Enzyme convergence is more than meets reductionist's eye

[Such_Saturation]

An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases

During the evolution of the malate and lactate dehydrogenase superfamily, pyruvate activity has converged multiple times despite strong constraints due to epistasis. While epistasis may constrain evolutionary options locally, there are nevertheless multiple ways to ‘skin the cat’ in more distant regions of protein sequence space. [...] Therefore, residues remote from the active sites necessarily affect the substrate specificity of the enzymes. In principle, these long-range epistatic residue interactions could differentially modify the structure of the active site. [...] However, the crystal structures reveal ancestral, intermediate, and modern active sites that are nearly indistinguishable, suggesting that epistasis has modified the protein dynamics or shifted the energy landscape, effects that are largely invisible to static crystal structures.

 

[visionofstrength]

Score one for Peatian metaphysics!

 

[jaa]

I'm not sure how that is a point against reductionism, probably because I don't understand much of what it's saying. Sounds impressive though. Do you mind explaining it in easier to understand language S_S and how it's a point against reductionism? And how Peat is against reductionism?

(I realize that could take a long time and understand if you don't want to)

 

[Such_Saturation]

I think Peat mainly talks of a reductionism as the idea that, for example,

would be indistinguishable from a real duck because what we perceive as its main characteristics are mimicked by the gears and belts. You always fail eventually if you base your theory on this idea.

In this particular example, the scientists thought that only parts of the enzyme close to its active site would be important for its function. Not only were the simple modifications they applied by this principle unable to mimick the natural evolution that brought it from MDH to LDH - and this made them think that parts far from the active site were responsible - but the active site itself did not change ("virtually indistinguishable") during evolution of the enzyme, while its function changed drastically. By active site I think they mean the part that actually comes into "contact" with the substances.

 

[visionofstrength]

Such_Saturation explains this better than I can in his post. I've just done a search of RP's works (http://www.toxinless.com/peat/search) for 'dogma' and quoted three instances of what RP sees as the "reductionist dogmas" below, followed by quotes of RP describing his Peatian reality:

1. The reductionist dogma that cells contained an internal map and an internal clock telling them when and where to move and how to change their form and function as they matured and aged.

In Peatian reality, cells communicate with surrounding cells and with the material between cells. The existence of long-range ordering processes between atoms, molecules, and cells threatened some of the central dogmas of the sciences.


2. The reductionist dogma that hormones act through "receptors" (or active sites).

In Peatian reality, a hormone such as estrogen, by influencing the cell's water-structure in a particular way, could in an organized way alter the function of a large number of enzymes and physiological processess. It is analogous to melting or loosening the structure of the water, which can be seen to occur in a variety of other cellular states, for example, in cancer, aging, and lack of oxygen.

3. The Central Dogma of molecular biology, namely, that information flows only from DNA to RNA to protein, and that the cancer tumor, for example, differs genetically from the host, as a result of mutations, and "Directed mutations" are impossible.

In Peatian reality, genetic changes are known to occur in response to specific substances, which lead to adaptation to that substance, and when tumors are grafted onto the amputated tail stump of a salamander, which has good regenerative ability, the tumor is transformed into a tail, by its envirornment, or morphogenic field.

 

[jaa]

Thanks for the clarification guys. The reductionism Peat refers to is different than reductionism as I understand it. My understanding of reductionism is that as you break physical laws down to their more fundamental constituents (say humans to cells to quarks), your model for how things work map better to reality. It may be impossible for humans to be able to compute how we function on a quark level, but in theory if we could we would be able to model our social interactions better than sociologist. Or if that gets doesn't jive with you because of your views on free will, the example I've heard before is modelling an airplane in terms of our current understanding of aerodynamics, vs if you had a model of the quarks of air on earth and the quarks making up an airplane. The latter would take much more computational power, but the model would be more accurate.

What Peat seems to saying is that the reduced cellular model most people use has major flaws. This isn't a flaw in the idea of reductionism, just the cellular model currently in vogue.

 

[visionofstrength]

The reductionism Peat refers to is different than reductionism as I understand it. My understanding of reductionism is that as you break physical laws down to their more fundamental constituents (say humans to cells to quarks), your model for how things work map better to reality. ... What Peat seems to saying is that the reduced cellular model most people use has major flaws. This isn't a flaw in the idea of reductionism, just the cellular model currently in vogue.

Thanks! I think I see what you mean. I think here Peat calls into question whether the goal of reductionism, as you say, breaking "physical laws down to their more fundamental constituents (say humans to cells to quarks)", can ever be achieved, or should even be attempted. For example, Peat fundamentally rejects the cartesian division between mind and matter, a view that others share. See haidut's post here: viewtopic.php?f=10&t=4334

I think Peat questions as misguided or corrupt the authoritarian patrinomy, beginning with Descartes, that has pursued reductionism in the first place, wasting much effort and ignoring much good science that did not conform to the prevailing "reductionist" model. See S_S's post here: viewtopic.php?f=10&t=4379&p=52625#p52625

 

[Such_Saturation]

Thanks for the clarification guys. The reductionism Peat refers to is different than reductionism as I understand it. My understanding of reductionism is that as you break physical laws down to their more fundamental constituents (say humans to cells to quarks), your model for how things work map better to reality. It may be impossible for humans to be able to compute how we function on a quark level, but in theory if we could we would be able to model our social interactions better than sociologist. Or if that gets doesn't jive with you because of your views on free will, the example I've heard before is modelling an airplane in terms of our current understanding of aerodynamics, vs if you had a model of the quarks of air on earth and the quarks making up an airplane. The latter would take much more computational power, but the model would be more accurate.

What Peat seems to saying is that the reduced cellular model most people use has major flaws. This isn't a flaw in the idea of reductionism, just the cellular model currently in vogue.

Any behaviour at any level maps perfectly to reality because it must use its language to exist. The problem is when reductionists think it's ok to isolate a problem and give it an isolated solution (reductionism says it's ok to do this because you have already "reduced" that subject of study to those gears and belts which can be removed without altering their function).

Think of membrane channels and pumps: when scientists saw that the membrane let potassium through (the membrane was already an invention) they thought about little openings for it. Then they saw sodium went through and had to imagine larger channels for sodium (why would you need more than one channel if they're bigger). Then they saw that sodium was less concentrated inside the cell, so they imagined little pumps working 24/7.

They turned biology into hydraulics because that was something they were accustomed to and which had a high degree of "reductionability". You can think of a pump spinning without thinking about anything else. However even that is not truly "reducible" being a physical system (think of the water hammer effect). It just allows such fallacies to reside in the margin of error.

If you envision every process as a global event you might find it difficult or slow at first, but that is just a state of mind (which is inherited from the previous generation). The key is to study the space between agents as a dynamic entity, not primarily the two agents that interact or the changes that they undergo.

 

[jaa]

"Any behaviour at any level maps perfectly to reality because it must use its language to exist."

I disagree with this, but agree with the rest of your post. As humans, we are adapted to our world. Our senses detected a narrow range of what exists and that pushes or pulls us in certain directions to hopefully help us survive. There exists a reality beyond our everyday senses that we do not experience. That's not to say the subjective experience is wrong, or doesn't exist, just that it's our own personal reality, and it's merely a model of reality that we experience because that's how we evolved. If you relied on your sight to delineate the entire light spectrum, you would be missing a huge chunk of the absolute light spectrum. As you reduce things further and further, you get closer and closer to this absolute reality. Newtonian laws are very accurate for explaining motion on our scale. General and special relativity are even more accurate, but take longer to compute. Theoretically, there is a fundamental reality that will explain the laws of physics even better than Einstein's equations. And everything else for that matter. We may never get there, but that doesn't mean it doesn't exist.

 

[Such_Saturation]

"Any behaviour at any level maps perfectly to reality because it must use its language to exist."

I disagree with this, but agree with the rest of your post. As humans, we are adapted to our world. Our senses detected a narrow range of what exists and that pushes or pulls us in certain directions to hopefully help us survive. There exists a reality beyond our everyday senses that we do not experience. That's not to say the subjective experience is wrong, or doesn't exist, just that it's our own personal reality, and it's merely a model of reality that we experience because that's how we evolved. If you relied on your sight to delineate the entire light spectrum, you would be missing a huge chunk of the absolute light spectrum. As you reduce things further and further, you get closer and closer to this absolute reality. Newtonian laws are very accurate for explaining motion on our scale. General and special relativity are even more accurate, but take longer to compute. Theoretically, there is a fundamental reality that will explain the laws of physics even better than Einstein's equations. And everything else for that matter. We may never get there, but that doesn't mean it doesn't exist.

It is about which approach is quickest at achieving progress. Nowadays a 4% response benefit in 3% of cases of one kind of cancer is posted on all major scientific journals as a breakthrough. Now you could give me the "little engine that could" speech, but the real issue is we have stopped researching how to best research. Ascribing something to the field of philosophy, or trying to dismiss fields that join two different academic areas are just a way for a powerful academic to retain his place and salary.

 

[Such_Saturation]

We were looking at insulin wrong: Protective hinge process enables insulin to bind to cells