I recently finished reading Peter Hochachka's book, Muscles as Molecular and Metabolic Machines. This book is simply a review of muscle cell physiology from the molecular machine perspective. In my opinion, it provides an excellent example of the way ID can be used to conduct and present scientific findings.

Hochachka begins by asking a truly insightful question:

The working parts of the complete muscle machine are proteins- contractile proteins, structural proteins, enzyme proteins, channels, pumps, transporters, and so forth - and a conservative count indicates well over 100 such machine parts in any given muscle. Since most occur as cell-specific isoforms, the random assortment of these machine parts or protein isoforms in theory could generate an astronomical number of muscle machines (fiber types). But this does not occur and the question is, why not?

Note Hochachka's angle on this question:

To attack this problem, I complemented the reductionist approach with an integrationist/adaptational one that again extended from genes to proteins, and this is where the fun really began. Analysis of how these components work led to the realization that all levels of the muscle machine - at information transfer to the contractile elements, at the energy consuming contractile elements per se, at the energy consuming relaxation processes, and at the energy regeneration pathways - the system is being driven more and more by highly efficient interactions between muscle components, less and less by diffusion-based processes proposed to be dominant in traditional paradigms.

The "intergrationist/adaptational" approach is simply the IC approach, where it is realized that for function to occur, many independent parts must be integrated in highly specific ways. What Hochachka finds is that muscle is more machine-like than anyone may have suspected. The process of diffusion plays a secondary role while the primary control mechanisms employed involve physical interactions between parts that channel substrates directly to each other and also mask or unmask the catalytic potentials of various components. In the future, I'll provide some examples if anyone is interested.

The bottom-line is that the Paleyian view of life is vindicated with muscles. The internal workings of a muscle cell fit very well with the features of the watch that led Paley to infer design. The machine paradigm also solves Hochachka's question:

In other words, since function depends on well-matched parts, only a small set of parts can carry out any specific function. Hochachka drives this point home with a simple example:

We suggest that the isoform design of the overall system is one reason why the realized number of muscle types is only a minute fraction of the maximum number theoretically possible. Just as the drive shaft of a sports car would not do in a cement truck, troponin c isoforms in fast muscles may not be suitable for slow muscles; fast muscle Ca ATPase may be debilitating to slow muscle, while slow muscle presynaptic Ca channels would simply not work well enough in fast muscle, and so forth.

Hochachka ends his book with the following paragraph:

The analogy with working machines seems entirely appropriate. It is biological machinery we are talking about, but machinery, nevertheless. As in any man-made counter-part, fine-tuning (of isoform content and composition) is of course possible and may be desirable, but large-scale change in any one component of the overall system may well be expected to reverberate throughout the whole system. That is why the effects of any one of the host of modest mutations (causing single but large magnititude change in any one component of the system) are, in machinery analogy, like a spanner in the works. Misplaced spanners are intolerable in man-made and muscle machines.

Of course, what is disappointing is that Hochachka doesn't see the implications. Despite treating muscles as machines and finding how this illuminates and solves problems, despite writing sections entitled, "Design Criteria for ...", despite recognizing that one change here is useless or detrimental without several other changes over there, Hochachka is willing to attribute the design to natural selection. No where in his book does he explain how natural selection built slow and fast muscles when intermediate forms and combinations don't work. No where does he even explain when muscle evolved, from what did it evolve, and how it evolved. This book is an excellent guide for showing not only the utility of the design approach, but how natural selection and evolution are added as after-the-fact considerations, incapable of guiding the research themselves.

One final quote:

One of the unexpected spinoffs of writing this book was the recognition, which all scientists probably consider from time to time, of how powerful are the constraining forces of prevailing paradigms in shaping thinking and research in science. When first introduced, new theories expand insight and are intellectually liberating, but the exact opposite can occur, especially in problem areas that are relatively intractable for prolonged periods of time (well illustrated in the field of regulation of muscle energetics). In such cases, prevailing paradigms become prevailing dogmas which tend to stifle creativity and to imprison the imaginative mind.

I don't think I need to explain the relevance of this quote.

Nitric oxide (NO) is a gas that plays an important role in the nervous system (memory/long term potentiation) and the cardiovascular system (regulation of blood flow). Every time your heart beats, epithelial cells (which line the inner wall of your blood vessels) release small bursts of NO which have long been thought to passively diffuse to the underlying smooth muscle to trigger their relaxation, thus increasing blood flow through the vessels. Yet this system has always seemed poorly designed, as the hemoglobin (Hg) that is carried by the red blood cells (RBC) has an extremely high affinity for NO. Thus, it would seem that much/most/all of the NO secreted by the epithelial cells is wasted (as it is scavenged by Hg).

However, a recent study (1) has cleared the air, such that Stephen Gross, in reviewing the study (2), writes, "Signalling by NO is not simple, random or mediated exclusively by diffusion."

It increasingly appears "that a physiologically significant fraction of the NO that enters red blood cells - previuosly thought to be irreversibly consumed by reactions with hemoglobin - re-emerges and returns to the blood vessel wall as a biologically active S-nitrosothiol molecule. Here, the S-nitrosothiol acts as a cloaked form of NO activity that is protected from reacting with hemoglobin."

But there is more to it than this:

Okay, so how does the cloaked NO get out of the RBC? It has long been known that the anion-exchange protein AE1 anchors a subpopulation of hemoglobin molecules on its cytoplasmic face. But thanks to the study Gross reviews, we now have evidence that hemoglobin is handing-off its NO to the AE1 exchange protein. In fact, Gross writes:

Thanks to the exquisite specificity of this system, we may have a situation here where NO is directly transferred into the endothelium every time a red cell bumps up against it.

As Gross states, "Simple passive diffusion as the prototypic mode of signaling by NO is a concept that is failing fast."

It was long thought that water enters and leaves a cell entirely by osmosis across the lipid phase of the membrane. Of course, those who specialize in studying water transport know better, as a whole class of water transporters, known as aquaporins, have been discovered in everything from humans to gm+ and gm- bacteria (acquaporins are even found in the simplest of cells, Mycoplasma).

A recent review (3) highlights some more crystal work that shows how individual water molecules can enter and leave a cell while excluding smaller things like ions and protons.

Aquaporins are proteins with six domains that cross the membrane connected by five loops. The six domains orient as pairs of three whereby two of the loops interact to form what appears to be an aqueous path through the protein. The channel structure is considered unique and has become known as an 'hourglass' because it has wide external openings and a central constriction. Let me simply quote from the review as it describes this channel:

1. Pawloski et al., 2001. Export by red blood cells of nitric oxide bioactivity. Nature 409: 622-625.

2. Gross, SS. 2001. Targeted delivery of nitric oxide. Nature 409:577-578.

3. Zeuthen, T. 2001. How water molecules pass through aquaporins. TIBS 26:77-79