Frontiers are in short supply. No explorer will again catch that first glimpse of the Pacific Ocean with “wild surmise,” take the first steps on the moon, or arrive first at the Challenger deep – the remotest corners of the earth are now tourist attractions. Even in science, great mysteries have fallen – life itself has gone from being the subject of metaphysical speculation about vital substances to the biophysical understanding of cellular processes. Uncharted territories, both physical and metaphorical, are hard to find.
Yet there is one largely unmapped continent, perhaps the most intriguing of them all, because it is the instrument of discovery itself: the human brain. It is the presumptive seat of our thoughts, and feelings, and consciousness. Even the clinical criteria for death feature the brain prominently, so it arbitrates human life as well. One would think, that after a century of intensive research, its outlines would be well known to us: after all, colorful pictures of brain activity have been making regular appearances in the news media for some time.
However, if one scratches the surface, our knowledge of how the human brain is put together remains limited: not in some esoteric, complicated manner, but in the straightforward sense that we have simply no means to visualize entire neurons in the brain (and the brain, being a collection of neurons, therefore remains a shut book in important ways). We can’t see them in their full glory, even with all our advanced technology.
The problem is that compared to other cells visualized under a microscope, neurons are at the same time very small, and very big. While their soma (cell bodies) are like other cells, neurons can send out branches (axons) that travel very long distances, sometimes several feet, which don’t fit into the sections of tissue that we do histology on. We can see the distribution of neuronal cell bodies in a slice of the brain. And we can divide the brain up into regions based on their properties; this is what Korbinian Brodmann did a hundred years ago. Unfortunately, the most interesting properties of neurons come from their extremely long filaments, which can span the entire brain or reach down into the spinal cord. We cannot effectively label these in their entirety. It is as if we were presented with a map of a vast land with states and cities marked, but not the roads.
There do exist labeling methods suitable for (postmortem) human brain tissue: the Golgi method, that sparsely labels neurons using a silver precipitate, or the passive diffusion of lipophilic dyes dissolved in neuronal membranes. However, these methods give us pictures of small portions of the full spatial extent of neurons in the human brain, or pictures of thin sections of brain, with pieces of the neurons in them. No one has yet seen, under the microscope or in digital reconstruction, a complete human brain neuron that sends projections to distant parts of the brain. To do that at the whole-brain scale, would be like seeing a new continent or planet.
In the live human brain, the methods at hand are even more indirect: rather than visualizing neurons directly, one observes the diffusive motion of water protons, using variants of magnetic resonance imaging. The basic idea behind these methods is to watch the diffusive spread of water protons starting from a point. If the diffusion was unrestricted, for example in a glass of water, the spread would be equal in all directions. If however diffusion was easier in some directions (eg parallel to a bundle of axons) and harder in other directions (perpendicular to the bundle) then one could figure out which way the fibers were running just by observing the diffusion of the water protons. This is the methodology used in a recent paper by Van Wedeen et. al., which has excited much attention.