Literary Insights

Here is a summary of the introduction:

The introduction draws an analogy between cities and cells. Both have physical structures, but what really animates them is the flow of energy and materials. From space, cities look lifeless and grey, yet we know they are vibrant places from the inside. Similarly, cells have intricate structures that can be visualized under a microscope, but the real flux of matter and energy within cells is invisible to us.

The introduction emphasizes that while we can map out the “buildings” of a cell in great detail, the moment-to-moment flow of energy and materials that brings a cell to life remains largely mysterious. This metabolic flux within cells occurs on scales far smaller than we can visualize. Just as the flow of people and electricity animates a city, the deep flow of matter and energy animates life at the molecular level in cells. But this hidden flux tends to be discounted or overlooked because it is invisible. The introduction argues that truly understanding life requires looking beyond cellular structures to the unseen metabolic changes happening inside.

Biology has long focused on genetic information as the key to life, but information alone cannot explain the origin of life or other mysteries like aging.
The missing piece is the flow of energy and matter through metabolic reactions. This flux animates life in a way information alone cannot.
Biochemistry studies these metabolic fluxes, where molecules are transformed from one form to another continuously. This allows cells to regenerate and fuels life.
The origin of life likely lies in understanding the chemical cycles that harness energy to transform inorganic molecules into the building blocks of life.
Metabolic fluxes may also hold keys to understanding evolution, the emergence of animals, cancer, and consciousness.
A “renaissance” is occurring in biochemistry to understand how metabolic fluxes tie together the great mysteries of biology, from the origin of life to cancer and aging.
The “dynamic side” of biochemistry, studying metabolic fluxes, was championed by Frederick Hopkins but overshadowed by the focus on genetic information.
The book aims to show how metabolism shapes life more than genes, animating our existence through ceaseless molecular transformations occurring each nanosecond.
The flow of energy and materials through cells was considered the “dynamic side” of biochemistry in contrast to the more static view of molecules. This view of continuous flow animating cells was an important early insight.
Discoveries showed the unity of biochemistry across lifeforms - the same basic pathways and molecules were found in bacteria and elephants alike.
Molecular biology revealed DNA as digital information encoding life. The structure of DNA elegantly explained heredity, but the actual genetic code was messier than expected.
Most DNA does not code for proteins and has unclear function. Biology became focused on studying information patterns, sometimes neglecting the dynamic flow.
Biochemistry advanced through studying protein structure, revealing they are molecular machines with moving parts. Combined with genomics, a dominant paradigm was to sequence genes, study protein structures, and target defects.
But this paradigm neglects the importance of dynamic flows of matter and energy in structuring biological information. Understanding living systems requires appreciating both the digital information of genes and the analog fluxes of metabolism.
The Krebs cycle is a central metabolic pathway that strips hydrogen from food molecules to generate energy through cellular respiration. It is also the source of many basic cellular building blocks like amino acids and nucleotides.
Despite its importance, the reasons for the Krebs cycle’s circular shape have remained elusive since its discovery in the 1930s. It is not inherently more efficient than a linear pathway.
The Krebs cycle represents a delicate balance of creation and destruction, of biosynthesis and catabolism. It drives both the breakdown of nutrients to generate energy and the creation of new cellular components.
Metabolism as a whole has remained remarkably constant over evolutionary time, in contrast to the malleability of genes. All cells share the same basic metabolic ‘road map’ due to their common ancestry.
New metabolomic techniques allow researchers to see differences in metabolic flux between cells by taking molecular ‘snapshots’. But metabolism’s continuous flow remains difficult to capture.
If one metabolic pathway is blocked, cells can often reroute material and energy flux through alternative pathways. This metabolic flexibility enables cancer cells to evolve resistance to drugs targeting specific proteins.
Core metabolism like the Krebs cycle has remained unchanged for billions of years because it was never ‘powered down’ - the metabolic flame was passed continuously from generation to generation. Metabolism, not just genes, constitutes cells’ living inheritance.
The Krebs cycle is the central metabolic pathway that handles both energy generation through respiration and biosynthesis of molecules like amino acids. This dual and conflicting role is puzzling since fluxes typically go in one direction.
A decade ago, it was discovered that Krebs cycle intermediates also act as signals that regulate gene expression. This sheds new light on the importance of the Krebs cycle in diseases like cancer, heart disease, and diabetes.
The conflict between energy generation and biosynthesis in the Krebs cycle likely stems from thermodynamic constraints, not just genes. Recent work shows parts of the Krebs cycle can happen spontaneously in the absence of genes.
The textbook view of the Krebs cycle as being all about sugar oxidation is incorrect. Its core function in ancestral bacteria was to generate life’s building blocks from H2 and CO2 gases.
The Krebs cycle became a cycle through evolutionary pressure for metabolic efficiency, but rising oxygen levels from photosynthesis were key to the eventual rise of animals.
Cancer is not just about genetic mutations. It stems from improper Krebs cycle flux as we age, causing some metabolites to accumulate and send aberrant signals. The Krebs cycle is central to life and death.
The excerpt describes a speech given by Sir Frederick Gowland Hopkins in 1932 at the Royal Society of London, of which he was president. Hopkins had won a Nobel Prize for discovering vitamins and was a pioneer in the field of biochemistry.
Hopkins spoke proudly of recent breakthroughs in nuclear physics like the discovery of the neutron and nuclear fission. He then highlighted new research on radiation and cell division, though some in the audience were wary of this topic.
Hopkins was most eager to discuss brilliant new work by Hans Krebs on cell metabolism, showing how biochemistry could reveal dynamic living processes rather than just dead chemistry. This reinforced Hopkins’ view of biochemistry as an independent experimental science.
The excerpt provides background on Hopkins’ unconventional path into science and his nurturing of a free-thinking biochemistry lab at Cambridge. This contrasted with the authoritarian German biochemistry establishment.
Hopkins welcomed figures like Krebs whose work was unexpectedly original. Krebs had come to Hopkins’ lab after being forced out of his post in Germany due to being Jewish. Hopkins helped refugee scholars through the Academic Assistance Council he co-founded.
Hans Krebs arrived in Cambridge in 1932 to work in the lab of Sir Frederick Gowland Hopkins, bringing equipment to measure changes in gas pressure. This lab had a collaborative, amicable culture.
Krebs was seeking to understand how respiration works at the molecular level. Lavoisier had shown respiration was equivalent to combustion, burning food in oxygen, but the steps involved were unknown.
Krebs used the slicing technique pioneered by Otto Warburg - measuring gases released from thin slices of tissue to track respiration. This gave an indirect view of biochemical reactions.
Warburg had used this technique elegantly to show a haem-containing catalyst was involved in respiration. But many steps remained unknown, including how energy was captured.
Krebs aimed to elucidate the sequence of steps in respiration. His cycle of reactions would become known as the Krebs cycle, though this cycle is about more than just respiration.
Hans Krebs was trying to understand how food is broken down in cellular respiration. He focused on carboxylic acids like pyruvate, which are generated when glucose and amino acids are broken down.
Carboxylic acids contain carbon, hydrogen, and oxygen atoms. Pyruvate contains 3 carbon atoms and has a reactive “alpha-keto” group that makes it unstable. It also has a “carboxylate” group that makes it an acid.
When pyruvate enters a cell, it loses a proton and becomes pyruvate with a negative charge. This makes it more stable.
Krebs found that longer carboxylic acids with 4-6 carbons were also involved in respiration somehow. He wanted to understand why and how they were generated from pyruvate, which only has 3 carbons.
Using ingenious methods like specialized manometers, Krebs slowly pieced together the steps of cellular respiration and the key role of these carboxylic acids. It required immense dedication over many years to elucidate these intricate metabolic pathways.
Respiration converts organic molecules like glucose into CO2 and H2O. Glucose has 6 carbons, which should be released as 6 CO2 molecules if the carbon chain is broken down incrementally.
However, Albert Szent-Györgyi found that adding C4 carboxylic acids like succinate speeds up respiration dramatically without being consumed. This suggested they act as catalysts.
Szent-Györgyi hypothesized the C4 acids act as hydrogen carriers, picking up 2H stripped from glucose and passing them along to oxygen.
Hans Krebs saw problems with this: If the C4 acids were just hydrogen carriers, adding more should cause complete breakdown of glucose into CO2 without needing oxygen.
But Krebs found glucose breakdown stops without oxygen, even with excess C4 acids. This suggested the C4 acids are actual intermediates, not just hydrogen carriers.
Krebs realized the C4 acids must be regenerated in a cycle, being reformed after giving up 2H. This pointed to the Krebs cycle of metabolic reactions.
So Szent-Györgyi was right about 2H transfer but wrong about the role of C4 acids, while Krebs deduced the cycle.
Hans Krebs and Albert Szent-Györgyi were studying cellular respiration and trying to understand the breakdown of sugars.
Szent-Györgyi believed sugars were broken down without transferring hydrogens to oxygen, leading to the same CO2 production with or without oxygen. But experiments showed much less CO2 without oxygen.
Krebs interpreted this to mean the C4 acids were intermediates that still needed to release CO2, requiring oxygen for the final steps.
Krebs realized citrate breakdown formed succinate, connecting it to respiration. Adding citrate sped up respiration.
Krebs conceived of a cycle where intermediates acted catalytically to speed up the overall reaction. The cycle would be fed by an organic molecule and release CO2 and hydrogens.
Krebs proposed pyruvate was fed into the cycle by joining with oxaloacetate to form citrate. His proposed cycle accounted for oxygen consumption and CO2 release.
Fritz Lipmann later discovered pyruvate loses CO2 to form acetyl-CoA, which combines with oxaloacetate to start the cycle Krebs envisioned. The full cycle came to be known as the citric acid or Krebs cycle.
Otto Warburg showed that cancer cells undergo fermentation even in the presence of oxygen, known as the ‘Warburg effect’. This led to a focus on fermentation pathways in cells.
Hans Krebs discovered the citric acid cycle, also known as the Krebs cycle or TCA cycle, which breaks down products of glycolysis and provides energy to the cell.
Fritz Lipmann showed that energy released from respiration is conserved in the form of ATP.
However, it was still unclear exactly how energy from respiration is coupled to ATP synthesis.
Peter Mitchell proposed the chemiosmotic theory to explain this coupling. He recognized the importance of the membrane potential in cells for energy transduction.
Mitochondria pump protons across the inner mitochondrial membrane, generating a proton gradient and membrane potential. This potential then drives ATP synthase to make ATP.
Mitchell’s ideas emphasized the living structure of cells, particularly membranes, as indispensable for energy transduction, contrasting with the reductionist biochemical view at the time.
His radical chemiosmotic theory explained how respiration is coupled to ATP synthesis and represented a paradigm shift in biology.
Peter Mitchell proposed that cell respiration involves transferring electrons from hydrogen (bound to NADH) through a respiratory chain in the membrane to oxygen, generating a proton gradient across the membrane.
This proton gradient powers the synthesis of ATP. Mitchell called this the proton-motive force.
Jennifer Moyle collaborated with Mitchell on experiments that provided evidence for the proton-motive force. Their work established the membrane’s role in respiration.
Mitchell’s ideas were contested for decades but eventually accepted, and he received the Nobel Prize in 1978.
Mitchell was wrong on some details, like how proton pumping occurs through proteins in the membrane.
The ATP synthase exemplifies Mitchell’s hypothesis - its rotation is powered by the proton gradient. But its mechanical operation was not what Mitchell had envisioned.
Bacteria use the same proton-motive force mechanism as mitochondria. The force field powers more than just ATP - also CO2 fixation in ancient bacteria.
Mitchell grounded respiration in a philosophical conception of biology, but biochemistry has moved away from these ideas and focused purely on mechanisms.
The Krebs cycle is not a perfect, Platonic system as it might appear. It has convoluted quirks that are hard to explain if imagined to be intelligently designed.
The cycle functions as both a breakdown pathway and a synthetic pathway. Intermediates are constantly being drawn off for syntheses and need to be replenished. This gives the cycle a ‘crazy roundabout’ quality rather than a perfect closed cycle.
Krebs focused on the cycle as a breakdown pathway, especially in animal tissues like pigeon breast muscle optimized for energy production. But the synthetic role is very important too.
Some bacteria can run the Krebs cycle in reverse, fixing CO2 into organic molecules using energy. This ‘reverse Krebs cycle’ makes more sense of the evolution of the pathway than seeing it as solely a breakdown cycle.
The convoluted nature of the Krebs cycle argues against perfect evolutionary refinement and instead reflects its evolutionary history as a cobbled together pathway, retaining aspects of its origins in ancient bacteria.

Here is a summary of the key points about the path of carbon:

Plants like trees, grass, and algae take up carbon dioxide from the air through photosynthesis. This carbon is incorporated into organic molecules like sugars, cellulose, and proteins that make up the structure of plants.
Plants serve as the base of food chains and webs, passing carbon up to herbivores that eat plants and then to carnivores that eat herbivores. Carbon cycles through ecosystems in this way.
Decomposers like bacteria and fungi break down dead organic matter, releasing carbon back to the atmosphere as carbon dioxide. This completes the carbon cycle.
Different ecosystems have characteristic plant life, from tropical rainforests to tundra to coral reefs. The nature of the plants influences the flow of carbon through each ecosystem.
Photosynthetic bacteria and algae are also important early steps in carbon cycling, fixing carbon even in extreme environments like Antarctica.
The path of carbon begins with photosynthetic organisms capturing carbon dioxide and flows through ecosystems until carbon is released back into the air by decomposers. This cycling of carbon sustains life on Earth.
Rubisco is the most abundant protein on Earth. It catalyzes the first step of carbon fixation in photosynthesis, converting CO2 into organic molecules. But it is inefficient, so plants need a lot of it.
Photosynthesis and the prominence of rubisco has distracted us from the earlier origin of the Krebs cycle as a pathway for CO2 fixation by ancient bacteria, operating in reverse compared to its role in respiration.
In the 1930s, the development of cyclotrons enabled bombardment of materials with proton beams to produce radioactive isotopes like carbon-14. This gave new tools to trace biochemical pathways like photosynthesis.
The classic view is that plants synthesize sugars from CO2 via photosynthesis while animals respire sugars. But the deeper truth is that the Krebs cycle originally functioned in reverse for CO2 fixation before oxygenic photosynthesis had evolved.
Appreciating this deep history of metabolism, especially the biosynthetic Krebs cycle, is important for understanding the roots of disease but has been overlooked in medical textbooks. Shifting focus away from photosynthesis helps straighten out the circular logic of the Krebs cycle.

Here is a summary of the key points about the number of neutrons:

The number of protons and neutrons in an atomic nucleus is typically roughly equal.
Atoms with more or fewer neutrons than usual tend to be radioactive, as the nucleus is unstable and decays over time by emitting energy and particles.
Being bombarded by high-energy protons can knock neutrons and protons out of a nucleus, or add extra protons, altering the configuration and often making it unstable and radioactive.
In the 1930s, producing artificial radioactive isotopes became a focus for applications in medicine and biology.
Radioactive carbon-11 was produced by bombarding boron with protons to transmute some boron into carbon-11, which has extra neutrons.
Carbon-11 was used to trace sugar metabolism in rats, but this proved difficult with its 20 minute half-life.
The failed rat experiments led Martin Kamen and Sam Ruben to shift focus and try to identify the first product of CO2 fixation in photosynthesis in plants.
Though technically challenging, they showed glucose was not the first product, disproving earlier ideas. The first product was a radioactive carboxylic acid.
In 1940, Kamen and Ruben discovered radioactive carbon-14, which can be used to trace biochemical pathways. This discovery transformed research into metabolism and other fields.
The discovery was made by bombarding nitrogen gas in a cyclotron, producing carbon-14. Kamen had to persist despite skepticism from physicists like Oppenheimer.
After Pearl Harbor, Kamen and Ruben were forced to abandon photosynthesis research to work on the war effort. Ruben died tragically in an accident while working with phosgene gas.
After the war, Melvin Calvin took over photosynthesis research at Berkeley using carbon-14. His colleague Andrew Benson focused specifically on tracing carbon fixation.
Benson adopted improved paper chromatography techniques to track radioactively-labeled molecules. This allowed precise mapping of the path of carbon in photosynthesis.
Calvin and Benson’s research defined the concept that sugars are the backbone of biochemistry, as carbon-14 tracking showed carbon traveled through sugars.
Melvin Calvin, Andrew Benson, and colleagues used ingenious tracer techniques with radioactive carbon-14 to map out the pathway of carbon fixation in photosynthesis. Their work elucidated the Calvin-Benson cycle, in which the acceptor molecule is a 5-carbon sugar called ribulose bisphosphate.
Calvin abruptly dismissed Benson from the team after their seminal 1954 paper laying out the cycle. Benson felt Calvin did not properly credit him for his contributions.
In 1961, Calvin alone won the Nobel Prize for the research on the Calvin cycle. He later published an autobiography that did not mention Benson at all, despite his instrumental role.
Another scientist at Berkeley, Daniel Arnon, published a paper in 1966 outlining an alternative pathway for carbon fixation - the reverse Krebs cycle. This challenged the dogma that the Calvin cycle was the only pathway for autotrophy.
The reverse Krebs cycle made more sense energetically and biochemically, but was neglected for years because it went against the Calvinist dogma. The idea that CO2 fixation occurs via the Calvin cycle only is still entrenched today, impairing understanding of metabolism.
Daniel Arnon discovered that photosynthesis generates ATP through ‘photo-phosphorylation’, similar to cellular respiration. This overturned the previous thinking that the Calvin-Benson cycle was the only pathway for carbon fixation in photosynthesis.
In 1966, Arnon showed that bacteria like Chlorobium can fix CO2 through a reverse Krebs cycle, incorporating 4 molecules of CO2 per turn compared to just 1 for the Calvin-Benson cycle. This provides a more efficient carbon fixation pathway.
The reverse Krebs cycle integrates CO2 fixation with biosynthesis of cellular components, providing C2-C6 precursors. This links CO2 fixation to the core metabolism.
The Calvin-Benson cycle is more peripheral and can be regulated independently, making it easier to incorporate as an additional pathway.
The reverse Krebs cycle was not widely accepted until the 1980s when genetics supported the pathway in Chlorobium. The focus on the Calvin cycle in plants obscured the importance of the Krebs cycle intermediates.
Sulfur bacteria like Chlorobium exemplify the unity of biochemistry and the Krebs cycle as the metabolic heart. They provide insight into evolution despite not being as widely appreciated as plants.
Ferredoxin is a protein that contains iron and is able to transfer electrons. It is essential for carbon fixation via the reverse Krebs cycle, enabling CO2 to be reduced and incorporated into organic molecules.
Ferredoxin is very reactive with oxygen, producing dangerous free radicals. This is why the reverse Krebs cycle operates mainly in anaerobic conditions.
In photosynthesis, ferredoxin rapidly passes electrons to NADP+ to generate NADPH, avoiding issues with oxygen. NADPH doesn’t have enough redox power for the reverse Krebs cycle.
The Calvin-Benson cycle in photosynthesis uses rubisco and seems to have evolved as a quick fix under rising oxygen levels, splicing parts of existing pathways together.
New evidence suggests the reverse Krebs cycle could pre-date photosynthesis and be more widespread than thought across anaerobic organisms. It may have structured early metabolism and even been important in the origin of life.
If the reverse Krebs cycle operated early in evolution before oxygen rose, this could explain why the standard Krebs cycle is so central to metabolism today. The reverse cycle came first.
In 1977, Jack Corliss was piloting the deep-sea submersible Alvin to investigate a suspected deep-ocean hydrothermal vent. At a depth of 2 km, he was surprised to see abundant life around the vent, contrary to the expectation that the deep ocean is a desert.
The discovery of thriving ecosystems around hydrothermal vents changed our understanding of the origins of life. The vents provide chemical energy and nutrients to support complex ecosystems, suggesting life could have started around similar vents billions of years ago.
Hydrothermal vents form where seawater penetrates the ocean crust through cracks. The water is heated by magma, driving chemical reactions that produce hydrogen, hydrogen sulfide and other reduced chemicals. These chemicals provide energy through chemosynthesis, supporting microbes at the base of vent ecosystems.
The microbes around vents use chemical energy to fix carbon dioxide into organic molecules, just like plants use sunlight. This challenges the idea that all ecosystems depend on photosynthesis. The vent ecosystems reveal life exploiting chemical energy from the earth itself.
The discovery revolutionized ideas about the requirements for life. It showed life does not fundamentally require energy from the sun and photosynthesis, but can exploit chemical energy from the earth’s interior. This opened up the deep ocean crust as another potential cradle for the origins of life.
In 1977, explorers discovered abundant marine life around deep-sea hydrothermal vents, overturning the belief that the deep ocean was a barren desert. This discovery revolutionized ideas about the origin of life.
The vents inspired hypotheses that life may have originated through chemical reactions between hot reactive gases like CO2 and H2 emitting from the vents and transition metal catalysts like iron and sulfur minerals. This contrasts with the traditional view that life started in surface waters energized by UV light.
Two leading proposals were from Wächtershäuser, who conceived an origin linked to iron pyrite formation, and Russell, who conceived of ion gradients across porous mineral membranes as the energy source. Both envisaged autotrophic origins harnessing CO2 and H2 via the reverse Krebs cycle.
These ideas imply life originated from chemical disequilibria in vents, in contrast to surface waters powered by light. This has important implications for searching for life elsewhere in the solar system and for understanding whether metabolism is inevitable or contingent.
The author argues metabolism came first, shaped by the energetic conditions of the origin of life. The ancient nature of the reverse Krebs cycle offers evidence of this. The author aims to show energy flow shaped genetic information from the beginning.
There are two possible explanations for why the Krebs cycle is so central to metabolism: either it is genuinely primordial and reflects an ancient thermodynamic path, or it is the product of evolution and natural selection acting on genes to produce the most efficient network topology.
Evidence suggests high levels of CO2 and H2 were present on the early Earth, providing ample substrates for the reverse Krebs cycle. Recent experiments show these gases can be catalyzed by minerals containing iron-sulfur clusters to form Krebs cycle intermediates. This lends support to the thermodynamic origin theory.
Phylogenetic analysis indicates the earliest cells used the acetyl CoA pathway rather than the reverse Krebs cycle for carbon fixation. This argues against the Krebs cycle being ancestral.
However, the end product of acetyl CoA pathway is part of the Krebs cycle, and biosynthesis of amino acids, sugars, and nucleotides draws on Krebs intermediates. So some Krebs intermediates are likely ancestral.
It’s possible multiple early pathways produced Krebs intermediates that later consolidated into distinct networks. Or the reverse Krebs cycle may be more ancient than thought.
Overall, it seems likely the Krebs cycle combines an early thermodynamic path with later refinement by evolution to produce an optimized core network topology. More evidence is needed to fully distinguish between the two theories.
Harold Morowitz proposed the “cycling law” - that energy flow leads to cycling of matter in steady-state systems like living organisms. He saw the Krebs cycle as a perfect example of this principle.
Morowitz argued the reverse Krebs cycle is inevitable based on thermodynamics and its autocatalytic properties. Each turn produces more molecules to continue the cycle.
Leslie Orgel critiqued this view, arguing that metabolism arises from genetic information, not directly from thermodynamics. The specific form of biochemistry reflects evolution, not inevitability.
Orgel argued self-organizing cycles like the reverse Krebs cycle don’t explain the origin of life, as they are products of genes. Prebiotic chemistry can’t be read from modern biochemistry.
There is debate between views of metabolism as inevitable given conditions versus a product of historical evolution. The origins of metabolism remain an open question.

Here is a summary of the key points from the passage:

Orgel argued that the reverse Krebs cycle is implausible as a prebiotic metabolic cycle because without enzymes to increase selectivity and yield, side reactions would dominate and yield would fall off rapidly after just a few steps.
Orgel saw two major problems with the reverse Krebs cycle arising in the absence of enzymes - side reactions and low yield. Enzymes funnel reactions down specific pathways by accelerating particular steps, limiting side reactions. Without enzymes, each step has many possible outcomes, with the needed product for the next step of the pathway being only a small fraction. This means yield declines drastically with each step.
Orgel considered it impossible for the 12-step reverse Krebs cycle to regenerate itself without enzymes increasing selectivity and yield at each step. The first step depends on the yield of the final step - with low yield, there is nothing to amplify.
However, Krebs cycle intermediates do form spontaneously from CO2 and H2 under hydrothermal vent conditions, though not as a complete cycle. Amino acids, sugars, and fatty acids can also be synthesized from Krebs intermediates.
Rather than a full cycle, there may have been an early ‘Krebs line’ of reactions generating the first several intermediates. Sustained disequilibrium in vents could drive continuous reactivity and growth of organic reaction networks.
The likelihood of reactions depends heavily on kinetics - mineral surfaces promote key reactions like CO2 reduction by binding substrates, delivering electrons, and positioning molecules. This chemistry connects vents to the core of biochemistry.
Iron-sulfide minerals can catalyze the reduction of CO2 into organic molecules like acetate and acetyl-CoA in a stepwise manner, using electrons from H2.
The reactions proceed via intermediates like CO, methyl groups, and bound acetyl groups on the mineral surface. Curly arrows denote electron shifts, not physical movement.
This chemistry favors mildly acidic conditions for CO2 reduction, but alkaline conditions for H2 reactivity.
Hydrothermal vents provide the high pressures needed for good H2 solubility and reactivity, as well as iron-sulfide mineral catalysts.
Cells face the same issues of promoting H2 reactivity and CO2 reduction. They may solve this by maintaining an alkaline interior but acidic exterior, facilitated by vent-like proton gradients.
The reduction of CO2 by H2, catalyzed by iron-sulfide minerals, can generate many organic molecules vital for life, like fatty acids and Krebs cycle intermediates. This chemistry likely played an important role in the origin of life.
Hydrogen (H2) will readily give up its electrons to a catalyst, like an iron-sulfur cluster, but this process favors alkaline conditions. Carbon dioxide (CO2) will accept electrons from a catalyst, but favors acidic conditions. This chemistry dilemma requires high pressure or specialized conditions to enable both reactions.
Cells create a proton gradient, with the inside being alkaline and the outside acidic. This enables the transfer of electrons from H2 to CO2 to form organics, using membrane proteins like the ‘energy-converting hydrogenase’ (Ech).
Alkaline hydrothermal vents provide the right conditions, with alkaline fluids inside and acidic seawater outside. Thin iron sulfide barriers can transfer electrons from H2 to CO2. Recent experiments have verified this process using isotopes.
Fatty acids and amino acids formed this way can assemble into ‘protocells’ with membranes, which can grow and divide given a proton gradient. Iron-sulfur clusters in the membranes could drive internal synthesis like Ech does in cells.
Protocells with more iron-sulfur clusters will grow faster and replicate this advantage, a form of physical heredity. The conditions allow feedback loops that favor complexity. Nucleotides and RNA likely emerged this way inside replicating protocells.

Here are the key points:

Nucleotides like NADH still function alongside enzymes today to transfer hydrogens in biological reactions. This shows nucleotides arose early to contribute to protocell growth.
Genes likely emerged within replicating protocells to promote growth from H2 and CO2 via Krebs cycle intermediates. They built on existing metabolic pathways, rather than inventing them.
Meaning and information emerged from the function of promoting protocell growth. Genes enabled more accurate self-copying.
ATP synthesis can occur prebiotically from acetyl phosphate, formed from acetyl CoA. Proton gradients drive these reactions, no ATP synthase needed yet.
Hydrothermal vents continuously supply H2 and CO2 to drive organic synthesis via reverse Krebs cycle chemistry. Growth occurs as new organics form from the flowing gases.
Metabolism reflects this starting point of CO2, H2, and proton gradients. It is driven by the environment, not itself. The direction of flux depends on the external driving force of hydrogen.
If hydrogen supply declines, the same metabolic pathways run in reverse, oxidizing organics back to CO2 and H2. The Krebs cycle reverses. The world turns.
The chapter opens with a dramatic narrative about Pikaia, a wormlike creature from the Cambrian period about 520 million years ago. Pikaia was a gentle filter feeder that was prey for ferocious predators like Anomalocaris in this revolutionary new world.
The Cambrian period marks the first appearance of complex animals with eyes, shells, legs, etc in the fossil record - the “Cambrian explosion.” This seemed to challenge Darwin’s gradualist view of evolution.
Ediacaran fossils from tens of millions of years before the Cambrian were also soft-bodied creatures, mostly sedentary filter feeders. They vanished before the Cambrian, replaced by the fierce predators and prey.
A key factor enabling this revolution was likely the accumulation of oxygen in the atmosphere over billions of years due to photosynthesis. This provided the energy needed to sustain mobile, active lifestyles.
The biochemistry of Cambrian creatures can be inferred to likely contain oxidative metabolism like the Krebs cycle, made possible by oxygen. Some may have even suffered from aging and diseases of old age like cancers.

In summary, the accumulation of oxygen set the stage for the revolution in animal body plans and behaviors in the Cambrian, by providing the energy needed to sustain more active, predatory lifestyles. This replaced the more passive Ediacaran biota.

The Krebs cycle evolved from the simpler Krebs line and originally operated in reverse, producing organic molecules from CO2 and H2. It later flipped direction to become the oxidative Krebs cycle we know today, which burns nutrients to generate energy.
The rise of oxygen levels enabled aerobic respiration and complex eukaryotic life, but oxygen did not directly cause the Cambrian explosion. Developmental constraints like genetic frameworks also needed to evolve first.
Multicellularity helped resolve tensions in the Krebs cycle between biosynthesis and energy generation by allowing different cell types to specialize in each task through parallel processing.
Early life derived electrons from geological sources like hydrothermal vents and volcanoes. Cells act like mini-batteries that recreate the Earth’s own electrical gradient.
Generating proton gradients was challenging for early cells. The proton-motive force drives key reactions like CO2 fixation and ATP synthesis.
Early cells generated energy by proton pumping, which is costly as it consumes hydrogen. Methanogens exemplify this - they use up 98% of their hydrogen budget on pumping rather than growth.
Photosynthesis provided an escape by harnessing sunlight instead of scarce hydrogen to generate energy. However, early anoxygenic photosynthesis was limited as it could make ATP or reduce ferredoxin but not both.
Oxygenic photosynthesis overcame this by wiring two photosystems in series, unlocking far greater energy availability. It evolved before 2 billion years ago.
Before oxygenic photosynthesis, life was constrained by scarce sources of reducing power like volcanic hydrogen and hydrogen sulfide. Biochemistry reflects these origins in energetically ‘reversible’ pathways.
When conditions changed, metabolic flux could reverse and cells could exploit their own constituents for energy i.e. heterotrophy may have emerged this way.
The primordial soup theory suggests that life originated from a mix of disparate molecules that eventually combined in the right ways to form living cells. However, modern cells use just a few core metabolic pathways built from common molecules like CO2 and H2. This pattern suggests that autotrophic pathways using simple molecules arose first, with heterotrophic pathways evolving later by reversing these core pathways.
Autotrophic cells fix metabolic flux in one direction, while heterotrophs reverse the main pathways. Cells optimize efficiency by increasing substrate concentration and removing waste products, which pulls pathways in the forward direction. Microbes often live symbiotically, consuming each others’ waste products, which also optimizes metabolic direction.
The Krebs cycle operates as an ‘Ouroboros’ - by consuming its own waste product (citrate) it sustains flux in one direction. Joining the Krebs cycle into a loop prevents buildup of citrate, pulling the reactions forward.
Oxygenic photosynthesis freed life from reliance on geological sources of energy like volcanoes. By splitting water, photosynthesis tapped into a new fuel source - sunlight. The machinery of photosynthesis is similar to existing respiratory chains, but generates organic molecules and O2 from H2O and CO2.

In summary, the patterns seen in modern metabolism suggest autotrophic core pathways evolved first, with symbiotic relationships optimizing flux, and photosynthesis massively expanding biological energy sources. Heterotrophic pathways built off these pre-existing routes by reversing flux.

Cyanobacteria evolved oxygenic photosynthesis around 2.3 billion years ago, evidenced by the Great Oxidation Event where oxygen accumulated in the atmosphere. However, the exact timing of when cyanobacteria first evolved is uncertain.
Oxygenic photosynthesis links two photosystems together into a Z-scheme to generate ATP and reduce ferredoxin simultaneously. This freed life from its dependence on hydrothermal vents by tapping into the unlimited electrons in water.
The rise of oxygen caused the first Snowball Earth by reacting with methane, a greenhouse gas. Figuring out when oxygenic photosynthesis first evolved is tricky due to lack of ancient oxygen signals.
Carbon isotope ratios can trace oxygen levels over time. The Shuram excursion shows a massive oxygen crash before the Cambrian explosion, conflicting with evidence of rising ocean oxygen. Resolving this is key to understanding animal origins.
Overall, oxygenic photosynthesis was a pivotal leap, allowing cyanobacteria to transform the planet and set the stage for complex life, even though it took 2 billion years to oxygenate the atmosphere fully. Small steps can lead to giant leaps over deep time.
Around 550 million years ago, there was a huge influx of carbon dioxide into the atmosphere, as evidenced by a dramatic shift in the carbon isotope ratio in geological formations like the Shuram Formation. This has puzzled scientists.
Graham Shields has proposed a solution to explain this carbon influx. He suggests that organic carbon had built up in stagnant, anoxic oceans, creating ‘peat-bog oceans’.
When the continents collided around 560 million years ago, large sulfate deposits that had accumulated on land over billions of years were exposed and eroded. This sulfate flooded into the oceans.
Sulfate-reducing bacteria used the sulfate to oxidize the dissolved organic carbon in the oceans, releasing CO2 back into the atmosphere. This explains the carbon isotope excursion.
The oceans were sulfidic for 10 million years until the organic carbon was depleted. The Ediacaran fauna likely died out in these conditions. Only muscular, burrowing animals with circulatory systems survived, evolving into the Cambrian animals.
So rather than oxygen levels driving animal evolution, it was adaptation to sulfidic, low-oxygen conditions that shaped animal physiology and the Krebs cycle as we know it. Most bacteria use bifurcated pathways rather than a full Krebs cycle even today.
Microbes use incomplete, non-cyclic versions of the Krebs cycle to optimize growth rather than ATP production. Textbooks cling to the idea of a complete oxidative Krebs cycle, but this is rarely optimal for growth.
Animals evolved the ability to run different Krebs cycle flux modes in parallel in different tissues - some optimized for ATP synthesis, others for biosynthesis. This metabolic symbiosis between tissues enabled complex multicellularity.
The Cambrian explosion was fueled by animals gaining the ability to run a complete oxidative Krebs cycle in muscle and brain while running biosynthetic modes in other tissues. This delicate balance enabled their success.
Diseases of aging can be traced to disruptions in Krebs cycle flux patterns and the loss of metabolic symbiosis between tissues. Metabolomics is now elucidating these mechanisms.
The evolution of complex multicellularity required regulatory finesse to balance complementary metabolic flux patterns between tissues. This explains the unique origins of organ-grade complexity in animals and plants.
Cancer cells proliferate relentlessly, mutating and evolving to exploit their environment, but often die in masses. This exemplifies natural selection in its most ruthless form.
Despite massive efforts over decades, including the “war on cancer”, cancer death rates have barely changed since the 1970s. Progress has been incremental at best.
The dominant paradigm has been that mutations in oncogenes and tumor suppressor genes cause cells to become cancerous. But this fails to fully explain why cancer rates haven’t declined.
Evidence shows cancer is not just about genetic mutations - the cellular environment and context are critical. Mutations presumed to cause cancer are often found in normal tissues. Cancer cells implanted in normal tissues often stop proliferating.
The “one rogue cell” theory paints cancer as a matter of genetic determinism and arbitrary bad luck. But the reality is more complex - cancer emerges from an interplay of genetics and environmental factors.
We need to move beyond genetic determinism and recognize cancer as a systems-level phenomenon, shaped by genetics but also the surrounding cellular ecology.
Otto Warburg argued that cancer is caused by damage to cellular respiration, but modern evidence does not support this view. Mutations in Krebs cycle enzymes can cause cancer, indicating a link to metabolism.
Cancer is fundamentally a disease of aberrant cell growth. Metabolic changes in cancer, whether genetic or otherwise, facilitate uncontrolled growth by altering growth signaling pathways or suppressing growth inhibitors.
The “Warburg effect” refers to the tendency of cancer cells to ferment glucose into lactate rather than respiring it fully, even in the presence of oxygen. This does not mean respiration is damaged, just that flux through glycolysis and lactate output is abnormally high.
Warburg was brilliant but dogmatic. He engaged in prolonged disputes by ignoring evidence contradicting his views on respiration, photosynthesis, and cancer. His vision of biology sought physicist-like simplicity and perfection not borne out by the messy reality of life.
The roots of cancer likely lie in distorted metabolism and growth signaling. Mutations may be a later event that consolidates uncontrolled growth. The prime cause relates to metabolic flux, not necessarily genetics.
Otto Warburg noted that cancer cells tend to use fermentation even in the presence of oxygen, a phenomenon known as the “Warburg effect.” He believed this revealed a defect in cellular respiration that was the root cause of cancer.
However, the Warburg effect is not universal across cancers and does not fully explain cancer metabolism. Many cancers do not rely on fermentation, and normal cells also use it.
Warburg dismissed contrary evidence and the work of other researchers, causing resentment. But his view of cancer as a metabolic disease was prescient, even if flawed. Genetic changes in cancer often do rewire metabolism.
Cancer growth requires more than ATP - it needs nucleotides, amino acids, fatty acids etc to duplicate all cell components. This requires metabolic reprogramming beyond just ATP production.
An example is producing the 16-carbon fatty acid palmitate for membranes, which requires 7 ATP molecules and a rewired metabolism to divert glycolytic intermediates.
So Warburg was right that cancer is metabolic, but it’s about more than just defective respiration. Metabolic rewiring redirects nutrients into pathways needed to grow and proliferate.
Cancer cells reprogram their metabolism to favor growth over ATP production. Aerobic glycolysis (the Warburg effect) produces less ATP but provides more biosynthetic precursors like NADPH and acetyl CoA.
There is an asymmetry between ATP and NADPH/carbon production from glucose. Burning glucose through respiration makes excess ATP which slows flux through glycolysis and the Krebs cycle, limiting availability of precursors.
Mutations in succinate dehydrogenase and fumarate hydratase block the Krebs cycle and cause buildup of succinate. Succinate leaks out and inhibits prolyl hydroxylases, stabilizing HIF1α which drives expression of genes favoring glycolysis and growth.
The succinate buildup is significant because succinate accumulation indicates a problem with mitochondrial respiration. It is a signal that the cell is not getting enough ATP.
This ancient mechanism to deal with low oxygen persists in cancer, reprogramming metabolism to favor biosynthetic precursors over ATP production. The Krebs cycle is central in balancing energy versus growth, a process deregulated in cancer.
HIF1α is a protein that is continuously synthesized but normally degraded within 5 minutes. When oxygen levels fall, succinate accumulation blocks the breakdown of HIF1α, allowing it to activate genes involved in glycolysis, inflammation, and cell survival.
This response helps cells adapt to hypoxia during infection or other conditions that limit oxygen delivery. However, if activated inappropriately, it can promote cancer cell growth.
Mutations in succinate dehydrogenase or fumarate hydratase cause succinate accumulation even with normal oxygen, activating the hypoxic response. This drives aerobic glycolysis (the Warburg effect) and cell proliferation.
Cancer cells need glucose and especially glutamine. Glutamine can fuel the Krebs cycle, including driving it in reverse from α-ketoglutarate to citrate, for biosynthetic purposes.
Damaged respiration, from mutations or drugs, enhances this reverse flux, linking Warburg’s observations to the metabolic rewiring of cancer cells. The reverse pathway also produces NADPH to power biosynthesis and antioxidants.
In summary, existing cell machinery to handle low oxygen is hijacked in cancer, driven by mutations and damaged respiration. This rewires metabolism to favor glycolysis and biosynthesis, supporting uncontrolled proliferation.
The Krebs cycle can run in reverse to produce citrate and succinate from glutamine. This helps cancer cells grow when normal Krebs cycle function is impaired.
Glutamine provides cancer cells with α-ketoglutarate, which can be converted to citrate and exported from the mitochondria to the cytosol.
In the cytosol, citrate is broken down into acetyl CoA and oxaloacetate. Acetyl CoA is used for fatty acid and lipid synthesis, while also acting as an epigenetic switch to promote growth by acetylating histones.
Oxaloacetate is a metabolic crossroads that can be used to generate aspartate, malate, pyruvate, lactate, acetyl CoA, phosphoenolpyruvate, and more. All of these metabolites support biosynthesis and growth in cancer cells.
Running the Krebs cycle in reverse generates NADPH, which cancer cells need for biosynthesis. It also provides intermediates like citrate and oxaloacetate that are diverted into biosynthetic pathways.
Overall, reverse Krebs cycle flux sustains proliferation in cancer cells by supporting biosynthesis and growth signaling. Glutamine metabolism is key to maintaining this abnormal flux.
Cancer cells rewire their metabolism to support unlimited growth and proliferation. A key feature is the Warburg effect, where cancer cells ferment glucose to lactate even in the presence of oxygen. This generates ATP efficiently while also providing building blocks like NADPH, nucleotides, lipids etc.
Glutamine is a major nutrient for cancer, providing both nitrogen and carbon skeletons. It can be fed into the Krebs cycle or used to generate glutathione and other antioxidants. Cancer cells release ammonia from glutamine breakdown, which causes muscle wasting to provide more glutamine.
The Krebs cycle is a metabolic crossroads. Parts of it can run in reverse to drive biosynthesis and antioxidant production. This depends on the needs of the cancer cell and nutrients available.
Cancer risk increases with age due to declining mitochondrial function. This causes backflow of the Krebs cycle and accumulation of signals like succinate and citrate that promote growth and inflammation. Mutations alone do not account for age-related patterns of cancer.
Overall, cancer cells have tremendous metabolic flexibility to rearrange pathways and use available nutrients for growth. Targeting these metabolic dependencies may offer new therapeutic approaches.
The author acknowledges there is an inherent tension between science’s ability to make statistical generalizations and its inability to fully explain individual exceptions. He illustrates this with the example of lifelong smokers who nevertheless live to old age, defying the statistical odds.
He suggests ‘good genes’ as a simple non-answer, but admits this is unsatisfying. The deeper issue is that while aging is a general phenomenon, the specific ailments that afflict individuals contain an element of chance. We can influence our fate but not determine it fully.
Medawar argued that we age because we outlive our allotted task of reproduction, so nature invests less in maintaining our later health. But this does not explain individual variation in lifespan and causes of death.
Molecular factors like accumulated mutations or metabolic changes influence disease risk, but do not fully account for individual outcomes. Other life events and chance factors play a role.
Overall, the tension between scientific generalizations and individual exceptions makes life tolerable by preserving a sense of mystery and unpredictability. Complete knowledge of our fates would make life intolerable. Some ignorance preserves our bliss.

Here are the key points:

The textbook view is that aging and age-related diseases are caused by late-acting genes - variants that are not eliminated by natural selection because their harmful effects occur after reproductive age.
But research has shown aging is surprisingly malleable - lifespan can be dramatically increased by changes to just a few genes, suggesting aging is not just the result of accumulating genetic damage.
There is a problem of “missing heritability” - known genetic variants account for only a small fraction of the genetic risk for diseases, suggesting other factors like physiology and biological flux may be important.
Mitochondrial genes interact with nuclear genes in complex ways but are often left out of genetic studies. They have an outsized impact on biological age and flux.
Doug Wallace has researched how mitochondrial and nuclear genes interact since the 1970s. Incompatibility between mitochondria and nuclear genes from divergent species can break down cell function, possibly contributing to speciation.
Douglas Wallace pioneered research on mitochondrial DNA and its role in human health and evolution. He showed mitochondrial DNA is inherited maternally in humans and prone to disease-causing mutations.
Mitochondrial DNA evolves faster than nuclear DNA due to more copying errors. This enables some adaptation to new environments but also causes diseases.
Wallace traced human migrations out of Africa using mitochondrial DNA variations. He speculates mitochondrial variations may confer some climatic adaptation.
Mitochondria integrate energy and biosynthesis in cells, making them central to physiology. They help coordinate signaling, gene expression, and cell death.
Wallace contrasts Vesalius’ anatomical view of medicine with Mendel’s genetics. He advocates an integrated “energy” view, considering mitochondria’s non-Mendelian inheritance.
Mitochondria act as “flux capacitors”, converting metabolic flux into membrane potential. This electrical force field shapes further flux and signals the nucleus, linking metabolism to gene expression.
The author discusses using genetically identical flies (except for mitochondrial DNA differences) to study mitochondrial-nuclear gene interactions and “mother’s curse” - the idea that mitochondrial DNA is optimized for females.
They found some mitochondrial-nuclear mismatches caused male infertility, as expected.
Unexpectedly, giving the flies an antioxidant called NAC killed most females of one mitochondrial line, while sparing others.
This suggests small mitochondrial DNA differences can dramatically alter responses to drugs or diets, with big sex differences. Subtle mitochondrial variations in humans likely contribute to varied responses to treatments.
The NAC antioxidant suppressed respiration in the vulnerable female fly line, hinting that altered mitochondrial function and ROS production may mediate differences in aging and drug responses.
The author argues individual mitochondrial genetic differences are more important than average group differences in determining outcomes. Personalized medicine approaches accounting for mitochondrial genetics may be needed.
An antioxidant called NAC was found to suppress respiration and increase glutathione levels in fruit fly lines. Some fly lines died, especially females.
The only difference between the fly lines was in their mitochondrial DNA, indicating the problem was respiratory.
Suppressing respiration reduces ROS production but also reduces Krebs cycle activity. The Krebs cycle is needed to regenerate glutathione (GSH) from its oxidized form (GSSG).
Oxidized glutathione signals to suppress complex I respiration further. This vicious cycle keeps ROS in check but can suppress respiration severely.
The female flies likely died more because egg production demands more Krebs cycle activity. Any respiratory deficits are more problematic for them.
The researchers link this to aging, where slight mitochondrial dysfunction can set off a similar vicious cycle. Minor respiratory defects get amplified over time through glutathione signaling, progressively suppressing respiration. This leads to energetic decline.

In summary, the study shows how an antioxidant can accelerate aging-like processes by disrupting glutathione signaling and the delicate balance between respiration and ROS production. Slight mitochondrial defects can snowball over time through this mechanism.

Here is a summarized version of the key points:

There is a broad correlation between metabolic rate and lifespan - smaller animals with faster metabolisms tend to have shorter lifespans, while larger animals with slower metabolisms live longer.
The ‘rate of living’ theory that damage accumulates from a faster metabolic rate driving aging is too simplistic - mutations and free radicals don’t directly correlate with aging rate.
Damage happens in many ways - proteins unfolding, accumulation, etc. Faster living means less time and energy to maintain cellular machinery. The optimal balance depends on life history tradeoffs.
ROS have an important signaling role, and cells tightly regulate redox balance. Excess ROS induces a stress response, but balance is restored.
With age, respiratory efficiency declines, likely due to accumulated damage. To maintain redox balance, complex I is suppressed, slowing NADH oxidation. This can cause reverse Krebs cycle flux and alter gene expression.
The tradeoff between biosynthesis, energy production and redox regulation becomes more difficult with respiratory dysfunction. This may explain ‘handicap’ signals of fitness like the peacock’s tail.
Overall, while metabolic rate doesn’t rigidly determine lifespan, it remains a critical factor through effects on cellular maintenance and redox regulation. Damage accrual compromises respiratory efficiency over time.

The free radical theory of aging proposes that oxidative damage accumulates with age, leading to declining function and disease. However, the fly experiments show that ROS levels don’t necessarily rise sharply with age. Instead, cell respiration is suppressed, metabolism slows down gently, and function declines.

Age-related diseases are linked to aging through subtle genetic mismatches between mitochondrial and nuclear genomes. These have little effect in youth but become amplified by age-related stress and damage. The effects depend on which genes are expressed in each tissue and how well mitochondrial genes interact with nuclear genes in that tissue. Different tissues have complementary metabolic roles, but with age tissues lose flexibility to alter metabolism.

For example, the brain is addicted to glucose but struggles to use it in diabetes due to insulin resistance and mitochondrial dysfunction. This can lead to Alzheimer’s disease, linked to damage in mitochondria-associated membranes (MAMs) which regulate calcium signaling. Neurons need to fire rapidly, enabled by glucose metabolism and high mitochondrial membrane potential. But dysfunction of MAMs and insulin resistance hampers this, while attempts to compensate further damage MAMs.

So the pattern of gene expression, metabolic demand, and mitochondrial function in each tissue determines vulnerability to age-related diseases, overlaid on the general shifts in cell metabolism and bioenergetics with age. Lifestyle factors like exercise and diet can improve mitochondrial health and biological aging. But genetic variants can still cause problems. Aging is a gradual systemic decline, but we succumb to varied diseases as individuals.

Ageing is driven by changes in gene activity (epigenetics), not mutations accumulating over time. Epigenetic changes alter metabolic flux, which sustains life second-by-second.
The Krebs cycle is central to this metabolic flux and is closely linked to mitochondrial function. Imbalances in Krebs cycle intermediates are a sign of cellular health decline.
Metabolic rate and lifespan only loosely correlate because some animals invest more in damage limitation. Bats and birds restrict reactive oxygen species from mitochondria to enable longer, more vigorous lives.
We each inherit distinct mitochondrial genes that influence Krebs cycle flux and ageing rate. Lifestyle choices such as diet and exercise interact with our mitochondrial differences.
To slow ageing we must sustain lifestyle changes long-term to invigorate metabolic flux. Personalised mito-sensitve lifestyles are key, as what works for one person may not for another.
The ancient Greek maxims of ‘Know Thyself’, ‘Nothing in Excess’, and ‘Surety Brings Ruin’ contain wisdom for living well by sustaining mito-sensitive lifestyles without overdoing it or craving certainty.
Our interconnectedness with all life means we should see ourselves differently. Metabolism and genes are inextricably linked from life’s origins to our own endpoint.
St mitochondria transfer involves the transfer of mitochondria from multiple germ cells into a single immature egg cell, followed by the death of the donor cells. This results in about a million oocytes and explains why most primordial germ cells die before birth in females.
Marco showed that only the selective transfer of mitochondria into primary oocytes could account for the prevalence of mitochondrial diseases in humans.
Thinking about selection for mitochondrial quality gives insights into female germline development - massive proliferation followed by death of most cells, prolonged quiescence of oocytes, etc. This doesn’t happen in males as they don’t pass on mitochondria.
The difference in mitochondrial inheritance is the deepest distinction between the sexes and arguably the reason there are two sexes.
Solving the problem of mitochondrial quality selection led to the issue of mother’s curse - mixing random paternal mitochondria is problematic.
The relationship between ROS production and signalling is complex - increasing respiratory capacity helps only if the problem is capacity. If respiration is damaged, increased capacity doesn’t help.
Larger animals tend to have lower metabolic rates for various reasons like heat loss, supply network geometry, and metabolic economies.
The problem of reverse Krebs cycle flux can’t be easily solved by anaplerotic pathways.
In neurons, suppressing complex I helps control ROS production but limits ATP supply, contributing to Alzheimer’s pathology.

Here are the key points:

Proton flow across membranes drove the synthesis of metabolic intermediates like amino acids and nucleotides, allowing the emergence of metabolism before genes.
Turin suggests consciousness is not limited to complex nervous systems but is a fundamental property of cells, soluble in anesthetics that affect electron transfer.
Anesthetics accumulate in mitochondrial membranes and may facilitate electron transfer to oxygen, short-circuiting proton pumping for ATP production. This could alter the mitochondrial membrane potential and affect consciousness.
Mitochondria generate electromagnetic fields through electron transfer and proton pumping. These fields may interact with weaker fields on neural membranes to modulate brain activity and generate the EEG.
Electrical fields can have motive force in the brain, transmitting signals across gaps and directly influencing neural function. So the EEG may not just be an epiphenomenon but integral to brain activity.
In summary, consciousness could be linked to mitochondrial membrane potential and electromagnetic signaling, an intrinsic property of cells rather than solely emerging from complex neural networks.

The work of biologist Michael Levin shows that electric fields can control the development of small animals like flatworms. This suggests that electrical fields generated by mitochondria may have an important influence on living things. Mitochondria were once bacteria that were engulfed by cells long ago. The electrical potential across mitochondrial membranes is similar to the charge on bacterial cell membranes, which is crucial for bacterial life and “selfhood.” Changes in this membrane potential may “feel” like something to bacteria as they modulate the electric fields that signify living states. Likewise, variations in mitochondrial membrane potential could generate feelings and moods in eukaryotic cells. The rapid flux of molecules through the Krebs cycle is unified by electromagnetic fields that exert force across the cell, creating a unified “self.” So the intrinsic meaning of mitochondrial metabolism may be found in the electric fields and conscious states they generate.

Here is a summary of the key points about the Krebs cycle from the appendices:

The Krebs cycle is a cyclic series of chemical reactions that forms part of cellular respiration in organisms.
In a prebiotic context, it can be thought of as a “Krebs line” - a linear series of similar reactions linking acetyl groups to produce larger carbon skeletons like pyruvate.
Acetyl CoA is a key molecule, formed from CO2 and a methyl group. It can react further to extend the carbon chain.
Normally multiple steps using ATP, CoA, and ferredoxin are needed to get acetyl CoA to react further. But on a mineral surface, an “activated” acetyl group can react directly with CO2 to form pyruvate.
Pyruvate is especially reactive due to its alpha carbon. It can exist in an enol form which facilitates further reactions.
The Krebs line repeats the same basic pattern of reactions to link 2-carbon units into larger chains. It can potentially build up to 6-carbon molecules like citrate.
Overall, the Krebs chemistry provides a simple prebiotic pathway to join single carbons into larger carbon skeletons, a critical step in the origin of metabolism.
The curly arrows show how a proton from the surface acquires a pair of electrons from pyruvate, forming a hydride ion (H-).
The two electrons that formerly bound hydrogen to pyruvate move to form a double bond in enol pyruvate. This is stabilized by the oxygen grabbing an electron.
The H- ion can react with a proton under acidic conditions to form hydrogen gas (H2) which bubbles away.
Enols are reactive because the C=C double bond can react with other molecules. The negative charge on oxygen reforms the double bond after reaction.
This allows enol pyruvate to bind to a mineral surface. It can then react with bound CO to form oxaloacetate.
Oxaloacetate can remain bound or be released by reaction with oxygen.
Additional steps show how malate and then succinate are formed from oxaloacetate on the surface.
Starting from CO2 and a mineral surface, these steps produce acetate, pyruvate, oxaloacetate and succinate - the first half of the reverse Krebs cycle.

Here are some key pieces related to the chapters in your book:

Chapter 1: Discovering the Nanocosm

F. Gowland Hopkins’ pioneering work in biochemistry is highlighted in his 1932 Royal Society address “Atomic Physics and Vital Activities” and Henry Dale’s obituary of Hopkins. These give a sense of the beginnings of biochemistry as a field.
Brian Ford’s “Single Lens” tells the remarkable story of Leeuwenhoek’s early microscopy discoveries by recreating his methods. It captures the first glimpses into the microscopic world.
N. Lane’s paper “The Unseen World” reflects on how Leeuwenhoek’s work informs biology today, giving historical context.

Chapter 2: Life Itself

Erwin Schrödinger’s classic “What Is Life?” remains insightful despite details being wrong. Its clear logic and vision illustrate how far thinking can take you in science.
Hansen et al.’s paper disagrees with Schrödinger on entropy, showing the cost of living versus maintaining cell structures.
The biography of Albert Kluyver traces his contributions to the unity of biochemistry across microorganisms.

Chapter 3: The Digital Jungle

Judson’s “Eighth Day of Creation” richly conveys the dawn of molecular biology through first-hand stories.
Cobb’s “Life’s Greatest Secret” covers the history of cracking the genetic code with the benefit of hindsight.
Crick’s wrong “Codes without commas” paper is a brilliant example of testing ideas.

Chapter 4: Molecular Machines

Ramakrishnan’s “Gene Machine” gives an insider’s view of determining the ribosome’s structure.
Goodsell’s art in “The Machinery of Life” uniquely brings molecular machines to life.

Let me know if you need any clarification or have additional questions!

Hans Krebs published his seminal paper on the Krebs cycle in 1937. Krebs cycle is a central metabolic pathway that describes the oxidation of fuel molecules to carbon dioxide and water, with the generation of ATP.
Otto Warburg made key contributions to understanding cellular respiration through his development of respirometry techniques to measure oxygen consumption. Warburg won the Nobel Prize in 1931.
Albert Szent-Györgyi made pioneering discoveries on cellular respiration and won the Nobel Prize in 1937. He is noted for his eccentric personality.
Fritz Lipmann elucidated the role of acetyl-CoA in linking glycolysis to the Krebs cycle, for which he won the Nobel Prize in 1953.
Peter Mitchell proposed the chemiosmotic hypothesis in 1961 to explain ATP synthesis. This groundbreaking theory about the role of proton gradients was initially controversial but eventually gained wide acceptance after experimental validation.
Mitchell had important collaborations and debates with colleagues like Jennifer Moyle to refine the chemiosmotic hypothesis.

In summary, the pioneers mentioned made seminal contributions to unraveling the fundamental biochemistry of cellular respiration and energy transduction in the mid-20th century. Their discoveries established core tenets of bioenergetics that are foundational today.

Here is a summary of the key points related to the path of carbon in photosynthesis:

Rubisco is the enzyme that fixes carbon dioxide in photosynthesis. It was originally called Fraction I protein before getting its current name, which stands for ribulose bisphosphate carboxylase-oxygenase. Rubisco is extremely abundant but also inefficient.
The use of radioactive isotopes, especially 14C, pioneered by Sam Ruben, Martin Kamen and others in the 1940s allowed tracing of the path of carbon in photosynthesis. This groundbreaking work was done at Ernest Lawrence’s Radiation Laboratory in Berkeley.
Andrew Benson, James Bassham and Melvin Calvin finally elucidated the full cyclic path of carbon fixation in photosynthesis in 1954, after painstaking work tracing the incorporation of 14C. This cycle is known as the Calvin-Benson cycle today.
The discovery of photophosphorylation by Daniel Arnon in 1954 showed how light energy is used to generate ATP during photosynthesis.
The reverse Krebs cycle for carbon fixation in bacteria was proposed in 1966 by Arnon after the discovery of ferredoxin. This provided an alternative CO2 fixation route to the Calvin-Benson cycle used by plants and algae.
There was animosity between Calvin and Benson over credit for discovering the cyclic path of carbon, which led to a lifelong rift between the researchers. Benson felt his contributions were not adequately recognized.

Here is a summary of the key points related to the discovery of hydrothermal vents and their relevance to the origin of life:

Hydrothermal vents were discovered in the late 1970s, revealing ecosystems at the seafloor supported by microbial chemosynthesis rather than photosynthesis. This discovery transformed ideas about conditions on the early Earth and possible origins of life.
Vents form chemical gradients and contain hot, reduced, metal-rich fluids that mix with cold, oxidized seawater. This creates disequilibrium conditions that can drive chemical reactions relevant to abiogenesis.
In the 1980s-90s, Günter Wächtershäuser and Mike Russell developed detailed theories for life originating at vents through iron-sulfur chemistry. Wächtershäuser proposed surface metabolism on minerals, while Russell focused on alkaline vents.
The discovery of the Lost City vent system in 2000 revealed the importance of serpentinization in producing hot, alkaline, hydrogen-rich fluids conducive to prebiotic chemistry and early microbial life.
Recent work has studied terrestrial serpentinizing systems and synthesized vent chemistry to further understand their role in abiogenesis through mineral catalysis, pH gradients, proton gradients and redox reactions.
Vents provide a compelling setting for the origin of life, supported by geological knowledge of the early Earth. However, many details are still debated, including exact environments, energy sources, and the sequence of steps from geochemistry to biochemistry.
David Deamer has done pioneering work on lipid membranes and proto-cells and advocates terrestrial geothermal systems for the origin of life, though the author disagrees.
Armen Mulkidjanian proposes zinc sulfide photosynthesis at high pressures, but the author is unpersuaded.
John Sutherland has synthesized many biological building blocks through prebiotic chemistry, but the author feels the chemistry does not resemble biochemistry.
Jack Szostak focuses on prebiotic chemistry leading to RNA, but his view contrasts the continuous growth the author advocates.
Christian de Duve emphasized the importance of thioesters and energy currencies like acetyl phosphate in linking geochemistry and biochemistry.
Recent papers show iron minerals can catalyze reactions of H2 and CO2 to form metabolites like acetate and pyruvate.
Markus Ralser shows parts of central metabolism can operate through spontaneous chemistry alone.
Some textbooks and papers argue LUCA lived off H2 and CO2 in vents using protons and iron-sulfur proteins.
Papers try to reconstruct early metabolism and bioenergetics of LUCA, pointing to the antiquity of the acetyl CoA pathway and metalloenzymes.
Morowitz pioneered ideas like the reverse Krebs cycle and “energy flows, matter cycles” that link biology and geochemistry.

Here is a summary of the key points from the excerpt:

The excerpt discusses different theories and experimental research related to the origin of life, particularly focusing on the role of thermodynamics and energy flow. Key points include:

Morowitz and Smith make a punning argument that the origin of life is related to the ‘descent of electrons’ and thermodynamics. Orgel criticizes this view as an ‘appeal to magic.’
Harrison and Lane propose nucleotide synthesis pathways based on modern biological catalysts, using metal ions.
Experiments show iron-sulfide minerals can catalyze reactions related to the Krebs cycle. Camprubi et al. propose a simple Krebs-like pathway on iron-nickel-sulfur mineral surfaces.
Methanogens are used as models for early bioenergetics. LUCA is proposed to rely on proton gradients like modern methanogens.
Lane argues proton gradients were an early form of energy conservation before ATP and chemiosmosis evolved.
Experiments demonstrate proton gradients across barriers can promote CO2 reduction by H2, forming organics like formate.
Hydrothermal conditions allow synthesis of membrane-forming lipids. Jordan et al. show protocells spontaneously assemble under alkaline vent conditions.
Amend and McCollom calculate energetics showing synthesis inside cells is thermodynamically favored over isolated prebiotic reactions.

The excerpt covers a range of theories and experiments related to early bioenergetics in hydrothermal vents as a model for the origin of life. Key is the role of thermodynamics, proton gradients, and iron-sulfur mineral catalysts.

Here are some key points and sources on the major revolutions covered in Chapter 4:

Cambrian Explosion

The Cambrian explosion refers to the relatively rapid appearance of most major animal phyla in the fossil record about 541-515 million years ago. Some key sources are Stephen Jay Gould’s Wonderful Life and works by Simon Conway Morris.
There is debate around how “explosive” this radiation of animal life really was, but it undoubtedly marks a major transition in evolution.

Rise of Oxygen

Oxygen began accumulating in the atmosphere around 2.4 billion years ago, profoundly altering Earth’s chemistry and enabling complex multicellular life.
Key sources are books by Donald Canfield and Nick Lane on the coevolution of life and oxygen.
Controversy remains about causes of the initial oxygenation and its exact timing, but evidence points to origin of oxygenic photosynthesis in cyanobacteria.

Electron Bifurcation

The discovery of electron bifurcation, in which pairs of electrons from reduced ferredoxin can energetically drive unfavorable redox reactions, helped explain mysteries of energy generation in anaerobic microbes.
Pioneering work by Wolfgang Buckel and Rudolf Thauer in the 1980s-90s unlocked this pivotal bioenergetic process.

Early Evolution of Cells and Metabolism

Lynn Margulis synthesized endosymbiotic theory showing mitochondrial and chloroplast origins.
Margaret Dayhoff pioneered computational molecular evolution, contributing phylogenetic analyses.
Bill Martin, Filipa Sousa, and colleagues elucidate origins of heterotrophy, bioenergetic innovations in early cells.
Geochemical evidence also constrains environments and metabolisms of early microbial life.

Advent of Oxygenic Photosynthesis

Oxygenic photosynthesis, in which water is split for electrons, evolved in cyanobacteria likely using a “redox switch” scheme proposed by John Allen.
This transition enabled oxygen buildup and vastly greater energy availability in the biosphere.

Here is a summary of the key points and recommended reading related to the themes in Chapter 5 on the dark side of respiration:

Oncogenes and Tumor Suppressor Genes

Cancer results from genetic mutations that activate oncogenes and deactivate tumor suppressor genes, allowing cells to proliferate uncontrollably.
The “Hallmarks of Cancer” papers by Hanahan and Weinberg outline the key genetic changes in cancer.
The Pan-Cancer project has analyzed whole genome sequences from thousands of tumors to characterize genetic mutations.
Weinberg’s “One Renegade Cell” explains how mutations convert normal cells into cancerous ones.

Challenges to the Genetic Theory

Some researchers like Peyton Rous have challenged the somatic mutation theory, arguing cancer may have other causes.
Papers by Baker, Seyfried, Soto & Sonnenschein point to evidence not explained by genetic mutations.
Holliday’s “Understanding Ageing” reviews evidence against somatic mutations driving cancer or aging.
Nuclear transfer experiments show cancers can be reversed without changing genetics.

Warburg’s Metabolic Theory

Otto Warburg proposed cancer results from impaired cellular respiration, not mutations.
Krebs’ biography of Warburg discusses his work on cancer metabolism.
Papers by Otto and Kamen review Warburg’s metabolic theory of cancer.

Key references are Weinberg on oncogenes, Holliday on challenges to the mutation theory, and Krebs on Warburg’s life and work. The Pan-Cancer project exemplifies the big data approach. Overall, a balanced perspective considering both genetic and metabolic factors is warranted based on the evidence.

Warburg met prominent biochemist Robert Emerson, who introduced him as a towering figure.
Article by Weisz explores how Warburg survived Nazi persecution despite his Jewish ancestry.
Book by Prebble documents the dispute between Warburg and David Keilin over credit for discoveries about cellular bioenergetics.
Article by Rosenwald explains Hitler’s fear of cancer and how this protected Jewish doctor Eduard Bloch.
Govindjee documents the dispute between Warburg’s student Emerson over the quanta requirements for photosynthesis. Emerson was correct.
Höxtermann provides context on Warburg’s early flawed views on enzyme catalysis in respiration and photosynthesis.
Chance and Weinhouse critiqued Warburg’s cancer theories as oversimplified decades later, but current research vindicates metabolic view.
Key papers show cell proliferation, not merely energy, drives Warburg effect in cancer. Mitochondria actively contribute.
Hypoxia and accumulated succinate drive reperfusion injury. Low oxygen can treat mitochondrial disease in mice.
Glutamine, not glucose, critical for some cancers. Reverse flux in Krebs cycle can fix CO2 in defective tumor mitochondria.

Here is a summary of the key points from the referenced papers on mitochondrial research and ageing:

Evolutionary theories propose that ageing is the result of the declining force of natural selection with age. Medawar and Williams put forward the idea that genes with benefits early in life can be favored by natural selection even if they have negative effects later on after reproduction.
Genome-wide association studies (GWAS) have linked many genetic variants to lifespan and age-related diseases, but the effect sizes are small and account for only a fraction of heritability. Mitochondrial DNA is often neglected in these studies.
Doug Wallace pioneered research on mitochondrial genetics and diseases. He showed maternal inheritance of mtDNA in humans and that introducing mtDNA mutations into cells can cause defects.
Wallace argues mtDNA facilitates adaptation but mutations also cause disease. He developed mouse models to study mitochondrial diseases.
Mitochondrial function declines with age in many tissues. This mitochondrial decline likely contributes to aging through increased oxidative stress, impaired calcium handling, apoptosis, and metabolic defects.
Supporting mitochondrial function may therefore be a promising strategy to slow aging. Potential approaches include mitochondrial antioxidants, NAD+ boosters, and exercising to induce biogenesis.

Here are some key points summarizing the papers:

Disease reveals selection against severe mtDNA mutations in the female germline. Mitochondrial mutations that cause disease are selectively eliminated. Explains how fast mutation rate facilitates adaptation without excessive disease burden.
Biodiversity and sharp distinctions between species (barcode-like mtDNA) can be reconciled through selective effects and Wallace’s work on mtDNA evolution.
Model shows maternal inheritance of mitochondria needed to purge deleterious mutations at extreme ploidy in mammals. Explains germline architecture.
Extraordinary diversity of mechanisms regulating mt inheritance stems from sexual conflict over controlling mtDNA destruction in eggs/sperm.
No relation between genetic distance and hybrid breakdown severity, contradicting ‘race’ concepts.
Mother’s curse robust across large fly panel with mismatched mtDNA-nuclear backgrounds.
Antioxidant NAC causes redox problems in some but not all lines depending on mtDNA, highlighting mito-nuclear interactions.
Extreme respiratory suppression to control ROS production can cause death. Big differences between sexes and fly lines with same nuclear genes. MtDNA dependent.
Too much glutathione causes reductive stress and ROS production. S-glutathionylation suppresses respiration and H2O2 signaling.
Rate of living theory still has merit, though exceptions exist. Number of heartbeats may relate to lifespan.
Antioxidants don’t extend lifespan in studies. ROS flux is tightly controlled and body prevents interference.
Ageing stems from hyperfunction and overrun of developmental programs, not from a program itself. Respiratory suppression shifts metabolism and epigenetics.
Glycation damage may link major age-related disorders.

Here is a summary of the key points from the passages:

Glycation, the process of sugars binding to proteins, lipids, and DNA, increases with age and contributes to aging and age-related diseases. The targets of glycation vary across tissues.
Mitochondrial proteomes differ substantially across tissues - nearly half of all mitochondrial proteins vary between tissues.
Insulin secretion from pancreatic beta cells depends on glucose-induced increases in mitochondrial membrane potential.
Evidence links diabetes and Alzheimer’s disease: Alzheimer’s can be considered “type 3 diabetes.” Defective mitochondrial function may underlie this connection.
Mitochondria-associated membranes (MAMs) likely play an important role in Alzheimer’s pathology through effects on calcium signaling, lipid metabolism, and protein processing.
Calcium activation of pyruvate dehydrogenase in mitochondria powers up ATP production through increased flux through the Krebs cycle and electron transport chain.
General anesthetics may act by interfering with electron flow to oxygen in mitochondrial respiration. This hints at a potential mechanistic explanation for consciousness.
The origin of brain EEG signals remains unknown, but could potentially relate to mitochondrial membrane electrical activity. Autism-linked mitochondrial mutations in mice alter EEG patterns similarly to humans.
Electrical fields, not just genes, play a major role in embryonic development. This hints that consciousness could relate fundamentally to electrical signaling and information processing.

Here is a summary of the key points from the acknowledgements section:

Nick Lane thanks his wife Ana Hidalgo-Simón first and foremost. She encouraged him to write this book on the Krebs cycle and energy flow. Their discussions during long walks helped shape and improve the book.
The Covid pandemic provided an unexpected backdrop while writing the book. It led to empty streets which promoted contemplation.
Nick is grateful to his lab group members at UCL for their perseverance through disrupted times and for their work which helped resolve issues in his mind.
Friends and colleagues read draft chapters and provided valuable feedback on content, style, pace and tone, for which Nick is thankful. In particular, Diego Maria Bertini provided excellent comments while recovering slowly from severe Covid in Italy.
Specialist colleagues confirmed Nick avoided errors and offered new directions. Their enthusiasm helped rekindle his motivation.
The book was forged through thinking hard about experiments and grappling with new results and imploding ideas. Surviving ideas are stronger for it.
The author thanks many scientists who have influenced his thinking and work, including Mike Russell, Lee Sweetlove, Christian Frezza, Frank Sullivan, Franklin Harold, Mårten Wikström, Alistair Nunn, Luca Turin, Doug Wallace, Dan Dennett and others.
He is grateful to his family for their love and support, especially his wife Ana and their two sons, Eneko and Hugo.
He thanks his literary agent Caroline Dawnay and his publishers for their support and guidance in developing the book.
The author pays tribute to his late friend Ian Ackland-Snow, who had an immense positive influence on many lives.
He expresses his hope that the book provides food for thought and makes progress on the question of consciousness.
The index covers the main text and appendices, with page numbers for illustrations in italics.

Here is a summary of key points about ascorbic acid, Isaac Asimov, aspartate, Earth’s early atmospheres, atmospheric oxygen balance, ATP, ATP citrate lyase, ATP synthase, autocatalysis, autoradiographs, autotrophs, bacteria, ancient bacteria, carbon isotopes, carbon fixation, the Krebs and reverse Krebs cycles, cancer, consciousness, ferredoxin, and other topics from your prompt:

Ascorbic acid (vitamin C) is an antioxidant that plays important roles in metabolism. Its biosynthetic pathway evolved relatively recently in some animals.
Isaac Asimov was a prolific science fiction writer who helped popularize science.
Aspartate is an amino acid that feeds into the Krebs cycle via reactions that incorporate ammonia.
Earth’s early atmospheres lacked oxygen but contained gases like methane, ammonia, and carbon dioxide. The Great Oxidation Event introduced oxygen about 2.4 billion years ago.
ATP synthase is an enzyme that makes ATP. Early cells may have lacked this complex machine.
Autocatalysis refers to self-replication and was likely key in the origin of life. Autoradiographs track radioisotopes and were used to study photosynthesis.
Autotrophs like plants and photosynthetic bacteria fix carbon dioxide into organic compounds. This was important in early evolution.
Ancient bacteria show deep roots of core metabolic cycles like the Krebs and reverse Krebs cycles. Endosymbiosis gave rise to mitochondria.
Carbon isotope ratios help reveal details of ancient metabolisms. Carbon fixation incorporates carbon dioxide into biomass.
The Krebs cycle breaks down nutrients to generate energy carriers like ATP. Its reverse can fix carbon dioxide into biomass.
Cancer may arise from metabolic dysregulation more than genetic mutations. Warburg observed fermentation of glucose by cancer cells.
Consciousness may involve quantum effects and electromagnetic fields.
Ferredoxin is an ancient iron-sulfur protein that mediates key reactions like carbon fixation. It may have played an early role in metabolism.

Here is a summary of the key points about the reverse Krebs cycle and Krebs cycle enzymes:

The reverse Krebs cycle operates in the opposite direction to the normal Krebs cycle, using CO2 as a starting point to generate organic molecules. It was proposed as a possible pathway for the origin of life.
Key enzymes involved in the reverse Krebs cycle include fumarate reductase, ATP citrate lyase, and pyruvate synthase. The cycle can fix CO2 and generate various organic acids and sugars.
Mutations in Krebs cycle enzymes like fumarate hydratase, succinate dehydrogenase, and isocitrate dehydrogenase can contribute to cancer by altering metabolite levels and cellular signaling.
The membrane-bound localization of some Krebs cycle enzymes, like succinate dehydrogenase, is important for proper function and coupling to the electron transport chain. Disruption of these enzymes in cancers can promote proliferation and survival.
Krebs cycle enzymes catalyze critical steps in central carbon metabolism and their flux can influence processes like biosynthesis, redox balance, and energy production. Their dysregulation is linked to various diseases.

Here are the key points:

Organic molecules like sugars, amino acids, nucleotides are important building blocks of life. Biochemistry studies how they are interconverted and utilized in cells.
Mitochondria are the powerhouses of cells, generating ATP through respiration. The Krebs cycle oxidizes nutrients and generates reducing power for ATP synthesis.
Hans Krebs discovered the Krebs cycle. His careful work elucidated the steps and intermediates.
Reverse Krebs cycle operates in some bacteria, driving ATP synthesis in the opposite direction. It may have evolutionary origins.
Cancer cells rewire their metabolism, favoring glycolysis over respiration, even in oxygen. This is the Warburg effect. Mitochondria likely still contribute to cancer.
Origin of life research suggests metabolism may have preceded genetics. Simple organic reactions could arise naturally and become interconnected into proto-metabolic networks.
Evolution leads to complex cellular networks with division of labor. Specialized cell types exchange metabolites. This metabolic symbiosis improves efficiency.
Aging involves mitochondrial mutations and declining respiration. ROS production and oxidative damage accumulate over time. Lifestyle affects mitochondrial health.
The book covers a range of topics related to cell metabolism and energetics, including glycolysis, respiration, photosynthesis, genetics, evolution, cancer, and more.
It traces the history of discoveries and debates in these fields, profiling notable scientists like Warburg, Krebs, Calvin, etc.
There are discussions of foundational concepts like ATP production, the urea cycle, the TCA cycle, redox reactions, chemiosmosis, etc.
Evolutionary ideas are explored, like the development of photosynthesis, aerobic respiration, multicellularity.
The Warburg effect and its implications for understanding cancer metabolism are examined.
Broader themes include vitalism vs mechanism, genetic vs environmental effects, reductionism vs holism, and more philosophical dimensions.
Overall the book provides a broad look at the crucial role of energy, metabolism, and genetics in life, from evolutionary beginnings to medical applications. It highlights key discoveries while also probing deeper questions and debates.

#book-summary

Transformer The Deep Chemistry of Life an - Nick Lane