Of Thermodynamics, Chemistry, Biology and Biochemistry

The detractors of energy balance theory often say something along the lines that thermodynamics goes out the window in living organisms, the rules don't apply.  Nope.  The existence of the Second Law does not violate the First Law!

This simply isn't true, and those who say similar must simply not understand these fields.  Humans are not bomb calorimeters or Carnot cycle/combustion engines.  When Dr. Eades tried to discredit Anthony Colpo a while back, he and his compadre Feinman waxed poetic and evoked nightmares of steam tables in their college thermo courses.

This application of thermodynamics doesn't have much meaning in human metabolism.  Our metabolic engines don't combust macronutrient molecules, physically contain the gasseous byproducts, and  harness the thermal energy (heat) expanding gasses to move pistons and gears.   A combustion engine basically converts chemical potential energy to thermal energy to mechanical energy -- conveniently combustion produces heat + gases, and if we contain the gas in a piston, heat expands the gas to move the piston.   Living systems getting energy from food involves more of a conversion of chemical energy from one form to another, chemical energy to heat, and chemical potential energy into electrochemical energy.  In a way, we're more like fuel cells than combustion engines.  Heat is often generated as a byproduct of our chemical reactions, but we do not use thermal energy to do work (we do use it to maintain temperature).  It's not the heat we generate "burning fat" that contracts our muscles.  We convert chemical energy to mechanical energy (see for example how muscles contract, animation) and we convert chemical energy to electrical energy (see for example how nerves work).  Mostly our internal engine "cycle" is an electrochemical one where molecules are constantly being oxidized and reduced.  No doubt there are some losses in the various conversions, but they are not analogous to the entropy losses in the Carnot cycle. 

Now I'm not trying to say that entropy has no place in chemistry, just that it "works" in a different way, and has nothing to do with converting heat energy to mechanical work.  All of which is somewhat of a moot point because Atwater factors are for metabolizable energy.  It's somewhat amazing how well they hold up given how they were determined and that these are averages.

But let's look at applying thermodynamics in a relevant context in chemistry.  The tables one would consult would be tables of heats of formation for various bonds and entropies of various compounds.  Then one does a free energy balance calcuation:    ΔG = ΔH - TΔS
   Δ = change in = final - initial
    G is free enery
    H is enthalpy (heat)
    S is entropy 
    T is temperature
A negative change in free energy means that a chemical reaction CAN occur -- not that it will occur, and more importantly not the rate at which it will occur.  Reaction rates are the study of kinetics and rates generally are mostly infuenced by concentrations of the chemicals (reactants), although other factors like temperature are involved.

Note my wording here:  Thermo only predicts that a reaction can occur but not that it will.  Regular combustion is a good example of this.  This is a thermodynamically favored reaction, but I can open the propane controls on my grill and let the tank run out and I won't get flames unless I ignite it.  Chemical reactions have an energy threshold that must be exceeded before they will proceed.  Those with low activation thresholds generally are considered spontaneous because ambient temperatures provide enough thermal energy to get the ball rolling, others, like combustion, need a little help to get started. 

Then there's the issue of kinetics.  In order for A & B to react they need to "collide".  If I've got 40 balls in a lotto tumbler and a sensor on #1 that goes off every time it hits another ball, it would be going off a lot.   If I've only got 4 balls in the same tumbler, #1's sensor will be much quieter!  A chemical reaction we're all probably familiar with is reacting acid (acetic acid in vinegar) with base (baking soda = sodium bicarbonate).  A typical elementary school science demo involves mixing the two in a vessel to which a balloon is attached resulting in gas evolution blowing up the balloon.  The neutralization reaction is thermodynamically favorable with a low activation threshold so it occurs spontaneously.  The whole thing will be over in a matter of seconds.  Now if instead we took dilute solutions of both and mixed them, the reaction would still occur, but it would take longer.

But can chemical reactions that are not thermodynamically favored ever occur?  Sure.  They just require energy from another source.  We also can't forget catalysts (applies to those thermodynamically favored but with high activation thresholds so they often appear not to be).

Congrats if you're still with me {grin}

I went through the whole chemistry -- thermo, kinetics, catalysis -- thing for a reason.  Most of it means NADA in applying biochemistry to metabolism, except that thermodynamics dictates the energy requirements to complete an unfavorable reaction and thermodynamics dictates the energy that can be produced.  We are not beakers full of chemicals sitting on a lab bench with some geek like me adding fats and carbs and proteins and watching what happens.  At any given time thermodynamically unfavorable reactions are occurring throughout our bodies because we input energy to "fuel" them.  And at any given time reactions occur at systemic concentrations well below those needed even for the energetically favorable reactions.  And we have enzymes (biological catalysts) that pretty much determine which reactions are occurring and at what rate, and those enzymes are controlled hormonally and by other factors and peptides.  Very few passive chemical reactions occur in our bodies.  Many "reversible" pathways are mediated by different enzymes -- for example fatty acid oxidation to acetyl-CoA uses entirely different enzymes from the reverse of de novo lipogenesis of fatty acids from acetyl-CoA.  Throw circulation and selective transport across membranes to manipulate local concentrations, and once you put the "bio" in chemistry most of the thermo and kinetics of the chemistry itself goes out the window.

BUT, from a whole body perspective, the first law of thermo still rules.  We can harness X amount of energy from our intake, and various bodily functions require Y amount of energy.  If XY gain fat.

But what of the second law and entropy and the so-called Metabolic Advantage?  If one compares fats to carbs they both are converted to the same Acetyl CoA for entry into the Citric Acid Cycle and Electron Transport Chain.  Aerobic complete glucose metabolism produces 36 total ATP, only 2 of which are directly created in the glycolysis process, another 2 in Krebs, and the remaining 32 in the electron transport chain.   So 2/36 is ~5%, the rest of the energy produced from glucose metabolism  is generated in the same Krebs Cycle and ETC as fats.  Using palmitic acid as an example fatty acid, the LCFA is broken down to acetyl CoA in the "fatty acid spiral".  This produces no ATP directly (each turn of the spiral producing an Acetyl CoA generates NADH & FADH2 that subsequently generate 35 ATP in the ETC), 8 are generated in Krebs, and the bulk of the net 129 ATP's are generated by the ETC.  In other words, 95% of the energy we obtain from carbs is generated by the exact same reactions as the energy we obtain from fats.

But what of gluconeogenesis requirements.  That pathway requires energy.  Fair enough.  But one can presume that other synthesis reactions are down regulated -- de novo lipogenesis for example.  It probably balances out.

But what of futile cycles and heat release?  Futile cycling to "waste" excesses has been demonstrated in humans with massive over feeding of fats.  There's NO evidence that this occurs to any degree with mild over-feeding and certainly not when one is in an energy deficit.

That we do convert some of the chemical energy in our food to thermal energy to maintain body temperature is no mystery.  And that thermal energy is lost to the environment.  So humans aren't closed systems.  But that thermal energy is part of our basal energy requirements and it doesn't violate the 1st law, thermal energy is a term on the "out" side.  Dr. Eades made a laughable comment regarding thermal energy in the comments of one of his Colpo posts -- w/o searching through the comments I'll paraphrase -- he basically said that if the 1st law applied we could gain weight sitting in a hot room and lose weight in a cold one.  Puh leeze.  Nobody has ever claimed the ability to harness heat energy to fuel chemical reactions in human metabolism.  That doesn't violate anything.  And you'll actually lose some weight if you are sitting in too hot a room because the body has to actively try to prevent over-heating.  And actually you can lose weight sitting in a cold room because your "energy out" increases to try to maintain body temp.  This occurs in brown adipose tissue (e.g. "fat burning", but as I've blogged previously that this effect is not diet induced.  Double whammy.

Another related topic is the influence of macronutrient intake on metabolic reactions and rates. Key metabolic pathways are tightly controlled by enzyme activity.  Yes, substrate availability, product concentration, etc. may have an impact on enzyme activity, but many of the common statements made in the LC community to support a theory or dietary strategy, wrongly presume substrates always stimulate a reaction.

First, one that is still on my mind is Taubes' G3P theory.  He basically says that dietary carb is the source of G3P, eat more carbs, make more G3P, esterify more fatty acids to triglycerides.  Another is the too much protein crowd that believes protein will drive gluconeogenesis (and I'm beginning to see more references along this line regarding glyceroneogenesis).  These are all wrong-headed interpretations IMO.  Both of these processes exist to maintain a baseline of critical things:  adequate BG levels and a continual FA/trig cycle.  The latter of which seems crucial in maintaining circulating lipid levels.  As such we seem to be "wired" to utilize these metabolic pathways only to the extent that our bodies need the products, not based on how much substrate is available.  Otherwise, when fasting, when glucose is low, pyruvate would also be low and we would expect slow "genesis" ... but the opposite is known to be true.

I used to think protein was third in line for energy production after carbs and fats, but according to this any "excess protein" can feed quite nicely into Krebs and the ETC and is generally considered first in line.  


Fred Hahn said…
I am posting this comment on behalf of Dr. Richard Feinman, professor of cellular biology at SUNY Downstate.

"I never had to go through steam tables but I still teach bioenergetics in biochemistry courses where we think thermodynamics has a lot to do with human metabolism.

Like most chemists and even some physicists, I would be willing to admit I don't understand the field that well but if you have a problem, feel free to write to me directly.

I think it is touching that people get excited about thermodynamics but I expect polite discourse.

Richard Feinman
Professor of Cell Biology
SUNY Downstate Medical Center
CarbSane said…
I'll reply in a separate post as my comments limit HTML formatting and characters.