124 highlights · 58 notes · last read May 2023
Highlights I wrote a note on are shown in full. The other 70 are scrambled: the words are the author's, so here you only see where in the book I underlined something.
Out of those possibilities, one candidate sticks out: a short cycle of chemical reactions called the citric acid cycle. The citric acid cycle uses ten chemical reactions to transform one molecule of citric acid, the substance that gives lemons their sour taste, through several intermediates with uncommon names—pyruvate, oxaloacetate, acetate, and others—until it has completed one turn and manufactured another molecule of citric acid.51 A chemical cycle that creates two molecules from one sounds fishy, like the long-discredited perpetual motion machines of the nineteenth century. But this cycle does not violate any laws of physics. It cleaves the starting citrate molecule into two smaller molecules, from which its reactions build new molecules step by step, using as materials the carbon from carbon dioxide, and feeding on energy-rich nutrients.
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My note The citric acid cycle
The molecules that it creates are also ingredients for many other building blocks of life. Oxaloacetate provides atoms to build multiple amino acids and DNA nucleotides, pyruvate does the same for some sugars, acetate contributes to lipids—all-important components of cell membranes—and so on.53 If you sought one metabolic core from which you could build what life needs, the citric acid cycle would be it.
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My note Citric Acid also creates lipids
What is more, the citric acid cycle is extremely versatile, for it can run in two directions.54 In the first direction, described above, it operates a bit like an engine that performs the work of building new molecules, powered by a chemical battery of inorganic molecules. The kinds of bacteria that live in hydrothermal vents, bacteria that chemosynthesize for a living, use it in this way.55 Run in the opposite direction, the cycle charges the chemical batteries that power life. Our bodies run it in this way to create chemical energy from the food we eat.
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My note Two ways it can run
The citric acid cycle is attractive for one more reason: It makes more of itself. With each turn, it transforms a starting molecule into two, each of which spawns a new cycle and all its molecules, eventually creating four molecules, and so on. Chemists call this property autocatalysis, a fancy word for a defining feature of modern cells and primitive RNA replicators alike: They all make more of themselves.
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My note Citric acid cycle replicates
This isn’t a shortcoming of the citric acid cycle, but another hint that a defining feature of life may not require RNA replicators and their genetic information: Life can exist before genes.57 We do not know—yet—whether the citric acid cycle is the grandfather of all metabolic activity.
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My note Autocatalyse needs a network of reactions. Not a bug but a features
life can exist before genes
We do know, however, that the very first thing in the planet’s history that deserves to be called alive needed an autocatalytic metabolism to still its hunger.
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My note Alive means to have hunger
Such a metabolism is more than a mere supply chain of parts, because each of its suppliers creates more suppliers, which can produce parts in ever-increasing numbers. And once both the factory and its supply chain are in place Darwinian evolution can kick in. It can preserve better factories, which demand improvements in the supplier, which permit better factories, and so on, in the unending cycle of evolution that lifts all boats.
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My note Hunger creates better factories that imptove
This is an example of horizontal gene transfer, a phenomenon tragically unavailable to disadvantaged humans but rampant in microbes.
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My note Horizontal gene transfer!
In another difference from sex as we know it, gene transfer occurs not just between similar organisms but also between baker’s yeast and fruit flies, between microbes and plants, and especially among bacteria, which can be as different from one another as humans are from oak trees.20 This is why gene transfer is so powerful, and the most important reason why bacteria are masters of metabolic innovation.
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My note The most important reason bacteria can innovate
Very different organisms harbor very different metabolic texts, and gene transfer can edit one text with borrowed passages that are very different yet meaningful within another text, the microbial equivalent of a musical mash-up that combines a Baroque instrumental track with a pop vocal.
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My note Like a baroque-pop mash-up
But because gene transfer is incredibly frequent, the odds for innovation aren’t bad: Even though many edits lack luster, the shelves of life’s universal library contain a virtually infinite number of masterpieces waiting to be found.
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My note Transfer happens very often
Every million years—a blip of evolutionary time, 20 percent of the time since humans diverged from chimpanzees—an E. coli genome acquires some sixty new genes, all of them through horizontal gene transfer.23 And these are only the successful edits—many others have gone out of print and left no descendants.
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My note Strains of e.coli can differ by millions of genes
My note 1.000.000 years +60 genes
Trying to discover the provenance of a particular gene is a bit like trying to trace the literary influences revealed in a single paragraph of a novel by reading a small and random selection of the Library of Congress.
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My note Provenance is almost impossible
This research had discovered thousands of genes that code for particular enzymes, and allowed us to draw maps that connect genes with enzymes, and enzymes with chemical reactions.26 In other words, we could translate a genome sequence into a metabolic genotype, and compare these genotypes among organisms.27 And that is what I did.
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My note Translate a genome sequence to metabolic genotype and compare across species
I had also suspected that bacteria living in the same environment—the soil, for example, or the ocean—might encounter similar nutrients and thus have similar metabolic texts. Wrong. Their metabolic texts were just as diverse, with a D just as different as that from bacteria living in different environments. This
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My note Even species living in the same environment , eatimg the same food differed in their genes
Everywhere on this planet, a relentless shuffling and mixing and recombining of genes takes place. Wherever microbial life occurs, in the depth of the oceans and on arid mountaintops, in scalding hot springs and on frigid glaciers, in fertile soils and desiccated deserts, inside and around our bodies, life is experimenting with every conceivable combination of new genes, rereading, editing, and…
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My note So .much remixing everywhere all the time
Likewise, a text in the metabolic library needs to be read to reveal its meaning: the metabolic phenotype that determines which fuels an organism can use,…
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My note Metabolic PHENOTYPE determines what food We can eat and what molecules can produce
We think of a phenotype as something we can see, and many metabolic phenotypes are plain as daylight. They include the melanins that protect our skin against radiation, that camouflage a lion’s fur, and that color the ink of an octopus. All of them are molecules synthesized by metabolism. And so are the various pigments that dye tree leaves, lobsters, flowers, and chameleons, whether for defense, courtship…
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My note Phenotypes can be seen
Their most important role is to ensure viability itself, which boils down to the ability to synthesize sixty-odd molecules very different from those pretty pigments—they are the essential biomass molecules I mentioned in chapter 2. Viability, viewed as the phenotypic meaning of a genotypic text, is like the simple moral of a complex story, or like a brutally straightforward court judgment: If you can’t make all essential biomass molecules, your sentence is death, and it is carried out immediately. Organisms with a mutation that…
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My note Phenotype ensures viability
To grasp this phenotypic meaning—viability or death—we need to read an organism’…
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My note Viability or death
to understand the moral, we have to understand the whole story—but also because our brains are not well practiced in reading chemical language. Fortunately, we can program the…
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My note Ww can use AI to help us read the genotypes story
A genotype tells us which reactions a metabolism can catalyze, the molecules these reactions consume, and…
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My note Genotype: reactions, input molecules, output molecules
To decipher its meaning, we would first need to know which nutrients are available—without the right ingredients, you cannot bake a cake—and whether the metabolism can use them to build an essential biomass molecule such as tryptophan. This is easiest for the austere minimal environments where survivalists like E. coli can thrive, because they contain so few nutrients, sometimes only a single sugar that provides all the carbon and energy the organism needs. Starting from the available nutrients, we would then write a list of all the molecules the metabolism’s reactions produce from the available nutrients, find the reactions in the genotype that consume these product molecules, and list their products…
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My note How to read translate genotype to phenotype to viability
Only when all essential biomass molecules can be…
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My note DEFINITION VIABILITY
My note Iterate and conclude viability
it shows that their computed viability is highly accurate—it is correct for more than…
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My note Fct-checking computers is 90% reliable
But more than just remarkable, the capacity to compute viability is profound and revolutionary, a legacy of a hundred years of…
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My note Te capacity to compute viability is profound ad revolutionary
But among all these aspects, viability is the most fundamental, and new methods of making biomass and using chemical fuels are by…
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My note Viablity most fundamental
new methods of Craeting biomass and chemical biologial fueling most important innovations
They are also the most far-reaching, opening new territories to life and its metabolic engines. The reason for the importance of fuel innovations is simple: The world changes all the time, and no matter how successful a metabolism is today, it will almost certainly become unsuccessful at some point in…
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My note Metabolic innovation opens new territory
imagine a list like that shown in figure 6, comprising a hundred or so potential fuels. Then compute whether the known metabolism of your favorite animal, plant, or bacterium is viable on a specific fuel molecule, such as glucose. If it can synthesize all biomass molecules from the carbon in glucose, write a “1” next to glucose, otherwise write a “0.” Then repeat this computation for the next fuel molecule, the next one after that, and so on, until each fuel has either a “0” or a “1” next to it. Every single “1” in this list means that the metabolism can synthesize the complete suite of biomass molecules from that particular fuel. The resulting string of a hundred ones and zeroes encapsulates the fuel molecules that a given metabolism can use to sustain life.
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My note Metabolic phenotype is 100 ones and zeros that show which fuels it can life o
Metabolic generalists like E. coli can survive on dozens of carbon sources, and their phenotype string contains many ones.35 Metabolic specialists can live on only a few carbon sources, and their phenotypes contain mostly zeroes.
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My note Metabolic generalist vs. Specialist
a hyperastronomical library.
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My note Wie das ende in interstellar
FIGURE 7. A metabolic innovation
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My note What an metabolic innovation looks lik
Recall that a string of five-thousand-odd ones and zeroes describes a metabolic genotype.
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My note Metabolic genotype: 5000 0s and 1s
The edges of a hypercube are equally long, adjacent edges are at right angles to one another, and each corner corresponds to a possible metabolism. And such cubes in high-dimensional space turn out to have curious properties well suited to house the metabolic library.
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My note Hypercubes make good bookshelve
My note We need a 5000-dimensional hypercube
All of a text’s neighbors form a neighborhood in this library, and such neighborhoods are as important for evolution as a city neighborhood is for people’s lives. City neighborhoods are useful because of proximity—everything is reachable within a few easy steps—and neighborhoods in the metabolic library are important for the same reason.
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My note Neighborhoods
The next insight it provides is the real bombshell, though: We can travel enormous distances through the library and encounter very different stories with the same moral, everywhere.
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My note Bombshell
Even after 3.8 billion years of evolution, life has explored only a tiny fraction of the library. For all of those billions of years, nature did not need to know what was around the next corner of the library for evolution to proceed.
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My note Nimble
But where to start, and how to travel?
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My note Great question
it would be utterly impossible to find this text through a blind search.
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My note Blind search
On the one hand, the odds against finding just one useful metabolism are vast. On the other hand, life’s diversity shows that evolution had no problem finding it. This means that our premise must be wrong: There has to be more than one metabolism—perhaps even many—that solves the problem of surviving on glucose.
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My note Calculation vs. Observation
Because each step alters a text at random, this walk is a random walk through the metabolic library, similar to how a drunkard might stagger home from a night out at the bar, with one difference: Each step in our random walk must encounter a text with the same meaning, the same phenotype.
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My note Random walk
An entire network of computers—a computing cluster—is required to speed up that computation. And that costs money.
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My note Money
Even if only one in ten thousand of them folds, you are still left with 10126 proteins, a 1 trailed by 126 zeroes, much greater than the number of hydrogen atoms in the universe. The number of meaningful proteins is itself large beyond imagination.30
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My note Meaningful proteins astronomical
How hard is it to find a protein with any one meaning, one whose function helps an organism to survive? If there is only one of it in the library, even the eons elapsed since the Big Bang would not suffice to find it.
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My note Random would not have enough time
Since meaningful proteins exist in huge numbers, just about every problem that life solved with a protein innovation must have more than one solution.
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My note Same problem, multiple solutions
In 2001, Anthony Keefe and Jack Szostak from Harvard University set out to answer this question for a family of proteins whose invention was as crucial as any in life’s history: the proteins that can bind the ATP that we encountered as life’s battery in chapter 2.
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My note How many can ATP?
Proteins that carry out work—they transport materials, contract muscles, build new molecules—cleave ATP, and in doing so, harness its energy for this work.31 To use ATP’s energy, a protein first needs to bind ATP.
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My note ATP for energy for work. Binding ability ATP
Keefe and Szostak found that four of them—unrelated to one another—can bind ATP. Four new ATP-binding proteins out of six trillion doesn’t sound like too many, but when the proportions are extrapolated to the number of potential candidates, the number is much larger. It comes out to more than 1093 proteins—a 1 with 93 zeroes—that can bind ATP. The problem of binding ATP has astronomically many solutions.32
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My note Four in six trillion proteins can bind ATP. Thats a GOOD ratio!!!
My note Binding ATP IS 4/600000000. Thats Gogol solutions across all possibilities
this virus can also remain dormant inside the bacterium, using this off switch to shut down its genes until the time is ripe to divide and kill the host. This time usually comes when the host falls on hard times—starved, poisoned by antibiotics, or irradiated with too much ultraviolet light. The virus then starts to replicate, and its children abandon the cell, rats scurrying from the proverbial sinking ship.33
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My note Virii make shit go from bad to worse
When they tried a similar approach on a different protein, an enzyme needed to synthesize amino acids, they found that some 1096 amino acid strings can do this enzyme’s job.34
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My note 10^96 protein solutions to a viral problem
Nature’s antifreeze proteins gave us a hint, and laboratory experiments like these prove it: Problems like that of binding ATP, shutting down a virus, or catalyzing a chemical reaction don’t have just one solution. Or even a million solutions. They have astronomically many solutions, each embodied by a different volume in the protein library.35 To imagine the sheer number of these solutions is difficult, but that says more about the limits of our imagination than about life’s innovability.
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My note There are astronomically many solutions to problems
The copying errors it suffers each generation are rare—about one for every forty million copied DNA letters in our cells37—but given enough time, all genes in a genome will suffer errors that alter the proteins they encode. An altered amino acid text that prevents a globin from folding also prevents oxygen from traveling where it is needed. In other words, it spells death. But an altered protein does not always lose its function and meaning. Some alterations impair neither folding nor function, and get passed on to the next generation.38 Over thousands and millions of generations, copy error after tolerable copy error can thus accumulate and slowly change a protein’s amino acid sequence. FIGURE 11. Proteins change in time
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My note Errrorr rate
The chicken lineage separated from us even longer ago—almost three hundred million years—and accrued six altered amino acids.41
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My note 300.000.000 years of evolution changed six amino acids in the dna for hemoglobin
Millions of other organisms harbor globins, not only warm-blooded vertebrates but reptiles, frogs, fish, sea stars, mollusks, flies, worms, and even plants. Some of these organisms grow on the same twig of life’s gigantic tree and have a recent common ancestor. Their globin texts shared most of their journey through time, split only recently, and are still similar. Others lie on different branches, share more distant ancestors, and harbor globins with different texts.42 But however different these texts are, each of them works just fine, since otherwise it would not have survived. Each surviving text encodes a different solution to the problem of binding oxygen.43
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My note Surviving means the solution works