I’m still on the Off Topic series.
The context of this diary is primarily cellular. We’ve moved up a level of biological scale from the previous diary, Transition. Some may suggest that the molecular and cellular scales also define the non-living/living divide (if such a thing actually exists). That topic is beyond the scope of this diary. [Besides, I tend to piss off the philosophers when I talk about the meaning of life, so let’s get better acquainted before we tear the lid off that one.]
One of the minor mysteries in biophysical chemistry is how cells manage to elicit sudden changes in various metabolic and physiologic characteristics, traits, or phenotypes. These changes are in response to signals of fuel availability and physiological exigencies pertaining to the multi-cellular individual as implied by homeostasis. The cohort of human beings pondering these mysteries as a matter of career define the word “manage” in terms of macromolecular conformational changes, enzyme catalysis, and a wide range of interactions between macromolecules and with smaller molecules. The shorthand jargon term for this is mechanism. These are not new questions. They have bugged us ever since the first moving cells were observed.
The question becomes: How do cells organize the molecules within them in order to accomplish the functions that these have been observed to fulfill?
This discussion is in context of all the caveats this community can conjure.
Reductionists search for irreducible dichotomies because they need a foundation (a base camp) from which to begin climbing back, up the mechanistic trail left by those searching for answers to How? They were (are) foiled by the fractal essence of the nested realities uncovered with great care and very skillful means. Posing and investigating questions of purpose, function and meaning, uncovers the conjunction between a purposeful array of these mechanisms. These responses, imbued with direction, spin, character, flavor and charm, are more subtle than engineering. But the prevailing winds of the hyper-Capitalist global market place in which (most) current scientific research is conducted, pushes everything toward potential profit-making paradises just over the horizon. So we rarely get around to Why? But this place is not like the others. It is time to Merge.
To a protein biochemist Why? is a way of asking about function. The question becomes: What roles do particular molecules have in maintaining the various physiological functions of cells, in culture and inside the multi-cellular organisms that constitute their natural environment? This is an extremely utilitarian perspective and any answers uncovered should be interpreted with that notable caveat firmly in mind. That the experimental data published in peer reviewed journals is tinged with the pressures of the market-place is another reason to reconsider extension of these mechanisms to less well-investigated levels of biological complexity. That said, the discussion has barely begun.
Proteins are amazing little shape-shifters that make things happen. These buggers are the workers that implement the genetic bosses’ business plans (so to speak in a potentially analogous tone). In other than political terms, the nucleic acids are the storage media and the proteins (along with lipids and carbohydrate) are the read/write device. The biological twist on the latter analogy is that at the root, the storage media encodes the creation of the parts that, together, comprise the disk drive. Watch Videodrome if you want a graphic version of this analogy (but don’t watch it twice!).
Despite the wide array of molecular mechanisms, each intricately described in terms of how many fractions of an Angstrom atoms move relative to each other, no single enzyme discussed in peer reviewed journals had properties that could account for the bulk of the cellular properties that were routinely observed in other laboratories and discussed in a different set of peer-reviewed journals. In retrospect the answer seems obvious. That’s how it is in the sciences. Understanding how something works, more precisely the act of uncovering how things work, normalizes those mechanisms and they become part of our collective knowledge database. (Thomas Kuhn did not see this, or underrated it, IMHO). Paradigms are nested (PDF), not mutually exclusive or incommensurate. It’s a reflection of how we humans were “raised up” by the whiles of our evolutionary history. The physical aspects of nesting are seen in “fossilized” genes and “vestigial” organs, which would appear as something like a brachial cul de sac within the finer structure of the tree of life.
Some folks climb up mountains to see what it looks like while the sun is high. Others let their mind conceive of what it is like at the active site of an enzyme while the substrate levels are on the rise. The natural beauty is stunning, like the pictures from Hubble or whatever natural wonder is found in your backyard. That much is true (enough). The shapes of these things are basically the same. The shapes of sand dunes are in every snow drift. Truly it is a matter of scale. Each is different, too, of course but the lay of the land; the schematics, reflect similar contours; analogous forces. Mountains are a very apt analogy for biological structure and mechanism because they clearly depict the intersection of multiple time frames (lifetimes) in a visual model that connects with (almost) every one. Mountains are built on the scale of plate tectonics, yet produce flash floods within minutes and influence weather patterns on the scale of months. Metabolic pathways (and the proteins that regulate them) were built on the scale of evolution, yet work to clear post-meal glucose spikes from healthy human circulation within 30 minutes, and also orchestrate the arc of a single human lifetime. Shouts (or mumbles) of “Timing is everything” barely suffice, even if delivered with a cynical sneer and an “I told ya so” glare. I am humbled before the prowess of these natural mechanisms and beseech each molecule to take me as apprentice, that I might learn their ways and dream about practicing their trades.
Some of these have been revealed by the work of J Ferrell, his co-workers and others that describe cellular traits, such as sensitivity to particular extracellular compounds, in terms of the organized interaction of macromolecules (signal transduction, we call it). By similar arguments, it was also possible to account for the progression through cell cycle. One common aspect of these mechanisms is the requirement that a massive response be initiated by some critical signal. Partial responses (to less than critical signals) are not induced. The rationale for this kind of regulation is generally presented in terms of energy and raw material. It is very wasteful of both resources were a cell to proceed partially down the pathway to duplicating its entire genome and checking it for copy errors, not to mention all the rest of the cellular organelles and cytoskeleton, only to reverse course or halt. The cell has to commit, there’s no turning back (other than surviving another turn of the cycle). Likewise for response to hormones and other such compounds, as these often induce massive changes in cellular function and/or growth.
Although many individual enzymes have tremendous cooperative mechanisms, none could account for the observed cellular traits. By nesting the protein kinases (what of phosphatases?) into a cascade, the pathway amplifies the signal from the interaction between receptor and ligand to > 10,000 active molecules of protein kinases by the “end”. But that is not the end of the story. The PKs (PPs) also mediate the appropriate cellular responses that satisfy the signals. The molecular responses are coordinated and thereby alter traits at the cellular level, effectively amplifying the response with regard to biological scale. This apparent amplification of scale, from molecular to cellular, is mirrored by the function of pancreatic beta islets that orchestrate systemic metabolism (homeostasis) by way of blood-borne molecules that act on multiple distal tissues such as muscle and liver.
Another example of scale amplification is the feed/fast cycle in mammals, well any animal really, but we humans prefer to study ourselves, and lab mammals are as close as our evolving brain will allow us to get (most of the time). Consider that all the food you eat on a daily basis is disposed of through the molecular metabolic pathways maintained inside the cells that comprise your body. These include the parts that make feces, urine and sweat. Obviously these are regulated in the temporal sense and coordination of a particular sort is required to maintain a human being for 80 some years. Of course, your cells and the molecules nested within each one are still not quite you, are they? Let alone an ecosystem, or a culture.
The analogies are shifting into focus, yes? It is certainly accurate to refer to the internet, the WWW, and cable TV as “signal transduction” mechanisms. Splayed across the newspapers and web-sites we see that these appear also to function as “amplification” mechanisms. Is it not also accurate to describe the Jasmine Revolution as a “massive response” to a 30-50 years long “signal”? Ultimately, I find these analogies comforting and empowering because they offer us an out as the world closes in. Situations can change quickly, we may not need incrementalism. That should not be interpreted as complacency. We need to maintain the “signals”. We need to maintain to social/political “signals”. We need to build associations between people (the “parts” that comprise the cultural “whole) that will amplify those signals. Moreover, we need to shape the pathways so that when the switches flip, they land where we had hoped. One element of this is embodied in the QH posted David (Reclaiming the Politics of Freedom) and it is rhetorical at the root.
This subject was broached toward the end of Open Left and in regard to the negative example of the attempted assassination in AZ, which may have been a response to the stream of rhetorical noise (another word of stochastic phenomena) broadcast 24/7/365 by those with intentions that oppose the progressive/liberal vision of a cooperative future. I see the Spring blooms of Jasmine as a net positive response, the shape/structure of which it shares with the negative example described. My hope is that by describing something of how these mechanisms appear to operate, I might marshal a few of my fellow humans to view their individual (and collective) actions in the context of everybody else. We need to figure a way to use chaos and instability to our advantage and to provide a purpose to our “noisy” debates and discussions. Recognizing the stochastic nature of the context in which we exist is a beginning.
What Do You Think?
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