How Life Works

Prologue

• Looking to the genome for an account of ho life works is rather like looking to a dictionary to understand how literature works.
• The new picture dispels the long-standing idea that living systems must be regarded as machines.
• Living entities are generators of meaning. They mine their environment (including their own bodies) for things that have meaning for them: moisture, nutrients, warmth. It is not sentimental but simply following the same logic to say that, for we human organisms, another of those meaningful things is love.
• Life is a hierarchical process, and each level has its own rules and principles: there are those that apply to genes, and to proteins, to cells and tissues and body modules such as the immune system and the nervous system. All are essential: none can claim primacy.
• Genes don't generally specify unique outcomes at the level of cells and organisms.
• Recurring themes and principles:
  • Complexity and Redundancy
  • Modularity
  • Robustness
  • Canalization
  • Multilevel, Multidirectional, and Hierarchical Organization
  • Combinatorial Logic
  • Self-Organization in Dynamic Landscapes
  • Agency and Purpose
  • Causal Power

1. The End of the Machine: A New View of Life

• Living things are, you could say, those entities capable of attributing value in their environment, and thereby finding a point to the universe.
• Meaning-generators are successful entities in a Darwinian world. Making meaning is a great way of staying alive and propagating - so much so, indeed, that it's probably the only way to be alive at all.
• The point is that we need to acknowledge what evolution does to matter: it gives matter goals and functions. That is what makes evolved life so special.

2. Genes: What DNA Really Does

• Each of our somatic cells contains 46 chromosomes: two copies each of 23 different varieties. Other animals have different numbers: cats have 19 pairs, dogs 39 pairs.
  • The gametes (eggs and sperm) are special in that they each contain only one set of chromosomes. This makes them haploid cells, as opposed to the diploid somatic calls.
  • The single exception in our bodies are the red blood cells, which contain no DNA; they are simply packed with oxygen-ferrying hemoglobin proteins.
• Chromosomes are made of protein and of deoxyribonucleic acid (DNA), which is in turn a polymer of four types of chemical unit (nucleotides), containing a sugar molecule (deoxyribose), a phosphate group, and a substance belonging to the general class of molecules called bases (adenine (A), cytosine (C), guanine (G), and thymine (T).
• The unification of Darwin's theory of natural selection with the Mendelian inheritance of particulate genes gave 20th C biology its central explanatory framework, dubbed the Modern Synthesis in 1942 by Julian Huxley.
• The gene's eye view of life (indeed, even of evolution) is shaped by a particular scientific model and is valid only within the context of that model. It does not and cannot deliver an account of the world as we find it. The problem with atomizing organisms into genes is that genes are not alive - and once you have set aside life to get to the gene, you can't get it back again. The gene is far too atomized a unit to tell us much at all about how life works.
• Genes with names awarded in one context turned out to be identical to genes given different names in another context. And genes associated with one trait proved to be implicated in a quite different trait too.
• The genome does not control the cell. Rather, it supplies resources for the cell as an autonomous and integrated entity. Genes are not a blueprint. They impart capabilities; the rest is up to us, in interaction with our environment.
• Most human traits are not simply genetic - they are also affected by the person's environment.
• How we are is correlated with our genotype, but genes are not what make us what we are.
• The many genes linked to IQ are sure to be implicated in other traits too - perhaps neuroticism or schizophrenia. There are no isolable intelligence genes. If we select embryos for highly polygenic traits like this, we will have little idea for what else we might be selecting.
• Many human traits are influenced by many genes. Even for traits that show a strong heritability, such as height, the genetic component derives from the tiny effects of many genes rather than big effects from just a few. This can make it very difficult to figure out what the respective genes are doing - or indeed, how causally relevant they really are.
• Sometimes the polygenic nature of traits is extreme, and hundreds or even thousands of genes might be implicated. The statistical associations observed between many complex traits and genes tend to be spread across most of the genome. 62% of common single-nucleotide polymorphisms (SNPs - where one base pair is different) are associated with height in parts of the chromosomes that are active across most cell types, and often in "non-coding" sequences.
• You can't compute from the genome how an organism will turn out, not even in principle. There is plenty that happens during development that is not hardwired by genes. And from a single protein-coding gene, you can't even tell in general what the product of its expression will be, let alone what function that product will serve in the cell.
• Evolutionary and developmental biology are seeing two different kinds of explanation - The first considers population-level phenomena, the second focuses on individuals. Organisms acquire their form twice over: by evolution (the history of which is imprinted in genomes), and by development (through the interactions of molecules and cells). Both are under genetic influence, but not in the same way.
• Genes don't compete with each other. Rather, a mutation to a gene that turns it into a variant that enhances survival of the organism carrying it will tend to spread through a population an eclipse the other less successful alleles. So different alleles of the same gene compete with one another, while different genes on the same genome cooperate. The first is a story about evolution, the second about individual development.
• Genes do not produce life, but on the contrary depend on it.

3. RNA and Transcription: Reading the Message

• The process of transcription:
  • First, each gene is read by an enzyme called RNA polymerase that steps along a single unwound template strand of DNA and assembles a corresponding mRNA molecule use the sam principles of base pairing that holds the double helix together. The double helix is unzipped by the enzyme's advance and reunited in its wake.
  • Once an entire gene has been transcribed into an mRNA molecule, the RNA detaches from the DNA and makes its way beyond the cell nucleus to the place where it can be converted (translated) into a protein by the ribosome.
• Genes - or more generally, functional sections of DNA - are not simply instructions for making proteins. Some of them determine what kinds of proteins cells, tissues, and organs can make. Some do other things: RNA-related things that don't directly involve proteins at all.
• Rather than DNA directly producing proteins, an RNA intermediary creates a buffer layer and gives flexibility and versatility to the readout process from the genome. It also allows many protein molecules to be produced rapidly from a single piece of DNA.
• DNA sequences are full of segments that don't feature in the mRNA:
  • Introns - Are edited out before the mRNA is presented to the ribosome for translation.
  • Exons - Are the retained sequences, spliced back together after the introns are removed.
  • Transposons - Are jumping genes that move about in the chromosomes, with about 65% of the human genome capable of exhibiting transposon behavior.
• The genome was meant to be a static blueprint, but it is dynamic and responsive to environmental stresses - more like an organ or an organism in an organism.
• microRNA - Is smaller than normal genes and may regulate regulate up to 60% of our genes as well as targeting other microRNAs (and a single mRNA can be targeted by many mRNAs). mRNAs seem to control embryo development and to control pluripotency is embryonic stem cells
• Now that the human genome is mapped, the ENCODE project is identifying which parts of the entire genome are transcribed in the cells of different tissues, characterizing the human transcriptome. The HGP showed that only 2% of our genome consists of protein-encoding genes, and most of the rest was considered "junk" (non-coding), but now it seems that genes as protein-encoders are maybe only a small part of what is going on with our genome.
• Encode identified around 37.6k long non-coding RNA (ncRNAs) genes, nearly twice as many as genes that encode proteins.
• It seems that, for mammals, the noncoding, regulatory regions of the genome are more important than the coding parts. Bacteria have 90% of the genome for protein coding, while we have 2%.
• Epigenetics (how your behaviors and environment can cause changes that affect the way your genes work) rather blurs the distinction between nature and nurture.
• Childhood trauma can be correlated with methylation in a person's genome, a biological embedding of experience.
• The gametes (eggs and sperm) have mechanisms that protect their genomes from much epigenetic alteration, and strip away more or less all of it anyway as these cells mature into the state that takes part in reproduction. At the stage of gamete maturation called the primordial germ cell, epigenetic marks in the genome are largely erased.
• Rather than waiting for the genome to evolve, it is more effective to evolve mechanisms for producing rapid revisions of how the genes are used when circumstances demand it.
• Life is according to Dennett and Michael Levin, "cognition all the way down".

4. Proteins: Structure and Unstructure

• There are thought to be around 80-400 thousand varieties of protein molecules in human cells, and they are the second key functional components of life after DNA and RNA
• Proteins are typically dubbed the workhorses of the cell. In this sense they are nearly synonymous with enzymes, the molecular catalysts that conduct life's chemistry.
• Proteins belong to the class of molecules called polypeptides, in which amino acids are strung together in a chain via chemical linkages called peptide bonds. In enzymes, these chains fold up into compact blob-like forms with specific shapes, sculpted by evolution, that allow each protein enzyme to do its job.
• Hydrogen bonding and the hydrophobic attraction are generally thought to be the two key forces that dictate how proteins fold. The "native fold" is the protein's folding target, which is the form with the lowest energy possible.
• Google's Alphafold has made predictions about the structures of more than 200m proteins - all those currently know to biology - in species ranging from bacteria to plants and animals.
• Protein molecules are huge and their structures are extremely complicated.
• Some proteins become embedded in cell membranes, others are structural - they don't function as enzymes, but rather as components of the cell's fabric, and som act not to catalyze reactions, but to regulate genes.
• Because we use crystallography to analyze proteins, and many won't form crystals, we only know about the structures of half of them that make up the human proteome. The rest are sometimes called the "dark proteome".
• Many don't have well-defined folded shapes - maybe up to half in the human proteome, and this disorder seems particularly prevalent in many of the most important proteins in the molecular ecology of the cell. Compare this to bacterial proteomes, where only 4% are disordered.
• Disordered proteins can increase the complexity and versatility of our regulatory networks, but at the cost of increased risk of toxic aggregates formed from misfolded proteins. Many proteins found to be associated with diseases are highly enriched in disoredered regions, including especially those implicated in other neuro-degenerative conditions such as Parkinson's and Huntingdon's.
• On average, each human gene encodes about six different proteins. Some genes may generate many variants, sometimes hundreds (though not all of these may be functional).
• From around 20k genes, our cells can make 80-400k different proteins.
• Gene sequences do not typically encode a specific protein with a specific shape. Instead, they are resources for making families of proteins.
• The amino acids in proteins seem to be organized into domains, and these domains can be mixed and match to produce new and different proteins with the capacity to stick together, to communicate with one another, and to differentiate into specialized forms.
• Just as disorder in protein structure creates flexibility for what a protein can do individually, so random associations in the evolvosome might open up fresh possibilities for what proteins can do collectively.
• Scaffold proteins (SPs) have the job of gathering other proteins together in the same space to communicate. They are good at forging new links between signaling pathways, opening up new developmental possibilities. They are not tailor-made, but good at improvising, often by a reshuffling of the binding domains they possess.

5. Networks: The Webs That Make Us

• Biologists began to think about genes as a network. They were speaking to one another, and the task was to figure out who was conversing with whom: to map out not just the genome, but the connectome through which it operates.
• For complex organisms like us, the network of interacting molecules, the interactome - sometimes seemed not just absurdly but impossibly complicated.
• DNA packaged into chromatin looks more like a cupboard stuffed full of documents in a random heap of loose pages. Yet somehow there is precise cross-referencing and coordination amid the chaos.
• With a combinatorial system you have many more options that will do the job, while retaining distinctions of use and meaning. It's a little like the way languages work: there's nearly always more than one combination of words that will convey much the same meaning, but those combinations aren't arbitrary. In many particular contexts, some choices work better - convey a clearer or more emphatic meaning - than others.
• Perhaps the most useful analogies for how cells work are themselves biological, such as olfaction or cognition. Maybe the only way to truly understand life is with reference to itself.
• It's possible that making promiscuous, reconfigurable networks doesn't just convey advantages but perhaps is the only way a complicated system like our cells can work, if it is to be robust against ineluctable randomness and unpredictability in the fine details.
• Cellular systems are very noisy. Molecular encounters in this crowded, jostling environment are very much a matter of chance, and there are also random fluctuations in the number of different proteins that get produced from moment to moment. That's one reason the cell's wiring can't be compared to the complex electronic circuits in a laptop: no two cells are ever in wholly identical states at any given moment, even when they are both ostensibly doing the same job, such as acting as muscle or kidney cells.
• Combinatorial logic has a certain amount of sloppiness that can absorb (and even exploit) such variation.
• It seems likely that metazoans have evolved this evolvability. Eukaryotes have chosen this sloppiness - probably because it allows new regulatory pathways to develop, opening up the potential for variation and evolvability.
• Causal emergence allows noise reduction - independence of the outcome on random fluctuations or chance events at the microscopic level. And, it makes the causes of behavior cryptic at the microscopic scale, hiding it from pathogens that can only latch onto particular molecules.
• Evolution doesn't so much shift all causation to higher levels as spread it among the various levels.
• Causal emergence seems to be a general design principle for life, but it is rarely evident in our own technologies. Machines tend instead to use simple chains of causation: this cog turns that one.
• Perhaps language is the only human technology that resembles how life works in the causal sense, in which meaning and causal power - the ability to induce thought, mood, action - increase as we go up the scale from letters (or phonemes) to words, sentence, paragraphs, and so forth. Zoom in on a text's component characters and you lose all meaning: the characters themselves are not only effectless but have no intrinsic function.
• The key reason causal emergence seems to be so widespread in how life works is, then, that this is how to "engineer" with noisy components. If you are making a machine from chunky, precision-milled cogs, you don't need causal emergence, because the parts can be relied on.
• The more complex multicellular organisms that appear later in evolutionary history tend to assign causal roles to higher levels of organization in their networks. In this way, these organisms can tolerate more noise and indeterminism in the microscales, because those scales aren't the primary determinant of phenotypic outcomes such as body shapes and behaviors.
• The switch to multicellularity seems to involve the appearance not of more primary genetic resources - more or different genes - but of new ways to regulate them.
• Is there, after all, really such an obvious advantage to being multicellular? If so, we don't know what it is. Complex multicellularity has arisen only twice during evolution: in animals and in plants (fungi might be deemed a third group, but they don't have anything like the tissue diversity of the others).
• Rather than there being smooth and gradual changes in the frequencies of CNEEs (conserved nonexonic elements), three distinct eras of change seem to have occurred over the past 650m years:
  • Until about 300m years ago, when mammals split from birds and reptiles, changes in regulation seem to have happened mostly in parts of the genome close to transcription factors and the key developmental genes that they control.
  • Between 300-100m years ago, those changes tailed off, and instead there were changes near genes that code for the protein molecules serving as receptors of signals at the cell surface. What seemed to matter was a shift in the way cells talk to each other
  • Since 100m years ago, as placental mammals developed, the regulatory changes seem to be associated with mechanisms for modifying protein structure after translation, especially for proteins that are associated with signal transduction within cells.
• Evolution might be considered to have successively discovered ways to innovate and generate new organisms by first reshuffling how developmental genes are switched on and off, then how cells communicate, and then how information gets passed around inside cells. In all cases, the action is taking place not at the genetic level but at higher levels of network organization (which nevertheless leave traces in the genomes.
• Aside from the well-acknowledged complication of viruses, all life is cellular, passes on hereditary information in DNA, and uses proteins and a relatively small palette of other molecular types.
• What seems to have changed over the course of evolution is nothing less than the locus of causation. I have called this causal spreading.
• I think we will find that what gave us cognitive abilities no other species possesses - in particular, the ability to develop language, to think abstractly, and to maintain highly nuanced social interactions - is a change at a higher level than the genomic: a change in the emergent properties of the brain. No single gene "made us human".

6. Cells: Decisions, Decisions

• We're not just a homogenous mass of cells.
• Cells commit to fates by noticing and assessing what their neighbors are doing. It's like voting with a show of hands: we might sneak a look at how others are voting before deciding which way to go ourselves. And if we're given new information, we might change our mind. As new cells are produced by division in the early embryo "they take care of their own further development, shaping both themselves and their local environments without any further instruction from their parents.
• Each cell inherits the epigenetically modified genome of its parent cell, in which some genes have been silenced while others are active - but it can incur further epigenetic modification, guided by the signals coming from outside, that change its fate still further. In this way, the development of the organism is a story about progressive cell-fate selection, at each stage of which the cell lineage commits to one path and the others become unavailable to it.
• A totipotent cell can elect to become:
  • A trophobblast cell
  • An embryoblast (inner cell mass) can become:
    • epiblast (will become the fetus) can become:
      • ectoderm - eventually become neural cells in the spinal cord, the nervous system, and the brain
      • mesoderm - inner organs, such as muscle, heart and kidneys, and blood cells
      • endoderm - the lungs and gut, etc
    • hypoblast
• The landscape isn't in some sense already waiting out there in biological space for cells to populate it. Rather, it builds itself during development. The growth of an embryo is like the growth of a city: it's the growth process itself, not some blueprint, that gives it form.
• Dimensional reduction - Within the frenetic pandemonium of many molecular interactions, only a few parts of the system really make a difference. A high dimensional space is reduced to a surface, or something like it. You won't figure out why this is, or what in the system truly matters and what does not, by staring at genome sequences.
• Almost by definition, the canalization implies the removal of causation from the genetic or molecular level to another, higher organizational tier. It seems to be a general property of complex, multicellular organisms.
• Cells decide on their fate according to their location in three types of space:
  • Familiar 3D space, having specific locations in the tissues of the embryo that determine which neighbors a cell has and what signals it receives.
  • Gene expression or transcription space - what kind of cell it is, how stem-like or how mesoderm like.
  • Decision space of valleys and bifurcations created by the development trajectory
• From the genetic to the behavioral level, life needs noise because it can't afford to be too deterministic. You never quite know what lies around the corner.
• Cognitive systems exist to integrate information from many sources to produce a goal-oriented response. To that extent, all living systems have to be cognitive agents almost by definition. And the fact that evolution grants this capacity should really be seen as unremarkable, for cognition is clearly a good way to deal with the unforeseen: to develop versatile and instantly adaptive responses to circumstances an organism has never encountered in its evolutionary past. The more complex an organism is (or its environment is), the more cognitive resources we should expect it to have.

7. Tissues: How to Build, When to Stop

• What do the cells that make up an organism know (individually and collectively) - and how?
• There are three main modes for transmission of external signals into a cell:
  • Chemical - As molecules attach to receptors
  • Mechanical - As other cells stick to or pull it
  • Electrical - As pulses pass across the membrane
• It seems likely that cognition using cells and brains is in some ways just an elaboration of the cognitive capabilities that all cells display, and which they use to coordinate their activities.
• The shapes of tissues and organisms may be attractors in the morphospace - There's some way the system is storing a large-scale map of what it's supposed to build. That map is not in the genome, however, but in a collective state of the cells themselves, which creates a policy for navigating the morphological space of the organism.
• The meaning of some developmental signaling molecule, such as Notch, Wnt, or BMP, can be altered by the electrical environment into which it is received.
• One of the fundamental puzzles of embryo and tissue growth is what physicists call symmetry-breaking: how a system that is initially symmetrical becomes one in which there is less symmetry.
• Gastrulation is the point at which we see the first hint emerge of a human body plan, namely, the formation of a central growth axis that will eventually become the channel of the mouth-gut-anus system and the orienting axis of the spinal column and central nervous system.
• The emergent body axis is called the primitive streak.
• The disk-shaped layer of cells in the epiblast acquires polarity - a head and a tail, or what biologists more delicately an interior and posterior.
• The embryo becomes a three-layer sandwich in which each cell type will produce specific kinds of tissue.
• The notochord is a temporary organizing structure, the main function of which is to dispense chemical signals to the surrounding tissues that specify which organs and tissues they are to become. It is an organizing center for the next stage of development.
• The neural tube will eventually become the spinal column and central nervous system, including the brain.
• With identical twins, there have been cases where one twin's fetus grows inside the other's brain or (more commonly) gut.
• Unless errors in development are truly enormous, the embryo can deal with them by using the constant conversation between cells to regulate development according to how things really are, not how they "should" be.
• It's all about generating difference: making form from initial uniformity.
• The cytoskeleton is a scaffold-like protein mesh that is woven over the inside surface of cell membranes.
• The presence of one tissue type can determine what kind of cells grow next to it by mechanical communication. Whether or not a tissue should keep growing is decided by what the cells "feel" from other cells around them. In this way, tissues and organs can feel their own size.
• Remarkably, it is the very onset of a heartbeat in a developing embryo that tells its cells what to become. The pressure of the pumping blood is "felt" by cells in the growing tissues and throws a biochemical switch that turns on genes affecting the eventual fate of those cells. The heart drives and shapes its own formation, bootstrapping itself into existence by virtue of its very function.
• Some morphological goals are best viewed as attractor states. In general, the system will produce the same thing regardless of where you start and how you get there.
• Life doesn't make systems that can do or construct a single thing, but produces entities - cells and their genetic, transcriptional, and protein networks - that embody a wide range of options. The trick it must master is then to ensure that, in normal circumstances, the system converges on the outcomes favored by natural selection, while still maintaining enough phenotypic variability to be evolvable. Evolution does not know, so to speak, what it is going to need tomorrow - so it must keep options open. Such variation is possible precisely because the rules by which development unfolds are loose ones.
• If there's a central feature of how life works, it is surely in this ability to create outcomes that are neither arbitrary nor wholly prescribed.
• What is really "normal"? The rules that govern bio-molecules, cells, and tissues are probably much more fallible that we think, and we probably all have some kinds of "defects". Eg, a study in 2022 concluded that 17% of people aged fifty and one-third of those over 70 have some amyloid plaques - thought to be agents or indicators of dementia - in their brains, with no obvious cognitive consequences. Many women have noncancerous growths called fibroids in or around the uterus, with no adverse symptoms. There are many types of benign skin growths.
• Most human zygotes (a single cell made by the fertilization, either naturally or artificially, of the female gamete (ovum or egg) by the male gamete (sperm)), perhaps 70-90%, never develop into a live birth, because things "go wrong" - either for genetic or environmental reason, or by chance.
• The body of conjoined twins is just one possible outcome of the developmental process, albeit one that almost never materializes.
• It is absurd to suppose that a system as complex as the human brain will have a single way of developing. Variance on the autistic spectrum is not aberration but just possible outcomes of the developmental process that creates a brain under the influence of a human genome.
• Life is a process, a literal unfolding.

8. Bodies: Uncovering the Pattern

• Positional information can be delivered throughout a tissue by a gradient in the concentration of some signaling protein, the expression of which is switched on in one place and which then diffuses through the tissue. It's a little like figuring out from the intensity of small how close you are to the kitchen.
• Morphogens are molecules that generate shapes.
• Zones of Polarizing Activity (ZPAs) define the up and down of wing or hand.
• By combining gap or patterning genes into a cross-regulating network, the process can be insulated from contingencies. Canalization in biology creates robustness from an underlying unpredictability.
• Turing proposed reaction-diffusion or activator-inhibitor systems to create patterns.
• In principle the Turing mechanism can produce any number of fingers, but there are just five because at the stage at which finger formation happens, the intrinsic size of the stripes is such that precisely five of them happen to fit into the space available. There is nothing in the human genome that enforces a five-digit rule - it depends on the patterning process playing out at the right time, when the bud is the right size.
• Controlled cell death (apoptosis) also plays a vital role.
• Turing patterning also produces our fingerprints.
• The formation of organs and bodies involves a delicate interplay between chance and necessity - a conversation between genes and gene networks, mechanical forces, and the environment.
• The rules allow growth to regulate itself, to adjust to unforeseen circumstances, to find a way. They are rules for making bodies that work.
• Even by just the two-cell stage, embryos seem to have a left and a right. But this distinction starts to become manifest around the time of gastrulation.
• The positioning of our organs on the correct side of our bodies is controlled by stirring!
• Nodal and Lefty genes create a kind of Turing pattern that is barely a pattern at all: they divide the embryo into two, with one half having relatively high Nodal concentration and the other high Lefty concentration.
• Turing's patterning mechanism occurs in all corners of the physical world, and not just in developmental systems.
• Physical laws are not suspended in living matter; evolution harnesses rather than subverts them, and in this way can sometimes get order and organization "for free".
• The division of our body plan into segments begins during gastrulation, when the different tissues are just beginning to emerge from the three-layer structure of ectoderm, mesoderm, and endoderm. The process is controlled by the Hox genes, and it supplies a perfect example of how the body becomes organized through a complex interplay of genes, regulatory networks and signaling molecules, epigenetic chromatin packing, and larger scale phenomena such as mechanical buckling of tissues.
• In mammals, there are 13 basic types of Hox gene, divided into four subtypes, A, B, C, and D.
• Evolution decided that segmentation produced by the positional information of concentration gradients was a handy trick for producing complexity of form that it could repeat again and again.
• Nature finds the right balance between top-down, bottom-up, and middle-out mechanisms for building organisms, so that adaptation and variation can happen, and innovations - dramatic new solutions to the challenge of "design" - are possible without producing a dangerous sensitivity to small changes. The forms that spontaneously emerge create a generic chassis on which to build and experiment.
• Genes do not so much produce as select from morphological possibilities. Those phenotypes are themselves determined by higher organizational principles.
• There is a tendency in evolutionary biology to regard natural selection as a process with an infinite palette: anything is possible so long as it doesn't break the laws of physics. But the laws of physics might impose more constraint than that, precisely because biology uses rather than merely suffers them.
• If very different shapes can be achieved with only a little genetic tweaking - to slightly alter the diffusion rates of morphogens, for example, or the strength of cell adhesion - then the Cambrian explosion is no mystery. This toolkit probably arose through the repurposing and integration of genes and regulatory networks that had begun to take shape before metazoa themselves did. Animals since the Cambrian have repeatedly reused the processes and components that had been evolved long beforehand to generate novel traits of anatomy and physiology.

9. Agency: How Life Gets Goals and Purpose

• At every level, from genes to proteins to networks to cells and tissues and bodies, distinct but interacting sets of principles operate to keep the show on the road and to leverage the affordances supplied by the levels below to create structure, function, and order. At each level of the hierarchy, events happen that are rather insensitive to the finer-grained details underpinning them, and which orchestrate matter into the forms and patterns in time and space that permit life to unfold.
• All these processes operate as if in thrall to some overall plan, with us as the goal. Biology looks uncannily teleological. That thought distrubs some biologists no end.
• One of the big challenges for biology is to develop a rational, productive framework for understanding concepts such as agency, information, meaning, and purpose.
• Life seems to go to extraordinary lengths to confound physics.
• The second law of thermodynamics says that the universe heads inexorably toward a state of greater disorder. This directionality is simply a consequence of probabilities. Entropy is really a measure of how many different but equivalent ways there are to rearrange the constituent particles - the atoms or molecules - of a system. In general, there are more - many, many more - options for a disorderly system than for an orderly, structured one. So processes tend to proceed in the direction of the most likely configurations.
• Living things seem to ignore this entropic imperative. Their animation relies on the creation and maintenance of order, which is to say, of very specific patterns and distributions of molecules that have negligible probability of happening by chance. Even our thoughts and memories are patterns maintained in the face of the Second Law's apparent demand that they dissolve into the random firing of neurons. All this happens through the marshaling or energy within organisms, which must be harvested and stored and used judiciously, squandering as little as possible.
• At equilibrium there is no net change in a system, for there is no driving force that compels it.
• Living organisms are nonequilibrium systems. Our hearts are constantly beating, pumping blood around the body. We are reflexively breathing in and out, without trying or even noticing. Our brains, even when resting, are a miasma of signals zipping through the neurons' tangled network - the living brain is never quiet. Every cell is burning up energy to drive its metabolic processes. We depend on a constant throughput of energy - for us it comes in the form of energy-rich food, but ultimately the energy source for nearly all life on Earth is the Sun, which powers the growth of plants at the bottom of the food chain. And you had better hope that you stay out of equilibrium for as long as you can - for equilibrium means death.
• Life is a learned affair, the learning inherited over eons.
• We are a qualitatively unusual sort of nonequilibrium system.
• Schrödinger:
  • "...the essential thing in metabolism is that the organism succeeds in freeing itself from all the entropy it cannot help producing while alive."
  • "How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?"
  • "...we must be prepared to find a new type of physical law prevailing in [life]."
• Living organisms have order and structure at both the microscale and the macroscale that they grow and sustain.
• Schrödinger divined that what was needed in the chromosomes was the sort of order in a crystal but without the regularity or "periodicity" of the lattice. The code script must be an "aperiodic crystal", a structure that is precise and, crucially, reproducible, yet not ordered by simple repetition. That's exactly what a text or scrip is like. The aperiodic crystal now seems an astonishing presentiment of the structure of DNA, discovered just 9 years after his book was published.
• But two concepts were missing from Schrödinger's picture:
  • Information - As in the information encoded in DNA.
  • Meaning - Animals feel something - which is to say, their response goes beyond automaton-like reaction. The animal finds some meaning in its environment: there is a relationship between the things it experiences and the goals and drives it possesses, and this is expressed in a mental valence imbued by the experience.
• What we need, but currently lack, is a proper understanding of meaning in biology.
• This is really what makes living things different from other self-organizing nonequilibrium structures: life ascribes values and meanings and has goals. To put it another way, living things are not nonequlibrium structures that happen to resist the disordering pull of entropic decay; they are structures that have evolved capabilities specifically to do so (and which I believe are best regarded as cognitive capabilities). We need to understand how they manage that.
• Does Maxwell's demon pick a hole in the second law? Probably not, but it seem very probable that there exist biological systems of such minute dimensions that the laws of classical thermodynamics are no longer applicable to them.
• The demon is deciding which information is useful for attaining its goal. It only pays attention to the information that is meaningful to that end.
• Maxwell's demon exhibits its agency, overcoming (if only temporarily) the randomizing, disordering tendency of the molecular world because of four characteristics:
  • It has a goal.
  • It collects information meaningful for that goal.
  • It stores it in a memory.
  • It acts on the information to manipulate its environment in a goal-directed manner.
• The modern analysis of Maxwell's demon reveals a striking connection between information theory and thermodynamics: information (and here we really do mean meaningful information, selected for a purpose) and energy are interconvertible. That's to say, by using information, the demon can build up a reservoir of heat (create some order) that can be used to do useful work. More properly, it's not exactly information that serves as a fuel here, but having a place to put it. We can let the demon go on accumulating heat and doing work so long as we keep supplying it with more memory. Only when it runs out of memory must it produce entropy by erasing the information it already has.
• Living organisms can be regarded as entities that attune to (correlate with) their environment by using meaningful information to harvest energy and evade equilibrium. Life can then be considered as a computation that aims to optimize the acquisition, storage, and use of such meaningful information.
• Natural selection has been hugely concerned with minimizing the thermodynamic cost of computation. It will do all it can to reduce the total amount of computation a cell must perform.
• A thermodynamically optimal machine must balance memory against prediction by minimizing the useless information it stores about the past. It must become good at harvesting meaningul information: that which is likely to be useful for future survival.
• Annie Crawford: What makes a creature alive. Its teleological process - a material from animated by the striving of a unique being to become and remain itself. To be an agent:
  • It must be out of equilibrium with its environment - ie thermodynamically distinct from its surroundings. The entity must have a boundary of some kind.
  • It must persist for some meaningful duration of time.
  • It must have an "endogenous activity", meaning it does things "for its own reasons", not just in a stimulus-response manner. ie, agents must have some internal complexity. ie only from the cellular level (proteins are not agents
  • It must show "holistic integration", it be more than the sum of its parts.
  • Most of all, it must have reasons. It must be selective about what it attends to. If it has higher-level reasons, if it has purposes and goals then this may free it from automatic stimulus-response behavior.
  • For agents, history matters. Agents hold a memory of past events that may determine future actions.
• The more complex a mind the evolutionary process makes, the less control it (the evolutionary process) has over the mind's goals and purposes.
• Purpose can exist without minds, but it's not clear how a mind could exist without purpose.
• Agency is arguably the fundamental feature of life: it is the goal-directedness and capacity for action on self and environment that all living things exhibit.
• Adaptation can be framed in broader, thermodynamic terms: by becoming correlated with an unpredictable, fluctuating environment, a well-adapted entity can absorb energy from it more efficiently.
• Darwinian evolution can be regarded as a specific instance of a more general physical principle governing nonequilibrium systems, whereby attunement to the environment via the formation of orderly structure facilitates energy dissipation and entropy generation. Far from evading entropy's demands, then, life might be especially adept at granting them. Life may be highly likely to arise, purely on thermodynamical grounds, in any environment that has the necessary chemical ingredients (whatever they are!- along with concentrated reservoirs of energy.
• There is now abundant reason to believe that life leverages physical principles at all scales for its own benefit. Ultimately, we will need to understand agency - the key to life, but currently still handled as a kind of modern-day vitalism - according to those principles too.

10. Troubleshooting: Rethinking Medicine

• For many conditions, genes and their protein products are simply not the right level of intervention. To treat disease at its root, we have to identify the level in the hierarchy of life where that root is embedded. We have to attune the cure to the problem.
• Diseases that have an inherited and thus a genetic basis tend to be associated with particular alleles of a given gene that only some individuals inherit.
• Genome sequencing has been successful in identifying new linkages between gene vaiants and diseases. Typically these are spotted in genome-wide association studies (GWASs), in which the disease-linked alleles are generally distinguished by a mutation at just a single nucleotide - a change called a single nucleotide polymorphism (SNP).
• But many common diseases that have a genetic component are highly polygenic: there are many genes involved, most of which have complex and nonunique functions. There may be hundreds of "risk alleles for these diseases, each contributing a tiny statistical influence, and they are typically widespread in the population: we'll all carry some of them, without incurring a significantly higher risk than average.
• For autoimmune diseases, 90% of all SNPs identified in GWASs are in noncoding genes.
• Various layers of information involved in making humans:
  • Genome - All the genetic information of an organism or cell.
  • Transcriptome -  Set of all RNA molecules (transcripts) in a cell or a population of cells.
  • Proteome - The entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time
  • Epigenome - The collection of chemical changes to its DNA and histone proteins that affects when, where, and how the DNA is expressed; these changes can be passed down to an organism's offspring via transgenerational epigenetic inheritance.
  • Microbiome - The community of microorganisms that can usually be found living together in any given habitat.
  • Immunome - The set of genes that code for proteins which constitute the immune system, excluding those that are widespread in other cell types, and not involved in the immune response itself. It is further defined as the set of peptides derived from the proteome that interact with the immune system.
  • Physiome - Describes the physiological dynamics of the normal intact organism and is built upon information and structure (genome, proteome, and morphome).
  • Anatome - The internal and external structure of organisms and their parts.
  • Exposome - Used to describe environmental exposures that an individual encounters throughout life, and how these exposures impact biology and health.
• Brains seem to have two different developmental settings - we can plausibly call them male-like and female-like - that are influenced by hormonal levels, and brain development predisposes the individual to feel male or female, and not necessarily in tune with their biological sex.
• Diseases all, to a certain extent, attack or hijack the same vulnerable pathways. In the wake of the COVID-19 pandemic we're redefining how to think about disease. There's cross-connectivity at so many levels that is going to blow open the study of all disease.
• Drug repurposing (testing existing drugs for their impacts on other conditions) is based on this canalization of disease vectors. You often have a better chance to save, cure, and heal not be attacking the supposed disease agent at the molecular level, but by targeting the physiological channel in which the disease manifests.
• The immune system and the inflammatory response it raises are the first line of defense against all manner of pathological and physiological afflections. If we are to seek a more unified and less disease-specific understanding of human health, we would do well to begin here.
• The immune system is, for a certain point of view, more complex than the brain. While the latter is just about synapses connecting to neurons in a very complex web, the immune system has so many different components doing so many things that it is "where intuition goes to die".
• The are two main components:
  • The innate immune system - the oldest in evolutionary terms. Mobilizes swiftly and generates inflammation which triggers the production of small proteins called cytokines that act as a kind of molecular elarm signal, summoning lymphocytes, "killer cells" capable of destroying the threating agents. Other cytokines can act as antivirals, interfering with a virus's replication.
  • The adaptive immune system - Is newer, and slower, but is better able to attune its response to the nature of the threat:
    • B cells produce proteins called antibodies that can identify and stick to antigens.
    • T cells carry a different class of antigen-binding "sticky" proteins on their surface and can learn to recognize and to kill infected cells. The T cells can remember the novel attackers (via T cells called "memory cells") and is ready to attack them again. This is how immunization works
• It is very important that the immune system responds proportionately, because it does a lot of harm, killing off cells it decides are infected or compromised and wreaking a degree of (local) havoc in tissue. Immune system misfiring can lead to a "cytokine storm".
• The immune system is like a brain - it must learn, adapt, innovate, and improvise to attain its goals.
• Instead of waiting for things to happen and then reacting, medicine could use "engineered health" or "closed-loop medicine" to maintain the body's status quo through constant physiological surveillance and guidance, informed by predictive models of the effects of afflictions and interventions. it would be less a matter of curing disease, and more of curating health.
• Cancer is different to other diseases in that it seems ever more like an inevitable consequence of being multicellular:
  • There are more than 70 known oncogenes
  • In general cancers stem from a change in the regulation of the cell cycle, the process by which cells divide and proliferate.
  • Some genes associated with cancer in fact play roles in preventing problems. They are tumor suppressors.
  • Apoptosis is the capacity of cells to spontaneously die in certain circumstances, and is an evolved protection against tumor formation. Apoptosis is in some ways a default state of our cells - they rely on signals from neighboring cells to not die.
  • Genes that tend to e most active in cancer cells are the "oldest" in evolutionary terms
  • Abundant proliferation is, a priori, the best Darwinian strategy for cells and if regulatory systems break down our cells can return to a Hobbesian "state of nature".
  • Cancer is a disease of organization, not of cells. It can be seen as the growth of a new kind of tissue or organ, a sort of deranged recapitulation of normal development.
  • If cancer is at root a matter of cells falling into the "wrong" state - the wrong basin of attraction - perhaps the real goal is to get them back out again.

11. Making and Hacking: Redesigning Life

• Bodies are not fully specified by a blueprint, they emerge as solutions to the rules that govern the production of tissues from cells. Guided by these rules, cells find solutions that work.
• By studying natural organisms, we are just exploring a tiny corner of the option space of all possible beings.
• Various new directions:
  • Synthetic morphology, or the creation of Multi-Cellular Engineered Living Systems (MCELSs).
  • Recombinant DNA technology and CRISPR-Cas9
  • Metabolic engineering
  • Synthetic biology
  • Organoids - Organized, artificial conglomerates of cells
  • Chimeric embryos - Which contain cells from more than one type of organism.

Epilogue

• Life works at all only in relation to its environment.
• In transitioning first from prokaryotic to eukaryotic life, then from unicellularity to multicellurarity, and after that to major innovations such as the origin of vertebrates and eventually mammals, evolution was in one sense ramping up the levels of complexity that it created from much the same basic ingredients. But this conventional view overlooks another crucial change.
  • For it became necessary, to support such complexity, for evolution to shift the locus of causation within the organism to higher organizational levels.
  • That in turn demanded the introduction of new ways of handling information, and new kinds of autonomy. Relying only on genetic hardwiring is inadequate to sustain the operation of robust multicellular systems, and I have argued the best way to think about the alternatives is as modes of cognition.
• To the extent that life becomes more cognitive, it depends less on genes for its actual functioning. You might say that the genes delegate the responsibilities for decisions, maintenance, and behavior to higher-level systems
• Evolution, it seems, doesn't come up with answers so much as generate flexible problem-solving agents that can rise to new challenges and figure things out on their own.
• We humans are probably anomalous. One of the attributes that most distinguishes us from other animals is our construction of complex cultures, which rely critically on systems and technologies for passing on information and learning) and thus causal influence - between generations through means other than genes. But all this is really just another way in which life has evolved to free itself from genes through an upward transition of power and authority. We are perhaps the prime example of how cognition does that: our minds are capable of promoting profoundly counteradaptive behavior, such as committing suicide at an early age or choosing celibacy.
• The anatomy-generating core system is highly conserved in metazoa: it doesn't change much between different species, simply because that would be disastrous. These DNA regions are effectively excluded from the list of targets at which genetic change could generate viable selectable phenotypic variation. They just cannot be tinkered with.