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Transformer: The Deep Chemistry of Life and Death
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.
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.
400 pages, Hardcover
First published May 1, 2022
About the author
Nick Lane
19 books835 followersDr 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...
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...
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Displaying 1 - 30 of 143 reviews
May 23, 2022
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.
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.
July 4, 2023
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.
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.
June 11, 2022
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.
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.
January 24, 2023
"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.
October 14, 2022
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.
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.
February 17, 2024
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
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
June 26, 2023
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.
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.
December 19, 2022
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)
*This is all to some level conjecture with foundation in science
(also the consciousness section, although interesting, doesn't solve the hard problem)
Read
June 29, 2023Leitura 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.
Gostei muito da introdução, mas depois não fui capaz de levar nenhum capítulo até ao final.
June 11, 2022
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.]
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.]
May 16, 2022
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.
July 18, 2022
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).
June 14, 2022
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.
June 17, 2023
This was science as fuk and I devoured every page.
December 12, 2022
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.
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.
This entire review has been hidden because of spoilers.
November 16, 2022
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'.😂😂
May 28, 2023
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.
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.
September 16, 2022
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
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
September 19, 2022
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)
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)
November 16, 2022
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...
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...
September 28, 2022
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.
June 17, 2023
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.
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.
January 2, 2023
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.
April 3, 2024
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.
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.
January 8, 2024
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!
October 13, 2023
biochemistry seriously over my head
May 27, 2022
Definitely not for the layperson! I really enjoyed the history/mini biography side of this book, but found the Biochemical paths very overwhelming ( Even with an used biochemistry degree albeit 40years ago) . I am sure more clever people than me will not get as lost, so would recommend it.
April 5, 2023
Lane writes about the latest understandings of respiration in animals. Central to respiration is the complex Krebs cycle which not only generates energy to power cellular processes, in the form of ATP, but also supplies the building blocks for the cells. Most amino acids are made directly or indirectly from molecules in the Krebs cycle. The Krebs cycle is the engine of biosynthesis. Strangely, it both creates and destroys.
The Krebs cycle is a set of nine reactions arranged in a circular fashion, each generating intermediate organic chemicals. In respiration, the primary output is ATP, but some of the intermediates are drawn off as precursors for the synthesis of amino acids, fats, sugars and more.
The green sulfur bacterium Chlorobium thiosulfatophilum lives by photosynthesis in stinking, sulfurous waters such as hot springs. It reverses the Krebs cycle by using ferredoxin which has a biologically unparalleled ability to press electrons onto even the most unreactive molecules. However, ferredoxin reacts spontaneously with oxygen, becoming readily oxidized by even low levels of the gas. So in the presence of oxygen the reverse Krebs cycle usually grinds to a halt. Bacteria that use it today are normally restricted to environments with very low oxygen levels.
The reverse Krebs cycle was more widespread on the early Earth before the rise of oxygen. Photosynthesis evolved in the cyanobacteria long after ancient bacteria were converting CO2 and H2 into organic molecules to drive growth.
Plants make use of rubisco for photosynthesis. Rubisco is inefficient and is as likely to fix CO2 as O2. CO2 levels were high when the molecule evolved, but even today the buildup of CO2 within the leaf causes crops to lose as much as one quarter of their yield. Amazingly, rubisco now turns out to be widespread in ancient bacteria, doing a totally different job: degrading sugars derived from the RNA of other cells, to support growth fueled by eating other cells.
Chapter 3 - From Gases to Life
The reverse Krebs cycle requires an input of energy (ATP) to work, which in modern bacteria is normally obtained from photosynthesis. H2 will react with CO2, using iron–sulfide catalysts, but works best at pressures of around 100 bar, equivalent to an ocean depth of about 1 kilometre.
H2 will push its electrons onto the catalyst in alkaline conditions, but CO2 will only accept them from the catalyst in acidic conditions. Virtually all cells pump H+ out, making the outside about three pH units more acidic than the inside.
Pores in hydrothermal vents provide a steady supply of H2 and CO2, in just the right conditions needed to promote their reaction to make carboxylic acids. These form through chemical mechanisms that resemble steps of the reverse Krebs cycle, implying that this chemistry really is the primordial basis for metabolism.
Lane notes "For my money, the first nucleotides, and eventually RNA and DNA, emerged inside such replicating protocells through positive feedbacks." "Only strings of RNA that enhance protocell growth would be favored, while RNA that impedes protocell growth (through ‘selfish’ behavior) would be selected against."
Chapter 4 - Revolutions
The chances of life starting on an oxygenated planet are arguably close to zero: hydrogen must react with CO2 to form organic molecules, but does so very reluctantly if at all in the presence of oxygen
The single biggest problem facing the first cells emerging from the deep-sea hydrothermal vents was the need to generate their own proton gradients, to drive the reaction between H2 and CO2. The topological structure of cells – reduced and alkaline inside, oxidized and acidic outside – is strictly analogous to a vent. Transferring 2H onto CO2 generates methane (CH4) and water (H2O) as waste products, but of all the H2 that a methanogen consumes, only a fortieth is converted into biomass and the rest is used to power pumping.
In anoxygenic photosynthesis, chlorophyll is used to strip electrons from H2S which are then passed onto ferredoxin directly. The waste product is not oxygen but sulfur. The huge advantage here is that the sun now powers the transfer of electrons, without the need for burning fuel to power pumping. The disadvantage is that these bacteria still derive all their electrons from geological sources such as volcanoes and hydrothermal vents.
Oxygenic photosynthesis first arose in cyanobacteria or their predecessors, but exactly when remains uncertain. The first unequivocal evidence is the Great Oxidation Event (familiarly called the ‘GOE’) around 2.3 billion years ago, when the planet turned rusty red and froze.
Aerobic respiration operates at about 40 per cent efficiency in converting food to ATP. Anaerobic respiration is closer to 10 per cent. With aerobic respiration, at 40 per cent efficiency, five trophic levels could be sustained before reaching 1 per cent. Without oxygen, only two trophic levels are possible. Complex food webs are only likely to exist in a well-oxygenated world.
The Shuram conundrum revolves around the evidence that most of the carbon on earth was bound up by sulfate, as shown by the carbon isotope balance in the Shuram formation in Oman. The survivors on the end-Permian extinction were those that had evolved to make use of oxygen and clear out excess CO2 and sulfide. Lane posits that it was at this time that the Kreb's cycle evolved.
Most bacteria and archaea don't use a closed Kreb's cycle; rather they use a forked pathway that allows them to adapt to oxygen availability. Lane suggests that the Ediacaran fauna (500 million years before the Cambrian) had little tissue differentiation and were unable to adapt to changing environmental conditions. In contrast, the bilateral ancestors of the Cambrian fauna had a variety of tissues that could work together to seek metabolic balance. By the dawn of the Cambrian, they were able to deal with oxygen and "Rising oxygen just gave them a turbocharge."
Chapter 5 - The Dark Side (cancer)
Lane notes that "cancer is a disease of the genome is too close to dogma." Different mutations are found in different parts of many tumours, often with little if any overlap, implying that the mutations accumulated during the growth of the tumor, rather than triggering its inception. Moreover, the same oncogene mutations are often found in normal tissues surrounding a tumor,
The greatest risk factor for cancer is older age: cancer incidence increases exponentially with age. One might think this is explained by the steady accumulation of mutations with age. But the buildup of mutations with age seems to be too slow to explain either cancer or ageing as a process. Nor can it explain why humans do not have a higher cancer rate than, mice, despite having ten times as many rounds of DNA copying to make an individual.
In glycosis, pyruvate is converted to lactate, allowing the cell to produce small amounts of ATP in the absence of oxygen. Warburg noted the propensity of cancers to ferment glucose in the presence of oxygen. However, many cancers don’t depend on aerobic glycolysis at all, normal tissues are also capable of aerobic glycolysis, and stem cells typically depend on ATP from aerobic glycolysis for their energy needs.
Cancer cells need NADPH for biosynthesis and growth, and it is as important to them as ATP. Cells must wire their metabolism to get the balance between ATP, NADPH and carbon skeletons right. Aerobic respiration produces too much ATP, which actually switches off the glycolytic breakdown of glucose. Cancer cells must not make too much ATP, as it slows down their growth. Cancer cells switch over to aerobic glycolysis precisely because it makes less ATP, favoring faster growth.
As we get older, our respiratory performance declines slowly. The rate of respiration is depressed the most at complex I, the largest and most complex of the respiratory complexes. Complex I is the main source of reactive oxygen species (ROS) from mitochondria, and the rate at which these escape (ROS flux) tends to creep up with age. Also, complex 1 is the only entry point for NADH. So the decline in complex I activity with age means that it’s no longer so easy to oxidise NADH.
The underlying problem in cancer is an environment that continuously and erroneously shouts ‘grow!’. This toxic environment can be induced by mutations, infections, low oxygen levels … or the decline in metabolism associated with ageing itself.
When NADH begins to accumulate in the mitochondria, the Krebs cycle must slow down and there will be a tendency for sections of it to run backwards. Any deficiency in respiration signals causes an increase in glycolysis. The gatekeepers to DNA in the nucleus, become acetylated. The epigenetic switch is pressed down, promoting growth, cellular proliferation and inflammation.
Ageing itself raises our risk, by switching metabolism towards aerobic glycolysis, promoting cellular growth. The combination of a cancer spawning event "set in a permissive metabolic context" allows proliferation and active cancer.
Chapter 6 - The Flux Capacitor (and ageing)
The great immunologist Peter Medawar said we age because we outlive our allotted time as determined by the statistical laws of selection. This textbook view sees ageing and the diseases of old age as little more than the unmasking of late-acting genes, whose effects do us in.
On average, we have one SNP every thousand letters, meaning that there are four or five million letters that differ across the human genome. Only a modest proportion of these are likely to influence the risk of a particular disease
Mitochondrial genes tend to evolve much ten to fifty times faster than nuclear genes, as they are copied far more than nuclear genes, and so they accumulate more mutations. A clean-up process in early life sieves out the most detrimental mutations. That’s why mitochondrial diseases directly affect only about 1 in 5,000 of us.
Mitochondria convert flux through the Krebs cycle into electrical membrane potential. The membrane is a capacitor: a thin insulating layer that separates two electrically charged aqueous phases, generating powerful electrical fields across the membrane. Changes in metabolic flux can increase or decrease this electrical forcefield, affecting everything from ATP synthesis to the flux of ROS or the synthesis of that powerful reductant, NADPH. If the electrical potential is too high (because ATP is not being consumed) then Krebs-cycle flux must slow or even reverse. That signals directly to the nucleus, through succinate and citrate, controlling the activity of thousands of genes, the epigenetic state of the cell. There is a subtle and continuous interplay between the x flux through the Krebs cycle and the epigenetic state of the cell.
Mitochondrial DNA inherited from the mother. The idea of mother's curse is that as male and female metabolisms differ, some mitochondrial mutations could be neutral for the female but bad for the male. Genes in the nucleus can evolve to fix problems with mitochondrial DNA in males. Crosses between species can cause ‘hybrid breakdown’, attributed to incompatibilities between mitochondrial and nuclear genes.
The response to drugs can vary dramatically, depending on a few tiny differences in mitochondrial DNA, with big differences in outcome between males and females.
Reactive Oxygen Species (ROS) are such vital physiological signals that cells go out of their way to keep ROS flux within tight physiological limits. Redox tone – the balance of electron sources and sinks in a cell – is as critical to homeostasis (our normal chemical balance) as temperature or acidity. Any damage to the respiratory chain will tend to increase ROS flux.
Ageing is not driven by mutations in genes accumulating over time, but by changes in gene activity – epigenetics.
Over time damage occurs to molecular machinery such as proteins. Repairing or replacing them is one of the most energy-sapping tasks that cells face. Eventually the respiratory machinery itself is damaged, and ROS flux creeps up. Cells do what they must and compensate by suppressing respiration a little. NADH is oxidized less effectively and the Krebs cycle loses forward momentum. Intermediates such as succinate start to accumulate and seep out from the mitochondria. They activate proteins such as HIF1α, which in turn alter the behavior of thousands of genes, pushing cells into a senescent state or to their demise.
Bats and birds live as much as ten times longer than animals with a similar body size or resting metabolic rate. It seems that restricting ROS flux enables bats and birds to maintain or increase their aerobic capacity without losing redox tone. That in turn postpones the age-related shift to a senescent epigenetic state. However, longer-lived animals must invest more in damage limitation, the cost being fewer offspring.
The Krebs cycle is a set of nine reactions arranged in a circular fashion, each generating intermediate organic chemicals. In respiration, the primary output is ATP, but some of the intermediates are drawn off as precursors for the synthesis of amino acids, fats, sugars and more.
The green sulfur bacterium Chlorobium thiosulfatophilum lives by photosynthesis in stinking, sulfurous waters such as hot springs. It reverses the Krebs cycle by using ferredoxin which has a biologically unparalleled ability to press electrons onto even the most unreactive molecules. However, ferredoxin reacts spontaneously with oxygen, becoming readily oxidized by even low levels of the gas. So in the presence of oxygen the reverse Krebs cycle usually grinds to a halt. Bacteria that use it today are normally restricted to environments with very low oxygen levels.
The reverse Krebs cycle was more widespread on the early Earth before the rise of oxygen. Photosynthesis evolved in the cyanobacteria long after ancient bacteria were converting CO2 and H2 into organic molecules to drive growth.
Plants make use of rubisco for photosynthesis. Rubisco is inefficient and is as likely to fix CO2 as O2. CO2 levels were high when the molecule evolved, but even today the buildup of CO2 within the leaf causes crops to lose as much as one quarter of their yield. Amazingly, rubisco now turns out to be widespread in ancient bacteria, doing a totally different job: degrading sugars derived from the RNA of other cells, to support growth fueled by eating other cells.
Chapter 3 - From Gases to Life
The reverse Krebs cycle requires an input of energy (ATP) to work, which in modern bacteria is normally obtained from photosynthesis. H2 will react with CO2, using iron–sulfide catalysts, but works best at pressures of around 100 bar, equivalent to an ocean depth of about 1 kilometre.
H2 will push its electrons onto the catalyst in alkaline conditions, but CO2 will only accept them from the catalyst in acidic conditions. Virtually all cells pump H+ out, making the outside about three pH units more acidic than the inside.
Pores in hydrothermal vents provide a steady supply of H2 and CO2, in just the right conditions needed to promote their reaction to make carboxylic acids. These form through chemical mechanisms that resemble steps of the reverse Krebs cycle, implying that this chemistry really is the primordial basis for metabolism.
Lane notes "For my money, the first nucleotides, and eventually RNA and DNA, emerged inside such replicating protocells through positive feedbacks." "Only strings of RNA that enhance protocell growth would be favored, while RNA that impedes protocell growth (through ‘selfish’ behavior) would be selected against."
Chapter 4 - Revolutions
The chances of life starting on an oxygenated planet are arguably close to zero: hydrogen must react with CO2 to form organic molecules, but does so very reluctantly if at all in the presence of oxygen
The single biggest problem facing the first cells emerging from the deep-sea hydrothermal vents was the need to generate their own proton gradients, to drive the reaction between H2 and CO2. The topological structure of cells – reduced and alkaline inside, oxidized and acidic outside – is strictly analogous to a vent. Transferring 2H onto CO2 generates methane (CH4) and water (H2O) as waste products, but of all the H2 that a methanogen consumes, only a fortieth is converted into biomass and the rest is used to power pumping.
In anoxygenic photosynthesis, chlorophyll is used to strip electrons from H2S which are then passed onto ferredoxin directly. The waste product is not oxygen but sulfur. The huge advantage here is that the sun now powers the transfer of electrons, without the need for burning fuel to power pumping. The disadvantage is that these bacteria still derive all their electrons from geological sources such as volcanoes and hydrothermal vents.
Oxygenic photosynthesis first arose in cyanobacteria or their predecessors, but exactly when remains uncertain. The first unequivocal evidence is the Great Oxidation Event (familiarly called the ‘GOE’) around 2.3 billion years ago, when the planet turned rusty red and froze.
Aerobic respiration operates at about 40 per cent efficiency in converting food to ATP. Anaerobic respiration is closer to 10 per cent. With aerobic respiration, at 40 per cent efficiency, five trophic levels could be sustained before reaching 1 per cent. Without oxygen, only two trophic levels are possible. Complex food webs are only likely to exist in a well-oxygenated world.
The Shuram conundrum revolves around the evidence that most of the carbon on earth was bound up by sulfate, as shown by the carbon isotope balance in the Shuram formation in Oman. The survivors on the end-Permian extinction were those that had evolved to make use of oxygen and clear out excess CO2 and sulfide. Lane posits that it was at this time that the Kreb's cycle evolved.
Most bacteria and archaea don't use a closed Kreb's cycle; rather they use a forked pathway that allows them to adapt to oxygen availability. Lane suggests that the Ediacaran fauna (500 million years before the Cambrian) had little tissue differentiation and were unable to adapt to changing environmental conditions. In contrast, the bilateral ancestors of the Cambrian fauna had a variety of tissues that could work together to seek metabolic balance. By the dawn of the Cambrian, they were able to deal with oxygen and "Rising oxygen just gave them a turbocharge."
Chapter 5 - The Dark Side (cancer)
Lane notes that "cancer is a disease of the genome is too close to dogma." Different mutations are found in different parts of many tumours, often with little if any overlap, implying that the mutations accumulated during the growth of the tumor, rather than triggering its inception. Moreover, the same oncogene mutations are often found in normal tissues surrounding a tumor,
The greatest risk factor for cancer is older age: cancer incidence increases exponentially with age. One might think this is explained by the steady accumulation of mutations with age. But the buildup of mutations with age seems to be too slow to explain either cancer or ageing as a process. Nor can it explain why humans do not have a higher cancer rate than, mice, despite having ten times as many rounds of DNA copying to make an individual.
In glycosis, pyruvate is converted to lactate, allowing the cell to produce small amounts of ATP in the absence of oxygen. Warburg noted the propensity of cancers to ferment glucose in the presence of oxygen. However, many cancers don’t depend on aerobic glycolysis at all, normal tissues are also capable of aerobic glycolysis, and stem cells typically depend on ATP from aerobic glycolysis for their energy needs.
Cancer cells need NADPH for biosynthesis and growth, and it is as important to them as ATP. Cells must wire their metabolism to get the balance between ATP, NADPH and carbon skeletons right. Aerobic respiration produces too much ATP, which actually switches off the glycolytic breakdown of glucose. Cancer cells must not make too much ATP, as it slows down their growth. Cancer cells switch over to aerobic glycolysis precisely because it makes less ATP, favoring faster growth.
As we get older, our respiratory performance declines slowly. The rate of respiration is depressed the most at complex I, the largest and most complex of the respiratory complexes. Complex I is the main source of reactive oxygen species (ROS) from mitochondria, and the rate at which these escape (ROS flux) tends to creep up with age. Also, complex 1 is the only entry point for NADH. So the decline in complex I activity with age means that it’s no longer so easy to oxidise NADH.
The underlying problem in cancer is an environment that continuously and erroneously shouts ‘grow!’. This toxic environment can be induced by mutations, infections, low oxygen levels … or the decline in metabolism associated with ageing itself.
When NADH begins to accumulate in the mitochondria, the Krebs cycle must slow down and there will be a tendency for sections of it to run backwards. Any deficiency in respiration signals causes an increase in glycolysis. The gatekeepers to DNA in the nucleus, become acetylated. The epigenetic switch is pressed down, promoting growth, cellular proliferation and inflammation.
Ageing itself raises our risk, by switching metabolism towards aerobic glycolysis, promoting cellular growth. The combination of a cancer spawning event "set in a permissive metabolic context" allows proliferation and active cancer.
Chapter 6 - The Flux Capacitor (and ageing)
The great immunologist Peter Medawar said we age because we outlive our allotted time as determined by the statistical laws of selection. This textbook view sees ageing and the diseases of old age as little more than the unmasking of late-acting genes, whose effects do us in.
On average, we have one SNP every thousand letters, meaning that there are four or five million letters that differ across the human genome. Only a modest proportion of these are likely to influence the risk of a particular disease
Mitochondrial genes tend to evolve much ten to fifty times faster than nuclear genes, as they are copied far more than nuclear genes, and so they accumulate more mutations. A clean-up process in early life sieves out the most detrimental mutations. That’s why mitochondrial diseases directly affect only about 1 in 5,000 of us.
Mitochondria convert flux through the Krebs cycle into electrical membrane potential. The membrane is a capacitor: a thin insulating layer that separates two electrically charged aqueous phases, generating powerful electrical fields across the membrane. Changes in metabolic flux can increase or decrease this electrical forcefield, affecting everything from ATP synthesis to the flux of ROS or the synthesis of that powerful reductant, NADPH. If the electrical potential is too high (because ATP is not being consumed) then Krebs-cycle flux must slow or even reverse. That signals directly to the nucleus, through succinate and citrate, controlling the activity of thousands of genes, the epigenetic state of the cell. There is a subtle and continuous interplay between the x flux through the Krebs cycle and the epigenetic state of the cell.
Mitochondrial DNA inherited from the mother. The idea of mother's curse is that as male and female metabolisms differ, some mitochondrial mutations could be neutral for the female but bad for the male. Genes in the nucleus can evolve to fix problems with mitochondrial DNA in males. Crosses between species can cause ‘hybrid breakdown’, attributed to incompatibilities between mitochondrial and nuclear genes.
The response to drugs can vary dramatically, depending on a few tiny differences in mitochondrial DNA, with big differences in outcome between males and females.
Reactive Oxygen Species (ROS) are such vital physiological signals that cells go out of their way to keep ROS flux within tight physiological limits. Redox tone – the balance of electron sources and sinks in a cell – is as critical to homeostasis (our normal chemical balance) as temperature or acidity. Any damage to the respiratory chain will tend to increase ROS flux.
Ageing is not driven by mutations in genes accumulating over time, but by changes in gene activity – epigenetics.
Over time damage occurs to molecular machinery such as proteins. Repairing or replacing them is one of the most energy-sapping tasks that cells face. Eventually the respiratory machinery itself is damaged, and ROS flux creeps up. Cells do what they must and compensate by suppressing respiration a little. NADH is oxidized less effectively and the Krebs cycle loses forward momentum. Intermediates such as succinate start to accumulate and seep out from the mitochondria. They activate proteins such as HIF1α, which in turn alter the behavior of thousands of genes, pushing cells into a senescent state or to their demise.
Bats and birds live as much as ten times longer than animals with a similar body size or resting metabolic rate. It seems that restricting ROS flux enables bats and birds to maintain or increase their aerobic capacity without losing redox tone. That in turn postpones the age-related shift to a senescent epigenetic state. However, longer-lived animals must invest more in damage limitation, the cost being fewer offspring.
October 8, 2023
Does the form create the movement, or is it movement that creates the form? Metabolism is the chemical movement organizing the flow of energy, matter, and information keeping living things alive. At the center of a metabolic web of reactions and feedback pathways of most organism on the planet spins the Kreb's cycle. Transformer recounts the series of remarkable scientific discoveries across the 20th century that pieced together today's modern grasp on both the forward and reverse Kreb's cycles and their roles within cellular metabolism, going on to explore their implications for understanding the origin of life, cancer, aging, and even consciousness. Most provocative is the emerging picture that the structure of life's metabolism is not written in the evolved genetic history of biology but lies deeper with matter's ability harnesses and cycle energy to self-organize and assembly towards greater complexity.
June 24, 2022
Transformer was good but not excellent like Lane’s last two books.
The focus was on how energy (metabolism) drives information (DNA), not the other way around.
Here’s my analogy. You discover oil and design a crude diesel engine. Then you use that engine to help you mine more minerals and oil to make more diesel engines. Then you use those engines to makes things that growth your wealth. Then you use that growth to enable abundant credit. Then you use that credit to invest in complex factories to make computer chips. Then you use those computer chips to make your diesel engine more fuel efficient with less emissions.
It’s not possible to construct a plausible story by starting with a computer chip. Energy drives everything and life began at an energy gradient.
There’s lots of detail in the book, too much for my taste, and not enough stepping back to explain the profundity of the detail. Lane does get across, once again, how amazingly complex life is. There’s something like a billion chemical reactions per second taking place in each of of 30 trillion cells!
Also interesting was that many of our diseases, like cancer, are caused more by respiration problems than genetic problems.
What does Lane say is the best thing we can do to have long healthy lives? You’d never guess. Eat a modest quantity of healthy food and stay active. 🙂 But be aware, there’s a large element of chance in health.
I’ll probably read the book again. I’m sure I missed some content. You really have to concentrate with this book.
The focus was on how energy (metabolism) drives information (DNA), not the other way around.
Here’s my analogy. You discover oil and design a crude diesel engine. Then you use that engine to help you mine more minerals and oil to make more diesel engines. Then you use those engines to makes things that growth your wealth. Then you use that growth to enable abundant credit. Then you use that credit to invest in complex factories to make computer chips. Then you use those computer chips to make your diesel engine more fuel efficient with less emissions.
It’s not possible to construct a plausible story by starting with a computer chip. Energy drives everything and life began at an energy gradient.
There’s lots of detail in the book, too much for my taste, and not enough stepping back to explain the profundity of the detail. Lane does get across, once again, how amazingly complex life is. There’s something like a billion chemical reactions per second taking place in each of of 30 trillion cells!
Also interesting was that many of our diseases, like cancer, are caused more by respiration problems than genetic problems.
What does Lane say is the best thing we can do to have long healthy lives? You’d never guess. Eat a modest quantity of healthy food and stay active. 🙂 But be aware, there’s a large element of chance in health.
I’ll probably read the book again. I’m sure I missed some content. You really have to concentrate with this book.
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