And that membrane has several different functions. One is to transport nutrients into the cell and also to transport toxic substances out of the cell. Another is that the membrane of the cell, which would be the plasma membrane, will have proteins on it which interact with other cells. Those proteins can be glycoprotein, meaning there's a sugar and a protein moiety, or they could be lipid proteins, meaning there's a fat and a protein. And those proteins which stick outside of the plasma membrane will allow for one cell to interact with another cell.
Two solutions containing two different initial concentrations of different salts are separated by a membrane. In this case, the membrane is impermeable to anions but permeable to cations. Donnan thermodynamic calculations and experiments showed that, contrary to what could be initially thought, the two cations do not just interchange with each other until they are equally distributed in the two compartments. Instead, equivalent quantities of both cations cross the membrane; as their initial concentrations are different, the cation which was initially less concentrated proportionally crosses the membrane more than the initially highly concentrated cation.
Nonetheless, the impermeability hypothesis was progressively abandoned when new works measured the outflow of radioactive cations more precisely and calculated a more reasonable amount of energy to account for the active cation transport—the active transport hypothesis became predominant [ ]-[ ].
The idea that cell membranes hosted important metabolism-related carriers or transporters was not totally new pink boxes in Figure 3.
Another transport suggestion was that the membrane had components to which ions could be linked and which could change their conformation to allow the ions crossing the membrane [ ].
It was soon suggested that proteins may be the agents of this ion transport [ ], although this option was not immediately accepted [ ].
Eccles depicts in the coupling between a metabolic-driven ion pump and several different channels [ ]. Burgen suggests in that molecules cross pores thanks to specific and dynamic interactions with them [ ].
Mitchell describes in an enzymatic-like protein transporter embedded in the membrane [ ]. From an early date, Danielli and collaborators considered the possibility that channels may have existed within their paucimolecular hypothesis redrawn from [ ].
Still, in the early s, very little was known about the active transporters themselves. Important progress came from studies on excitable membranes and the transport of non-electrolytes. For some decades, the membrane breakdown was a popular mechanism to account for ion crossing even among those authors who thought that membranes had pores [ ],[ ].
Of course, according to this hypothesis, the action potential could not possibly surpass the resting potential. Yet, when direct measures between an internal and an external electrode became possible in , it appeared that the action potential was larger than the resting potential [ ]: A mechanism different from the membrane breakdown was necessary to explain these observations.
In his lecture for the Nobel prize, Hodgkin highlighted the fact that, in spite of their radical discovery, little was still known about how these ions flows took place. Another related issue also attracted much attention: How could the ions cross the membrane against their gradient after the action potential to recover the values observed at the resting state? This question had already been asked by Overton 50 years before [ ],[ ] and the proceeding answers had been the same as those trying to explain ion distribution asymmetry see previous section.
For instance, Conway suggested that his mechanism based in the Donnan equilibrium could also explain the resting potentials in the nerve [ ], but attention progressively moved to active transport as this hypothesis became dominant [ ]. Excitable tissues became one of the favorite models for the study of active transport.
In , Skou found a connection between the ATPase and the ion-dependent activity present in the hydrophobic fraction—membrane—of the nerve for which he also earned a Nobel prize [ ]. This observation launched an overwhelming interest on ATPases that led to a fast accumulation of data covering ATPases from different species, tissues and functions [ ]. By , some ATPase features relevant in understanding membrane structure had become conventional wisdom: 1 the active transporters were located in the cell membrane Figure 11 A ; 2 they spanned the membrane and were asymmetric, i.
As we will see next, this progress in transport understanding was paralleled by simultaneous studies on non-electrolyte uptake.
The combination of all these different studies reinforced the notion that membrane proteins were enzymes strongly related to metabolism and cell bioenergetics. How non-electrolytes entered the cell was also a matter of speculation for a long time [ ].
Initially, if non-electrolyte molecules had crossed the membranes either through their lipid component or through a putative pore, regular diffusion should have been sufficient in predicting their permeability rates. On the contrary, several puzzling observations started to accumulate in the first quarter of the XX th century. For instance, it was shown that the intestine absorbed some sugars more easily than others, even when stereoisomers were compared [ ]-[ ], and that some sugars entered the erythrocytes faster when the external concentrations were lower [ ],[ ].
This result advanced the involvement of transporters in non-electrolyte permeation [ ]. In the s, a revitalized interest in transporter kinetics revealed that some molecules acted as transport inhibitors [ ],[ ] and that transporters were regulated by their own substrates [ ].
These results bolstered the connection between transporters and enzymes not only in eukaryotes but also in bacteria [ 63 ],[ 71 ],[ ],[ ]-[ ]. As a result of the accumulation of kinetic, genetic and energetic data, new transporter hypotheses emerged in the s.
The classical view was that the transporter was a molecule present in equivalent amounts on both sides of the membrane and able to simply shuttle the attached molecule from one side to the other [ ],[ ]. Figure 11 summarizes the many new transporter modalities envisioned in the s and s [ ],[ ]: 1 a mechanical small transporter propelled from one side of the membrane to the other [ ]; 2 a membrane-spanning carrier able to flip-flop; 3 a division of the membrane into rotating segments; or 4 a channel-like protein in which the substrates could specifically interact with different amino-acids along the pore [ ].
An additional, provocative and fruitful hypothesis was added by Mitchell in [ ]. His model Figure 11 C is striking at first because it clearly assumed the transporter to be a protein embedded in the membrane; such a protein was metabolically-driven, enzyme-like and able to swing its attaching site from one side of the membrane to the other according to its conformational changes.
As a former student of Danielli, he actively tried to fill the gap between the community working on cell membranes and those who studied the metabolism [ ]. In addition to his suggestion for a transporter, his chemiosmotic hypothesis certainly marked a turning point in the way membranes were envisioned.
Here too, it would be inappropriate to trace back a detailed account on bioenergetics from their origin see [ ],[ ] for details. Suffice it to recall that in the formulation of the chemiosmotic hypothesis accounted for the inclusion of the respiratory chain within the proton-impermeable membrane. According to this hypothesis, the membrane-located respiratory chain employed the energy liberated from redox reactions to translocate protons across the proton-impermeable membrane, and the resulting proton gradient was then available for use by membrane-embedded ATPases to synthesize ATP [ ].
Although this suggestion first encountered a vigorous opposition, it became progressively accepted as supplementary studies refined it and some of its predictions were confirmed [ ],[ ],[ ]. Of particular interest for us was the demonstration that uncoupling agents of ADP phosphorylation and electron transport did not mediate their effect through a direct enzymatic inhibition but through the increase of proton permeability across lipid bilayers [ ],[ ].
This experiment supported the hypothesis that lipids were accessible in the cell surface while contradicting the dominant paucimolecular model in which phospholipid bilayers were insufficient to keep an ionic gradient. In summary, the s and s were full of discoveries seemingly tangential but actually tightly related to cell membranes.
These debates concerned the cell permeability, the formation of gradients or the connection with metabolism. The sound transformation that took place in these fields during those years improved knowledge of many membrane components, especially proteins.
The pumps, transporters, respiratory chains and ATPases studied in these lines of research required that membrane proteins had access to both sides of the membrane.
Although the existence of transmembrane proteins was far from being totally accepted, these hypotheses certainly impacted contemporary ideas on membrane structure at a time not yet dominated by the fluid mosaic model. Electron microscopy emerged in the s and the first attempts to apply it to the elucidation of cell structure rapidly followed. However, it was not until the s that sharper resolutions allowed the direct observation of cell membranes [ 88 ],[ ],[ ].
In addition to corroborating their existence, the visualization of cell membranes was expected to provide a powerful tool to investigate their structure. Paradoxically, instead of making things clearer, electron microscopy images launched 15 years of a passionate debate over cell membrane structure light green boxes in Figure 3. Indeed, the interpretation of the pictures obtained was difficult and naturally influenced by former conceptions of membrane structure.
This hypothesis tried to reconcile both the paucimolecular model and the pore theory: on the one hand, the plaques and fibers were thought to correspond to the protein envelope of the membrane of the paucimolecular model; on the other hand, the variable space left among the plaques was suggested to account for the variability of pore diameter in the mosaic model. The same year, , Frey-Wyssling and Steinmann examined the thylakoid surface of plant chloroplasts with the electron microscope [ ].
They saw a granular surface and suggested that thylakoid membranes were made up of globular lipoprotein subunits—a possibility that would be extensively explored in the next decade.
The improvement in electron microscopy resolution and sample preparation also allowed for the observation of membrane cross-sections. These pioneering works raised the question of what visual structure should be assumed as the limit of the cell [ 8 ].
This question was very challenging given the biological materials that were often used for these observations: Muscle, nerves and microorganisms displayed complicated external structures that made it difficult to determine which layer corresponded to the cell membrane. Even when extracellular structures had been discarded, the interpretation of the remaining superficial layer of the cell was still not self-evident. Yet, which one among the whole structure or one of the dense parts should be considered as the quintessential cell membrane?
In , Robertson compared a collection of cross-section pictures and observed that the whole railroad track was consistently observed in a variety of cells. He thought that the railroad track fit the paucimolecular model, assuming that the dark parts were the protein layers sandwiching and the lighter, the lipid bilayer. As a result, he considered the whole structure to be the cell membrane. The controversial formulation of the unit membrane hypothesis announced a relentless confrontation in the s between the predominant model at the time the paucimolecular hypothesis and the plethora of other membrane explanations suggested by the increasing amount of contradictory information.
Many authors called into question the idea that one unique membrane model could account for all biological membranes because it seemed contradictory to the large membrane diversity that was being discovered at the time [ 9 ],[ ]. For example, it had been observed that the protein-lipid ratio from different membranes could vary from to , suggesting that the amount of membrane proteins was not always enough to entirely cover the cell surface [ 9 ].
In addition, the lack of resolution prevented the observation of the railroad track in some bacteria, thus implying that the three-layer structure was either not always visible or not universal [ ]. The wide functional diversity of membranes also seemed to contradict the unit membrane: How could the insulating membrane of myelinized nerves have the same structure as the metabolically active membranes responsible for oxidative phosphorylation and photosynthesis [ 9 ]?
For some time, the idea that biological membranes could be made up of specific subunits seemed appealing. These hypotheses were natural extensions of the previous thylakoid electron microscopy images by Frey-Wyssling and Steinmann and were popularized by the observation of similar repetitive structures in the chloroplast [ ],[ ], mitochondria [ ],[ ] or even plasma membranes [ ].
These hypotheses generally implied that the subunits could be different from one membrane to another and account for membrane functional diversity [ 9 ]. As it was becoming more generally accepted that lipids and proteins mainly interacted through their hydrophobic parts, some authors imagined the subunits as dynamic micellar mixes of proteins and lipids [ ],[ ].
Electron microscopy images from viral capsides also lent credit to the view that membranes could be made up of subunits [ ]. From an historical perspective, it is noteworthy that these models emphasized the dominant role of proteins as the major structural components of membranes—a fashionable idea at a time when radical developments were being made in molecular biology [ ]. The so-called subunits that were being observed most likely corresponded to the functional proteins that dominated the mitochondrial and chloroplastic membranes, for example, ATPases or photosystems.
Given the criticisms, even advocates of the paucimolecular model were compelled to adopt some modifications. For example, in a review, Brady and Trams incorporated some characteristics that prefigured the modern formulation of the fluid mosaic model: 1 the proteins also penetrated the membrane and, therefore, the membrane was a lipid-protein mosaic; 2 membranes were not homogeneous but could have membrane segments specific for some permeability functions; 3 the lipid components of the membrane were fluid; and 4 membrane formation was ruled by the thermodynamic search of the lowest energy structure [ ].
Although the debates mostly crystallized around the unit membrane and the subunit-based hypotheses, the change in perspective that allowed the prevalence of the fluid mosaic model was highly impacted by the gathering of conclusive evidence from new techniques.
Most studies on amphipathic molecules so far had been focused on molecular monolayers. The first lipid bilayers were artificially prepared in the s by Mueller and collaborators red boxes in Figure 3 , thus providing a much more suitable model to be compared to the biological membranes [ ].
Synthetic membranes showed that lipid bilayers were stable even when proteins were totally absent. The addition of proteins to artificial lipid membranes gave some insight into the capacity of peptides to confer permeability and excitability in membranes [ ],[ ].
Moreover, when artificial lipid bilayers were examined with the electron microscope, it revealed a railroad track similar to biological membranes [ ]; this result was at odds with the idea that dense layers corresponded to the proteins coating the membrane in the paucimolecular model.
Finally, a better understanding of the parameters that ruled lipid interaction allowed Bangham and collaborators to prepare the first liposomes i. In fact, liposomes had been observed as early as by Virchow [ ],[ ]; they had been studied by Lehmann and Reinitzer at the turn of the century [ ],[ ] and lipid suspensions had been made throughout the century, but previous authors had failed to understand that liposomes enclosed an aqueous phase [ ].
Now the liposomes would rapidly become important structures in the study of membrane permeability and allowed a fruitful comparison to the biological membranes.
The first electron microscopy results had been criticized because the native structures were suspected to be modified by the chemical fixation of the biological material [ 9 ]. In this technique, the sample is frozen for fixation and fractured before it is examined with the electron microscope light green boxes in Figure 3.
Branton and collaborators carried out further analyses both with natural and artificial lipid membranes in the late s. They found that the freezing technique kept the hydrophilic interactions at the surface but canceled the hydrophobic forces in the interior of the membrane, thus allowing the membrane to be broken apart between the two lipid bilayers [ ],[ ].
As the interior of the natural membrane became visible, some protuberances were reported on the internal side of each monolayer that were mirrored by depressions in the opposite monolayer.
One of the earliest questions of membrane studies was if the membranes were better depicted as liquids or solids [ 65 ],[ ],[ ]. A giant step forward was made in by Frye and Edidin when they fused two cells one human, one mouse together in order to monitor the fate of their membranes [ ] dark green boxes in Figure 3. Each cell carried different surface antigens whose movements could be monitored using a fluorescent antibody.
After the cell fusion, the two membrane fluorescences became progressively intermixed, thus suggesting that the membrane components were able to freely diffuse in the membrane plane. As previously explained, the first definitions of amphipathy, hydrophobicity and hydrophily were sought in the s dark green boxes in Figure 2 and 3.
However, it was not until the s that works like those from Haydon and Taylor emphasized the dramatic role of thermodynamics to determine the structure of biological membranes [ ]. Even once the thermodynamic argument had entered the discussion of biological membranes, the first attempts to account for these constraints failed to fully assess their intensity.
Hydrophobic and hydrophilic interactions were shown to rule the contact between lipids and proteins [ ], yet the early hypotheses often assumed that micellar mixes of lipids and proteins would have been the more stable structures [ ], thus favoring the subunit-based models. A significant breakthrough was achieved when the study of membrane protein conformation became possible.
The early paucimolecular model had depicted the coating proteins as globular [ ], but in the s the evolution of the model had led to the assumption that the proteins were unwrapped in a conformation similar to a beta sheet [ ].
In , several studies showed that the membrane proteins had an alpha or globular conformation rather than a beta structure [ ]-[ ]. The alpha helices were suggested to cross the membrane, thus providing a structural framework to the transmembrane proteins that had been predicted in the permeability and transport studies.
These works also acknowledged the importance of the thermodynamic constraints to determine the lipid-protein interactions and were especially influential because some of their authors, especially Singer, took part in the formulation of the current version of the fluid mosaic model. In and , Singer and Nicolson presented their fluid mosaic model of cell membrane structure.
The basics of the model have remained the same ever since: the membrane is a lipid bilayer with hydrophilic parts on the sides and hydrophobic parts in the interior; proteins can interact with the surface through transient polar contacts, but a lot of proteins are partially or totally embedded in the lipid bilayer where their hydrophobic parts also interact with the hydrophobic parts of lipids Figure 1.
In the light of the historical account on cell membrane discovery that I have reported, it is apparent that the success of the fluid mosaic model lay not so much in its originality as in its timeliness and scope: It accommodated most of the evidence available at its time and made predictions that would be demonstrated later.
On the one hand, the model was supported by evidence from different origins: 1 the permeability and transport studies that predicted enzyme-like transmembrane proteins [ ]; 2 the apparent lack of lipids to make up complete bilayers [ 94 ], thus pointing out to the participation of proteins in the membrane plane; 3 electron microscopy pictures, including freeze-etching studies that suggested the presence of proteins within the membranes [ ]; 4 the stability of artificial lipid bilayers that supported them as suitable and sufficient components to make up structures similar in the biological membranes [ ]; and 5 the favorable conformations predicted for the membrane proteins [ ].
On the other hand, the model was even more influential owing to the assumptions that it highlighted or newly predicted. First, as it was soundly established on thermodynamic grounds, the model enhanced the study of hydrophobic forces, which would subsequently become one of the major explanatory parameters to describe the biological macromolecules [ 2 ]. It is important to point out that, more than any generalization from biological observations—as was the case in the unit membrane, for example—the fact that the model is based in universal physico-chemical constraints is the most convincing argument for its general application in biology.
Moreover, the acknowledgement of the thermodynamic hydrophobic constraints improved our understanding of membrane proteins, which in turn significantly improved our picture of membranes [ 6 ]. Some dramatic landmarks in membrane protein depiction were the early resolution of the first tridimensional structure of a transmembrane protein the archaeal bacteriorhodopsin, [ ] ; the development of the patch-clamp technique, which allowed the understanding of single ion channels [ ],[ ]; the discovery of the rotatory catalysis that allows the ATP synthesis by ATPases [ ]; and the late discovery of the aquaporins [ ],[ ], which are water channels essential to understanding the water movements that have intrigued cell biologists for more than a century [ ].
Interestingly, now that our knowledge on membrane proteins has developed, the importance of lipid interaction for protein folding is becoming clearer and is still a promising line of research for the future [ ],[ ]. Second, since this model is intrinsically fluid, it predicted that the distribution of most molecules in the lateral range would be essentially random, but it also suggested that specific clusters i.
Although mainly ignored for some time, these microdomains have been the subject of intensive research in the last 20 years and the recent introduction of new techniques should continue to improve our understanding of interactions among membrane components [ ],[ ]. Finally, the asymmetry of membranes has also proven to be a fruitful characteristic to explore.
The idea that membranes had different components in the inner and outer sides of the membrane was not new, but this hypothesis was taken one step further because the model provided an explanation: The high, free energy of activation necessary for the hydrophilic part of a membrane component to cross the hydrophobic membrane core prevented the random tumbling [ 1 ].
Hence, the asymmetry which was already suspected for the oligosaccharides [ ],[ ] was rapidly extended in the s to lipids, transmembrane proteins or peripheral proteins—for instance those related to the cytoskeleton [ ],[ ]-[ ].
In summary, since its formulation in the s, the fluid mosaic model has been modernized to account for further observations, but it has barely been altered. It remains the most explanatory hypothesis to understand biological membranes. Although the subject of cell membrane discovery could certainly be developed further, the information reviewed here should already be enough to point out the major limitations of the majority of previous, short historic accounts on this topic [ 5 ]-[ 7 ],[ 9 ],[ 10 ],[ ].
These criticisms are not necessarily related to his well-known concept of scientific revolutions, but I will also briefly tackle the question in order to broaden the perspective of this review. Interestingly, the formulation of the modern fluid mosaic model has recently attracted some epistemological interest [ ]. This recent work suggested that the fluid mosaic model did not drive out its predecessor through a complete revision of available data in a Kuhnian sense; instead, it was the result of a synthesis effort between new pieces of evidence and different models.
According to this analysis, I think that if the history of the discovery of cell membranes can illustrate some dramatic change in perspective in biology, it should be the transition from the understanding of the cell as a colloid to the bounded, highly concentrated solution currently in use. I think that this transition could be understood in Bachelardian terms as a discontinuity between the pre-scientific era of biology and modern science [ ].
Yet, it is not in the scope of this review to carry out a detailed epistemological analysis on the history of the Cell, so I will now move on to the other Kuhnian arguments that I think to be directly relevant to the critical analysis of the cell membrane historiography. When Kuhn tried to explain the difficulty in accounting for scientific revolutions, he made a particular case for the analysis of the sources of authority, i. He criticized that most of these sources did not provide a comprehensive historical account of the actual events in the way they were understood at the time of their discovery.
These texts instead presented individual experiments or thoughts that could be easily viewed as explanatory contributions to the current paradigm. Although these devices may be adequate for pedagogical purposes, such a presentation distorts the actual historical reconstruction. The stake in this strategy is not only that it may contribute to hide a scientific revolution, as Kuhn feared, but also to make an inaccurate and oversimplified historiography become repeated and established.
These inaccuracies have probably little impact on our current membrane research, but we should be aware of their existence in order to avoid perpetuating a historically questionable timeline. I hope that this review will encourage other scholars to critically revise our short accounts on fields traditionally underrepresented in the History of Science studies as, for example, cell biology, microbiology and biochemistry. The historical analysis of the formulation of the current membrane model is not only relevant to those interested in membranes: it may also provide some lines of reflection on early evolution, the minimal cell concept, the origins of life and synthetic life.
All these subjects question our vision of the cell, and the membrane is arguably one of the most essential components of the unit of life concept. To begin with, we can step back to ask the question of the very necessity of the unit of life notion. It has been argued that the Cell Theory stands on the biological atomism, which postulated the existence of a basic indivisible unit of life well before any precise description of this unit could be made [ ]. According to this appealing analysis, the atomistic idea remained implicit along with the new discoveries that led to and established the Cell Theory.
Determining the appropriateness of biological atomism is a deep epistemological question, which is not the matter here. Yet, if we accept that the unit of life is a reality that we can study in spite of the diversity of opinions on the identity of this unit, the current preferred candidate for this position among biologists remains the Cell.
Therefore, as all known cells are bounded by cell membranes, understanding the importance of these structures becomes crucial to our current definition of the unit of life. The historical analysis supports the progressive acknowledgement in the last decades of the importance of cell boundaries in the fields of early evolution and the origins of life [ ]-[ ]:. As the unit of life, the cell entails some kind of identity that differentiates it from other cells and from the environment.
Since it also has a composite structure, the cell requires a mechanism to keep all its components together. Historically, two mechanisms have been envisioned: either all the components remain together because they establish direct interactions in a physical network the colloid chemistry or they are compartmentalized by some structure.
It is important to remember that even after the discovery of the cell membrane, the colloid hypothesis survived many years and was only replaced when the biological macromolecules started to be analyzed as discrete structures. This is relevant to the origins of life, as well as synthetic life studies, because it supports current thinking that the compartmentalization is one of the very basic characteristics of any cell [ ]-[ ], no matter how primitive or minimal it may be.
The membrane embodies one of the main paradoxical characteristics of life: a cell is a system dependent on external compounds and energy to keep the differences that it maintains with the same environment where it gets its raw material. Although membranes were thought for a long time to be passive structures that just allowed solutes to diffuse across them, we now know that modern membranes are necessarily endowed with the ability to control the entry and exit of molecules depending on their needs, even sometimes against the chemical gradients.
According to this observation, it seems important to include a thought about active transport mechanisms in all works trying to describe the nascent life. This does not mean that complicated structures, like proteins, had to be present from the very start of compartmentalization. For instance, transmembrane gradient formation based on membrane dynamics and alternative transporter molecules e.
RNA molecules have been studied in recent years [ ]-[ ]. We can expect that the awareness of the importance of active transport for all cells will soon attract more attention to this fascinating subject from the researchers working on the origins of life. Contrary to early assumptions about membranes, one of the major foundations upon which the fluid mosaic model is built is their ever-changing dynamic structure. This allows modern membranes to constantly change their activities according to the requirements of the cell and it is likely that the same could have occurred in early membranes.
Such a hint is promising because it could intersect with the increasing interest of the origins of life field in studying the changing abilities of membranes made up from mixed amphiphile solutions [ ]-[ ]. Finally, there are at least two fundamental aspects of membranes that have not been discussed in this review because their contribution to the understanding of membranes was low, but they cannot be neglected when referring to membrane contributions to cells.
These are the division of membranes and their role as transducers of messages from the environment. Although membrane division has already attracted some attention in the context of the origins of life [ ], very little is known about the interactions among early cells. Hopefully, both subjects will be further explored in the near future. I thank the reviewers for their comments. The manuscript has been revised twice taking into account their remarks.
This manuscript by Jonathan Lombard provides a very thorough and detailed historical account of the evolution of the notion of cell boundaries over the years that spanned between the initial recognition that living organisms were comprised of cells, in the middle of the 17th century, and , with the advent of the fluid mosaic model, and the now generally accepted view that all living cells are surrounded by biological membranes made of lipid bilayers.
Although I am not competent to judge the accuracy of this historical report, and would not know if equivalent works have been published previously, I feel that this manuscript should represent a valuable addition to the field, and that the final parts of the manuscript, and the discussion in particular, raise several interesting questions and prospects.
All these good things being said, despite the tremendous amount of historical work which has clearly gone into assembling this manuscript, I must admit that I have found the reading of this manuscript to be rather cumbersome, and even very hard work for the early historical parts. I have communicated numerous corrections and editorial suggestions to the author directly, and hope that this will help him to produce a revised manuscript that will be easier to read, and thus more useful for the scientific community.
The overall structure of the new version of the manuscript has remained unchanged, but I have rewritten many paragraphs and shuffled some sections in order to clarify their message. I have also tried to make the transitions between paragraphs more fluent and I have removed redundant information to make more obvious the common thread of the text.
The new version of the paper has been checked by a professional journalist native in English who helped me to make the reading smoother. Thus, I think that the current version of the manuscript should be more easily readable than the first version. In this long paper, the author describes, in considerable detail, the history of biological membrane research, with an emphasis on the role of the membrane as the active cell boundary that determines what gets into or out of the cell and what remains inside or outside.
It is rather surprising to read, as a submission to a biology journal, an article that earnestly addresses the intricacies of the history of research in a particular field, without making much effort to formulate any new concept on the functions or evolution of membranes. This is not a criticism, the history of concepts and misconceptions is useful and interesting in itself.
What is missing, from my perspective, in this article, is any discussion of organellar and other intracellular membranes as well as membranes found in virions. The intracellular membranes are indeed a fascinating subject of study and I would have been glad to introduce them in my review. Therefore, I have preferred to stick to the core of the subject, namely the origins of the membrane concept and the fluid mosaic model. As for other fields, I referred to intracellular membranes only when their study directly contributed to the storyline that I was trying to highlight in this paper.
But I will consider the possibility of preparing a separate review about the history of intracellular membranes. 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.
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. 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. 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.
Like transport proteins, receptor proteins are specific and selective for the molecules they bind Figure 4. Figure 4: Examples of the action of transmembrane proteins Transporters carry a molecule such as glucose from one side of the plasma membrane to the other.
Receptors can bind an extracellular molecule triangle , and this activates an intracellular process. Enzymes in the membrane can do the same thing they do in the cytoplasm of a cell: transform a molecule into another form. Anchor proteins can physically link intracellular structures with extracellular structures. Figure Detail. Peripheral membrane proteins are associated with the membrane but are not inserted into the bilayer. Rather, they are usually bound to other proteins in the membrane.
Some peripheral proteins form a filamentous network just under the membrane that provides attachment sites for transmembrane proteins. Other peripheral proteins are secreted by the cell and form an extracellular matrix that functions in cell recognition.
In contrast to prokaryotes, eukaryotic cells have not only a plasma membrane that encases the entire cell, but also intracellular membranes that surround various organelles. In such cells, the plasma membrane is part of an extensive endomembrane system that includes the endoplasmic reticulum ER , the nuclear membrane, the Golgi apparatus , and lysosomes. Membrane components are exchanged throughout the endomembrane system in an organized fashion. For instance, the membranes of the ER and the Golgi apparatus have different compositions, and the proteins that are found in these membranes contain sorting signals, which are like molecular zip codes that specify their final destination.
Mitochondria and chloroplasts are also surrounded by membranes, but they have unusual membrane structures — specifically, each of these organelles has two surrounding membranes instead of just one. The outer membrane of mitochondria and chloroplasts has pores that allow small molecules to pass easily. The inner membrane is loaded with the proteins that make up the electron transport chain and help generate energy for the cell.
The double membrane enclosures of mitochondria and chloroplasts are similar to certain modern-day prokaryotes and are thought to reflect these organelles' evolutionary origins. This page appears in the following eBook. Aa Aa Aa. Cell Membranes. Figure 1: The lipid bilayer and the structure and composition of a glycerophospholipid molecule. A The plasma membrane of a cell is a bilayer of glycerophospholipid molecules. Figure 2: The glycerophospholipid bilayer with embedded transmembrane proteins.
What Do Membranes Do? Figure 3: Selective transport. Specialized proteins in the cell membrane regulate the concentration of specific molecules inside the cell. Figure 4: Examples of the action of transmembrane proteins. Transporters carry a molecule such as glucose from one side of the plasma membrane to the other. How Diverse Are Cell Membranes? Membranes are made of lipids and proteins, and they serve a variety of barrier functions for cells and intracellular organelles.
Membranes keep the outside "out" and the inside "in," allowing only certain molecules to cross and relaying messages via a chain of molecular events.
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