Chapter 5 - Membrane Flow Models
Membrane Flow Models
Some theories of capping and particle movement propose that the entire cell membrane, or parts of it, are continuously circulating around the cell surface. The inadequacy of those theories is explained and the published evidence refuting them discussed.
5.1 Membrane Flow Models
5.2 Criticisms of the Flow Models
5.3 The Response of the Field
5.4 My View of the Flow Models
5.5 Current Status of the Membrane Flow Model
Summary
5.1 Membrane Flow Models
It is traditional, during Oxford and Cambridge summers, for young people to take to the water. The young undergraduate will invite his undergaduette friend for a picnic and punt ride. While he poles upriver, against the current, she will recline in the front of their craft and trail her hand lightly in the water, while admiring his youthful masculinity. Together, in the countryside and sunshine, they will consume a picnic of sandwiches and champagne. Then, finally, they will lie together in their punt as they drift back downriver, discussing matters of mutual interest, such as the shape of her nose, or Hegel's contributions to contemporary philosophy.
Drifting with the current is the mechanism proposed by the flow model (Fig. 5.1). The idea that the whole membrane of the cell flows from front to back, arose following observations of particle movement (Bray (1973)). Bretscher, modified these ideas to suggest that only the lipids of the membrane were flowing (Bretscher (1976)). This, they reasoned, would account for capping and particle movement, because the patches or particles would move with the current of lipid, while smaller proteins would diffuse faster and not be swept along by the current of lipid. Both Bray and Bretscher published their flow hypotheses in the journal Nature.
The flow pattern suggested has certain requirements. It can occur only if the cell takes in membrane (endocytosis) largely at the rear of the cell while the reverse (exocytosis) must occur largely at the front. Some mechanism of rapid transport of the membrane vesicles from back to front through the cytoplasm is then needed to complete the cycle and set up a continuous membrane flow (See Fig. 5.2). The rate of endocytosis and exocytosis must be large. Cells can cap in a couple of minutes, so the membrane flow models require that the entire membrane of the cell turns over in less time than this. Bretscher suggested that only the lipid, not the membrane proteins, circulated this way and consequently that some filter existed in endocytosis to remove proteins but permit lipids through. He has since advocated this idea with great force and determination and seems to have worked on nothing else during this period.
The rates of endocytosis and exocytosis can be estimated experimentally and are not nearly fast enough to make the flow models viable. In addition there is nothing to suggest that endocytosis is confined to the rear of the cell, or even predominates there. The situation is exactly the same for the insertion of membrane at the front. Likewise, there is nothing to support the belief in a protein filter that would enable flow to be confined to lipid and not take place among proteins. There is no evidence that the interior of the cell can move vesicles along at the rates required for this model. Finally, the process of continuously circulating the cell membrane would be very energy consuming. It is not clear why the cell would expend such a large amount of energy.
The hypotheses involved are all very ad hoc. In other words, the flow model entirely fails to relate capping and particle movement to the remainder of cell biology. Similar mechanisms are not known elsewhere in biology so the evolvability criterion is broken. The flow models have large metaphysical elements incorporated into them; flow itself, lipid filters, localised exocytosis and endocytosis, a rapid transport mechanism for vesicles inside the cell are all postulates of existence. Positive evidence for them is necessary before the flow model should sensibly be accepted or even seriously considered.
All of the above was apparent very soon and most scientists have been unwilling to accept the flow models. Even so, they have been the subject of careful experimental tests culminating in the work of Kucik, Elson & Sheetz (1989); Sheetz et al. (1989); Lee et al. (1990) published by Nature and Science. Of these, the last is the most direct and easy to understand (though not to carry out in practice). Lee et al. used a technique called photobleaching to, effectively, draw a line on the membrane of active cells. They argued that, if the membrane were flowing, this line would move across the surface of the cell. They looked for such movement and found none. They were able to directly conclude that the membrane does not flow at the rates required by the membrane flow models.
This is very elegant and very clear. A classic application of Popperian logic - the flow model should be rejected. So far as it goes this is true but "A Habit of Lies" would be unnecessary if things were so clear and easy. The point to emphasise is that, although not accepted, the flow model was treated seriously, placed on the scientific agenda and tested. The gatekeepers opened their gates to the flow model and held it to be serious science deserving of serious test.
This author reacted to the lipid flow hypothesis with disbelief. Bearing in mind the necessary link between capping and motility, it proposed that the cell moves essentially as a tank does, on tracks or that the cell surface is like a conveyor belt. The concept survives today in the cytoskeletal flow model (discussed in Chapter 6) but nowhere in biology, known to this author, is such a mechanism known to have evolved. Bretscher's model is tantamount to suggesting the caterpillar track as the motile mechanism for almost every cell of the body. Truly a revolutionary and daring idea but its metaphysical concepts enjoy almost no positive support.
Even this upheaval is not sufficient to make the flow model work. Cell surface particles move backwards faster than the cell moves forward, in some cases very much faster. To account for the observations in particle movement, in some cases the membrane must move at 50 or more times the rate at which the cell itself moves. This would involve phenomenal expenditure of the cell's energy to no apparent purpose and once more break the link between capping and motility. The flow models are entirely unrealistic.
The membrane flow model remains an interesting scientific phenomenon if only for the socio-scientific questions it throws up. Why was such an idea, with extremely complex and improbable connotations, treated so seriously for so long? Why did the gatekeepers of the field admit it so willingly as a realistic and important scientific idea? Why was so much money spent on it?
The flow models were proposed, indeed Nature, an extremely influential scientific journal, published and gave great prominence to them. The ideas had considerable impact and were widely cited in scientific papers. Scientific quality indicators, such as citation analysis would certainly show these ideas to be excellent. Even after the published disproofs, Bretscher still professes to believe the ideas he advanced, although the evidence against flow seems clear and unequivocal.
Faced with the failure of such predictions and the lack of positive evidence for its assumptions, most observers now discount membrane flow as wrong. Nevertheless, that is not the end of the matter. The years of thinking about flow have taken their toll and its concealed influence lingers. The underlying absurdities of the membrane flow model hide in the ideas advanced to replace it. The very scientists whose studies so convincingly eliminate the flow model proffer in its place the cytoskeletal flow model, little more than a hybrid of the flow and cytoskeletal models. This chimera brings to its task all the deficiencies of its inadequate parents and is the subject of the next chapter.
This Chapter has :-
- Reviewed the history of the flow models - the idea that cell membranes continuously flow.
- Explained the deficiencies of this as an explanation of the phenomena of capping and particle movement.
- Summarised the present status of the field and mentioned the evidence disproving the flow models.
- Noted that the underlying ideas of the flow model, remain influential in the cytoskeletal flow model.
© Copyright John A Hewitt.
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Last Modified 22 October 2005