Strengthening of the weary, empowering of the weak

For want of a nail the shoe was lost.
For want of a shoe the horse was lost.
For want of a horse the rider was lost.
For want of a rider the message was lost.
For want of a message the battle was lost.
For want of a battle the kingdom was lost.
And all for the want of a horseshoe nail.

This is a longish story, but it’s worth it.

It all began in the olden times, long time before the last common ancestor of all living things came into being. A molecular miracle has happened. A DNA helicase – a protein that removes the phosphate group from ATP to make energy to untwist the double helix – accidentally connected to a proton pump in the cellular membrane. The combo started to work in reverse: it used the energy of the proton gradient across the membrane to rotate the helicase and synthesize ATP. Adenosine triphosphate is the universal energy carrier in our cells, and this operation is like a dynamo. Over time, this new enzyme, ATP synthase, became the main source of ATP in aerobic proteobacteria that subsequently became our mitochondria, the organelles in which food is burned to power our bodies. The chemical energy released in oxidation of food is stored as a proton gradient across the membrane. The protons are then released across the membrane through the ATP synthase in order to make ATP.

Now, imagine a pump that lets the protons to diffuse across the membrane negating the gradient. Instead of the ATP synthesis, one obtains a futile cycle, in which the chemical energy released by oxidation of food is wasted as heat. Who needs that? A bacterial cell does not need warmth. If it is cold outside, it means there is no food, and the best thing is to become dormant. However, there are less obvious advantages to futile cycles, and all of aerobic bacteria, plants, and most of animals have this proton pump (called uncoupling protein-1, UCP1).



I can explain the advantages of having the futile cycle, but it is technical. A good way to store energy is to produce fats, which consumes both ATP and the universal reducing agent, NADH. It is this molecule that gets oxidized to make the proton gradients to power ATP synthase. Having a leakage allows to control the reductive power to optimize storage of fat.

...partial uncoupling can control the NAD+ to NADH ratio and regulate metabolic pathways such as ketogenesis, lipogenesis and amino acid synthesis, which are dependent on the levels of these coenzymes. Lipogenesis consumes ATP and requires NADPH, but the first steps of lipogenesis from glucose generate NADH which, when oxidized by mitochondria, results in ATP formation. Surprisingly, the synthesis of fatty acids from glucose may result in a net synthesis of ATP. Since a significant part of this ATP comes from mitochondria reoxidizing NADH, the coupling state of mitochondria could limit the speed of fatty acid synthesis from glucose. Therefore the rate at which an animal could store energy would be limited by the capacity of mitochondria to waste it. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1220743/pdf/10620491.pdf

As eukaryotic cells periodically need to store energy in a more permanent form as rapidly as they can, and they improve storage efficiency by decreasing the efficiency of ATP synthesis. Our brown fat cells are doing precisely that, and it is the tissue in which we have UCP1. Animals have been doing this from time immemorial.

Then another miracle happened, which has direct bearing on our very existence. In one lineage of vertebrate animals, this UCP1 became lost; perhaps it became garbled by a virus infection. As the synthesis of fat can be carried out in several ways, there was no immediate payback for this loss. These mutants had flourished; in fact, they had conquered the world, becoming the ancestors of the dinosaurs and birds. Meanwhile, our furry ancestors served as food to these mutants.

This sorry state lasted for millions of years, and then the world started to get colder and colder. Keeping warm became important, and the simplest way to generate heat was by having a futile oxidation cycle. Generating heat is especially important for small animals and their young, because they lose heat rapidly. To this end, we have brown fat, in which 2/3 of the heat that warms our bodies is produced. Our predators did not have it. The only way left to them was to generate heat in their skeletal muscle. The more muscle they had, the bigger they grew, the warmer they became. As the production of heat in muscle is much less efficient than in the fat cells, they needed massive muscle, much more than they needed for locomotion. That had unexpected consequences:

...For endothermic animals, the ability to sustain elevated body temperatures during the cooling of the late Jurassic would have been important to survival. For the hatchlings of egg-laying endotherms (e.g. the ancestors of birds), it would have been a matter of life or death. Mammals gestate internally and their newborn have ample stores of brown fat. Modern birds brood both their eggs and hatchlings, and some theropod dinosaurs also apparently brooded their eggs. Improving the means of heat generation would have been even more useful to brooding animals and their hatchlings. The saurian ancestors of modern birds, insofar as they were endothermic, would thus have been under strong selective pressure to increase their skeletal muscle mass. This was evidently realized first in the thigh regions, leading to the side effect of upright posture, also found in many dinosaur groups. The embryological consequences of the increased forces associated with larger thigh muscles would have included increases in long bone growth and the formation of the fibular crest; the lower limb modifications facilitated folding of the legs into an efficient brooding posture, synergizing with the heating effect of the increased muscle mass. The imperative to increase skeletal muscle mass could now encompass greatly enlarged pectorals, which would have compromised locomotion in quadrupeds. While the selective pressure may have once more been for improved heat generation, the enhanced size and strength of pectoral and biceps muscles would have enabled evolution of new functional modalities for the fore limbs. The intermediate stages leading to the functionally transparent endpoints of wings and paddles would no longer be enigmatic in this scenario. Since selection was not initially for the adaptive efficacy of the limbs themselves, the suitability of the resulting appendages for flying or swimming could have been be a matter of niche occupation after the fact rather than progressive refinement of a barely functional structure. http://www.nymc.edu/sanewman/pdfs/bioessays%20bird%20origins+cover.pdf

The excess muscle and the increased aerobic capacity to feed this muscle had powered the mighty limbs that first learned bipedalism, then flapping, then gliding, then flying. The endothermic ancestors of modern birds became birds, because they had overdeveloped skeletal muscle and numerous preadaptations needed for controlled flight.

Meanwhile the scary dinosaurs were gone, as all large animals were gone when things went really bad, and the mammalian comeback began. Dinosaurs and raptors were above competition as large animals, but not so competitive as small animals in a cold world. For all ingenuity of their anatomy, nothing has replaced the loss of UCP1 in their mitochondria. In the absence of serious competition, mammals gradually grew big and strong. Birds also grew big and strong, but these large birds could not fly. Starting from the late Eocene, a gang of furry carnivores pushed the flightless birds to the margins of our world. Presently, we do not think twice about birds. A midsize or large mammal does not have to fear those things. We eat them, period. The only reason they are still around is that they can fly. Strengthening of their skeletal muscle may have saved them from extinction, but the mastery of the world slipped away from their talons. And all of that could’ve been quite different for the loss of the stupid proton pump in their ancestors!

We have been suffering these feathery devils for 100 Myr, and we still did not completely recover from the humiliating losses they inflicted upon us, but we, mammals, with the single exception, have never lost what they so carelessly did. This only exception is the swine. I am not sure whose side it is on.... We keep away from it.

Blessed be the one who gives strength to the weary and increases the power of the weak.