Epigenetics - leading to a personal crisis about free will (coming soon)

(....tackling the small issues today, hey Lexskigator....)

I'm reading a book on epigenetics. Some reviewers of this book think it's a bit technical for a non-bioscience audience, but I find it absolutely enthralling. It's a summary of the exploding research field, where science is gradually getting a grip on the magnitude of the complexity of interaction between genes, junk DNA regulating gene operation, epigenetic 'tags' regulating gene operation, and a person's physiology, behaviour, habits and life trajectory. And bioscience is starting to realise that if they mess with any of it, the downstream effects are multiple, complex, and not really predictable.... although drug companies don't usually let that do more than slow them down a little bit.


My summary of epigenetics from this book follows - from the very beginning, as fast as I can!

For all earth lifeforms with cells which have nucleii and reproduce sexually:

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• Every nucleus in an organism has the same DNA. The DNA of cells in identical twins is also the same. DNA is a double helix: a dual-chain linear chemical base-4 code, notated in A, C, G and T.  Each letter denotes a chemical in the chain, and they always pair up to the same partners. A (adenine) always connects to T (thyamine). C (cytosine) always connects to G (guanine).
• The bulk of our DNA sequence is contained in the chromosomes, which are twisted-up little squiggles in the nucleus of each cell of our body. Each chromosome is a big long string with two ends. The ends are called 'telomeres' and they have repeating sequences which get shorter as you get older.
• Chromosomes look like this under an electron microscope:
• You can see that chromosomes come in pairs, joined like four sausages twisted at the middle. Most people know that half of your DNA comes from your mum, half from your dad. More specifically, one out of each chromosome pair comes from your mum, and the other one from your dad. This is common to every organism that reproduces sexually, including flowering plants.
• The only exception to chromosomes in identical pairs is the non-identical X and Y chromosome "pair". Your mum has two X chromosomes and she gave you one of them. Your dad has an X and a Y chromosome and he either gave you his X - making you female - or his Y chromosome - making you male. Only one X chromosome functions in any cell at any given time. So this means that in every cell of a female organism, one of the X chromosomes is switched off (it is apparently 'gaffa taped' up in methylation, hangon a sec I'll get there...)
• As cells do their daily work, sections of the DNA chromosomal strands are constantly being unzipped, being copied by mRNA, and zipping up again. One protein unzips the strand. A special little DNA-copier called messenger RNA (mRNA) walks along the strand matching up the base pairs to their partners, and producing the matching half of the strand. Sometimes this is for the production of a new piece of mRNA. Sometimes for the production of proteins. Sometimes this is to exactly replicate the entire chromosome for cell division. Sometimes this is for we-don't-know-exactly-why-yet. 
• There are also tiny fragments of DNA outside the nucleus of each cell, which are called mitochondrial DNA. Unless you are a honeybee or a mussel, you would have got them from your mum.
• DNA are too small to see directly with anything except an electron microscope or a particle accelerator. We can't see them in action at all. X-ray crystallography has been used to image DNA for decades but you have to know what you are looking at to see it. The people who work on the how and why of the zipping and unzipping are extremely clever.
• Within the chromosome, specific sections are identified as genes, meaning that they produce proteins. We know where they are because they are all a similar length, have a known starting sequence (intron), and a known stopping sequence (extron). 

 For humans specifically:

• We are genetically remarkably like a bunch of other species. In the 1990s, we expected to have more genes than, say, mice, because our chromosomes are bigger and have many more base pairs (Human: 3.08x10^9 vs Mouse: 2.64x10^9). But we have just about exactly the same number of genes (20,000), just bigger non-coding sections of DNA in between them.
• There are long sections of chromosome which are called non-coding DNA but they used to be called junk DNA, back when geneticists didn't know what they did. Now, some sections are called regulatory DNA because the mRNA copiers tend to look there before they go make a protein from a gene. The rest is still a puzzle.
• Anthropologists can trace ancestry along the male line using the Y chromosome, and mitochondrial DNA along the female line. Both mutate very slowly. The idea was clever, but the results were fabulous. Here is the genetic tree up to the Roman Empire. I might get to mention other stories later.

Epigenetics is:

1) A chemical explanation of why, if every cell has identical DNA, how does it know to be a skin cell and not a liver cell - ie, why don't we grow liver on our skin?

Methylation is a process which explains how a fertilised egg (a 'totipotent' stem cell) splits into two parts, the 'pluripotent' embryonic mass and the placenta, and then over the pregancy, differentiates into all the various parts of a perfect little baby. In each stage of cell division, the cells become more specific. More genes are 'methylated': a methyl molecular fragment is stuck to the cytosine at the intron of the gene. This prevents that gene ever unzipping and being copied, and in practical terms 'switches it off' for that cell forever, and for all its descendent cells (except sperm and egg cells whose methyl bonds get mostly erased). If you look at any single cell in a mammal body, somewhere between 60% and 90% of the genes on that cell's chromosomes are methylated.... but any particular gene may be active on a different type of cell elsewhere in the body. So only the liver cells maintain active genes to produce bile, blood plasma etc. Skin cells have those genes permanently switched off.

I imagine the chain reaction in a fertilised egg cell to be a microscopic version of this, where triggers cascade to a single outcome and subsequently cannot really be set back up again within that cell. Nifty video, anyway.

Epigenetics is:

2) A chemical explanation of how parts of the body can change the extent to which they do certain kinds of things, over time or under certain environmental conditions - ie. How come my 13YO cousin grew 6cm last year as he hit puberty, or alternatively how did an uncle of mine develop pancreatic cancer at age 89 and not before?

Methylation is more or less permanent-ish. Other epigenetic tags come and go under different environmental circumstances. In particular the book describes in detail how histone bonds allow a partial activation/deactivation of certain genes to change the level of, for example, cortisol in a neglected baby mouse's bloodstream. Histone bonds also are involved in time-dependent activation/deactivation of particular genes, for example in puberty, aging, and developing age-related illnesses such as certain types of inherited cancer. Histone mechanisms are also implicated in obesity. And schitzophrenia, And violence and autism and depression and just about anything our bodies or minds do. Most of the data comes from first animal studies and then human twin studies. The nice thing is that these tendencies are not fixed, they can be "up regulated" or "down regulated" on a sliding scale, cell nucleus by cell nucleus, and rockstar geneticist Dr. Tim Spector said recently on the radio in a hand-wavy way that roughly 60% of most traits have these kinds of genetic/epigenetic origins and 40% is up to you to change.

Methylation and histone bonds are not simple up- and down-regulators either. A histone bond can cause higher expression of a gene. Or it can cause expression of a section of DNA which produces a tiny fragment of mRNA (a micro RNA, or miRNA) which blocks a protein from exiting the cell. Or it can cause expression of a section of DNA which then makes a methyl group attach elsewhere and deactivate something else. 

It's a complex system. Don't lose heart. I'm getting there. Honest. You can see how much the book captivated me.

Identical twin studies also provide a lot of rich data about epigenetics. Identical (monozygotic) twins grow from the same fertilised egg, in the same placenta, and are born and grow in very visually similar ways. But as they age, the differences between their epigenetics (histone and methyl bonds) increase, and their psychological and medical characteristics and their life paths diverge. The book "Identically Different: Why You Can Change Your Genes" is supposed to discuss this in more detail and it is on my reading wishlist.

Epigenetics is:

3) A chemical explanation of a multi-generational, non-genetic source of individual differences - ie. how come we look and act so differently to each other when 99.99% of our DNA is identical? How can I be affected by how my parents and grandparents lived?

In certain regions of the genome, methylation and histone bonds can be modified within a cell responding to the environment, and these changes can not be erased but they can persist for generations. The paper "Persistent epigenetic differences associated with prenatal exposure to famine in humans" links previously studied growth and weight gain habits following a famine with an identified epigenetic marker. In other words, sixty years after being born in the first year after a famine, a particular cohort of people were overweight and had always struggled to lose weight because of a periconception or in-utero methylation of a growth gene IGF2. The subsequent rat experiment of exposing a male rat to a high-sugar diet, which triggered methylation of this gene, showed that the expected BMI gain was actually passed down to 4 generations of descendents, and that the change was less pronounced each time.

So this is the technical background to my recent existential crisis. I will post on the actual existential crisis shortly.