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.
In order to account for the suggestions made by the third reviewer, the final section of the conclusion has been considerably changed. The review by Lombard is a nice survey on the evolution in understanding the nature of cell envelopes in the course of past three centuries. It is an entertaining reading indeed and there is not much to comment. Introduction, line 31ff : The reader can get an impression that any lipid molecules tend to join into a membrane bilayer as the most thermodynamically stable structure.
This is not the case. One of conditions of forming a bilayer is a match between the sizes of the hydrophobic and hydrophilic parts of the molecules involved [1]. If the hydrophilic head is larger, then the most stable structure is not a bilayer, but a micelle. In biological conditions, cell phospholipids form a bilayer in which hydrophobic tails face each other in the core of the structure whereas the hydrophilic heads interact with the water molecules in the sides Figure 1.
It might be interesting to know whether they remained a historic curiosity or there is a historic connection with modern chemical engineering of nanoscale systems. I had never thought about precipitation membranes in the perspective of nanostructures. Unfortunately, I do not know anything about chemical engineering of nanoscale systems, and this would be a subject too distant from the rest of the review to be included in it.
But I appreciate the comment and I will keep it in mind for the future. While Singer, as it can be followed from his publications, was particularly interested in understanding the nature of biological membranes, Peter Mitchell was more interested in the processes of membrane transport and mechanisms of energy conversion.
Thereby Mitchell - and his colleagues - needed implicitly some working model of a biological membrane. Thereby Mitchell did not make any statements on the nature of biological membranes. Furthermore, the very fact that chemically quite different, small proton-carrying molecules could uncouple oxidative phosphorylation by diffusing across membrane bilayer as shown first by Skulachev and co-workers [4], this reference should be included , implies the presence of free lipid patches accessible from the water phase for these small molecules; it is across such patches that the uncoupling molecules could diffuse.
Again, Skulachev and co-workers did not discuss the presence of these free patches because they were interested in understanding the mechanism of energy conversion. Still, their working model of the membrane should have been that of a mosaic membrane.
However, the studies of energy conversion did not provide - at least at that time - any information on the lateral motility of proteins in the membrane. It is not incidental that the paper of Singer and Nicolson [5], in addition to an extended analysis of literature data, also provided experimental evidence of the protein mobility in native membranes.
This was the truly new piece of evidence that helped to compile a whole picture of a fluid, mosaic membrane. Their work certainly influenced the way membranes were considered, but it was not used as a piece of evidence to directly oppose the predominant paucimolecular model. The citation to Skulachev and colleagues has been included in the new version of the manuscript. Thomas Kuhn has developed his theory based on the history of physics, therefore his model does not work as nicely with less exact subjects.
This kind of development can be hardly imagined in physics. I would suggest skipping or modifying this section. Apparently the message was not clear enough in the first version of the paper, so I have modified the text to emphasize more this point. This does not imply that early membranes had to have a developed protein apparatus for selective transport, but whatever the nature of the specific transporters present in the primordial cells, their functions are arguably very ancient.
From my opinion, several different subjects are mixed up in this passage. They deserve being sorted out. The very fact that proteins and lipids diffuse within the liquid matrix of the bilayer means that biological membranes are dynamic. As far as I know, the dynamic nature of biological membrane has not been challenged neither by authors of the mentioned references and [7, 8]. The apparent usage of dynamic and active as interchangeable terms by the author makes this passage even more confusing.
The models in the mentioned references and [7, 8], which are accused in implying passive membranes, in fact, build on an assumption that the very first membranes could be impermeable to large polymeric molecules but leaky to small molecules. This vision of primordial membranes is not quite original and could be traced to the studies of Deamer, Luisi, Szostak, Ourisson, Nakatani and their co-workers [].
These authors argued that abiotically formed amphiphilic molecules, most likely, fatty acids of phosphorylated, branched polyprenol-like compounds [10, 12, 14, 18, 19], which may have enveloped the first cells, could not be as sophisticated as modern two-tail lipids. Vesicles formed from such molecules are million times more leaky that vesicles from modern, two-tail lipids [18]. Hence, such vesicles could trap large polymers but not small molecules and ions.
This leakiness, however, could have been a key advantage. In turn, this would favor the development of systems that could trap small molecules by attaching them to intracellular polymers - and thus preventing their escape.
Hence, leaky membranes could have driven the emergence of different polymerases, including the translation system. The feasibility of such a mechanism has been experimentally shown [13]. Accordingly, even the first abiotically formed membranes mentioned in [7, 8] should have been both dynamic and active according to Lombard.
The leakiness to ions per se neither makes a cell membrane passive nor obligatory kills the cell. Even a leaky membrane will faithfully maintain all disequilibria that concern large polymeric molecules.
Modern cells are quite robust concerning the tightness of their membranes. In a previous version of this manuscript, I used both terms indistinctly to refer to what should only be considered as active transport. Although I had found the reading of the initial version of this manuscript to be rather cumbersome, I must say that I am impressed by how improved and easier to read the revised version has become, and I am now confident that it represents a very useful addition to the scientific literature.
For instance, recent works have shown that transmembrane gradients across lipid bilayers could spontaneously arise in prebiotic conditions [,]. It has even been argued that RNA molecules could have acted as transporters [ ],[ ].
From this wording, the reader can get an impression that refs. However, this is not the case. Such a difference could not arise spontaneously, i. Accordingly refs. The ref. And, finally, the ref. However, Chen and Szostak themselves emphasized that the formation of the proton gradient was driven by thermodynamically favorable incorporation of the new hydrophobic fatty acid molecules into the membranes of the vesicles.
Hence, the formation of the proton gradient was not spontaneous. Chen and Szostak observed the formation of the transmembrane pH difference under very special conditions where polar, charged, and bulky arginine molecules were used as the only cations in the medium. The seminal article of Chen and Szostak, in fact, shows that:. To summarize, the author of the review fails to provide any experimental evidence of a spontaneous formation of transmembrane gradients across primitive lipid bilayers in prebiotic conditions.
I thank the reviewer for his careful lecture of the article. I did not mean this part of the paper to be as controversial as the reviewer seems to find it to be. The main objective of my review is to provide a new survey on the history of the discovery of cell membranes. I think that this subject is even more exciting when it is placed in the context of modern debates about early membranes.
But the issue of early membranes is a wide and hot topic and this review is not the place to discuss it into detail.
This review was never intended to provide experimental data about transmembrane gradient formation in early membranes. I hope that the reviewer will find these changes satisfactory. I request explicitly that my comments to the manuscript should be published together with the complete reference list [that I provided].
The following are the references cited by the reviewer in his comments:. Q Rev Biophys , 13 2 — Mitchell P: A general theory of membrane transport from studies of bacteria. Nature , — Lenard J, Singer SJ: Protein conformation in cell membrane preparations as studied by optical rotatory dispersion and circular dichroism. Science , — Szathmary E: Coevolution of metabolic networks and membranes: the scenario of progressive sequestration.
Deamer DW: The first living systems: a bioenergetic perspective. Microbiol Mol Biol Rev , 61 2 — Orig Life Evol Biosph , 42 5 — Chem Biol , 14 3 — Ourisson G, Nakatani Y: The terpenoid theory of the origin of cellular life: the evolution of terpenoids to cholesterol. Chem Biol , 1 1 — Chem Biodivers , 4 5 — Mansy SS: Membrane transport in primitive cells. Cold Spring Harb Perspect Biol , 2 8 :a Trends Biochem Sci , 34 4 — Orig Life Evol Biosph , 35 2 — RNA , 10 10 — Trends Genet , 21 12 — JL is responsible for the conception of the review, the bibliographic analysis and the manuscript.
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Arch ges Physiol. Brooks SC: The accumulation of ions in living cells-a non-equilibrium condition. Brooks SC: The intake of radioactive isotopes by living cells. Annu Rev Biochem. And those proteins which stick outside of the plasma membrane will allow for one cell to interact with another cell. The cell membrane also provides some structural support for a cell. And there are different types of plasma membranes in different types of cells, and the plasma membrane has in it in general a lot of cholesterol as its lipid component.
That's different from certain other membranes from within the cell. Now, there are different plants and different microbes, such as bacteria and algae, which have different protective mechanisms.
In fact, they have a cell wall outside of them, and that cell wall is much tougher and is structurally more sound than a plasma membrane is. In water, these molecules spontaneously align — with their heads facing outward and their tails lining up in the bilayer's interior. Thus, the hydrophilic heads of the glycerophospholipids in a cell's plasma membrane face both the water-based cytoplasm and the exterior of the cell.
Altogether, lipids account for about half the mass of cell membranes. Cholesterol molecules, although less abundant than glycerophospholipids, account for about 20 percent of the lipids in animal cell plasma membranes. However, cholesterol is not present in bacterial membranes or mitochondrial membranes.
Also, cholesterol helps regulate the stiffness of membranes, while other less prominent lipids play roles in cell signaling and cell recognition. In addition to lipids, membranes are loaded with proteins. In fact, proteins account for roughly half the mass of most cellular membranes. Many of these proteins are embedded into the membrane and stick out on both sides; these are called transmembrane proteins.
The portions of these proteins that are nested amid the hydrocarbon tails have hydrophobic surface characteristics, and the parts that stick out are hydrophilic Figure 2. At physiological temperatures, cell membranes are fluid; at cooler temperatures, they become gel-like. Scientists who model membrane structure and dynamics describe the membrane as a fluid mosaic in which transmembrane proteins can move laterally in the lipid bilayer.
Therefore, the collection of lipids and proteins that make up a cellular membrane relies on natural biophysical properties to form and function. In living cells, however, many proteins are not free to move. They are often anchored in place within the membrane by tethers to proteins outside the cell, cytoskeletal elements inside the cell, or both. Cell membranes serve as barriers and gatekeepers.
They are semi-permeable, which means that some molecules can diffuse across the lipid bilayer but others cannot. Small hydrophobic molecules and gases like oxygen and carbon dioxide cross membranes rapidly. Small polar molecules, such as water and ethanol, can also pass through membranes, but they do so more slowly.
On the other hand, cell membranes restrict diffusion of highly charged molecules, such as ions, and large molecules, such as sugars and amino acids. The passage of these molecules relies on specific transport proteins embedded in the membrane.
Figure 3: Selective transport Specialized proteins in the cell membrane regulate the concentration of specific molecules inside the cell. Membrane transport proteins are specific and selective for the molecules they move, and they often use energy to catalyze passage. Also, these proteins transport some nutrients against the concentration gradient, which requires additional energy. The ability to maintain concentration gradients and sometimes move materials against them is vital to cell health and maintenance.
Thanks to membrane barriers and transport proteins, the cell can accumulate nutrients in higher concentrations than exist in the environment and, conversely, dispose of waste products Figure 3. Other transmembrane proteins have communication-related jobs.
These proteins bind signals, such as hormones or immune mediators, to their extracellular portions. Binding causes a conformational change in the protein that transmits a signal to intracellular messenger molecules. 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.
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