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.