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", but now it seems that genes as protein-encoders are maybe only a small part of what is going on with our genome.