Last night, I headed down to the beautiful Bell House, for this month's Secret Science Club lecture, featuring neurologist and radio host Dr Carl Schoonover of Columbia University. Dr Schoonover's lecture concerned the topic of his book Portraits of the Mind: Visualizing the Brain from Antiquity to the 21st Century, the development of our ability to look at the brain.
Dr Schoonover began the lecture with the observation that researching the structure of the human brain is no easy matter- C. elegans, a nematode with a fondness for English compost heaps, was used to study neural development because it has a simple nervous system of 302 neurons. Neurologists studying the human brain, with its 100 billion neurons, have their work cut out for them. Topics of interest to neurologists are, what part of the brain is connected to mental life and how do the different parts of the brain communicate with each other? One problem with studying the brain is that it appears to be gray undifferentiated matter, resistant to observation.
One of the earliest attempts to map out the brain was Alhazen's Book of Optics, written by Alhazen (not to be confused with Alhazred) in the 11th Century. Earlier guesses about the brain's function were really off-the-mark, Aristotle believed that the heart was responsible for thought, and that the brain merely acted to cool the blood. The physician and anatomist Galen, performed animal dissections that revealed fluid-filled cavities in the brain, which he believed were filled with the "humors" thought to regulate human disposition. Because scholars didn't not actually handle human brains, their view of the brain was distorted- texts were valued over empirical engagement and the "ventricular theory" of the brain held sway for over a millennium.
Leonardo DaVinci was one of the pioneers of studying the physical brain, being dissatisfied with the ventricular model- DaVinci believed that the structure and function of the brain were connected. In order to study the brain, a researcher must denature and manipulate the brain. In order to map out the ventricles of the brain, DaVinci dissected an ox brain (PDF link) and made a wax cast of its ventricles. DaVinci realized that his eyes alone were insufficient to the task of modeling the brain. One modern technique of modeling the brain is to make a resin cast of the brain structure and use acid to "eat away" the actual brain tissue.
In 1543, the anatomist Vesalius published De humani corporis fabrica, a text that drew upon his dissections of human subjects. Vesalius' work represented a turn away from Galen's models- the human body needed to be studied, dissecting animals was not sufficient.
Christoper Wren, the famed architect, studied the structure of the brain, notably injected ink into brains in order to study their structure, producing striking images. The technique of injecting dyes or contrast agents into the brain is still used, in the form of the cerebral angiogram. By the 18th Century, the use of stains hit its stride and a bewildering world of structures was discovered.
In the late 19th Century, Camillo Golgi developed the Golgi method of staining tissue with a silver solution to facilitate the use of light microscopy to study tissues. The Golgi method opened up the complex structure of the brain. The new approach to stained tissues was facilitated by refinements in microscopy, with Zeiss microscopes being of particular importance.
Golgi was unable to fully "atomize" the brain, but his work was built on by Santiago Ramón y Cajal, who wished to be a painter, but was forced by his family to attend medical school. His skill at drawing helped him to depict the structure of the brain. Using the Golgi method, Ramón y Cajal was able to observe the dendritic structure (he likened these structures to "spines") of neurons- the dendrites of the neuron receive incoming information and the axon transmits outgoing information. Ramón y Cajal drew the structures he had observed from memory, and the "maps" of the brain that he drew (including those of such structures as the hippocampus and neocortex are still useful. Golgi and Ramón y Cajal shared the 1906 Nobel Prize in Medicine for their work in neurology.
Electricity is the "lingua franca" of the brain, and the dendritic "spines" observed by Ramón y Cajal, which he guessed played a crucial role in transmission, are connections now known as synapses.
Dr Schoonover then displayed moved on to the use of molecular biology to model the brain. He discussed the use of green fluorescent protein to mark neurons- the neurons are lit from within so that structures can be studied. Other fluorescent proteins yield different colors, so approximately 100 hues can be used to highlight different structures of the brain. This part of the lecture was accompanied by breathtakingly beautiful images of the brain, similar to this gorgeous image of the hippocampus. The use of multiple stains alleviates the "tangle" problem- it's hard to distinguish structures if everything is tagged in the same way. The techniques used to "unravel" the brain's structure have yielded some strikingly beautiful images.
Another method of tagging brain structures utilizes protein antibodies- each antibody reacts to a specific protein so specific molecular "shapes" can be detected. Efforts are now underway to determine the "scaffolding" of the brain- without this structure, the brain would pretty much break down into a goo composed mainly of lipids and water. The glial cells are instrumental in providing the structure of the brain. Antibodies in stains can target glial cells for imaging purposes.
The use of GFP and antibodies depends on an understanding of how nature normally works so that it can be "hijacked" to serve other purposes. These staining methods are useless without the imaging technology. Laser microscopy is now yielding images of the brain over the span of weeks. Dr Schoonover displayed a series of images of the neural "spines" over the course of two weeks, noting the changes in their shapes. He quipped that the brain we woke up with in the morning was anatomically different from the brain we went to bed with.
Synapses are just big enough to see with light microscopes, but they are too small for details to be learned- for that, electron microscopes are needed- abandoning light opens up new vistas. With electron microscopy, the dendritic spines of the neuron and the configuration of synapses become clear.
The 2014 Nobel Prize in Chemistry was awarded for the development of "super-resolved fluorescence microscopy", an optical microscopy technique which "beats light at its own game" in order to view smaller structures. This development signals a return to light microscopy.
The lecture then veered into a quick discussion of the electric nature of the brain. Luigi Galvani famously observed that an electric spark could make a frog's leg twitch. The electrical signals in the nervous system encode information with spikes in voltage. Dr Schoonover described an experiment in which a monkey was given a cup of juice, and its neurons encoded the administration of this reward. The electrical signal was accompanied by a vascular effect- there was increased bloodflow to provided needed oxygen to the neurons. The influx of oxygenated blood caused dark areas to appear in an MRI, producing a "smiley face" image of a happy monkey, an image Dr Schoonover ended his lecture with.
In the Q&A, some bastard in the audience asked if Loligo, with its giant neurons, was still used in neurological studies. Dr Schoonover noted that Loligo was a true workforce back in the 50s, so the aforementioned bastard is hopelessly behind the times.
Here's a video of Dr Schoonover giving a similar lecture, so you can get a taste of the lovely imagery, not the least of which (for those of you who are so inclined) is Dr Schoonover himself:
Once again, the Secret Science Club served up a fantastic lecture. For more on GFP, check out this recap, and for more on Ramón y Cajal, check out this recap. One of these days, I'll label my posts.