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Kindle Notes & Highlights
by
Nick Lane
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November 17 - December 20, 2022
In the seventeenth century, when the Dutch microscopist Antonie van Leeuwenhoek unveiled the cosmos hidden in a drop of water, he marvelled at the little ‘animalcules’ that lived out their lives there, all whirring parts and purpose.
Some 350 years after van Leeuwenhoek, we now know what most of these whirring parts do, what they’re made of, how they function.
The difference between being alive or dead lies in energy flow, in the ability of cells to continually regenerate themselves from simpler building blocks.1
To a first approximation, biology is understood in terms of information networks and control systems.
what processes animate cells and set them apart from inanimate matter?
This book will explore how the flow of energy and matter structures the evolution of life and even genetic information, leaving an indelible stamp on our own lives. I
Genes and information do not determine the innermost details of our lives. Rather, the unceasing flow of energy and matter through a world in perpetual disequilibrium conjures the genes themselves into existence and still determines their activity, even in our information-soaked lives. It is the movement that creates the form. I
One of the founding fathers of biochemistry, Sir Frederick Gowland Hopkins, dedicated much of his long career through the first four decades of the twentieth century to promoting what he called the ‘dynamic side’ of biochemistry: the idea that the basic molecules of life are quite simple and can be analysed by conventional chemical methods – but that they are funnelled down specific pathways, in which one molecule is converted through some small chemical change into another form, again and again, each time fashioned by a catalyst with specific properties. Life, for Hopkins, was the combination
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In biochemistry, flux is the flow of things that are transformed along the way.
Metabolism is what keeps us alive – it is what being alive is – the sum of the continuous transformations of small molecules on a timescale of nanoseconds, nanosecond after nanosecond.
These are the building blocks that make up cells, little more than a few hundred types of molecule in total.
The first attempts to decipher the code of life were made by physicists, including Crick himself, who sought (and found) a mathematical beauty; but all of them turned out to be utterly wrong.
This book aims to show that the flow of energy and matter through cells structures biological information rather than the other way around. Information is obviously important, but it’s only part of what makes us alive.
The greatest advances have drawn on the same recondite technique that Rosalind Franklin brought to bear on DNA in the early 1950s, X-ray crystallography, albeit with an enormous increase in power and resolution since then.
Perhaps the consummating achievement of crystallography was Venki Ramakrishnan’s structure of the ribosome – the astonishing molecular machines, virtually whole factories, that process the genetic code to build new proteins. This is no repetitive structure like DNA, but an enormous assemblage of a quarter of a million atoms, each with its own precisely defined positions.
These two themes, information and structure, have combined as the dominant paradigm of medical research in recent decades.
There’s a new name for this that reflects the modern ‘omic’ age: metabolomics. We have known all the steps in the major metabolic pathways for decades – they were laboriously worked out, step by step, from the 1930s onwards, with a leap forward in the post-war years, when radioactive tracers enabled the fate of specific carbon atoms to be tracked (as we’ll see in Chapter 2). Metabolomics is much the same thing, but now with the aid of powerful techniques such as mass spectrometry. Instead of seeking the commonalities – the same metabolic pathways in different cells – metabolomics looks for the
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As the poet Edna St Vincent Millay wrote, ‘life isn’t one damn thing after another, it’s the same damn thing again and again’.
Core metabolism has changed little in part because it was never powered down in its four-billion-year history. The genes are custodians of this flame, but without the flame life is – dead.
At the heart of the cell is a merry-go-round of energy and matter known as the Krebs cycle, after the venerated biochemist Sir Hans Krebs, who first conceived this iconic cycle of reactions in the 1930s.
The raison d’être for the Krebs cycle is muddied even further by the fact that the cycle supplies many of the basic building blocks for the fabric of the cell. Most amino acids are made directly or indirectly from molecules in the Krebs cycle. So are the long-chain lipid molecules needed to make cell membranes. New sugars are made from the Krebs cycle too. Even the ‘letters’ of DNA (termed nucleotides) are made from sugars and amino acids, and so also derive from the Krebs cycle. I could go on but suffice to say that the Krebs cycle is the engine of biosynthesis, driving cellular growth and
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merry-go-round
molecules accumulating in the Krebs cycle can signal the state of the cell to the genes, switching on or off hundreds or even thousands of genes.
The driving force for metabolism is thermodynamics.
The experiment for which Warburg won the Nobel Prize in 1931 was just so beautiful I have to tell you about it.
Science is an emotional roller-coaster no matter how much scientists strive to build an objective and unemotional framework. It’s a wholly human pursuit.
Albert Szent-Györgyi was a true original.
He completed his medical degree during his convalescence.
In general, one enzyme catalyses a single reaction, being honed to the shape and charge of a specific molecule known as its substrate.
It’s also worth noting that, even though Szent-Györgyi’s idea turned out to be wrong in detail, it was valuable nonetheless, because it focused attention on a primary feature of the cycle – the removal of hydrogen (2H) from carboxylic acids. Again,
A full decade later, in 1947, Fritz Lipmann discovered that pyruvate was indeed stripped of one CO2 (and 2H) leaving a C2 carboxylic acid attached to a larger molecule that acted as a kind of molecular handle. He
Peter Mitchell arrived as an undergraduate in Cambridge several years after Krebs had left, at the outbreak of war in 1939.
the Glynn Institute, the remarkable eighteenth-century manor house near Bodmin in Cornwall that Mitchell lovingly restored as a laboratory and home.9 The Glynn was animated by Mitchell’s unique vision of science, and became a place of pilgrimage for bioenergeticists the world over, who would stay for weeks or months to work in the lab, discuss the physics of biology, and drink deeply from the source.
So ATP synthesis is powered by what Mitchell called the proton-motive force.
If we were to iron out all the mitochondrial membranes in the body, so they were flat, they would cover an area equivalent to about four football pitches – all charged with the power of a bolt of lightning.
‘Energy flows, matter cycles.’ This axiom from the legendary biophysicist Harold Morowitz might one day be elevated to a fourth law of thermodynamics, but in the meantime it is more informally known as Morowitz’s cycling law.
He later declared that outscoring Gell-Mann by a couple of marks in one test was his greatest achievement in physics.
‘Conformity is not necessarily a virtue. Hard work is almost never vice. Hopefulness is a moral imperative. And, a sense of humour helps.’
The Earth is of course an open system, continually drenched by sunlight, and Morowitz had formally shown that ‘the energy that flows through a system acts to organize that system’. The judge, William Overton, ruled that so-called creation science did not qualify as science, so should not be taught in science classes.
‘Science is guided by natural law. It has to be explanatory by reference to natural law. It is testable against the empirical world. Its conclusions are tentative (not necessarily the final word). It is falsifiable.’
Morowitz had laid out his cycling theorem in a 1968 book, Energy Flow in Biology: ‘In steady state systems, the flow of energy through the system from a source to a sink will lead to at least one cycle in the system.’
The bottom line is that the dissipation of heat means that no pathway is perfectly reversible, hence energy flow powers the cycling of matter.
Even better than that. As noted in the last chapter, the reverse Krebs cycle is autocatalytic. Starting with one molecule of the C4 oxaloacetate, one spin of the reverse cycle generates two molecules of oxaloacetate; the next spin generates four molecules, then eight, sixteen and so on. Not only is this exponential growth, but each doubling forms a copy of the original, combining stability with growth.
Morowitz’s conception is beautiful and full of meaning. It suggests that life can’t help but emerge on any wet, rocky planet flooded with light from a nearby star.
Leslie Orgel.
The lesson I took away was simple: cells rarely live alone, but collaborate in the most intimate ways to optimise the driving forces of each other’s metabolism.
I suspect that this reasoning applies to the Krebs cycle itself, which the biochemist Erich Gnaiger has compared to that ancient Egyptian (and later alchemical) symbol, the Oroboros, a serpent or dragon consuming its own tail.3 This mythical beast is usually interpreted as a symbol of eternal cyclic renewal, the cycle of life, death and rebirth. Gnaiger sees thermodynamic meaning too. The Oroboros cycle operates at 100 per cent efficiency: the energy for the serpent’s rebirth is captured entirely by consuming its own tail, with no external supply of energy. Life is plainly not a perpetuum
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‘The dream of every cell is to become two cells’ said François Jacob, the most lyrical revolutionary of molecular biology. No cell lives the dream so wholly or so senselessly as a cancer cell, turning dream to nightmare. Nothing else captures the myopic immediacy of natural selection so starkly. The moment is all that matters for selection: there is no foresight, no balance, no slowing at the prospect of doom. Just the best ploy for the moment, for me, right now, not for the many, and often mistaken. Cancer cells die in piles, necrotic flesh worse than the trenches. The decimated survivors
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A mature oocyte (egg cell) has nearly half a million copies. This means that a mutation, if present in only a few copies, might be masked by numerous normal copies. But it can be much more confusing. The same mitochondrial mutation often produces differing outcomes at different doses, or if set against different nuclear genes, or in distinct tissues, or if interacting with other mitochondrial DNA in the same cell, much of which exhibits tortuously complex behaviour, making mitochondrial diseases elusive and esoteric to this day.
Falling in love with people from other cultures is as human as we can get, and I will always celebrate it. But we ought to know if hybrid vigour can be undermined by a higher risk of mitochondrial diseases. Spoiler alert: I don’t think so. But there’s plenty else to ponder on here.
