Scientist Spotlight: Seth Grant

Even as science rolls through the 21st Century, the brain remains a mystery. From sub-cellular neurochemical transmission mechanisms to the abstractions of thought, personality, and intelligence, theories of cognition are constantly being formed and reconsidered. Dr. Seth Grant, a researcher at the Wellcome Trust Sanger Institute, has been studying the links between human cognition and the brain. Specifically, the Grant laboratory's focus centred on building a complete understanding of synapses and how their proteins' molecular organisation influences how the brain functions. He is also active in the Genes2Cognition project.

Recently, the Grant laboratory's synapse research led them to the discovery that the electrochemical composition of a given animal's neuronal system plays a significant role in determining unique characteristics of that animal's brain. While it does not run completely contrary to current theories regarding neuronal development and evolution, it represents a significant and novel contribution to the on-going discourse. Scientist Live spoke with Dr. Grant about his work.

 

What were your initial goals in this study?

Our initial goal was to simply ask - when did synapses evolve? Along the way we hoped to gain some insight into why synapses have so many components. In other words, why are they so complex?

 

Can you explain your methodology and why it was chosen?

The methods we chose began with a set of proteins - the membrane-associated guanylate kinase (MAGUK)-associated signalling complexes (MASCs). They are a major set of synapse proteins embedded into a collection of roughly 1000 proteins. That was our starting point. From there, we looked at the genes that encode them, examining the genome of 19 species that included vertebrates, invertebrates, and a single-celled animals, in this case yeast. This essentially represents the broad sweep of evolution. In studying the genomes of those species, we discovered when the different synapse genes in mammalian brains first evolved.

We made several striking observations.

First, a quarter of the synapse genes present in the human brain were also found in animals without nervous systems. Single-celled animals have many synapse genes, and in the same what they play a role in human behaviour, it turns out these molecules control the behaviour of single-celled organisms. They respond to nutritional challenges, stress, etc. From these observations, we reasoned that the evolutionary ancestral origin of synapses and, therefore, the brain lies in a set of proteins that control the behaviour of single-celled animals.

We then observed that this simple set of proteins is not the same number in invertebrates. There were twice that number in the invertebrates. This indicates that the ancient set was added to and embellished. This doubling of numbers happened again during the evolution of vertebrates.


Were there certain conditions that acted as evolutionary pressures, ultimately influencing how the synapses developed?


The principal driving force behind the doubling of proteins at different evolutionary boundaries was the changes in the structure of the genome. Genome duplication events led to the doubling of many genes. That was a major driving force behind the expansion of gene numbers. Although the genome duplications provided more genes for the animals to utilise, we found that there were certain proteins that were preferentially used by the synapses of invertebrates and vertebrates. These were the type of proteins that are on the surface of the cells, such as neurotransmitter receptors.

The second type of complexity - a fascinating puzzle - emerged as a result our study.

We were interested in the vertebrate nervous system - mammalian, in particular - and we calculated that these complex synapses arose hundreds of millions of years before the anatomically big mammalian brains. We wondered whether there was some connection. Was having more synapse proteins a prerequisite to the subsequent growth and expansion of the large mammalian nervous system? Did the large set of synapse proteins make it possible to evolve a more complex anatomical brain with many more classes of nerve cell?

Here is the mechanistic connection. What we did was to examine the mouse brain and look into its many parts. We found that the synapse proteins were expressed in different combinations in different parts of the nervous system. A simple picture emerged - the proteins that made the brain areas distinct were also the proteins that evolved most recently. In other words, the molecular evolution of these big synapses was exploited in making the specialised parts of the brain, which are characteristic of mammals and other recently evolved species. I am sure there would be evidence of selection processes in the aspect of evolution that would have influenced the size, shape, and success of different animals and that the synaptic proteins were involved with this. The combinations of synaptic proteins produces diversity in synapses, brain regions and behaviours. This molecular mechanism for generating behavioural diversity could be a template upon which natural selection could act, and thus different environmental niches of animals might favour different combinations of synaptic proteins.

 

Are there any other benefits?

Providing more behaviours allows the animal to fit into very large, perhaps infinite, number of environmental niches. Vertebrates have managed to adapt successfully to a number of habitats and environmental niches. That means they must have mechanisms that generate diversity and flexibility. These combinatorial aspects achieve that goal.


How do these factors play a role in neurological disorders?

More synapse proteins provide us a greater range of behaviours and specialised brain regions. Unfortunately, there is no free lunch. If the new genes fail to work properly, mental illness develops. Some of these recently evolved genes, when defective, produce autism, schizophrenia, and learning disabilities.


Can you elaborate on how disease and evolution are linked?

Underneath the human brain lies the story of the evolution and diversification of synapses. Two questions arise. First, in what way are these proteins influenced by any disease? One would expect that if you took brain samples of patients with Alzheimer's disease or autism you might find the biochemical combinations of proteins altered. We know that to be true, because in some of these diseases a gene mutation appears, meaning the gene is no longer part of that combination.

The second question then is this: if you have a set of proteins working together, how might you achieve a therapeutic intervention that might modify or correct the problem? To achieve that we need to understand the set of proteins and how they interact. How they are connected and how do they signal to each other? We are currently pursuing that line of research.

 

Can you place your finding within the greater context of current theories on how the brain developed?

The idea that there is an ancient proto-synapse comprised of a core set of proteins that has been added to in a sequential fashion is new. There is a general view that neurons of all species are the same, and that the electrical properties of invertebrates and vertebrates are thought to be similar. As a result of those observations, it has generally been thought that what makes animals different is fundamentally the number of nerve cells they possess. It is a case of quantity of cells. What our study demonstrates is that this is not necessarily the case. There are major differences in the molecular composition between invertebrates and vertebrates. Different parts of the nervous system use different combinations of these proteins. To take a conservative view, brain power or intelligence is the product of both the number of synapse proteins and number of nerve cells. These are two important dimensions to be studied side by side. What we have done is shown that there is a connection between the synapse protein composition and brain rationalisation. This is a new way to think of the organisation of the brain.


What is next for you in the way of research?

We are heading in two directions. One is to pursue the understanding of the complexity of the human brain with the goal of trying to find fundamental principals that explain it. What we have done now is to identify perhaps two of these rules. Our second direction is to apply this knowledge in a way relevant to human diseases.

 

For more information about Seth Grant, the Grant Laboratory's work, and a select bibliography click here.

For more information about the Wellcome Trust Sanger Institute, click here.

 

(Reporting by Marc Landas)

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