Cell Membranes

Molecular Biologist Richard Henderson on the lipid bilayer, mitochondria, and the evolution of organisms

videos | December 12, 2016

The video is a part of the project British Scientists produced in collaboration between Serious Science and the British Council.

Cell membranes are very important, they’ve been around for about 4 billion years, since the very first cells on Earth were developed, at the early stages of the evolution of life. The cells became more important, but the key characteristic of cells is that they’re surrounded by an envelope that seals them from the outside world. So the key function of the cell membrane is to separate the inside of the cell, which is controlled by life processes, from the outside of the cell, which is the environment. And then through time different functions of the cell membrane have evolved to give to cell the ability to cope in the big world.

So for many years it wasn’t known what the cell membrane was made of other than that it’s a barrier between the inside and the outside of the cell. But about… probably about a hundred years ago from now originally Gorter and Grendal studied the red blood cell in the human body and extracted from the cell the fats, the lipids that are now known to be one component of the membrane. And they showed that there are enough lipid molecules in the membrane of a cell to make two complete layers covering the cell, and that was the origin of what was the original lipid bilayer theory of the cell, which is that it’s made up with largely lipid molecules which have a hydrophobic (that means “a water-repelling”) end to them and then a hydrophilic (a “water-loving”) end, so the hydrophobic is fat, and the hydrophilic is sugars and phosphates and things like that. So you have this molecule, the lipid, that has a hydrophobic and a hydrophilic end, and they pair together to form a bilayer. A lipid bilayer surrounds the cell. And for quite a while that was mostly what was known about the cell membrane.

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But about half of the matter in cells is also made up of protein, so it’s protein and lipid. And so about 1935 Davson and Danielli enhanced this original theory of the lipid bilayer and thought, hypothesized that the membrane  was made up of the lipid bilayer with the protein on each surface. And that again stood for a while until in the mid-70s  Singer and  Nicolson came up with a more sophisticated model and that is our current view of cell membranes and their structure. And it was called ‘the fluid mosaic model’. And in this model, the membrane is a two-dimensional fluid in which lipids flow around as a bilayer, and then interspersed among the lipid there are the protein molecules essentially diffusing and floating around in the lipid. Some of these protein molecules are loosely attached to the outside, some on the inside, but some go completely through the membrane. And actually Mark Bretscher who is in the MRC, laboratory of molecular biology, at that time, he was the first one to show that two different membrane proteins, again in the red blood cell, could span the membrane from the inside to the outside, he labeled it with different chemical labels and showed that they span the membrane. And these two proteins, glycophorin and band 3 (it’s their nickname), band 3 transports ions across the membrane and glycophorin simply acts as a tag for the sugar. That was the first time when it was known that you have the lipid bilayer, you have the proteins associated with it, but this showed how the proteins were associated with it.

And then, mid 70’s to mid 80’s, people started to study the proteins and how they are incorporated into the membrane. And our work, that’s work that I did with Nigel Unwin back in 1975, we determined the very first low-resolution structure of the membrane protein called bacteriorhodopsin and then, about ten years later, there was another membrane protein structure, the reaction centers from bacteria or green plants which absorb light and convert that light energy into other forms of cellular energy. And so with those two membrane protein structures you had a real image of the protein structure with the polypeptide chain, proteins are made up of a polypeptide, the polypeptide crosses the membrane back and forward in the form of a helical structure, that’s the α-helixes that Linus Pauling had hypothesized back in 1950 and that had been found in the myoglobin – the very first protein structure, but not in the membrane.

So now we’ve gone from knowing the structures of some nonmembrane proteins to now knowing the structure of the first two membrane protein structures. And then with time our understanding of the nature of the cell membrane has become more detailed, and so now we know, for example, that the lipid molecules (which before were just a generic class), we know partly from Mark Bretscher’s work, but partly from subsequent work that all the glycolipids (that means these fatty hydrophilic/hydrophobic molecules that have a sugar molecule on it; “glycolipid” means having a sugar molecule), those lipids are all on the outside facing the outside world, and then on the inside you have acidic or zwitterionic (that means they have two charges, positive or negative) facing the inside. And then similarly there are now known thousands of membrane [components], each one of them has a different structure and the membrane proteins have a different function, so there are multiple different functions in the membrane, each one catalyzed or activated as by a little molecular machine which is either the protein molecule or complex of protein molecules.

So all of the multiple functions of the membrane sensing the outside world are transporting small molecules inside or outside the membrane or signaling to the outside world. Each one of the functions of the proteins in the membrane, which help the cell to communicate and interact with the outside world, they are performed by all these different protein molecules.

And then with time as life evolved from single-celled organisms up through higher eukaryotes, many different types of specialized membrane evolved under Darwinian natural selection evolution and in a normal cell, for example, in a human or in an other eukaryotic organism, there are many different types of membranes that characterize the different substructures in the cell, for example, there is the nucleus, it has a membrane, the nuclear membrane; there are the mitochondria which are the energy center of the cell, they produce ATP, they have two different membranes, and in fact it’s thought that mitochondria and chloroplasts, two subcellular organelles, it’s thought that they are both derived from the capture of an early type of bacteria by other single-celled organisms, so you have the so-called endosymbiont theory and everybody believes this now. So that’s two of the organelles, but there’s also the endoplasmic reticulum, where molecules are synthesized on ribosomes and are secreted, or put in the membrane, or put into the cytoplasm, and then through the Golgi apparatus through lysosomes they are secreted to the outside world. So now you have a much richer understanding of how cell membranes work based on the specific proteins that are put there under genetic control from the DNA and allow the cell to have its normal function and interact with the outside world. That’s a reasonably good overview of cell membranes.

One interesting question is – what is the difference between the membranes that surround cells, which would be a single membrane, and the membranes that form the compartments within cells. And there are probably ten or a dozen well-characterized different types of membranes, and of course, each one of them could be the topic of another lecture, but let me just give a brief summary of them.

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So in the beginning, there would be single celled organisms with a single membrane communicating with the outside world. As life evolved, many of these bacteria developed a double membrane, so, for example, in bacteria you have an inner membrane and an outer membrane. The inner membrane usually carries out all of the most complicated and difficult to engineer activities of the cell: transpoting, recognition, signaling and so on. The outside membrane, by contrast, is often a protective layer to protect is against [the ourside world], so it has a cell wall or an outer membrane that isn’t so complicated in its function but is acting as a buffer to screen the cell from adverse conditions outside, that would be in a bacterium, and you then go to higher forms of life, multicellular organisms and there you have tissues and cells and organelles and so on – many different organelle types, like kidney cells, liver cells, the cells in the retina, brain cells, neurones, and each one of those cells will have a different organization. But in many eukaryotes there is a similar underlying structure: the nucleus, mitochondria, and chloroplasts in energy production or in plants that are responsible for a large part of the energy budget – producing and consuming the energy in the cells. So mitochondria and chloroplasts are specialized organelles that have a particular function, and again, each one of those has an inner and an outer membrane. And you could have a lecture about how mitochondria work, but generally they absorb nutrients, metabolize them, produce ATP and then (ATP is the molecule that is a chemical store of energy that is commonly called the ‘energy currency of the cell’), so when it goes out into the cytoplasm, it is used by the many different functions of the cell. ATP has a phosphate group on the end of the molecule, cleaved off it becomes ADP which is then imported back into the mitochondria, re-energised and sent back out, so mitochondria have an ADP–ATP translocase that is exchanging and charging up the cell. So the mitochondria are producing all the energy in the cell. Chloroplasts, on the other hand, are absorbing light and then they are converting that into initially a membrane potential, which is then converted again into ATP, which goes out into the cell.

And then in eukaryotic cells, you have a nucleus containing all the DNA. The nuclear membrane separates nucleus from the cytoplasm, so the DNA is transcribed into RNA that goes out into the cytoplasm, translated by a ribosome into proteins that are either secreted into the cytoplasm or through the endoplasmic reticulum (sort of another membrane structure that’s in the cytoplasm), and in the endoplasmic reticulum in eukaryotic cells the proteins are either put into the membrane or secreted through into the interior of the endoplasmic reticulum and there via the Golgi and various vesicles they eventually end up outside the cell. So there’s a secretion pathway that is organized by a series of different membranes and in each and all of these different membranes you have different proteins that give each of the membranes their character.

And what is not known, and this is one of the future secrets that a young scientists wishing to win a Nobel Prize might like to aim for, we do not know quite what it is that makes the Golgi apparatus into the Golgi, the endoplasmic reticulum into the endoplasmic reticulum, but it’s a self-organizing system for which there is a missing theory that a lot of the cell biologists, neurobiologists in this laboratory, as well as in other parts of the world, are quite interested in trying to understand. In the area of cell membranes, this is probably the one big problem that is not solved: exactly what is it in each cell that gives each type of membrane its particular characteristic. Obviously, once it’s constructed, it’s synthesized, we know how it works, we know the proteins in them, but what it is that controls how is it that the endoplasmic reticulum remains endoplasmic reticulum, how does the cell membrane remains [the cell membrane], how does the Golgi remains [the Golgi apparatus]… That is an unsolved problem, and so that’s something for the future.

Professor of Molecular Biology, University of Cambridge
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