a challenge to the idea that these disorders were “polygenic” – caused by the inheritance in each individual of a large number of genetic variants. As more and more mutations in other genes are being found to cause these disorders, the DISC1 situation can no longer be dismissed as an exception – it is the norm.

It also was the first example of a principle that has since been observed for many other genes – namely that the effects of the mutation can manifest quite variably – not as one specific disorder, but as different ones in different people. Indeed, DISC1 has since been implicated in autism as well as adult-onset disorders. It is now clear from this and other evidence that these apparently distinct conditions are best thought of as variable outcomes that arise, in many cases at least, from disturbances of neurodevelopment.

Since the initial discovery, major research efforts of a growing number of labs have been focused on the next obvious questions: what does DISC1 do? And what happens when it is mutated? What happens in the brain that can explain why psychiatric symptoms result?

We now know that DISC1 has many different functions. It is a cytoplasmic protein – localised inside the cell – that interacts with a very large number of other proteins and takes part in diverse cellular functions, including cell migration, outgrowth of nerve fibres, the formation of dendritic spines (sites of synaptic contact between neurons), neuronal proliferation and regulation of biochemical pathways involved in synaptic plasticity. Many of the proteins that DISC1 interacts with have also been implicated in psychiatric disease.

This new study adds another possible function, and a dramatic and unexpected one at that. This function was discovered from an independent angle, by researchers studying how the two hemispheres of the brain get connected – or more specifically, why they sometimes fail to be connected. The cerebral hemispheres are normally connected by millions of axons which cross the midline of the brain in a structure called the corpus callosum (or “tough body” – (don’t ask)). Very infrequently, people are born without this structure – the callosal axons fail to cross the midline and the two hemispheres are left without this major route of communication (though there are other routes, such as the anterior commissure).

The frequency of agenesis of the corpus callosum has been estimated at between 1 in 1,000 and 1 in 6,000 live births – thankfully very rare. It is associated with a highly variable spectrum of other symptoms, including developmental delay, autistic symptoms, cognitive disabilities extending into the range of mental retardation, seizures and other neurological signs.

Elliott Sherr and colleagues were studying patients with this condition, which is very obvious on magnetic resonance imaging scans (see Figure). They initially found a mother and two children with callosal agenesis who all carried a deletion on chromosome 1, at position 1q42 – exactly where DISC1 is located. They subsequently identified another patient with a similar deletion, which allowed them to narrow down the region and identify DISC1 as a plausible candidate (among some other genes in the deleted region). Because the functions of proteins can be affected not just by large deletions or translocations but also by less obvious mutations that change a single base of DNA, they also sequenced the DISC1 gene in a cohort of callosal agenesis patients and found a number carrying novel mutations that are very likely to disrupt the function of the gene.

While not rock-solid evidence that it is DISC1 that is responsible, these data certainly point to it as the strongest candidate to explain the callosal defect. This hypothesis is strongly supported by findings from DISC1 mutant mice (carrying a mutation that mimics the effect of the human translocation), which also show defects in formation of the corpus callosum. In addition, the protein is strongly expressed in the axons that make up this structure at the time of its development.

The most obvious test of whether disruption of DISC1 really causes callosal agenesis is to look in the people carrying the initial translocation. Remarkably, it is not known whether the original patients in the Scottish pedigree who carry the DISC1 translocation show this same obvious brain structural phenotype. They have, very surprisingly, never been scanned.

This new paper raises the obvious hypothesis that the failure to connect the two hemispheres results in the psychiatric or cognitive symptoms, which variously include reduced intellectual ability, autism and schizophrenia. This seems like too simplistic an interpretation, however. All we have now is a correlation. First, the implication of DISC1 in the acallosal phenotype is not yet definitive – this must be nailed down and replicated. But even if it is shown that disruption of DISC1 causes both callosal agenesis and schizophrenia (or other psychiatric disorders or symptoms), this does not prove a causal link. DISC1 has many other functions and is expressed in many different brain areas (ubiquitously in fact). Any, or indeed, all of these functions may in fact be the cause of psychopathology.

One prediction, if it were true that the lack of connections between the two hemispheres is causal, is that we would expect the majority of patients with callosal agenesis to have these kinds of psychiatric symptoms. In fact, the rates are indeed very high – in different studies it has been estimated that up to 40% of callosal agenesis patients have an autism diagnosis, while about 8% have the symptoms of schizophrenia or bipolar disorder. (Of course, these patients may have other, less obvious brain defects as well, so even this is not definitive).

Conversely, we might naively expect a high rate of callosal agenesis in patients with autism or schizophrenia. However, we know these disorders are extremely heterogeneous and so it is much more likely that this phenotype might be apparent in only a specific (possibly very small) subset of patients. This may indeed be the case – callosal agenesis has been observed in about 3 out of 200 schizophrenia patients (a vastly higher rate than in the general population). Another study, just published, has found that mutations in a different gene – ARID1B – are also associated with callosal agenesis, mental retardation and autism. More generally, there may be subtle reductions in callosal connectivity in many schizophrenia or autism patients (including some autistic savants).

Whether this defect can explain particular symptoms is not yet clear. For the moment, the new study provides yet another possible function of DISC1, and highlights an anatomical phenotype that is apparently present in a subset of autism and schizophrenia cases and that can arise due to mutation in many different genes (of which DISC1 and ARID1B are only two of many known examples).

One final note: formation of the corpus callosum is a dramatic example of a process that is susceptible to developmental variation. What I mean is this: when patients inherit a mutation that results in callosal agenesis, this phenotype occurs in some patients but not all. This is true even in genetically identical people, like monozygotic twins or triplets (or in lines of genetically identical mice). Though the corpus callosum contains millions of nerve fibres, the initial events that establish it involve very small numbers of cells. These cells, which are located at the medial edge of each cerebral hemisphere, must contact each other to enable the fusion of the two hemispheres, forming a tiny bridge through which the first callosal fibres can cross. Once these are across, the rest seem able to follow easily. Because this event involves very few cells at a specific time in development, it is susceptible to random “noise” – fluctuations in the precise amounts of various proteins in the cells, for example. These are not caused by external forces – the noise is inherent in the system. The result is that, in some people carrying such a mutation the corpus callosum will not form at all, while in others it forms apparently completely normally (see figure of triplets, one on left with normal corpus callosum, the other two with it absent). So, an all-or-none effect can arise, without any external factors involved.

This same kind of intrinsic developmental variation may also explain or at least contribute to the variability in phenotypic outcome at the level of psychiatric symptoms when these kinds of neurodevelopmental mutations are inherited. Even monozygotic twins are often discordant for psychiatric diagnoses (concordance for schizophrenia is about 50%, for example). This is often assumed to be due to non-genetic and therefore “environmental” or experiential factors. If these disorders really arise from differences in brain wiring, which we know are susceptible to developmental variation, then differences in the eventual phenotype could actually be completely intrinsic and innate.

Osbun N, Li J, O’Driscoll MC, Strominger Z, Wakahiro M, Rider E, Bukshpun P, Boland E, Spurrell CH, Schackwitz W, Pennacchio LA, Dobyns WB, Black GC, & Sherr EH (2011). Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene. American journal of medical genetics. Part A, 155 (8), 1865-76 PMID: 21739582

Halgren C, Kjaergaard S, Bak M, Hansen C, El-Schich Z, Anderson CM, Henriksen KF, Hjalgrim H, Kirchhoff M, Bijlsma EK, Nielsen M, den Hollander NS, Ruivenkamp CA, Isidor B, Le Caignec C, Zannolli R, Mucciolo M, Renieri A, Mari F, Anderlid BM, Andrieux J, Dieux A, Tommerup N, & Bache I (2011). Corpus Callosum Abnormalities, Mental Retardation, Speech Impairment, and Autism in Patients with Haploinsufficiency of ARID1B. Clinical genetics PMID: 21801163

A very discomfiting realisation, discovering you are an android. That all those thoughts and ideas and feelings you seem to be having are just electrical impulses zapping through your circuits. That you are merely a collection of physical parts, whirring away. What if some of them break and you begin to malfunction? What if they wear down with use and someday simply fail? The replicants in BladeRunner rail against their planned obsolescence, believing in the existence of their own selves, even with the knowledge that those selves are merely the products of machinery.

The idea that the self, or the conscious mind, emerges from the workings of the physical structures of the brain – with no need to invoke any supernatural spirit, essence or soul – is so fundamental to modern neuroscience that it almost goes unmentioned. It is the tacitly assumed starting point for discussions between neuroscientists, justified by the fact that all the data in neuroscience are consistent with it being true. Yet it is not an idea that the vast majority of the population is at all comfortable with or remotely convinced by. Its implications are profound and deeply unsettling, prompting us to question every aspect of our most deeply held beliefs and intuitions.

This idea has crept along with little fanfare – it did not emerge all at once like the theory of evolution by natural selection. There was no sudden revolution, no body of evidence proffered in a single moment that overturned the prevailing dogma. While the Creator was toppled with a single, momentous push, the Soul has been slowly chipped away at over a hundred years or more, with most people blissfully unaware of the ongoing assault. But its demolition has been no less complete.

If you are among those who is skeptical of this claim or who feels, as many do, that there must be something more than just the workings of the brain to explain the complexities of the human mind and the qualities of subjective experience (especially your own), then first ask yourself: what kind of evidence would it take to convince you that the function of the brain is sufficient to explain the emergence of the mind?

Imagine you came across a robot that performed all the functions a human can perform – that reported a subjective experience apparently as rich as yours. If you were able to observe that the activity of certain circuits was associated with the robot’s report of subjective experience, if you could drive that experience by activating particular circuits, if you could alter it by modifying the structure or function of different circuits, would there be any doubt that the experience arose from the activity of the circuits? Would there be anything left to explain?

The counter-argument to this thought experiment is that it would never be possible to create a robot that has human-like subjective experience (because robots don’t have souls). Well, all those kinds of experiments have, of course, been done on human beings, tens of thousands of times. Functional magnetic resonance imaging methods let us correlate the activity of particular brain circuits with particular behaviours, perceptions or reports of inward states. Direct activation of different brain areas with electrodes is sufficient to drive diverse subjective states. Lesion studies and pharmacological manipulations have allowed us to map which brain areas and circuits, neurotransmitters and neuromodulators are required for which functions, dissociating different aspects of the mind. Finally, differences in the structure or function of brain circuits account for differences in the spectrum of traits that make each of us who we are as individuals: personality, intelligence, cognitive style, perception, sexual orientation, handedness, empathy, sanity – effectively everything people view as defining characteristics of a person. (Even firm believers in a soul would be reluctant recipients of a brain transplant, knowing full well that their “self” would not survive the procedure).

The findings from all these kinds of approaches lead to the same broad conclusion: the mind arises from the activity of the brain – and nothing else. What neuroscience has done is correlated the activity of certain circuits with certain mental states, shown that this activity is required for these states to arise, shown that differences in these circuits affect the quality of these states and finally demonstrated that driving these circuits from the outside is sufficient to induce these states. That seems like a fairly complete scientific explanation of the phenomenon of mental states. If we had those data for our thought-experiment robot, we would be pretty satisfied that we understood how it worked (and could make useful predictions about how it would behave and what mental states it would report, given enough information of the activity of its circuits).

However, many philosophers (and probably a majority of people) would argue that there is something left to explain. After all, I don’t feel like an android – one made of biological rather than electronic materials, but a machine made solely of physical parts nonetheless. I feel like a person, with a rich mental life. How can the qualities of my subjective experience be produced by the activity of various brain circuits?

Many would claim, in fact, that subjective experience is essentially “ineffable” – it cannot be described in physical terms and cannot thus be said to be physical. It must therefore be non-physical, immaterial or even supernatural. However, the fact that we cannot conceive of how a mental state could arise from a brain state is a statement about our current knowledge and our powers of imagination and comprehension, not about the nature of the brain-mind relationship. As an argument, what we currently can or cannot conceive of has no bearing on the question. The strong intuition that the mind is more than just the activity of the brain is reinforced by an unfortunate linguistic accident – that the word “mind” is grammatically a noun, when really it should be a verb. At least, it does not describe an object or a substance, but a process or a state. It is not made of stuff but of the dynamic relations between bits of stuff.

When people argue that activity of some brain circuit is not identical to a subjective experience or sufficient to explain it, they are missing a crucial point – it is that activity in the context of the activity of the entire rest of the nervous system that generates the quality of the subjective experience at any moment. And those who dismiss this whole approach as scientific reductionism ad absurdum, claiming that the richness of human experience could not be explained merely by the activity of the brain should consider that there is nothing “mere” about it – with hundreds of billions of neurons making trillions of connections, the complexity of the human brain is almost incomprehensible to the human mind. (“If the brain were so simple that we could understand it, then we would be so simple that we couldn’t”).

To be more properly scientific, we should ask: “what evidence would refute the hypothesis that the mind arises solely from the activity of the brain”? Perhaps there is positive evidence available that is inconsistent with this view (as opposed to arguments based merely on our current inability to explain everything about the mind-brain relationship). It is not that easy to imagine what form such positive evidence would take, however – it would require showing that some form of subjective experience either does not require the brain or requires more than just the brain.

With respect to whether subjective experience requires the brain, the idea that the mind is associated with an immaterial essence, spirit or soul has an extension, namely that this soul may somehow outlive the body and be said to be immortal. If there were strong evidence of some form of life after death then this would certainly argue strongly against the sufficiency of neuroscientific materialism. Rather depressingly, no such evidence exists. It would be lovely to think we could live on after our body dies and be reunited with loved ones who have died before us. Unfortunately, wishful thinking does not constitute evidence.

Of course, there is no scientific evidence that there is not life after death, but should we expect neuroscience to have to refute this alternative hypothesis? Actually, the idea that there is something non-physical at our essence is non-refutable – no matter how much evidence we get from neuroscience, it does not prove this hypothesis is wrong. What neuroscience does say is that it is not necessary and has no explanatory power – there is no need of that hypothesis.