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SUBCELLULAR COMPARTMENTS | Lead Editor: Mike Adams

Discovering the Lipid Bilayer

By: Mike Adams, Ph.D. (Dept. of Biology, Eastern Connecticut State University) 2010 Nature
Education
Citation: Adams, M. (2010) Discovering the Lipid Bilayer. Nature
Education 3(9):20

We are taught that plasma membranes are a typical lipid bilayer, but how do we know this, and who figured it
out?
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Most books mention that membranes have a typical "lipid bilayer," but why lipids, why should it be a bilayer, and how was this basic structure determined? Although it is now
generally taken for granted that membranes are based on the presence of a lipid bilayer, that was not always the case. Early experiments, often by physicists, led to the
understanding that the cell membrane was lipid in nature. A key experiment using the Langmuir trough provided the basis for accepting that the membrane is a bilayer and laid
the groundwork for the current model of membrane structure.

The Membrane Concept

All cells, prokaryotic or eukaryotic, are surrounded by a plasma membrane. This thin, flexible, and potentially very fragile structure is all that stands between the interior of the
cell and the environment. In addition, the insides of eukaryotic cells are subdivided into a series of specialized compartments. Each of these compartments is also surrounded
by a membrane (sometimes two or more) that separates the contents from the rest of the cytoplasm. What is it about membranes that make them so critical to the functioning
of a cell? The answer comes from the nature of the cell itself and from a couple of basic laws of physics.
First, cells are mainly water. This simple observation is at the heart of much of the physics and chemistry that
determine cell structure and function. The interior of a cell is an aqueous environment, so, not surprisingly,
most of the molecules that are important to the cell's operation are water-soluble. The first question, then,
is: What makes something soluble in water? In general, the major factor in determining solubility is the
similarity in polarity between the solvent and the solute. If both of them are polar (have an uneven
distribution of electrons and therefore of charge within the molecule) or both are nonpolar (an even
distribution of charge), then solubility will be high, but if one is polar and the other is nonpolar, then
solubility will be poor. Sodium chloride is very soluble in water (both polar), is far less soluble in a less polar
environment such as methanol, and is almost insoluble in a nonpolar liquid such as benzene. Substances
that, like water, are polar and hence dissolve readily in water are hydrophilic. Conversely, nonpolar molecules
do not dissolve readily in water and are hydrophobic. The basic behavior of lipids in contact with water is due
to their unusual nature. One end of the molecule is hydrophilic and the other is hydrophobic (Figure 1A), so
lipid molecules will react to the presence of water (Figure 1B).
Second, we must remember that diffusion is one of the fundamental processes that dictate many of the cell's
operations. Molecules will always tend to move from regions of higher concentration to areas of lower

Figure 1: The orientation of phospholipids in the

lipid bilayer.
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concentration. Most cells are surrounded by a dilute aqueous medium, which means that key compounds
would, if not prevented, constantly leave the cell. The answer to this problem is to enclose the cytoplasm with a membrane that prevents the free movement of molecules. As
described above, a nonpolar material would work well for this membrane because it would not wash away in the surrounding water and would not dissolve water-soluble
substances out of the cell.

Discovery of the Lipid Bilayer

Early researchers studying cells recognized that there was a boundary layer, but little was known about its structure until, in the 1880s, Charles Overton started a series of
studies to determine which molecules were able to cross this boundary layer. Until this time, it was accepted that water was the only material that could easily move into and out
of the cell. Overton showed that nonpolar chemicals were usually able to cross the boundary quite easily, and he published an account of his work (Overton 1889) in which he
explicitly suggested that the boundary layer was a lipid and that other lipids were able to freely enter and pass through. For a more complete description of Overton's work, see
Tanford (1989).
So, if the cell membrane were a lipid, how would it be organized? In 1890, Rayleigh, working on simple oils, showed that they tend to spread over the surface of water. By

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measuring the original volume of oil and the final area it covered, he was able to calculate the thickness of
the film. This initial observation was improved on by the work of Agnes Pockels. Working in her kitchen, and
with no formal training, she devised a simple apparatus to quantify the area covered by the oil film. Her
apparatus was refined by Langmuir (1917) and is now generally referred to as a Langmuir trough (Figure 2),
although it really should be a Pockels trough.
In 1925, Gortner and Grendel performed some key experiments using a Langmuir trough and blood cells
(Gortner & Grendel 1925). They were interested in determining the amount of lipid in the membranes of red
blood cells. Why use red blood cells? These cells were an excellent choice for this experiment because they
have no nucleus or other membrane-bound organelles in the cytoplasm; therefore, any membrane lipids that
are found must be those that make up the plasma membrane. First, the scientists extracted the lipids with a
variety of solvents, including acetone, from a known number of cells. Then they used the Langmuir trough to
determine how large an area the lipids could cover. Because they could measure the actual size (surface area)
of a red blood cell and knew approximately how many of those cells they had in their sample, they could
calculate the total surface area that would have to be covered by membrane. When the two numbers were
compared, it was clear that the amount of lipid they had extracted could cover

twice the area needed to

enclose all the cells. Why would there be so much? Additional experiments showed that lipids could

Figure 2: Langmuir trough

2010 Nature Education All rights reserved.

spontaneously form a bilayer when mixed with water (Figure 1). Together, these observations suggested that
there may be a simple explanation for the results with the red blood cells. The plasma membrane of these cells likely consists of a

double layer of lipid surrounding each

cell.
As it happens, Gortner and Grendel made some errors in their experiment. They failed to completely extract all the lipids from the cells, and they also underestimated the total
surface area of the individual red blood cells. However, because these two errors canceled each other out, their final conclusions turned out to be correct, regardless of their
miscalculations. Thereafter, the idea of a lipid bilayer became the basis for future models of membrane structure. (Sadava 1993).

Experimental Follow-Up with Microscopy

When the use of electron microscopy started to allow examination of the plasma membrane at high resolution, people noticed that the image clearly showed three layers, not
two. In a key paper, Stoeckenius (1962) provided clear pictures of the three-layer structure. He then described in both words and diagrams how the lipid bilayer results in a
three-layer image. As it turns out, the inner and outer edges of the bilayer have a different composition than the interior. Under the view of the electron microscope, the
outsides of the lipid bilayer show up as two darker layers, whereas the hydrophobic interior stains less densely, thus showing three apparent "layers" (outside layers are
represented as blue in Figure 1C).

Summary
The first clues to lipid bilayer structure came from results with red blood cell membranes. The ultimate discovery that the plasma membrane is a lipid bilayer with hydrophobic
and hydrophilic properties changed the way this structure was viewed. Its semipermeable and liquid nature provided the groundwork for understanding both its physical and
biological properties.

References and Recommended Reading

Edidin, M. Lipids on the frontier: a century of cell-membrane lipids

Nature Reviews: Molecular Cell Biology 4: 414418 (2003).

Gortner, E. & Grendel, F. On bimolecular layers of lipoids on the chromacytes of blood.

Journal of Experimental Medicine 41, 439443 (1925).

Langmuir, I. The constitution and fundamental properties of solids and liquids II: Liquids.

Journal of the American Chemical Society 39, 18481906 (1917).

Vierteljahrschrift der Naturforschende gesselschaft 44, 88135

Biological Membrane Structure, trans. Park, R. B. Boston: Little Brown, 1968.

Overton, E. The probable origin and physiological significance of cellular osmotic properties.
(1899). In

Sadava, D. E.

Cell Biology, Organelle Structure and Function. Boston: Jones and Bartlett, 1993.

Stoeckenius, W. Structure of the plasma membrane: An electron-microscope study.

Tanford, C.

Circulation 26, 10661069 (1962).

Ben Franklin Stilled the Waves. Durham, NC: Duke University Press, 1989.

Outline | Keywords | Add Content to Group

Explore This Topic

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Discovering the Lipid Bilayer

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