page_title: History of cell membrane theory
section_title: Discovery of lipid bilayer structure
hierarchical_section_title: History of cell membrane theory / Discovery of lipid bilayer structure
caption_attribution_description: English: Annular Gap Junction Vesicle
context_page_description: 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, 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.
context_section_description: 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.
  A decade later, Davson and Danielli proposed a modification to this concept. In their model, the lipid bilayer was coated on either side with a layer of globular proteins. According to their view, this protein coat had no particular structure and was simply formed by adsorption from solution. Their theory was also incorrect in that it ascribed the barrier properties of the membrane to electrostatic repulsion from the protein layer rather than the energetic cost of crossing the hydrophobic core. A more direct investigation of the membrane was made possible through the use of electron microscopy in the late 1950s. After staining with heavy metal labels, Sjöstrand et al. noted two thin dark bands separated by a light region, which they incorrectly interpreted as a single molecular layer of protein. A more accurate interpretation was made by J. David Robertson, who determined that the dark electron-dense bands were the headgroups and associated proteins of two apposed lipid monolayers. In this body of work, Robertson put forward the concept of the “unit membrane.” This was the first time the bilayer structure had been universally assigned to all cell membranes as well as organelle membranes.
caption: A micrograph from a Transmission Electron Micrograph showing a lipid vesicle. The two dark bands are the two leaflets comprising the bilayer. Similar images taken in the 1950s and 1960s confirmed the bilayer nature of the cell membrane
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