Cerebral Darwinism

Darwin_divergence pbwikimedia commonsIt is widely believed that the complexity of the human brain, with thousands of different neurons, has led to the surfacing of sophisticated behavioral repertoires, such as language, the use of tools, the perception of “ I,” symbolic thought, cultural learning and awareness. This complexity has led to the emerging of works of extraordinary technological and artistic content during the relatively short cultural history of our species.  This seems to indicate that cerebral complexity has a creative purpose, unlike other much more widely complex yet raw systems, such as galaxies and the thousands of stars that comprise them. Understanding how neural complexity is shaped during development is akin to diving into fundamental issues of the origin of our species.

The formation of the human brain is not an optimized process.  On the contrary – most of the generated cells will be discarded and only a tiny fraction will be used.  The mechanism behind this selection is obscure and there are evidences suggesting that extrinsic and intrinsic factors might contribute to cell survival or death. Only the precursory cells with the correct properties at the perfect time and place will flourish and mature into functional neurons, thus contributing to the construction of nerve networks.  In this competition, the forces of variation and selection act to shape each neural network in each human brain, neuron by neuron, generating a real individuality in the form how each one of us receives, processes and interacts with the outside world.

It is important to keep in mind that natural selection needs variation to generate the different neural types in the brain. Initially, it was believed that this variation was contained in the protein-coding genes.  However, after the sequencing of the human genome, it became clear that the quantity of genes is not sufficient to justify such enormous neural complexity.  In view of the fact that the genome contains less than 2% of protein-coding genes, it becomes difficult to generate enough information for the thousands of cell types contained in the human brain. Even if one considers molecular events such as the alternative processing of the RNA or posttranslational modifications, enough variety is still non-existent. The variation must reside somewhere else.

The lack of an obvious function for the remaining 98% of the genome inspired the concept of junk DNA, illustrating the idea that these sequences are evolutionary leftovers, accumulated in the course of thousand of years in the genome.  Like a garage full of junk, the genome seems to be able to deal very well with this excess of sequences, but it is difficult to understand why it doesn’t get rid of this junk, and thus save on cell energy. Part of this junk DNA is comprised of transposable elements or leaping genes, able to replicate themselves, inserting new copies into the genome and possibly altering the expression of nearby genes. The activity of these elements was witnessed during evolution and these genome parasites became known as selfish genes, whose only purpose was to remain alive for the next generations through the replication of germinating cells in individuals.  The replication in non-germinating, somatic cells that will not form a new individual was not, apparently – at least so far – a survival strategy.

In 2003, during my post-doctorate studies at the Salk Research Institute in California, we observed something unusual.  While studying from stem cells how genes were regulated during neural specialization,  we noticed that the transposable elements were activated as soon as a cell opted for neural differentiation.  Nothing was detected when stem cells were induced to differentiate themselves from other cell types, indicating that the phenomenon was specific to neurons. This finding confronted everything we knew thus far about the behavior of these elements and their “ intention”  to pass on to future generations.  After all, what were they doing as they proliferated in the brain?

Two years later, after battling the natural resistance of the paradigm in effect, we were able to demonstrate that the neurons had unique genomes. Unlike the attractive concept that all the cells of the body have the same genome, and that the differences are mere consequences of gene regulation, we had gathered strong evidence to show that this was not the case in the brain.  Each neuron seemed to be unique, each neuron presented new insertions into the genome, causing an impact on nearby genes. This activity seemed to amplify the effect of gene regulation, generating an enormous cellular variation and increasing the repertoire of cell types able to be formed by a given group of genes.  This mechanism of variation and flexibility seems to contribute towards the originality of each brain, explaining why even the same genetically identical genes have different personality characteristics.

Philosophically, the data seemed to be pointing to a portion of “ chance,” in the shaping of each personality.  New data from our lab shows that the activity of the transposable elements is altered in an autistic brain or in a brain with syndromes of the autistic specter. The view of the world is different in autistic people, which suggests an alteration in the neural network.  The increase of the neural variability might perhaps be able to produce individuals outside the normal curve, with different qualities. Organisms out of the curve might perhaps have more chances of adapting themselves to new environments or to react against drastic changes in the environment. In addition, perhaps there are prodigies with a superior cognitive capacity in the midst of the population. And perhaps it is individuals such as these that increase the creative capacity of the human species, which would help dominate new territories, for example. In this sense, the transposable elements would continue being selfish genes, because, by manipulating the human brain, they ultimately increase the reproductive changes of the species.

Strangely enough, during the evolution of the primates, it is possible to observe an impressive correlation between human adaptation and the surfacing of new transposable sequences. Evidences of global climate changes suggest that colder, dryer environments with sharper temperature variations seemed to have occurred approximately 3 million years ago.  The abrupt changes led to a drop in the supply of food and water, putting huge pressure on our ancestors to adapt to new environments. Interestingly enough, new families of transposable elements in the genome appear at the same time that humans acquire bipedalism, gain more brain mass, and present the first evidences of the use of tools, awareness, or artistic motivation.

On the other hand, the phenomenon of somatic insertions in the brain might perhaps be an evolutionary leftover. Both the brain and the reproductive system went through enormous changes during evolution. The genetic expression of these two organs is relatively similar and both have several signaling pathways in common. In this context, finding molecular phenomena existing only in these organs does not seem like anything new. If this is truly the case, the activity of the transposable elements in the nervous system is disposable and does not contribute to the neural networks, to cognition or to behavior. This is possible, but one still needs to find out why the genome would be willing to carry all this junk for nothing.

No matter what the function of the neuron’s genetic mosaic make-up is, it is necessary to proceed with caution when designing the experiments that will allow this phenomenon to  be investigated.  At present, it is impossible to use the classic technique of gene knockout to eliminate the leaping genes from the genome. Various genes of this kind are active in the genome.  In addition, they are spread throughout the chromosomes.  A lot of creativity will be necessary to seek experimental situations where this hypothesis can be tested. No matter what kind of finding will come out of  this, it will only be real if it makes sense from the evolutionary point of view.

Alysson Renato Muotri is a neuroscientist and professor at the MedicalSchool of the University of California, San Diego (UCSD).