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Paradigms Revisited and Chemiosmosis

September 27, 2011

From time to time, it will be appropriate to offer updates (or upgrades) of previous posts when it seems appropriate. In late March, I looked at ‘paradigm shifts’ in biological science, particularly in the context of so-called biological ‘dark matter’. Here a Table was provided with a list of some developments in recent bio-history which could qualify as paradigm shifts, especially against the current background where the meaning of a scientific ‘paradigm’ has been diluted in much of the literature. While this Table was not originally intended to be completely comprehensive, after the fact I have noted that a particularly important case was inadvertently overlooked. That is the subject of the current post.

The Chemiosmotic Hypothesis

Cellular processes require energy, and a universal energy ‘currency’ is the molecule adenosine triphosphate (ATP). It has been long recognized that the hydrolysis of ATP to the corresponding diphosphate (ADP) provides the free energy for driving a host of biological reactions. The synthesis of ATP itself is therefore of crucial significance, and naturally requires an energy source in order for this to be accomplished.

In 1961, a British biochemist by the name of Peter Mitchell published a paper in Nature outlining a novel proposal for the mechanism of the generation of ATP  through the electrochemical properties established in certain biological membranes. These are found in prokaryotes, and also eukaryotes via their mitochondria (the ubiquitous organelles concerned with energy production) or chloroplasts (the plant cellular organelles mediating photosynthesis). Mitchell’s ‘chemi-osmotic’ hypothesis postulated that, rather than relying on an energy-rich chemical intermediary, oxidative phosphorylation (the synthesis of ATP from ADP occurring during respiration) was dependent on proton (hydrogen ion) flow across membranes. In essence, respiratory processes pump protons across an enclosed membrane boundary such that an electrical potential is generated across the membrane. Mitchell termed the ‘pull’ of protons back across the membrane as the ‘proton motive force’, or a proton current. This flow of protons could be directed through protein-mediated channels for the purposes of performing useful work.

Although now enshrined within the modern biochemical world-view, in the early 1960s this notion was quite radical, and not at all in tune with many of the ideas of most major researchers in the field at that time. In fact, it took over a decade a half before enough evidence was garnered to convince most remaining doubters. But Mitchell certainly had the last laugh, being awarded a Nobel Prize for his innovative proposal in 1978.

ATP Synthase and the Chemiosmotic Hypothesis

A remarkable catalytic complex at the core of ATP generation, the membrane-associated ATP synthase (ATPase), has had a central role in the ultimate acceptance of the chemiosmotic hypothesis. This resulted from studies on purified components of the synthase complex and reconstitution experiments, where directed proton flow across sealed model membranes (liposomes) was shown to be crucial for ATPase activity. In some ingenious experiments, the required proton flow was produced by the introduction of a protein involved with prokaryotic photosynthesis (bacteriorhodopsin) as a light-driven proton pump. (Other proton pumps from diverse biochemical sources could also perform similar roles). Such findings were subsequently reinforced by numerous structural and functional studies.

The ATPase has been revealed as a molecular motor driven by proton flow directed through the transmembrane (‘Fo’) component of the catalytic complex. The proton current is harnessed to provide energy for driving the physical rotation of the soluble (‘F1’) ATPase component, resulting in ATP synthesis at three catalytic sites. In some amazing cases of experimental virtuosity, this molecular rotation has been visualized in real time using fluorescent tags, and the association of rotation with ATP synthesis demonstrated by magnetic bead attachment to the F1 subunit, followed by artificial rotation induced by appropriate magnets.

The striking nature of the membrane-associated ATPase as a rotary molecular motor has inspired many offshoot thoughts and speculations. As a demonstration of a ‘natural nanomotor’, it would come as no surprise to hear that that the nascent field of nanotechnology has paid particular notice.

Why a Paradigm Shift?

So, it might be immediately seen that the proposal, experimental testing, and ultimate support for the chemiosmotic hypothesis is of great scientific significance, but is it really meaningful to refer to it as a paradigm shift? Well, yes, it is. Firstly, the initial resistance to this idea in itself is consistent with the view of shift in a paradigm requiring the upheaval and dismantling of an earlier view – if not by the death of an aging cadre of reactionary biologists, at least via their eventual accession to the concept through the accumulated weight of evidence.

But perhaps the most fundamental novelty of Mitchell’s ideas came from the inherent aspect of spatial organization of cellular structures in determining function, as he explicitly stated. In his own words, from his 1961 Nature paper:

 “the driving force on a given chemical reaction can be due to the spatially directed channelling of the diffusion of a chemical component or group along a pathway specified in space by the physical organization of the system”.

In other words, structures on a cellular scale (membranes, in this case) can serve as a basis for directing biochemical reactions in specific ways, and this general effect has also been termed ‘vectorial biochemistry’. This view was a radical proposal in the early 1960s – and accordingly met with considerable resistance.  In fact, cells are not just ‘bags of enzymes’, but partitioned in complex ways into different compartments, and this partitioning is very significant for specific functioning. This is particularly so (as we have seen) for bioenergetics.

The development of some form of membrane compartmentalization of proto-cells during the early stages of the origin of life is recognized as a major evolutionary transition. Its importance can be inferred from simple logic, since an evolving molecular biosystem could never undergo progressive selection and functional advancement were its components not restricted into a bounded spatial compartment. Dilution of reactants would otherwise rapidly remove any useful molecular innovations, and bring in potentially interfering molecules. Included among the latter are likely parasitic systems, whose unchecked activities would be a permanent stumbling block. But the long-term implications of the chemiosmotic principle show us that biological membranes are much more than just phospholipid sacks demarcating collections of biological molecules from the external environment. They are integral and essential parts of biological operations in their own right. And their evolution into these roles is a very ancient event in the history of life. Leaping from early biogenesis to future human aspirations, the importance of membranes and higher-level structures for vectorial direction of function should not be forgotten when artificial cell design is contemplated.

So Mitchell’s contribution is duly inserted into the original ‘paradigm shift’ Table thus:

It is also notable that this year marks the 50th anniversary of the publication of Mitchell’s seminal paper.


And finally, a biopoly(verse) salute to the pioneer:

The hypothesis chemiosmotic

Made Mitchell seem quirky and quixotic

But opinions revise,

And then a Nobel Prize

Sealed the field as no longer exotic.

References & Details

(In order of citation, giving some key references where appropriate, but not an exhaustive coverage of the literature).

‘……a British biochemist by the name of Peter Mitchell published a paper in Nature…’     See Mitchell 1961.

Mitchell’s hypothesis……’     For perspectives of both Peter Mitchell and the chemiosmotic hypothesis see Harold 2001 and Rich 2008.

‘….Mitchell ….. awarded a Nobel Prize for his innovative proposal in 1978.’    See Harold 1978; also the Nobel organization site for the 1978 Chemistry prize.   See also a relevant piece in Larry Moran’s Sandwalk blog.  Mitchell died in 1992.

‘…..studies on purified components of the synthase complex…..’.    A major contributor to these studies was Efraim Racker (1913-1991), A biographical memoir by Gottfried Schatz (National Academies Press, online) provides an excellent background to this and numerous related areas. Paul Boyer and John Walker also were pivotal in structure-function studies regarding ATP synthase, for which they received the Nobel Prize for Chemistry in 1997. For a very recent and comprehensive review of the membrane-associated rotary ATPase family, see Muench et al. 2011.

‘…..the introduction of a protein involved with prokaryotic photosynthesis….’    See Racker et al. 1975.

‘…..nanotechnology has paid particular notice….’    See Block 1997 (Article title “Real Engines of Creation”,  which refers to K. Erik Drexler’s book Engines of Creation, a pioneering manifesto of the potential for nanotechnology – Doubleday, 1986). Also see Knoblauch & Peters 2004.

‘…..artificial cell design…..’    See a previous post on synthetic genomes and cells for more on this cutting-edge topic.

Next Post: Regrettably, work commitments enforce a temporary hiatus on biopolyverse posts until early December. But will return then!!

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