The 17th and 18th centuries witnessed a revolution not just in politics and philosophy, but in humanity's understanding of its own brain. As the Scientific Revolution dismantled medieval worldviews, pioneering thinkers turned their attention to the enigmatic three-pound organ governing thought, sensation, and identity. Rejecting Aristotle's belief that the heart housed intelligence, these early neuroscientists embarked on a radical quest: to decipher the brain's chemical composition and mechanistic principles. Their theories—bridging alchemy, chemistry, and mechanics—laid the groundwork for modern neurochemistry amid a landscape of competing ideologies and ingenious, if sometimes bizarre, experiments 1 4 .
The Alchemical Prelude: Beyond Myth and Magic
Before the brain could be studied as a physical entity, it had to be liberated from mystical interpretations. Ancient Egyptian embalmers discarded the brain as "cranial stuffing" during mummification, while Greek philosophers debated whether the heart or brain governed consciousness. By the 1600s, Renaissance alchemists like Paracelsus began framing the brain in chemical terms, albeit through an occult lens:
Vital spirits and vapors
Many viewed neural function through alchemical transformations, where "animal spirits" (elusive fluids) flowed through nerves like rivers of consciousness 1 .
The phlogiston fallacy
Combustion and metabolism were explained by phlogiston—a hypothetical fiery substance. This theory seeped into neurochemistry, with some proposing phlogiston enabled thought 1 .
This period, termed the "pre-history of neurochemistry," saw fact and fantasy intertwine as scholars groped toward material explanations 1 .
The Mechanistic Revolution: Nerves as Pipes, Brain as Hydraulic Pump
The rise of mechanical philosophy ushered in a new metaphor: the body as machine. René Descartes epitomized this shift, proposing nerves were tubes carrying animal spirits that inflated muscles like bellows. His dualism split mind from body, relegating the brain to a hydraulic pump managing fluid flows 3 .
Yet dissections soon exposed flaws in this model. Andreas Vesalius meticulously detailed brain structures like the putamen and corpus callosum, challenging Galen's ancient teachings. Meanwhile, Jan Swammerdam debunked hydraulic theories by placing frog nerves in airtight syringes; when muscles contracted, water levels didn't rise, proving nerves transmitted force without fluid 4 .
| Scientist | Contribution | Limitations |
|---|---|---|
| Thomas Willis | Proposed chemical fermentation in the brain; linked anatomy to function | Relied on speculative "vital spirits" |
| Isaac Newton | Theorized vibrating "ether" and electrical nerve signals | Lacked experimental validation |
| Pierre Gassendi | Argued nerves carry information, not force | Philosophical, not empirical |
| Antoine Fourcroy | Conducted first systematic brain chemistry analyses | Primitive analytical methods |
Thomas Willis: The Brain as Chemical Reactor
Amid this upheaval, English physician Thomas Willis emerged as a pivotal figure. His 1664 treatise Cerebri Anatome (The Anatomy of the Brain) married dissection with bold chemical theories:
Fermentation theory
Willis proposed that blood fermented in the cortex, releasing "vital spirits" that powered cognition. Sulfur and nitrogen compounds, he argued, fueled this process 1 4 .
Neurological cartography
He mapped the circle of Willis (arterial loop) and linked the cerebellum to motor control, noting its dense structure versus the cerebrum's "soft" sensory role 4 .
Spiritous liquors
Willis described distilled brain extracts as containing volatile "spirits"—an early nod to neurotransmitters 1 .
Inspired by French atomist Pierre Gassendi, Willis shifted neuroscience's focus: nerves weren't force transmitters but communication lines carrying coded signals—a precursor to information theory 3 .
Newton's Vibrations: Electricity Meets Chemistry
Isaac Newton, best known for gravity and optics, secretly probed the brain's chemistry. Rejecting Descartes' hydraulics, he envisioned nerves transmitting "vibratory motions" through an ethereal medium:
Electro-chemical fusion
In Principia Mathematica, Newton suggested nerve impulses blended electrical vibrations with chemical reactions—a prescient model echoing modern ion-channel theories 3 .
The "Ether" hypothesis
He speculated that "animal electricity" flowed via "elastic fluids," with thoughts arising from molecular interactions 3 .
| Theory | Mechanism | Proponents | Legacy |
|---|---|---|---|
| Hydraulic | Fluid pressure in nerve tubes | Descartes | Debunked by Swammerdam |
| Vibratory | Electrical ether vibrations | Newton | Presaged bioelectricity |
| Fermentation | Chemical distillation of spirits | Willis | Early neurochemistry |
The Birth of Brain Chemistry: Iatrochemists and Elemental Analysis
By the mid-18th century, iatrochemistry (medical chemistry) dominated brain research. Franciscus Sylvius, a Dutch physician, attributed thought to acidic and alkaline brain fluids reacting like laboratory reagents. This culminated in Antoine Fourcroy's landmark studies:
- Elemental breakdown: Fourcroy decomposed brain tissue into carbon, hydrogen, nitrogen, and phosphorus—revealing its organic complexity 1 .
- Comparative anatomy: He analyzed brain matter across species, noting higher phosphorus levels in "smarter" animals—a crude but innovative link between chemistry and cognition 1 .
- The phlogiston downfall: Chemists like Joseph Priestley tried reconciling brain metabolism with phlogiston, but Antoine Lavoisier's oxygen theory soon dismantled this, reframing respiration as combustion 1 .
| Reagent/Method | Function | Limitations |
|---|---|---|
| Solvents (alcohol, ether) | Extract "spiritous" compounds | Coarse separation; impurities |
| Acid/Alkali tests | Detect reactivity of brain fluids | Non-specific reactions |
| Elemental combustion | Quantify carbon, nitrogen, etc. | Destroyed organic complexity |
| Microscopy | Observe nerve globules | Low resolution; artifacts |
| Electrical stimulators | Test nerve conductivity | Primitive electrodes |
Legacy: From Spirits to Synapses
The 17th–18th century debates birthed foundational concepts for modern neuroscience:
Information over hydraulics
Gassendi and Willis's view of nerves as communication channels anticipated neural signaling 3 .
Chemical specificity
Fourcroy's analyses paved the way for identifying neurotransmitters like dopamine 1 .
Yet misconceptions lingered for centuries. The "10:1 glia-neuron myth"—that glial cells outnumber neurons 10-to-1—persisted until 2009, when the isotropic fractionator technique revealed a near 1:1 ratio. This error stemmed from 19th-century histological overestimates, showing how quantitative rigor was needed to correct speculative legacies 2 .
The Frog Nerve Experiment – Newton's Heirloom
Objective: Test if nerves transmit "animal electricity."
Procedure:
- Dissect a frog leg, preserving sciatic nerve.
- Touch nerve with iron hook during thunderstorm (Galvani) or via static generator (Aldini).
Results: Muscles jerked without direct contact—proof of electrical conduction.
Impact: Validated Newton's vibratory ether hypothesis; launched bioelectrics 3 4 .
As Suzana Herculano-Houzel notes, quantifying brain cells finally allowed separating "fact from fantasy" in cellular composition—a task initiated when Enlightenment thinkers first dared to analyze the mind's material essence 2 . Their alchemy became our chemistry; their spirits, our synapses.