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A further twist on the Krebs cycle
Inside the cells of breathing organisms –micro-organisms, fungi, plants and animals– a cyclically configured sequence of chemical reactions transfers the energy provided by the organic substances –based on carbon chains– incorporated in the food into ATP molecules. This process, which we call the Krebs cycle, starts with acetyl coenzyme A (or acetyl-CoA), a derivative of acetate.
The oxidation –combustion in tiny steps in a controlled manner– of acetyl-CoA to produce ATP also involves the combination of oxygen –obtained from the atmosphere through respiration– and hydrogen atoms, which come from organic molecules in the food. The acetyl CoA that is oxidised in this sequence can come from carbohydrates, lipids or amino acids. Some reactions of the Krebs cycle lead to the release of CO2. In eukaryotic cells, all this takes place in the matrix of the mitochondria, cell organelles specialised in these tasks. The final part of the process –acceptance by O2 of electrons accompanying the hydrogen atoms from acetyl CoA– and the final synthesis of ATP, outside the Krebs cycle, takes place in the mitochondrial inner membrane.
What I have just explained is as brief and clear a description as I have been able to give of the core of energy metabolism in aerobic eukaryotic cells. Therefore, it seems clear that the Krebs cycle is an essential part of our metabolism and that of all living things that breathe oxygen to live. But although it is extremely important, Nick Lane, the author of the book I am reviewing here, believes that there are other phenomena in life, beyond the catabolism of carbon chains, in which it plays a very important role.
Before going any further, I must warn that the reactions involved in this cycle can, depending on the circumstances, run in the opposite direction. This is what happens in certain routes of synthesis of new compounds (biosynthesis) and, as we shall see, what may have occurred in the first forms of life on Earth.
In the following paragraphs, I briefly outline the notions that the author has elaborated in this book.
Life and its origin
Biology gives enormous importance to information, that contained in hereditary material, RNA and DNA. However, Nick Lane reminds us that there is no difference in information content between a living cell and one that died a few moments ago. The difference between being dead or alive lies in the flow of energy, in the ability of cells to regenerate themselves from simpler structural elements.
This does not imply that genetic information is of minor importance. It is not, because that information structures the flows of energy and materials, but it does not determine the most intimate details of our lives. In fact, the incessant flow of energy and matter through living beings in perpetual disequilibrium enables the very existence of genes and determines their activity.
Metabolism keeps us alive; indeed, that is what being alive is all about. Life could be conceived as the sum of the continuous transformations of small molecules on nanosecond timescales, nanosecond after nanosecond. Moreover, we do not only inherit information in the form of genes. Our inheritance includes that metabolic network that burns in the germ cell, a flame that takes us back from generation to generation, without pause, to the beginning of life. The core metabolism has changed little through the history of life, partly because it has never been extinguished in its 4 billion year history. Genes are the custodians of that flame, but without the flame, life is dead.
Life may have arisen in fumaroles or hydrothermal vents at the sea bottom. It is surely no accident that the Earth provides CO2 and H2 in abundance, along with the iron sulphide catalysts that facilitate their reaction to form carboxylic acids and some intermediary metabolites of the reverse Krebs cycle that still remain at the core of metabolism.
If the Krebs cycle, starting from organic molecules, transfers energy and leaves CO2 and H2O (2H + O) as end products, a reverse sequence of the same cycle may well, starting from CO2 and H2, produce organic compounds. In this respect, thermodynamics and geology are clear: CO2 and H2 are ubiquitous and can react to form Krebs cycle intermediates. And cracks and fissures in the rocks in the vicinity of the outflow of hydrothermal vents could provide the right substrate for living structures capable of growth and replication –protocells– to settle and thrive.
This is something that may well happen when CO2 binds to mineral surfaces in the presence of hydrogen. By continually transforming the simplest and most abundant gases into the essential molecules of life, the Krebs cycle (its reactions running in reverse) may well bring about life in this way.
The relevance of this sequence of reactions is not only limited to its role in the earliest forms of life. Nor to the crucial role it plays in aerobic metabolism. In addition to being the engine of catabolism, the Krebs cycle is the engine of biosynthesis too, thus driving cell growth and renewal.
Krebs cycle metabolites can signal the state of the cell to genes; different patterns of metabolic flux through them can generate powerful signals. And those signals tell transcription mechanisms which operations to perform –which genes to express or not to express– so that the regulation of metabolic pathways is fine-tuned as needed. Metabolism runs according to the imperatives of thermodynamics, its reactions are facilitated by catalysis, and genes improve their efficiency over the course of evolution through the coding of catalytic proteins.
But the genetic code does not invent information out of nothing: the information took its meaning from the growth of protocells from the beginning of life. From this point of view, genetic information enables a more accurate form of growth: genes reproduce their own system more accurately and more quickly, which is to say that they help protocells to copy themselves better. As long as replicating protocells can arise spontaneously –and we know they can– then there is no conceptual problem with the origin of the information.
The big picture that emerges is as follows: Hydrothermal vents provide a stable supply of H2 and CO2 under the right conditions to promote their reaction to manufacture carboxylic acids. These are formed by chemical mechanisms that resemble the steps of the reverse Krebs cycle, implying that this chemistry really is the primary basis of metabolism. Krebs cycle intermediates are universal precursors for the synthesis of amino acids, fatty acids, sugars and, eventually, nucleotides.
From inflammation to cancer
Hypoxia, inflammation, mutations, all of these factors can alter the flow patterns through the Krebs cycle, with an ageing effect that turns hundreds or thousands of genes on and off, changing the stable (epigenetic) state of cells and tissues.
The most life-threatening form of hypoxia for most animals is that caused by infection. Proliferating bacteria and immune cells consume oxygen faster than it can be supplied, resulting in swelling, damage and partial capillary occlusion.
Thus, the genes activated by HIF1a (hypoxia-inducible factor) are not limited to those that have to cope with the oxygen shortage: they orchestrate the entire inflammatory response. Inflammatory signals promote the growth of new blood vessels, the proliferation of immune cells, and the resistance of other cells to further cell death. In short, HIF1a helps coordinate a response to low oxygen levels that stimulates cell growth by activating (accelerating) glycolysis and balancing cellular needs for ATP, NADH and carbon. If these pro-growth, pro-survival, pro-inflammatory conditions persist too long they can promote uncontrolled cancer cell growth.
There is a robust correlation between metabolic rate (rate of living) and lifespan. The faster we burn resources, the faster we burn ourselves out.
It takes time and energy to build the perfect protein, and there are tens of millions of them in every cell. If either energy or time are limited resources (and the faster you live the less you have left of both), then it is only a matter of time before some proportion becomes dysfunctional.
The question is, does it matter? The answer depends very much on the context: how long do we expect to live? How much of your resources do you need to invest in reproduction or in competing for a mate? How much do you want to spend on cleaning up the mess or, before it even accumulates, avoiding it? Possible alternative answers to these questions explain why lifespan correlates only slightly with metabolic rate; but to ignore metabolic rate altogether, as old-fashioned and genetically nebulous, is to ignore perhaps the single most important determinant of longevity: how quickly cellular machinery needs to be built, how intensively it needs to be used, and how soon it needs to be replaced. The axiom "live fast, die fast" is not a law written on stone, but it is a hard thermodynamic reality that cannot be easily evaded.
In Transformer, Nick Lane has turned the standard view of various phenomena linked to the Krebs cycle on its head. There is an amazing sequence of reactions that uses energy to transform inorganic molecules into the building blocks of life, and vice versa, converting organic substrates into usable energy for living things. It is involved in multiple processes –both catabolic and anabolic– and its implications –origin of life, cancer, longevity– are so important that it is crucial that we know (and understand) them in their most intimate details. According to Lane, to understand this cycle is to understand the deep coherence of the living world.
This book, like Lane's previous books –particularly The Vital Question– is exciting for those who, like me, have done research in the field of physiological energetics of animals and for those interested in unravelling the logic of the living. But the reader should be warned that this is not a text for a wide readership. It is dense, full of ideas and, what makes it less accessible, basic notions of chemistry and biochemistry should be kept in mind all along the whole text.
Title: Transformer - The Deep Chemistry of Life and Death
Author: Nick Lane
Ed. by W W Norton & Co Inc (2022)