Edinburgh was rightly chosen for the ISIR conference this year, since it must now rank as the world leader in intelligence research.
120 delegates gathered in the grand surroundings of the Royal Society of Edinburgh, bathed in the almost perpetual Northern sunlight of this noble city, to start at the beginning, which was 530 million years ago with a synapse complexity expansion, which itself was followed by a genome duplication event 30 million years later. It was the mutation of all mutations, since the duplication then duplicated again, and it is from that freak 4 duplicated genomes that all vertebrate life descends. Truly, our ancestry depends upon a mistake, and we are the spawn of error.
Seth Grant explained how the synapse functioned. Synapses are the junction boxes through which brain cells communicate with each other. One cell has a long connecting axon coming out of it which ends in several synapses right next to other brain cells and clasps them together. The transmission has to leap a tiny synaptic gap by chemical means. Most drugs operate by affecting this synaptic gap. I confess that when I learned physiology I was a very poor student and thought of it as no more than a messy junction box, and would have preferred it to be made of copper wires rather than a chemical exchange soup. Wrong, wrong, utterly wrong. In fact, the synapse takes the digital signal from the nerve and converts it into a highly informative analogue signal depending on the time intervals of the arriving digital signals. The synapse counts, and then draws a graph. This exquisitely informative shape provides patterns, and even a 9 by 9 array of synaptic receptor will provide a rich mental map of every move an organism takes, like a film. It is a Youtube of events registered at the synaptic level. Given that there are so many receptors, each with different triggering sensitivities, complex computation can be carried out at the synaptic level. In short, it was good to hear all this laid out before us. The relays are doing a lot of the thinking.
Seth Grant went on to discuss a puzzle: why does schizophrenia have such a late onset? Autism reveals itself very early. Attention deficits and other problems are detectable at 3 years of age, and by 11 years of age most of the psychological problems a child may have are already evident. Schizophrenia, on the other hand, seems to come almost out of the blue in the 17 to 25 year period. How can the heritable susceptibility lie dormant so long, and what triggers the breakdown?
Skene, NG, Roy, M & Grant, SG 2017, ‘A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia’ eLIFE, vol 6. DOI: 10.7554/eLife.17915
The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.
Schizophrenia tends to run in families and it is likely that different combinations of faulty genes that affect the connections between nerve cells increase the chance of having the disease. Until now, scientists have assumed that certain situations and environmental factors trigger the condition, but it was unknown if genes could influence the age at which the disease will begin.
To explore whether genes in the brain change at certain time points, Skene et al. examined how the genes are turned on and off across the lifespan of healthy mice and humans. The results showed that in both mice and humans, a ‘genetic lifespan calendar’ controlled every cell type in the brain and directed the way they worked at different ages. The timing was so precise that it was possible tell the age of a mouse or a person simply by looking at the way the genes were expressed in a tissue sample.
Skene et al. then studied how the genetic lifespan calendar controlled the genes damaged in schizophrenia, and found that the calendar caused a major reorganization of the genes at the time when the symptoms started. This suggests that the genetic lifespan calendar is a crucial factor that can determine at what age the disease will start.
The next step will be to study how the genetic lifespan calendar programs changes throughout the brain and to explore if it could be manipulated to change how the brain ages. This could help to develop new types of treatments for schizophrenia and other conditions of the brain.
It could be that mutation load accumulates in post-synaptic proteins, and gene regulation changes a lot during that period, so that brains also change considerably, and it is enough to trigger a major disorder in the vulnerable 1%. Since therapies might not be able to target all the specific causes of schizophrenia, it might be better to find a pharmacological way (for genetically vulnerable teenagers) of slowing down the general gene regulation changes until such time as the person is more resilient. I likened it to being a good mountaineer, but lacking oxygen as you get experienced enough to climb the highest peaks.
What this lecture shows is that real subjects develop and are altered by discoveries in related fields. Essentially, we are studying the brain, and doing so with the best tools available. The tool set has expanded considerably in the last decade. This should boost our understanding, as when a walker in a city discovers that the edge of their familiar neighbourhood links to other neighbourhoods in ways they had not realized. I call it the London Underground Pop Up phenomenon. Places formerly seen as disparate countries with their tube station capitals are revealed, by one long intrepid walk, to be adjoining principalities in a grander continent.