Cell theory has its origins in seventeenth century microscopy observations, but it was nearly two hundred years before a complete cell membrane theory was developed to explain what separates cells from the outside world. By the 19th century it was accepted that some form of semi-permeable barrier must exist around a cell. Studies of the action of anesthetic molecules led to the theory that this barrier might be made of some sort of fat (lipid), but the structure was still unknown. A series of pioneering experiments in 1925 indicated that this barrier membrane consisted of two molecular layers of lipids—a lipid bilayer. New tools over the next few decades confirmed this theory, but controversy remained regarding the role of proteins in the cell membrane. Eventually the fluid mosaic model was composed in which proteins “float” in a fluid lipid bilayer "sea". Although simplistic and incomplete, this model is still widely referenced today.
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Early barrier theories
Since the invention of the microscope in the seventeenth century it has been known that plant and animal tissue is composed of cells : the cell was discovered by Robert Hooke. The plant cell wall was easily visible even with these early microscopes but no similar barrier was visible on animal cells, though it stood to reason that one must exist. By the mid 19th century, this question was being actively investigated and Moritz Traube noted that this outer layer must be semipermeable to allow transport of ions. Traube had no direct evidence for the composition of this film, though, and incorrectly asserted that it was formed by an interfacial reaction of the cell protoplasm with the extracellular fluid.
The lipid nature of the cell membrane was first correctly intuited by Georg Hermann Quincke in 1888, who noted that a cell generally forms a spherical shape in water and, when broken in half, forms two smaller spheres. The only other known material to exhibit this behavior was oil. He also noted that a thin film of oil behaves as a semipermeable membrane, precisely as predicted. Based on these observations, Quincke asserted that the cell membrane comprised a fluid layer of fat less than 100 nm thick. This theory was further extended by evidence from the study of anesthetics. Hans Horst Meyer and Ernest Overton independently noticed that the chemicals which act as general anesthetics are also those soluble in both water and oil. They interpreted this as meaning that to pass the cell membrane a molecule must be at least sparingly soluble in oil, their “lipoid theory of narcosis.” Based on this evidence and further experiments, they concluded that the cell membrane might be made of lecithin (phosphatidylcholine) and cholesterol. One of the early criticisms of this theory was that it included no mechanism for energy-dependent selective transport. This “flaw” remained unanswered for nearly half a century until the discovery that specialized molecules called integral membrane proteins can act as ion transportation pumps.
Discovery of lipid bilayer structure
Thus, by the early twentieth century the chemical, but not the structural nature of the cell membrane was known. Two experiments in 1924 laid the groundwork to fill in this gap. By measuring the capacitance of erythrocyte solutions Fricke determined that the cell membrane was 3.3 nm thick. Although the results of this experiment were accurate, Fricke misinterpreted the data to mean that the cell membrane is a single molecular layer. Because the polar lipid headgroups are fully hydrated, they do not show up in a capacitance measurement meaning that this experiment actually measured the thickness of the hydrocarbon core, not the whole bilayer. Gorter and Grendel approached the problem from a different perspective, performing a solvent extraction of erythrocyte lipids and spreading the resulting material as a monolayer on a Langmuir-Blodgett trough. When they compared the area of the monolayer to the surface area of the cells, they found a ratio of two to one. Later analyses of this experiment showed several problems including an incorrect monolayer pressure, incomplete lipid extraction and a miscalculation of cell surface area. In spite of these issues the fundamental conclusion- that the cell membrane is a lipid bilayer- was correct.