Awaiting the New Neurobiology, by Edward Ziff

darwin-message-to-gopEvolutionary biology is undergoing a revolution, or in fact, its third revolution. Surprisingly, this revolution has profound implications for understanding the brain. The first evolutionary biology revolution came with the Charles Darwin’s Theory of Natural Selection, which provided a mechanism for how traits could become more or less common in a population through natural variation and interaction with the environment. The second came through the discovery of the structure of DNA, and the implications of that structure for the mechanisms of origin and transmission of new genetic traits. These two revolutions synergized to create what is often called the New Synthesis or the Modern Synthesis. This Synthesis was especially powerful because the structure of DNA provided a molecular basis for the process of natural selection. To many, the New Synthesis solved the fundaments of the problem of evolution. But soon the New Synthesis theory began to weaken and be questioned as new complexities of evolution became apparent. As described in an article entitled “The New Biology: Beyond the Modern Synthesis” , authors Michael Rose and Todd Oakley explain the new understanding we have of evolution. As our knowledge of the structures of genomes increased, and as tools for genetic analysis became stronger, it became apparent that the simplistic conception of evolution based on Darwinian principles and the structure of DNA was inadequate. Genes were not the stable entities they were once thought to be and could travel from cell to cell by unexpected mechanisms using mobile genetic elements and transposons. Just as surprising, sometimes evolution seemed to take a course that reduced the fitness of the organism, contrary to the Darwinian view. Our new view of the genome revealed it to be chaotic rather than well organized. Large segments of the genome had no apparent function. Many copies of individual genes could be found, suggesting duplication or triplication. Genes were broken into pieces distributed through the genome and separated by apparently nonfunctional segments of DNA. It became clear that genes were not single functional entities but in fact could work in various ways making a number of proteins, albeit related ones.

These changes in our conception of evolution arose from an avalanche of new data about the genome and its products. It became trivial to isolate and determine the structure of any gene, from any source, even from extinct species. We could measure the structures and levels of transcripts of genes, even from a single cell. Massive new computers could be employed to analyze this avalanche of data and allow us to draw novel conclusions. New principles emerged. It became clear that genomes were chocked full of apparent junk DNA with no clear function for the organism. Much of this DNA arose from the DNA’s ability to proliferate within the genome without an obvious benefit for the organism. The DNA sequences that appeared to be most stable were the sequences that coded for protein, indeed the very sequences which, according to the principles of the New Synthesis, should mutate as evolution and speciation take place. It also became clear that genomes could change much more rapidly than expected. And indeed the genome was revealed as a “complex and shifting patchwork subject to many evolutionary and biochemical constraints and pressures”. This findings implied that the mechanism of evolution must itself be complex and have no easy explanation.

 

This third Revolution, and our understanding of the evolutionary process that it provides, arose from the development of new genomic tools. Among these new tools are rapid DNA sequencing and the ability to carry out massively parallel assays of gene expression. The new science of Bioinformatics enables us to make sense of all these new data. Our methods for genetic analysis have also improved. We can now connect features of the ecology to the molecules that create the form of the organism. We now have an unparalleled power to carry out directed mutagenesis of genomes, giving us great power to understand genome function. We now see the world of biological evolution as a continuum stretching from the molecule, to the intracellular biochemical pathway, to the cell biological mechanism that shapes the cell, to the mechanism of development that forms the organism, to the anatomy of the organism itself, and ultimately to the behavior of the organism. The Synthesis provided by this third Revolution in evolutionary biology far outstrips the New Synthesis of Darwin and the DNA helix.

 

What is the significance of this new understanding of evolution for our understanding of brain function? First, the brain has a complexity that far exceeds the complexity of the genome. So the challenge in understanding the brain in depth is great. Moreover, our tools for grasping, measuring and assessing this complexity fall far short of the tools we have for understanding the genome and its evolution. With the modern tools for brain analysis, of what are we capable? We can map the gross anatomy of the brain precisely. We can dissect out many of the functional molecules of the brain, for example neurotransmitter receptors, transporters, protein modifying enzymes, etc. We can clone the genes for these factors and analyze their structures. We can measure the activities of synapses in individual neurons and in large circuits of neurons. We can analyze brain activity at the systems level and analyze how this activity contributes to the behavior of the organism. We can compare these properties of the brain from one species to another. From the application of our current tools, we have learned much about the brain.

Yet our understanding of how the brain functions, as a complete entity, is still scant. We have moved away from the conception that different brain components have isolated, individualized functions, and that the brain operates like a car engine, with the piston and the battery and the wheel each separately providing its own function. We are beginning to appreciate that the full brain functions as an integrated whole. We are beginning to appreciate that although the brain does consist of different components, for the brain to operate, all of its components must operate together in a fully integrated manner, attuned to one another, exchanging information and function. We must understand the brain at this level.

epigenetic marks

epigenetic marks

And here lies the challenge, a grand challenge that becomes more evident through a comparison between the brain and the genome. The human genome contains about 3 billion base pairs. We may argue that the base pair is the functional counterpart of the synapse in the brain, a fundamental unit of function. If we accept this, we can get an idea of the brain’s complexity relative to the genome by estimating how many synapses there are in the brain. A typical neuron might possess 10,000 synapses. And perhaps there are 1011 neurons in the human brain. This means that there are about 1015 (100 trillion) synapses in the human brain, or about 100,000 synapses for every base pair in the genome! The brain’s synapses establish innumerable neuron linkages, to form a vast number of circuits whose activities together establish brain function. Not until we can grasp the entirety of the activities of these circuits, neurons and synapses, can we claim to have a complete view of brain function.

Such information about brain activity would be the counterpart of the massive array of data that we have amassed about the genome. And here lies the problem. We utterly lack the tools to obtain this information about the structure and activity of the brain. We can measure the activity of an individual neuron in the living brain by inserting an electrode. And indeed we can now introduce arrays of electrodes, but these arrays are limited to measuring the activities of dozens or perhaps hundreds of neurons at a given time. Even if we measure these activities, we have no information about the activities of individual synapses. Thus our grasp of brain activity at the neuron level is limited.

Using powerful new techniques, in particular the new procedure reported by Kwanghun Chung and Karl Deisseroth at Cal Tech and called CLARITY , we are on the verge of being able to visualize the brain’s complement of synapses. Indeed with CLARITY, the cell bodies, dendrites and axons of neurons in the brain can now be viewed in relatively intact form, and resemble the beautiful, diaphanous and delicate filamentous processes that string from jellyfish, but studded with synapses and marvelously formed for executing brain function. Yet these views of neurons can only be captured on the nonliving brain, as a tissue-hydrogel hybrid from which many of the functional components have been dissolved away, and to which fluorescent dyes have been added to visualize the structures. All knowledge of how the neurons operated when the brain was still living is lost in visualizing their delicate structures. So there remains a great gulf between neuron form and function.

We do have a counterpart of gene mutagenesis for use in the brain. Indeed we can alter any gene that contributes to brain function and measure the consequences. The new technique of optogenetics, another brainchild of Deisseroth, together with Ed Boyden, employs light beams to turn individual neurons on or off at will. This has given us great power in dissecting brain function. And using functional MRI (fMRI), we can get a glimpse of whole brain function in animal or human, but scarcely at the resolution of individual neurons or even simple circuits.

What could we learn if the resolution of our analysis of the function of the brain were increased? The secrets to memory storage, to the molecular and cellular mechanisms of representation of visual, auditory, tactile and other sensory perceptions, in precise form and detail: how can I recall your face and distinguish it from others, what makes us choose chocolate cake over vanilla, how we can interpret a romantic poem, or compose a song? These challenges for the understanding the brain are comparable to the challenges of evolutionary biology that are now being understood: how species evolved, what patterns of gene activity take place in development, how these patterns vary from species to species, how transposons populate every nook and cranny of our chromosomes. The level of understanding that the New Biology and its third Revolution have provided for our understanding of evolution of life forms, the New Neurobiology, when it arrives, will provide for our understanding of the most highly evolved component of all life forms, the human brain.

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