Transformer: The Deep Chemistry of Life and Death

by Nick Lane

What brings the Earth to life, and our own lives to an end?

For decades, biology has been dominated by the study of genetic information. Information is important, but it is only part of what makes us alive. Our inheritance also includes our living metabolic network, a flame passed from generation to generation, right back to the origin of life. In Transformer, biochemist Nick Lane reveals a scientific renaissance that is hiding in plain sight —how the same simple chemistry gives rise to life and causes our demise.

Lane is among the vanguard of researchers asking why the Krebs cycle, the “perfect circle” at the heart of metabolism, remains so elusive more than eighty years after its discovery. Transformer is Lane’s voyage, as a biochemist, to find the inner meaning of the Krebs cycle—and its reverse—why it is still spinning at the heart of life and death today.

Lane reveals the beautiful, violent world within our cells, where hydrogen atoms are stripped from the carbon skeletons of food and fed to the ravenous beast of oxygen. Yet this same cycle, spinning in reverse, also created the chemical building blocks that enabled the emergence of life on our planet. Now it does both. How can the same pathway create and destroy? What might our study of the Krebs cycle teach us about the mysteries of aging and the hardest problem of all, consciousness?

Transformer unites the story of our planet with the story of our cells—what makes us the way we are, and how it connects us to the origin of life. Enlivened by Lane’s talent for distilling and humanizing complex research, Transformer offers an essential read for anyone fascinated by biology’s great mysteries. Life is at root a chemical phenomenon: this is its deep logic.

Genres: Science, Biology, Nonfiction, Chemistry, Evolution, Audiobook, Biography

400 pages, Hardcover

First published May 1, 2022

About the author

Dr Nick Lane is a British biochemist and writer. He was awarded the first Provost's Venture Research Prize in the Department of Genetics, Evolution and Environment at University College London, where he is now a Reader in Evolutionary Biochemistry. Dr Lane’s research deals with evolutionary biochemistry and bioenergetics, focusing on the origin of life and the evolution of complex cells. Dr Lane was a founding member of the UCL Consortium for Mitochondrial Research, and is leading the UCL Research Frontiers Origins of Life programme. He was awarded the 2011 BMC Research Award for Genetics, Genomics, Bioinformatics and Evolution, and the 2015 Biochemical Society Award for his sustained and diverse contribution to the molecular life sciences and the public understanding of science.

Nick Lane is the author of three acclaimed books on evolutionary biochemistry, which have sold more than 100,000 copies worldwide, and have been translated into 20 languages.

Nick's first book, Oxygen: The Molecule that Made the World (OUP, 2002) is a sweeping history of the relationship between life and our planet, and the paradoxical ways in which adaptations to oxygen play out in our own lives and deaths. It was selected as one of the Sunday Times Books of the Year for 2002.

His second book, Power, Sex, Suicide: Mitochondria and the Meaning of Life (OUP, 2005) is an exploration of the extraordinary effects that mitochondria have had on the evolution of complex life. It was selected as one of The Economist's Books of the Year for 2005, and shortlisted for the 2006 Royal Society Aventis Science Book Prize and the Times Higher Young Academic Author of the Year Award.

Nick's most recent book, Life Ascending: The Ten Great Inventions of Evolution (Profile/Norton 2009) is a celebration of the inventiveness of life, and of our own ability to read the deep past to reconstruct the history of life on earth. The great inventions are: the origin of life, DNA, photosynthesis, the complex cell, sex, movement, sight, hot blood, consciousness and death. Life Ascending won the 2010 Royal Society Prize for Science Books, and was named a Book of the Year by New Scientist, Nature, the Times and the Independent, the latter describing him as “one of the most exciting science writers of our time.”

Nick's next book, due to be published in 2015 by Norton and Profile, is entitled The Vital Question. Why is life the way it is? It will attack a central problem in biology - why did complex life arise only once in four billion years, and why does all complex life share so many peculiar properties, from sex and speciation to senescence?

Nick was also a co-editor of Life in the Frozen State (CRC Press, 2004), the first major text book on cryobiology in the genomic era.

Peer-reviewed articles by Nick Lane have been published in top international journals, including Nature, Science and Cell, and he has published many features in magazines like New Scientist and Scientific American. He has appeared regularly on TV and radio, and speaks in schools and at literary and science festivals. He also worked for several years in the pharmaceutical industry, ultimately as Strategic Director of Medi Cine, a medical multimedia company based in London, where he was responsible for developing interactive approaches to medical education.

Nick is married to Dr Ana Hidalgo-Simon and lives in London with their two young sons, Eneko and Hugo. He spent many years clinging to rock faces in search of fossils and thrills, but his practical interest in palaeontology is rarely rewarded with more than a devil’s toenail. When not climbing, writing or hunting for wild campsites, he can occasionally be found playing the fiddle in London pubs with the Celtic ensemble Probably Not, or exploring Romanesque churches.
http://www.nick-lane.net/About%20Nick...

Reviews

[Brian Clegg · Rating 5 out of 5]

This is probably the best book on biology (and more specifically biochemistry) that I've ever read.
Ever since Richard Dawkins wrote The Selfish Gene, we've been dazzled by the importance of the genetic code (or, as Lane points out in one of his many asides, what should really be called the genetic cipher) - but this focus has tended to give an exaggerated importance to the information stored there. Of course it's essential to life - but as this book explores, chemistry and energy are what life is really about. Nick Lane points out that there is no difference in the information in an organism just before and just after it dies - but there's quite a lot of difference in terms of its life.

Biology and chemistry can both be extremely difficult to put across in popular science. Biology because it's so complicated with vast numbers of molecules and processes involved, and chemistry because, dare I say it, it can appear a bit dull. What Lane does wonderfully well is to bring biochemistry to life. He demonstrates this marvellously in his description of the discovery of the Krebs cycle - central to the process of respiration and at the heart of this book. Read a standard description of the cycle, and it's pretty much impenetrable to the non-biochemist. But first by using a very elegant way of visually portraying molecules and then by combining the mechanism of the cycle with the story of its discovery, Lane turns it into something accessible and exciting.

The Krebs cycle is a series of chemical reactions that take place (in part or entirely) in most living organisms. Running in one direction it explains respiration, the process by which organic molecules undergo controlled combustion to produce energy, while in reverse it is one of the ways that complex organic molecules can be constructed. At the same time we see the importance of flows of energy and electrical potentials in understanding life. It's heady stuff. Lane goes on to show how the same processes that support life can produce cancers - and why these processes change over time, resulting in ageing and death.

Another impressive aspect of this book is the way it brings the real scientific method into the spotlight. This is something that science writing tend to over-simplify and treat with almost religious awe. Yet it is undertaken by flawed human beings. In showing how explanations of the Krebs cycle, the workings of mitochondria and more were gradually developed, Lane gives us plenty of stories of human endeavour and how the development of good science is not a straight line to success, but involves detours, misunderstandings and, yes, sometimes human pettiness.

Although I love this book, it does inevitably suffer part way through from the problems of a biology book being read by non-biologists. To start with I was carried along with enthusiasm engendered by those stories and Lane's novel presentation, but there are a couple of chapters midway through where the sheer volume of molecules named becomes somewhat overwhelming and I had to fight myself not to skip to a more interesting bit. It's hard to see how this could be avoided - but it does remain an issue.

We emerge back into the sunlight of comprehensibility and interest, though. In this book, Nick Lane challenges us to see the nature of life differently - not dismissing genetics, but making it an equal partner with the physical and chemical processes that keep life going. A challenge is even presented to the way that biology is taught - Lane sometimes points out aspects of traditional biology teaching that are simply wrong by modern standards. But what keeps us engaged is the author's enthusiasm and insider insights that make this far more than the kind of simplified textbook that is the way many scientists see popular science. It's a fascinating book.

[Max · Rating 4 out of 5]

Lane explains cellular processes for producing energy particularly cellular respiration in animals. He recounts the history of key discoveries that underlie our understanding of cellular respiration and profiles the scientists involved. He compares cellular respiration with photosynthesis in plants and variants of these processes in microbes, pointing out the similarities and differences. He shows how early forms of the same processes could have initiated life detailing a specific scenario in hydrothermal vents. Lane explores how cellular respiration impacts health and aging. He makes the case that increasing dysfunction in cellular respiration is a primary factor in the increased rate of cancer and Alzheimer’s as we age and in aging itself.

This is a dense book. I read two others by Lane that discuss cellular respiration and its variants. Both cover many of the same points and were challenging but far more accessible. In particular, reading The Vital Question before reading this one was very helpful to me. I recommend it highly for those of us who prefer following fewer chains of chemical reactions and more text aimed at the non-biochemist. My review of The Vital Question covers much of what is in this book, so I will just write some brief notes here.

Lane describes cellular respiration and specifically the Krebs Cycle in detail showing us the long chains of chemical reactions that take place and explaining each step. While with effort I could follow them, it soon became too tedious. I mainly focused on the explanations. The Krebs cycle is a complex process that uses oxygen to break down primarily sugars freeing up protons and electrons. These are funneled to opposite sides of a membrane that becomes electrically charged. Pumping the protons across the membranes creates the energy we need to survive. This takes place constantly in the 10 million billion mitochondria that are in each of our bodies. Photosynthesis essentially operates the cycle in reverse. It creates sugars using energy from the sun and CO2. All life runs some variant of the cycle even bacteria that derive their energy from hydrogen sulfide.

The Krebs Cycle provides not just energy but some of the basic building blocks of the cell contributing to cell growth. It makes lipids for cell membranes as well as amino acids to build proteins along with new sugars to construct DNA. When life first developed Lane believes the earliest versions of the Krebs Cycle had to come before DNA or RNA. Building them requires energy. Lane details a scenario that he believes took place billions of years ago in hot undersea vents where the necessary component elements and conditions were present to run a reverse Krebs cycle. Oxygen would have been derived from abundant CO2 in the ocean and hydrogen from the vent’s gases. He shows how spaces in these vents could provide walls that work as electrically charged membranes to get things started until natural processes eventually form lipids to create cell walls and membranes. From there life takes off.

The Krebs cycle is very flexible. It adjusts its functions based on availability of oxygen and nutrients. It senses the cell’s needs and can signal the cell turning on and off hundreds of genes. Mutations in genes associated with the Krebs Cycle are implicated in cancer and inflammation. But Lane posits that genetic mutation is not the fundamental reason for the increase in cancer due to aging. He points to breakdowns in the chemical flows in the Krebs Cycle that lead to leakage from the mitochondria into the cytosol. This causes inflammation and leads to genetic mutations. He outlines in great chemical detail how these incredibly complex processes become flawed and this does involve free radicals. But he doesn’t believe antioxidant supplements are a solution, again going into chemical detail to show how these can even possibly be harmful if overdone.

[Allyson Dyar · Rating 4 out of 5]

When I saw this book being offered up on NetGalley, I was particularly interested in the subject, having majored in Biology/Human Anatomy and Physiology in college. Besides, the Kreb’s Cycle (and my favorite organelle, the mighty mitochondria) is one of the most important processes in the human body, one that provides the energy that allows it to hum along.

Evolutionary biochemist Nick Lane details the discovery of the Kreb’s and other cycles that contribute to the production of energy for the body. He brings to life the scientists who toiled in the laboratories to eke out the secrets that the energy cycles kept hidden. He also explores how the early organisms may have produced energy and how they may have led to the Kreb’s cycle.

I thought the best part of the book was how the author detailed the scientists’ quest to discover those elusive secrets. I also quite enjoyed the appendix and source material that he used. Rather than just a list of articles and books, the author took the time to review most of the research material in detail, giving the reader many starting points should they wish to further investigate the subject on their own.

Despite my praise of parts of the book, I found it a slow-going read, especially when the author detailed the Kreb’s and other cycles. I am the first one to admit that it is difficult to take a complex subject such as biochemistry and explain it in a text-heavy scholarly medium like a book. Despite the illustrations, which I don’t find all that compelling, it was still difficult to follow, and I had the advantage of already understanding how it all worked.

This brings me to ask the question: “For whom was this book written?” It’s not a book that a casual reader can pick up and merrily go on their way to understanding the complexity of the Kreb’s cycle. Conversely, I’m not sure if someone who is well-versed in the subject is going to enjoy it either, except for the history of the discoveries that the even a more learned reader may not have known.

I reluctantly rate this book 3.5/5. It’s really well-written and enjoyable in spots, but I found myself slogging through the rest. I wouldn’t say that this is a book in search of an audience, but the audience has to be carefully found.

[Elentarri · Rating 3 out of 5]

Rating: 3.5 stars

I didn't find this book as enjoyable to read as Power, Sex, Suicide, or The Vital Question. Nor was it as clearly (or beautifully) written. The text tended to ramble and would have benefited from being reigned in and more structured. All the history relating how every step of the Krebs Cycle and anything vaguely relating was elucidated, and all the people involved, was incredibly dull. It does however show quite well all the fiddley bits in doing science (especially biochemistry). The text got more "exciting" for me once Lane decided to discuss the Krebs cycle, especially in terms of cell origins, metabolism and biosynthesis, and the implications in cancer and aging Interesting, but could have been written more clearly.

Date: 17 February 2024

[Mansoor · Rating 3 out of 5]

"When we think about inheritance we tend to think about genes, but to leave any descendants a cell must be capable of growing, repairing and ultimately replicating itself, and to do that it needs a fully functional metabolic network. To be alive means to have a continuous flow of energy and materials through this whole network, nanosecond by nanosecond, minute by minute, generation after generation. We do not merely inherit inert information in the form of genes – our inheritance includes this living metabolic network in the egg cell, a flame passed from generation to generation, without pause, right back to the emergence of life. 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."


Image: John Everett Millais, Ruling Passion.

[Sabin · Rating 4 out of 5]

Transformer is a monstrous tome. And it's even more of a chimera in audiobook form. Having read the author's previous book, The Vital Question, I knew a bit of what to expect, a high-level explanation of an important biochemical process, with all the history, false starts, important scientists and, most crucially, the chemistry behind it.

The chemistry in this book is made more accessible by the narrative elements, but it sure as hell (pardon my French) isn't a layperson's level of, let's say high school chemistry. The chemical reactions that he speaks about here are achievable only under very strict laboratory conditions, with the right ingredients, enzymes, and environmental conditions, like pressure and temperature. Or, as it happens, in every one of the cells in our body.

Since it's so important to the book, the author spends a few chapters going through those chemical processes, why and how they happen, in quite a lot of detail. What he attempts to do, in order to make it more manageable for people who don't explore oxidation and reduction in the lab, is to use metaphors. And, well, some of them unfortunately miss the mark.

In the beginning of the book, he describes flux through the cells as traffic. I'm not quoting here, but I think I can capture the gist of it. So, just like in traffic through a city, the cars change at every intersection between origin and destination. Let's say one of them starts off as a station wagon, then it becomes a truck, then it becomes a motorcycle, then a bus and ends up as a 2 seater coupé. But wait, because it turns back into a station wagon and what do you know, the destination is also the origin. Just like your typical commute. And you know what happens when there are too many cars on a street? Well, in this case, by literally stretching the traffic metaphor, the streets get wider to accommodate all the traffic.

Truth be said, the author admits that some of the metaphors don't really do justice to what happens inside the cell, and that's because we don't make things like nature does them. We plan infrastructure, construction and resources, we don't go into something head first and hope something useful comes out at the other end. But nature's way is like that. No trace of intelligence, just throwings stuff at the wall enough times until something sticks. Einstein was right when he defined stupidity as doing something repeatedly and expecting different results. Nature's stupid in that way. But sometimes you do get different results, and they're useful, so you keep on doing them and sooner or later you get life.

And with life, you get climate change, intelligence, cancer, aging and all the other topics that the author addresses from the perspective of biochemistry and metabolics. Once you enter the whirlwind and get on with the Krebs Cycle, everything's possible. So, for my part, I enjoyed the book very much, even if I had to listen to the audiobook and read the ebook at the same time to really understand some parts. Maybe describing a chemical reaction involving lots of carbon, hydrogen and oxygen atoms seems like a good idea, but in practice it doesn't always work that well.

[Rossdavidh · Rating 4 out of 5]

So, I recall in my high school chemistry class, that our teacher tried to teach us about the Krebs cycle. I cannot actually claim that I understood it all that well, but I got the impression that it was really important. But, my path in life did not end up taking me in a direction that utilized my knowledge of organic chemistry, so I didn't remember much beyond the name when I came upon this book. If I had not previously read (and liked) another book by the author, I don't suppose I would have been all that likely to pick this one up; I certainly wasn't looking for a book on the Krebs cycle. But, give the man credit as a writer, he kept my attention.

If I have understood the author's thesis (and this is not 100% certain, but I think so), it could be summarized thusly:

1) the Krebs cycle is really, really old. Not quite as old as life, but as old as oxygen in the atmosphere, at least.

2) it can run backwards, especially in environments without oxygen, and in fact that may be how it ran originally.

3) the backwards-running Krebs cycle, is associated in a deep way with cancer, which may be a sort of atavism of life, cells reverting to a state more like the time before multi-celled life.

Now, there are all kinds of ideas about what cancer fundamentally really is, and this is just one of them. But then, "cancer" is almost undoubtedly one word describing many different health issues that have some characteristics in common, kind of like "cold" or "infection" or "broken bone". In any case, I am not qualified to judge if Nick Lane's science is well-supported on this. But it is one way for him to convince you that all this talk, and all these pictures of molecules made of wiggling atoms, is actually important.

Oh yes, the pictures. I must say that I wish my first introduction to chemistry had used these style of illustration (as far as I can tell, done by the author?). The tricky part of any diagram showing just about any scientific phenomenon, is how to simultaneously avoid being so abstract that you cannot learn much from it, and also avoid including so much detail that it is overwhelming. Lane is trying to convey to us multi-step chemistry here, and it requires a lot of wiggly lines for chemical bonds, ping-pong balls for atoms, circles and arrows and labels and the occasional chemical equation. He does an excellent job of giving just the right level of detail, and I did more or less feel like I could keep up.

Let's be honest, a book about the Krebs cycle is not going to be a stay-up-at-night-in-bed-pageturner, it's a sit-up-straight-and-pay-attention book, that frequently required me to back up and read something again. I think it also benefited from taking a chapter at a time, so that my subconscious could digest each part, but then I often prefer to read any book this way. But, the fact that I did in fact find it interesting, and often felt like it was possible I was being told an ancient, ancient, truly ancient secret about life, was occasionally very exciting.

[Stetson · Rating 4 out of 5]

Transformer is biochemist Nick Lane's recent meditation on a deceptively familiar subject: the Krebs (tricarboxylic acid, TCA) cycle. Lane’s approach is to pry the cycle loose from its textbook conceptions as a tidy step in cellular respiration and to show it as a generative, reversible, chemical engine whose structure and dynamics reach back to the origin of metabolism, the rise of biological complexity, the breakdown of the body (aging and cancer), and even to higher order neurological processes, consciousness. The book both synthesize a great deal of scientific history and research while delivering a sort of manifesto about the evolutionary role of energy flux in life. Lane argues that the deep chemistry embodied by the TCA cycle is a recurring, causally potent motif that organizes life’s beginnings and endings.

Lane’s presents his ideas on the TCA cycle as a sequence of interlocking claims:

First, the Krebs cycle is not just a basic metabolic outer-belt highway but a central chemical transformer. Lane emphasizes the cycle’s topology including the hubs (pyruvate, acetyl-CoA, citrate, α-ketoglutarate, oxaloacetate) that appear again and again in the long evolutionary history of metabolism. He repeatedly stresses that the cycle can run in both directions: oxidative (breaking carbon down to CO₂, releasing electrons) and reductive (fixing CO₂ into biomass). Because those same intermediates recur across biosynthetic pathways, Lane frames the TCA cycle as the chemical centerpiece around which core biochemistry organized itself.

Second, Lane uses that biochemical centrality to advance a metabolism-first model for the origin of life (a well-known but less popular alternative to the RNA World hypothesis), specifically anchored to alkaline hydrothermal vents on the early seafloor. In this view, porous iron-sulfide chimneys provided compartments, catalytic surfaces (Fe(Ni)S minerals), and a natural proton/electrochemical gradient analogous to the proton-motive force modern cells use (e.g. the electron transport chain). Those conditions, Lane argues, could have driven the formation and turnover of TCA-like intermediates before sophisticated enzymes or genetic systems existed. In short: energy-handling (i.e. chemiosmosis, redox flow) and small-molecule chemistry is alleged to have preceded modern biopolymers, and the earliest proto-metabolisms were born in the chemistry of vents.

Third, Lane connects bioenergetics to evolutionary transitions. He and collaborators (notably William Martin) have argued that the acquisition of mitochondria in an ancestral eukaryote fundamentally rearranged energy supply and so unlocked genomic and cellular complexity that prokaryotes rarely achieve (an argument that also appeared in Power, Sex, and Suicide). In Transformer this largely recapitulated: mitochondria are central to why complex eukaryotic life exists, and their energy architecture (membrane bioenergetics, chemiosmotic coupling) has deep consequences for physiology and evolutionary potential (see my review of Power, Sex, and Suicide for my review of the Lane's thesis there -> https://www.goodreads.com/review/show...)

Fourth, Lane frames aging and cancer through a metabolic lens. Rather than treating aging and cancer as primarily the consequences of stochastic DNA damage and mutational accumulation (the dominant paradigm), Lane emphasizes the progressive decline in cellular energetic fidelity as cancer's more proximal cause, citing mitochondrial wear, slowing mitophagy, chronic inflammation and altered flux through the TCA cycle. These metabolic changes are allegedly push cells into the alternative metabolic regime commonly observed in cancer cells (e.g. fermentation dominant Warburg-style flux) that favor anabolism and oncogenic activity. Lane doesn't entirely discount the important role of genomic integrity but believe it is less central than the field of cancer biology currently believes.

Finally, in a short and clearly labeled speculative turn, Lane wonders whether mitochondrial bioelectric states, such as membrane potential changes and the large pool of redox chemistry inside cells, might illuminate aspects of consciousness or qualia. He carefully flags this as conjecture rather than established science, but uses it to underline his thesis that “transforming” flows of electrons and protons are the deep mechanical language of life and its subjective fringes.

Lane's writing is erudite and addresses itself to an interested subset of the scientific literature, but it is also not without its own blind spots and is often confident in what are altogether speculative theories. In an attempt to call attention to the importance of energetics in evolution, Lane downplays the importance of information (i.e. genes and genomes). Energetics are very important and impose certain constraints on biological system, but they are also in a meaningful way downstream of what the genome, genome-environment interactions, and the environment itself dictate. It is true that some of the interactions that feedback on the expression of genes are mediated by energy flux or status, but it doesn't detract from the primacy of information in evolution. I think any totalizing theory of life will have to integrate information, energy, and time.

Nonetheless, I can largely recommend this book without reservation to most readers, though I warn them that they will probably find it to be a challenging read. Moreover, they should probably not share the exact same enthusiasm for the ideas presented as does the author. Yet, it does impressively manage to take the drab TCA cycle and turn it into something worthy of a book.

[Cindy · Rating 4 out of 5]

Lord, all I have to say is that I'm glad there was some payoff to this Oak Island-style infinite (Krebs) cycle of drudgery. This book contains coordinates to the ark of the covenant, the holy grail, and the hidden city of Atlantis. But in order to get to them, you need to overcome three different Herculean challenges. First it's the history, which is already enough to thwart most mortals, but then there's the chemistry, so by this time you've already lost sight in one eye, and then they start piling on biological mechanisms. Boy, it's a trek. It's a lot to follow, even if you already know a little bit about cell metabolism. Your reward? Oh, just a new perspective on the way life started, and how cancer, aging, and consciousness work*.

*This is all to some level conjecture with foundation in science
(also the consciousness section, although interesting, doesn't solve the hard problem)

[Allyson Dyar · Rating 3 out of 5]

When I saw this book being offered up on NetGalley, I was particularly interested in the subject, having majored in Biology/Human Anatomy and Physiology in college. Besides, the Kreb’s Cycle (and my favorite organelle, the mighty mitochondria) is one of the most important processes in the human body, one that provides the energy that allows it to hum along.

Evolutionary biochemist Nick Lane details the discovery of the Kreb’s and other cycles that contribute to the production of energy for the body. He brings to life the scientists who toiled in the laboratories to eke out the secrets that the energy cycles kept hidden. He also explores how the early organisms may have produced energy and how they may have led to the Kreb’s cycle.

I thought the best part of the book was how the author detailed the scientists’ quest to discover those elusive secrets. I also quite enjoyed the appendix and source material that he used. Rather than just a list of articles and books, the author took the time to review most of the research material in detail, giving the reader many starting points should they wish to further investigate the subject on their own.

Despite my praise of parts of the book, I found it a slow-going read, especially when the author detailed the Kreb’s and other cycles. I am the first one to admit that it is difficult to take a complex subject such as biochemistry and explain it in a text-heavy scholarly medium like a book. Despite the illustrations, which I don’t find all that compelling, it was still difficult to follow, and I had the advantage of already understanding how it all worked.

This brings me to ask the question: “For whom was this book written?” It’s not a book that a casual reader can pick up and merrily go on their way to understanding the complexity of the Kreb’s cycle. Conversely, I’m not sure if someone who is well-versed in the subject is going to enjoy it either, except for the history of the discoveries that the even a more learned reader may not have known.

I reluctantly rate this book 3.5/5. It’s really well-written and enjoyable in spots, but I found myself slogging through the rest. I wouldn’t say that this is a book in search of an audience, but the audience has to be carefully found.

[Thank you to NetGalley and the author for the advanced ebook copy in exchange for my honest and objective opinion which I have given here.]

[Nelson Zagalo]

Leitura muito difícil, apesar de ter tido química até ao 11º ano, é algo excessivamente abstrato para se poderem fazer livros narrativos sobre assunto, pelo menos usando de tanta descrição factual, sem usar e abusar de metáforas mais acessíveis.

Gostei muito da introdução, mas depois não fui capaz de levar nenhum capítulo até ao final.

[Steve · Rating 2 out of 5]

I thought the biographies in the book were well done and the historical context was well-described. I also enjoyed the conversational tone. However, I found the discussion of the Kreb’s Cycle itself and its early iterations so detailed that I kept losing the thread of the discussion. At around halfway through the book, I stopped reading because I felt that the book had lost all cohesiveness as a story. I think that had there been less detail about the Kreb’s Cycle or if the book had focused more on history, I would have enjoyed it a lot more. Thank you to Edelweiss and W. W. Norton & Company for the digital review copy.

[Kish · Rating 4 out of 5]

Eye opening for those from the biochemistry field, and it certainly gives new perspectives on traditionally gene dominant diseases. For example, highlighting the importance of the proton motive force to the origins of life, and life’s demise (hence the title). I enjoyed the detours to the human side of academic research, expertly woven to provide context to scientific discovery. My only criticism is in the technique used to describe biochemical processes; presented largely using pros. I would have preferred a more diagrammatic approach, but the theory and biochemistry were described concisely nonetheless (at least for anyone with a degree level biochemistry background).

[Popular Science Books · Rating 5 out of 5]

Great book that explains how life builds itself around metabolism. There is a particular focus on carbon flux through the cell and how this relates to the origin of life, disease, ageing, and even consciousness. Overall, it’s a highly recommended read.

[Gabby · Rating 5 out of 5]

This was science as fuk and I devoured every page.

[Vladimir · Rating 5 out of 5]

This is another amazing book by Nick Lane, and for me among the best of his work.

I read several of previous Lane's books, namely Vital Question, Life Ascending and Oxygen. My thinking about origins of life was since dominantly shaped by his work, which filled a major gap for me in my worldview about abiogenesis.

In this book Lane goes further than Vital Question and earlier than LUCA by newly claiming that life originated as a chemical reaction between H2 seeping from hydrothermal vents and CO2 from air dissolved in water, catalysed by FeS minerals and encapsulated by pores in the vents rocks. He argues that this environment of externally forced H+ flow naturally (perhaps unavoidably) forced parts of Krebs' cycle to spontaneously run (in a backwards direction), stripping C atoms from CO2 and adding H, O and more C into molecular chains and thus generating entire plethora of organic building blocks needed for life, including lipids that later encapsulated these reactions into primordial cells and allowed them to separate from the original vents. So life originated, according to Lane, as a chemical reaction of reducing atmospheric CO2 i.e. stripping C atoms from CO2 to build all organic matter, powered by external flux of H+ ions, catalysed by rocks, i.e. by high electric fields generated across rock pores from H+ flow.

He finds evidence of this in today's mitochondria, which are today's heirs that still convey these same reactions, and now can run Krebs' cycle in either direction. In today's dominant forward direction, mitochondria strip C and O from glucose (or other food) releasing CO2, burn remaining H+ with O to generate energy and release H2O, in a process of pumping H+ (protons) across mitochondrial membrane storing this energy as electric potential in first step and later as ATP (by voltage propelling rotating ATP synthase and closing H+ electrical circuit), the energy currency of cells. In another (ancient backward) direction, they still reduce CO2 with NADH across respiratory complex I, which contains protein ferredoxin containing FeS minerals of ancient originating rocks, and strip C atoms to build organic components and growth. So, forward direction is burning food for energy (ATP), and reverse direction is using energy (ATP) to power growth. In both cases mitochondria convert the chemical energy (from food/forward or ATP/reverse) into electric voltage across their membranes, storing thus energy in a form of capacitor.

Lane proposes a new theory of ageing, which is essentially about slowing of Krebs' cycle due to declining efficiency of mitochondrial respiration (to avoid excessive reactive oxidative species to seep from damaged respiratory complex I). This slowing of Krebs cycle causes byproducts to seep into cytoplasm, causing different gene expression and pushing cell toward senescent state or apoptosis. In worst cases, Krebs' cycle can start spinning backwards promoting growth, and with some related catastrophic breakdown in signalling can lock cell into permanent growth state, causing cancer.

In the last chapter about consciousness, he goes a bit far off for my taste into the realms bordering mysticism. Based on observations that consciousness is suspended by anaesthesia probably via short circuiting respiration i.e. by discharging mitochondrial electric field, as well as that there is EEG activity which could originate from either nerve cells or mitochondria (not known), he concludes that consciousness is in the "dance" of electric fields. I understand that electric fields may sound like a realm of mystery to a biologist or even a biochemist, but as an electrical engineer familiar with how we juggle the fields in power and telecommunications all the time without any special phenomena emerging, I see no room there for consciousness to mysteriously appear or eerily exist in a ghost-like form. From information theory point of view we need a very complex structure (more bits) rather than cumulative oscillating EM fields to explain the brain; if consciousness was in the EM fields, then connections of neurons might be redundant and needless; on the other hand, powering down mitochondrial fields could also power down the neural network, which could as well explain how anaesthetics and sleep work (on that note, mitochondria do not need sleep but brain does).

If all this language sounds like Klingon, that is because this book is really far from an easy read, which can be said for all Lane's books I have seen. He is an excellent writer (albeit prone to digressions), but the topic is so disconnected from other popularized science that it requires a lot of new learning and understanding. It does not help that all claimed rules have many exceptions, leaving me with a fuzzy feeling that I got a glimpse of something great, but cannot dare to make my own conclusions (such as, should I give up my metformin while I follow a ketogenic diet and active lifestyle because it seems to follow from the book outlook applied to metformin-related published papers that metformin acts like a handbrake i.e. that it hinders my progress and increases cancer occurrence risk, while it could help sedentary carb-overloaded persons).

So the main takeaways for me shall remain:

- abiogenesis explanation moved all the way back to simple pure chemistry in primordial vents, and made testable
- strong focus on mitochondria as sanctuaries of this ancient life force, instead of genome
- ageing, related diseases and cancer newly explained as consequences of slowing and reversing the Krebs cycle

Excellent book by any standard, and will remain my occasional reference.

[Meg Knox · Rating 4 out of 5]

I deserve an award, and owe an apology. The apology is just to myself really, because no one gives a shit if I get to my reading goal at the end of this year. I guess the apology is also to Nick Lane and this beast of a book. For some reason, some stupid fucking reason, I chose to start this book during finals week and then during three weeks ECC/start of clinical rotations/12+ hour day nonsense. Why did I choose to start a non-fiction book about metabolism and biochemistry, equipt with organic reaction diagrams, during this period of time in my life??????? That was a stupid fucking choice on my part. But, that's also why I deserve an award. I finished this PJ book, even the two appendices (which were rich in those organic reaction diagrams, might I add) and all the little stinky footnotes.

I will stop my self pity and move on from how long it took me to finish this book. Instead let's talk about how good it was!

Lane writes with writer awareness in such a beautiful way. No silly pedantic scientific passive tense. He outlines every chapter in the intro but not in an annoying 3rd grade reading level type of way. It actually made me excited for what was to come. And he writes likes he just having a passionate fun biochemistry conversation at brewery happy hour, like "the experiment for which Warburg won the Nobel Prize in 1931 was just so beautiful I have to tell you about it" (35). What a wonderful strategy for keeping a reader engaged about the Krebs Cycle for a couple hundred pages. I feel like this book would engage/interest anyone who got up to the level of honor's chemistry in high school. But would be best served for those who actually enjoying organic chemistry at the college level (and biochemistry +/-). I HATED chem lab but I lived for organic chemistry lecture. Electron flow, synthesis reactions, all of that shit what my bitch. The first half of this book made me pull out my Ochem textbook for fun and subsequently got me second guessing my career choice and entire life path lmao. But then life got busy and the book became a chore which really sucks because the book itself had nothing to do with it, it was the period in my life that fucked my emotions about reading it (flashback to Once and Future King).

My favorite part of this read was when Lane starts talking about hydrothermal vents and he literally mentioned a professor I had in undergrad lmao. I took an interdisciplinary hydrothermal vents class back when I thought I would minor in Oceanography and had to go up to that professor after class because I got like a 70 on the midterm because even though there were no pre-reqs, I was sorely unprepared for the free-response nonsense they asked on their tests. Either way, it made me cherish the fact that I legitimately already have a degree and I got something out of it!!!! I love chemistry and I don't use it directly on a daily basis anymore. This book reminded me of that love and applied it to such cool revelations. The idea that Alzheimer's is directly linked to diabetes, hyperglycemia, and insulin resistance???? The idea that mitochondrial genes could be related to aging???? Or that mitochondrial membrane potentials and electrical fields might create consciousness, sense of self, and emotion????? Excuse me???????

Here's some quotes:
"This is experiment as work of art, creative imagination allied to virtuosic technique, giving a beautiful insight into the workings of nature. This is why some scientists are put on pedestals, even though, like great artists, they often have all the vices of their virtues." (36) ARE YOU FUCKING KIDDING ME. IS IT ART OR IS IT SCIENCE OR IS IT BOTH NO ONE WILL EVER KNOW.

"Thinking about life only in terms of information is distorting. Seeking new laws of physics to explain the origin of information is to ask the wrong question, which can't be answered precisely because it is not meaningful. A far better question goes back to the formative years of biology: what processes animate cells and set them apart from inanimate matter? The idea that there is a vital force, that life is fundamentally different from inanimate matter, was disproved long ago and is now only wheeled out as a straw man to burn - even though it's an understandable illusion for anyone who shared van Leeuwenhoek's captivation with busy animalcules. Yet biochemistry - my own discipline, which deals with the flow of energy and materials through cells - has, with a few notable exceptions, been blithely indifferent to how this unceasing flux might have arisen, or how its elemental imprint could still dictate the lives and deaths of cells today, along with the organisms they compose. You and me" (5). That was a doozy. But wasn't it worth it??????

"'The dream of every cell is to become two cells' said Francois Jacob, the most lyrical revolutionary of molecular biology. No cell lives the dream so wholly or so senselessly as a cancer cell, turing 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 mutate, evolve, adapt, exploit their shifting environment, selfish to the bitter end.Their horror is that they know no bounds. They will eat away at our flesh to fuel their pointless lives and deaths, until, if we are unlucky, they take us too. I am writing about cancer, but must confess that I have the pointless greed and destruction of humanity at the back of my mind. May we find it within ourselves to be better than cancer cells" (191). Like how do I even follow that up with a comment. Who the fuck can write like that in a book about biochemistry. Holy fucking shit. The imagery, the artful flow of his syntax. The emotion that rushes out of this description. MY GOD.

"The third Delphic maxim is a little more ambiguous. It is usually translated as 'surety brings ruin.' I imagine this to mean that we should never crave certainty, for nothing is certain, least of all science. Science is not a collection of dusty facts, but a way of exploring the unknown, of making out the contours of a long mysterious coast. I have tried to write this book in that spirit, connecting the first stirrings of life on a geologically restless planet with the glorious pinnacles of evolution, and ultimately our own demise. I can't be right about all of it. But even if the details of the coastline that are emerging through the mist are distorted, this is a thrilling new continent, which transforms the relationship between metabolism and genes: what it is to be alive. We are not islands, but a part of this continent, connected with the main, with all life on our planet from the very beginning. I hope that you'll see yourself a little differently now. And with that in mind, let's end our journey with an unfurling view of the final frontier" (273) WHO DOES THIS METAPHORICAL BEAUTY IN THE SCIENCE COMMUNITY WHO WHO WHO I GUESS NICK LANE DOES DING DING.

"Plainly that powers work, but it also gives scope to the full dynamic range of mitochondrial membrane potential. To the full range of electrical fields. To the full music of the orchestra. Until now, biology has tended to study the materials that make up the instruments. The time has come to close our eyes and listen to the music. I want to suggest to you that this music is the stuff of feeling, of emotion. Electrical fields are the unifying force that binds the disparate flowing molecules of a cell together to make a self with moods and feelings. Alzheimer's disease is the fading of the music as the fields fragment" (280). Another insane description and insane idea about aging, alzheimer's, consciousness, and emotion.

Ok now I'm fucking tired of typing out passages from the book and I'm sure you're tired of reading them if you've even gotten this far, time for some fucking fiction maties xx

[Idarken · Rating 4 out of 5]

Possibly, it's just me: I had hoped for even more chemistry! 😂 The beginning is full of biographical stories in between the biochemistry, which I do appreciate, as the people behind the science are important, but they diverted my attention from the science facts and the argument to the point where I had forgotten them when Lane picked it up again. But in the second half the chemistry gets...deeper, as promised by the book's title. So deep, that I definitely have to read it again, as I commited the grave mistake of not taking notes. And I'll gladly read it again, skipping over the biographical parts, because I learned much more than school textbook dogma and it entertained me. 'Pyruvate the Pirate'.😂😂

[Richard Thompson · Rating 4 out of 5]

For a popular science book, the level of science presented is quite challenging. I would get a lot more out of this book if I were to come back and reread it after studying some basic biochemistry. It wouldn't take a lot. The main subject of this book is the Krebs Cycle, which is the cell's principal mechanism for capturing and using energy and creating the building blocks of proteins. It's not that hard to understand, but I never studied Organic Chemistry, so I struggled a bit with the chemical mechisms as the proteins change from one form to another over the different stages of the cycle. I was able to easily take in the basic points of the book, but I think that there is another level of appreciation that I could have, if I just would take the time to absorb a bit more background knowledge.

Mr. Lane gives us a view of cell biology from the point of view of energy and metabolism, explaining how the Krebs Cycle works, how it was discovered and how it fits into the bigger pictures of cell biology, genetics, the origin of life, cancer and aging. Mr. Lane's thesis is that metabolism is more fundamental than genetics, that proto-organisms had ways of making and using energy before they had DNA/RNA driven heritability. His argument is persuasive, though I have no way of judging whether it is correct. He also explains how the Krebs Cycle could have evolved. Here again he is interesting and persuasive, but still speculating. He makes another important point, which is most definitely correct, which is that, as fundamental as the Krebs Cycle may be, it isn't the only way that cells have of capturing and using energy and it isn't a single simple thing because it has variations and side paths and goes backwards and forwards in response to environmental stimuli. The huge strides that have been made in genetics have caused metabolism to become a field of secondary interest, which is a shame, because there is much that is interesting and important here and much to be learned that is beyond current scientific knowledge. And metabolism and genetics need to be studied together in order to get to a fuller understanding of both fields.

[Ricardo Moreno Mauro · Rating 2 out of 5]

Nick Lanes tiene varios libros sobre el origen de la vida, pero creo que particularmente este no es de los mejore. Los dos primeros capítulos son para adentrarnos en la bioenergética: El ciclo de Krebs y la fotosíntesis. Lo mejor son todas las historias de pasillo que cuenta Por ejemplo como se trabajaba con radioactividad. O como Benson descubrió casi todos los pasos de la Fotosíntesis, pero Calvín se llevó el crédito.
En el siguiente capítulo es un resumen de su pensamiento del origen de la vida, en los fondos marinos. Es interesante, pero no aporta nada nuevo, si ya lo han seguido en sus papers.
Los dós últimos son uns devarío en e que suguiere como el ciclo de kkrebs estaría involucrado en el origen del cáncer y la conciencia.

No lo recimiendo mucho

[Dana Slaughter · Rating 5 out of 5]

Lane changes the focus of metabolism from the forward running Krebs Cycle, churning out CO2 and producing ATP, to a Krebs roundabout which can run forwards or backwards depending on the cells chemical environment, and spin off major building blocks for cell biosynthesis.

He challenges to notion that genes direct metabolism by developing the idea that energy flux is the mainstay of life. The Krebs intermediates that are foundational to cell chemistry can be derived in deep sea vents from self organised protocells. "There is something thermodynamically and kinetically favoured by the innermost chemistry of life." (p 275). "For me, the first genes were random strings of a few letters of RNA, polymerising inside protocells growing in those deep sea vents. From the beginning, genes copied themselves inside protocells, spreading when they promoted cell growth, regenerating what had come before faster and better. Genes never supplanted he deep chemistry of cells. They conserved it, and they built on it" (p.275)

[Steve · Rating 3 out of 5]

Way too much chemistry for me! Lane tries valiantly to explain it to non-scientists but only so much is possible. Page after page was incomprehensible. But I liked his writing, he’s very enthusiastic and even tho I couldn’t understand much, some of it did sorta sink in. And in some funny way, I just liked reading through the descriptions of long complicated chemical processes, it had a nice rhythm in a way.

Here’s a fantastic review of the book in the New Yorker - if you’re leery of too much chemistry you might want to read this instead of the book: https://www.newyorker.com/science/ele...

[Philemon - · Rating 2 out of 5]

This was supposed the illuminate the Krebs cycle and other biochemical pathways, but instead dwelt on the history of discoveries with a focus on British researchers. (*TV Error Buzzer*) Can anyone recommend a book that conveys the dynamics of cellular chemistry at an appropriate mid-level? Thanks.

[April Bell · Rating 1 out of 5]

Siddhartha Mukherjee was LYING when he praised this book

[Nick Tedrow · Rating 5 out of 5]

Every life sciences major remembers learning about the Krebs cycle in college; if your undergraduate experience was anything like mine, then you also remember forgetting it immediately. When we learn about this cycle at the heart of metabolism, it’s presented almost exclusively in the context of energy production. Producing ATP is important, but so is generating the macromolecules that come to constitute tissues and organs. Metabolism does both, utilizing the Krebs cycle as a sort of roundabout to accomplish the needs of the cell.

In this book, Nick Lane synthesizes aspects of chemistry, biology, physics, and some history to elaborate on the context of the Krebs cycle. In doing so, he goes beyond the canonical view that regards it as a way to generate energy, and explains how its fundamental thermodynamics can be exploited to give rise to various pathological states. This book probably cemented Lane as my favorite science writer, but it’s by no means an easy read. He does as good a job as any to make the science accessible to the educated layman, but it certainly helps to have some background in the field.

I’ve always found that biochemistry unfairly loses all relevance in medical science. If Nick Lane is right, and I think a lot of his arguments are pretty close, it begs the question of what we should do to integrate the two. The author discusses a paradox in the Krebs cycle’s dual function of catabolism and anabolism, but there’s also a paradox at the heart of medical science: medical students learn about biochemistry in terms of a few eclectic and obscenely rare diseases, such as Lesch-Nyhan syndrome or G6PD deficiency, but it bears relevance on the function of an organism as a whole. Lane diagnoses this problem astutely, but doesn’t provide much in the way of solutions (to be fair, that isn’t his goal).

Perhaps the only real critique I can make of the book regards the bit at the end about consciousness. Lane’s presentation of the hard problem of consciousness, as well as his argument for electric fields as a causative agent of consciousness, warranted more of a footnote than an epilogue. His arguments here weren’t particularly strong, and I almost think he’d be the first to admit this.

Nonetheless, I was a biochemistry major in college, and my only regret is that I wasn’t able to learn under a professor like Nick Lane. He brings biochemistry to life in a way that’s been missing from the discipline, at least since I've been immersed within it.

[Santiago Figueroa · Rating 5 out of 5]

Brillante! Qué rico es un cambio de panorama de este tipo. Una postura nueva (para mi) acerca varios temas como el origen de la vida, la conciencia, la evolución, el cáncer y más. Sumamente pesado de leer a ratos para alguien que detesta la química (como yo), pero aun así, me acabé una libreta en apuntes. Muchísimo que reflexionar, muchísimo que aprender y seguir leyendo.

Dejo una frase muy interesante que me dejó apendejado como 10 minutos. La dijo un cabron que está metido en investigar qué es la conciencia, no recuerdo exactamente quién: "lo que sea que sea la conciencia, es soluble en cloroformo (y otras sustancias)"

(Evidentemente esa no es la cita actual y le compuse muchísimo desde la memoria, pero espero que se entienda).

[Michael Billig · Rating 3 out of 5]

This book is a little advanced for a layman like myself but I still really enjoyed it! Nick Lane is a great communicator and this book shines when his personality peeks through. The only critique I can think of other than the advanced material, is that “Transformer” can read more like textbook at times. I’m pretty forgiving though given the subject matter. You can only spice up something like a straight forward chemical reaction so much. Other than what I mentioned, this book really changed the way I view the scope of biology and really gave me insight into how life on this planet got started. Fascinating read.

[Anshuman Swain · Rating 4 out of 5]

4.5 rounded down to 4.

A wonderful book about metabolism. Even though most people will find it terse, the author has done a wonderful job in simplifying the concepts and portraying a holistic picture of biochemical phenomena. The book touches upon a variety of evolutionary phenomena including but not limited to the origin of life, cancer, photosynthesis etc. from a biochemical perspective with a touch of history.

[Josh · Rating 4 out of 5]

Depressing how much of A-Level biology around the krebs cycle I'd completey forgotten! Either way a fascinating book, some interesting ideas put forward around cancer and conciousness and the role of metabolism in these areas. Nick Lane probably my pick for, pound-for-pound, the most interesting pop-science writer right now!

[Martha · Rating 2 out of 5]

biochemistry seriously over my head