A Crisis on Free WIll Most Recently Triggered by Epigenetics Research

"Some people think that science takes the wonder out of the world."

"Nonsense. [It] absolutely baffles me about how anyone can think that how learning more about something can take the wonder out of it. I mean, you look at the stars and they are [just] pretty points of light in the sky... and once you know about it, once you learn some more about the physics and that just blows your mind!"

- Elise Andrew, founder and maintainer of Facebook page and very nifty blog "I Fucking Love Science", responding to Natasha Mitchell on ABC Radio National a couple of weeks ago.

..."OK I'm here... I read your last post on epigenetics. We made it through all that sciency stuff. Where's your free will crisis? Isn't a deeper scientific understanding clearly more marvellous?"

I am just getting worried that there isn't very much of 'me' in this brain and body. Nor of any other human in theirs. That our 21st century Western cultural conception of self, of freedom of action, and of mastery of our own destiny, is (broadly speaking) totally false. Just about all the time, we are reactive, contextually adaptive, neural systems with only a very tiny capacity for self-control or self-change, and what we perceive as self-change is actually the consequential shifts in habits following a series of standard epigenetically driven life-stage transitions, awakening latent multi-generational adaptations at the key trigger points of time (eg. puberty) or contextual stresses (eg. a tricky work situation or a new best friend). 

Any human being is a complex system. But complex systems can be modelled, if you know the parameters. Here is the history of that modelling of 'self', in super-fast-forward and in diagrams. (These are mine, not ganked, If you're pinching them, have the courtesy to drop me a message & say hi.)

Enlightenment (1650-1709) philosophy provided the following simple and happy framework based around clever well-to-do gentlemen:

In 1921, Sigmund Freud published a revolutionary and highly controversial idea that everyone had a 'subconscious', which made a person do things without their conscious awareness and shaped their perceptions, and that this was worth exploring in conversation. These days it seems obvious but at the time it was very difficult for the medical and philosophical communities to swallow. This might be because Freud instantly halved a person's capability to control their actions (although this had been coming; the law had invented "criminally insane" as a defence some time before....)
Here is a diagram of that revolutionary idea.

Come with me to the year 1985. Through the 'science' of marketing, the modelling of human behaviour was no longer a purely intellectual pursuit - large amounts of money were being made. The models of human behaviour had been divided into sub-populations, mostly for the purpose of predicting and manipulating buying habits. Based on age, gender, socio-economic origins, current profession, income, and geographic location, a good marketing database can predict purchasing habits quite precisely. The spooky thing is that what works very well for aggregated humans also works quite well for each individual in that demographic. Any 6 yr old girl is very likely to covet a set of pink butterfly hair clips. Any reasonably affluent, urban young man is extremely likely to have an interest in car audio. Any mid-50's male is likely to be totally unwilling to change his political stance. Thus, our model of 'self' now includes an age, gender, and socio-economic context component - all embedded deep in Freud's subconscious.

Psychological research in the 20th century included a number of fragments, which, when pieced together in the 1990s, give a picture of how this 'subconscious' might work. Kahneman's "Thinking Fast & Slow" (...have you read it yet? It's a very good book. Just sayin.....) assembles a number of these fragments to provide a construct of two different systems of thinking, 2 different bosses job-sharing the task of being in charge of your decisions. 'System 1' works quickly, automatically, without conscious effort, and uses short-cuts like emotional preference and whatever is stored in your short-term memory to make its decisions. It is very good at answering questions of preference (eg. Do you like apples?). Its counterpart, 'System 2', finds mental effort a bit painful, and works much more slowly, but is better at weighing up alternatives (Do you like apples more or less than you like peaches?) and providing answers to non-intuitive problems (148 x 51 = ?). But System 1 almost always interferes with the result that System 2 gives.
Kahneman and Tversky's 2-system model leads me to draw up a model of 'self' a bit like this:

See how that conscious part, where "I" have conscious control, is shrinking. Every time the model gets richer, the conscious part gets smaller.

And now here is my crisis of self.
The book "The Epigenetics Revolution" describes in some detail the intercellular mechanism that allows trees, mice, bees etc. and certain human bad-behaviour and disease populations to be shaped, and triggered at key times, sometimes for multiple generations, providing extraordinary degrees of flexibility for the organism to adapt to its environment. And the book keeps mentioning how 'tagged' (in long words: multigenerationally persistent epigenetically modified) sections of chromosome are more active in human brain cells, to up-regulate and down-regulate neurotransmitters and hormones, sure, but also possibly to store memory, control synapse growth and activity, and in short, shape the structure that holds our 'self'. But that's only speculation because we don't know yet. Genes and proteins are very very small, and it's unethical to set up experiments on live human brains (which wasn't a problem for those the enlightenment-era gentlemen, by the way!)

So, my epigenome drives how my experiences alter the structure and function of my brain (and body), and the brain holds 'me', and the structure keeps adapting itself at the neurochemical level to all the immediate situations and changes in life, refining how I react moment-by-moment. All of my actions are reactions by my epigenome and my physical soma to my life up until then. I cannot control anything in the moment. The consciousness is an observer, running a commentary on the things the mammal body and brain does. In the moment, nothing is a choice.

A little pathetically, this is the model that I am left with.

So here I am, a human, with a genome almost identical to every other human, plus a bunch of unique epigenetic marks. What is 'me', as opposed to my genetic, epigenetic, demographic, and somatic reactions to my environment? How much control do I really have over what I choose? How much of my life is destined by my epigenome - how long I live? My faith in a higher power? My physical abilities? The way I look? My intelligence? The way I will adapt to situations in my future, of which I have no idea yet?

• Based on honeybee studies, the book thinks that memory is a function of DNA methylation.
• Based on rat studies and backed up by psychological evidence, the quality of my relationships is linked to my emotional self-regulation and my ability to love. These are built on histone bonds in my hippocampus, which were mostly set when I was being held and cuddled and carried around by the people who loved me when I was an infant, and in early childhood, while my brain was growing neurons and laying down synapses in the hippocampus, amygdala, and related deep brain structures. Emotional intelligence is a combination of the epigenome and childhood circumstances.
• Based on the outcomes of the "Terman" longevity study, as a vaccinated and urban 21st century woman, my life expectancy up to age 40 is more or less determined by my 'conscientiousness', ie my natural temperament and tendency to look after myself (and temperament is loosely linked to epigenetically-set neurochemical base levels, from environmental conditions during my mum's pregnancy with me). A component of my life expectancy includes my predisposition to early-onset disease, both genetic and epigenetic, eg. diabetes, asthma, breast cancer, schitzophrenia, alcoholism.
• Based on the same longevity studies, my life expectancy past 40 is more or less determined by the quality of my physical and mental lifestyle up to age 40. These are somatic variations, or the way the human organism in question bounces off their environment and circumstances. If I smoke, drink, party hard, take performance-enhancing drugs or get psychologically traumatised, I could change my late life trajectory, in particular my predisposition to disease, and my socioeconomic status. But my highly conscientious temperament makes such somatic variations unlikely.
• Various meditation frameworks including Tibetan Buddhism and Alcoholics Anonymous provide a suggeston on how to have some power over self. The first step is almost always to acknowledge that a person is powerless over their destructive actions. Then by submitting to faith in a higher power and by engaging in deliberate, difficult, persistent reflection, you can retrain your old habits, incrementally, painfully, day by day.

While I gaze in wonder at our species (and all mammal species) and consider our capacity to adapt to environments and situations, the science of self has indeed blown my mind. It has also, inadvertantly, blown 'me' into a very insignificant and powerless little spot on the periphery of what I used to think of as my mind. I feel very very small.

I might stop reading neuroscience and go study some theology for a bit.

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:

• 
  
• 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.

Prefixes and Standard Non-Scientific Measurements - What fun!

coco
seca
kilo
milli
mega
micro
giga
forever ever more
nano
tera
pico
femto
exa
peta

When I was a young Physics student, I was convinced that the SI system of measurement was a critically important component in the collective understanding of the universe. Combined with the standard prefixes used by the Presets in the lyrics above, just about anything could be described in SI, and scientists and laypeople everywhere could comprehend size, mass, energy, and just about every possible dimension in the universe.

Hah. 

Apparently there are different units of measurement which are more practical for ordinary people, according to science, journalism and communications, and popular culture. Sometimes they are silly. Sometimes they are intuitive. Sometimes they are critical to ongoing scientific progress.
I figured this contradiction was worth a post.

Silly: The large African herbivore as a measure of mass or dimension

This is strange to me for two reasons. 

Firstly, animals do not have standard weights. A tram weighs as much as 30 rhinos? How about that! Hangon, which gender? Which species?

Rhinos range in mass from the smallest, the Sumatran, averaging 800kg, to the largest, the Greater One-Horned Rhino averaging 1900kg. The males of both species are typically 130% the weight of the females. 

The second problem is lack of familiarity with large mammals.

Rhinos are endangered. I do not live in a rhino habitat. I have seen no more than a dozen rhinos in my life, in various zoos. In a 500km radius of my house, there are only about 6 rhinos, all at the Werribee Open Range Zoo. 

On the other hand, there are 6 trains an hour on my local tram route, outside peak times. 12 trams during peak times.

(Trams do not have standard weights either. The chock-full peak hour tram is clearly going to be heavier than the 11AM tram with only the two feral kids wagging school and the smelly hobo lady with the trolley who is talking to herself.)

So how is it that a poster which compares a completely unfamilar, and highly variable, large mammal with a very familar form of transport can in fact help people better understand how a tram stops?

Also in common use are:

"... as tall as [n] giraffes"

"... [n times] as fast as a cheetah"

And not so commonly used, but I do find it quite upsetting when I hear this standard non-scientific measurement of money:
"... [a/b proportion] of the [black market size/per kilo cost] of [rhino horn/elephant tusk/tiger spleen/other endangered African or Asian mammal body part]

The animal thing just doesn't work for me.

Intuitive: The local football stadium as a measure of population

Our iconic local football stadium is the MCG, with a capacity of 100,000. So when a million people are rendered homeless by a natural disaster, or infected with a nasty disease, the 6PM news presenter invariably says "... the equivalent to ten full MCGs...". 

 

When we lived in Toulouse, France, the local stadium only had a capacity of 35,000. So all the news disaster estimates were out by a factor of 3.

Then living in Newcastle, New South Wales, the Hunter stadium can only hold 27,000 people. We had to recalibrate again. 

Neurologically, this makes more sense than the rhino thing.

Human brains are not built to deal with large population numbers.

According to a British anthropologist called Robin Dunbar, human cognitive capacity can only conceptualise and cooperate with about 150 other human beings. To think about more people than this is hard. And to feel sympathetic emotions about anything over 150 people is harder than empathising with one individual's story. In fact, a detailed personal account is always much more compelling to other people than any numerical population statistic. So in order for the news to be watched, it must evoke concern and sympathy for lots of strangers, and this requires use of specific emotive analogies. For most urban or suburban humans, a full stadium is about the largest mass of other humans they are likely to see, and the nice thing about a home crowd is that everyone is screaming in support of the home team at full volume, they are all bonded by a powerful common emotion: CARN THE KNIGHTS! (or whoever).

Thus the way to convey human feeling and meaning following a natural disaster is to remind TV viewers of the largest group of people they have ever had a powerful sympathetic feeling in common with, and then multiply that population by a small integer, less than 20. And then get a presenter to follow it up with an on-the-ground personal account of some kind.

Silly: The "If we laid all the [objects of a type] in the world [end to end/side by side/one on top of the other] it would reach [around the world/to the moon/to the sun] n times" ie distance as an analogy for quantity

In my view this is mental sloppiness. I have what I begin to understand as uncommon familarity with large numbers of objects. In Grade 5, I folded six hundred paper cranes - it took me another 2 years to get to the 1000. I have counted 15,050 white stripes on the road during an overnight bus trip from Chicago to Houston. I have helped in stocktakes by emptying and counting packets of 500 capacitors for numerous consecutive days. Ten thousand components fill a medium bin. I can think and convert between massive scales with reasonable fluency.

I begin to understand that this is not a universal talent. Terry Pratchett has a joke about dwarf counting, which applies to all of us at some breakpoint. It goes like this:
One

Two 

Three

Many

Many-one

Many-two

Many-three

Lots.

My 2 yr old bugs out at 20 objects - which is pretty good for a 2 yr old. That's when she hits "lots".

A friend of mine gets bored after a million. She's a good woman, not numbers-minded, and she reads the glossy magazines and says'wow' about very rich people. But after a million she loses track. A million is "lots".

As for me, I automatically convert money into what they could do: 1 million is of the same order of magnitude as your basic civil works project: building a big roundabout normally costs about 3 million. Ten million is the annual turnover of a company of about 15 people. A hundred million will almost buy you half a desalination plant. A billion is a modest defense budget. Ten billion dollars is a year's space program.

I bug out not very far past that.

Where a large number of dollars (or occasionally objects) is involved, and the science journalist is concerned that the raw number loses impact, how exactly does it help to calculate the linear length of all the crayons/blood vessels/bottles/dollar bills in your question, and then convert them to earth circumferences? Is it as simple as taking a more-or-less-incomprehensible large number and converting it to a smallish integer multiple of a marginally-comprehensible large distance? OK every person has something in common, we all live on the same planet with an equatorial circumference of about 40,000km (24,000 miles), but my brain has no real concept of how far that really is. If I piloted an aircraft or sailed a boat across, say, the Pacific Ocean, it might have a little more tangible meaning.

In India, where the gap between rich and poor has been mind-bendingly large for a very long time, there are handy words for dealing with large amounts of money.
A lakh is 100,000 rupees.
A lac is a million rupees (although a proportion of people explaining it on the web get this wrong - indicating that this is the "lots" point for many people)
A crore is 10 million rupees.

And these can be multiplied. A lakh lakh is 10^10. A lakh crore is 10^12, which I call a trillion, but this is not a consistent global definition.

And a crore crore is "lots".

So I ask all those science journalists again:

How, exactly, does it help your readers understand large numbers to mentally stack up US$1 bills and measure the height of an unfeasible tower? Can't we just get the community accustomed to the perfectly adequate larger-number definitions of lakh, lac and crore?

Critical for scientific progress: The selective use of a prefixed SI unit as a framing mechanism

Scientists struggle like anyone else when trying to conceptualise numbers in context. Throughout the history of science, as a new unit was invented it was often disconnected from other units - and after some experimentation and often a heated academic argument, some retrospective conversion factor brought it into line with the other units. Often these are named after the grand old gentleman who "discovered" them (the link goes back to a previous rant of mine). In time, a proportion of these personalised measurement units were found to be redundant, while others have been accepted for ongoing use with SI.

In science, the unit selected always has a framing function. The progress of scientific research is highly dependent on funding from public grants and private patronage, to whom scientists must pitch. Raw numbers with a (x 10^ something) don't immediately give general scientists a meaningful reference point on the field-specific small-to-big scale - and when nuclear physics grants are being evaluated by marine biologists and industrial chemists on the grants committee, lack of an appropriate unit can be the death of a whole field of research. Massively successful science programs always always always use snappy and exciting units of measurement.

For example, back in the 18th century, a new unit was invented to pitch the steam engine: "So that an engine which will raise as much water as two horses, working together at one time in such a work, can do, and for which there must be constantly kept ten or twelve horses for doing the same. Then I say, such an engine may be made large enough to do the work required in employing eight, ten, fifteen, or twenty horses to be constantly maintained and kept for doing such a work…"

The framing function of the choice of unit was a large component of the marketing success of steam power.
Unsurprisingly, there was much quibbling over the breed and gender of the horses in question. Retrospectively, the SI value of one horsepower finally stabilised at 746 watts.
But for electrical motors and internal combustion engines, power is still always measured in horses.
I am, for reasons I won't go into yet (hi Geoff!), watching the Ninja Mega Kitchen System telemarketing ad. They are advertising the power of the blender as two horses. Not 1400 watts. Who counts up to 1400? Only geeky engineers who actually make electric motors. Anyone who has to sell one measures it in horses.

 

Here's another example. The Large Hadron Collider team chooses to measure particle energies in 7 tera electron volts rather than 1.12 microjoules. Same energy value, but 'tera' sounds big and 'micro' sounds small. And for a particle, one electron volt is a normal number. 7 tera is indeed a lot.

I unequivocally support the selective use of standard non-scientific units to market scientific research. I would like undergraduate science and engineering students to be taught this in a marketing subject. I also look forward to the retrospectively standardised rhino-stop replacing the kilogram meter per second to measure the linear momentum of a tram.

But Geoff, I am still not buying the Ninja Kitchen System.