"The space between the young readers eyeballs and the printed page is a holy place and officialdom should trample all over it at their peril."
Sir Pterry's - and I'll explain that nickname in a moment - first novel was The Carpet People, published in 1971, when he was 23. The first of his novels that I read was Only You Can Save Mankind, when I was ten-years-old, in 1999. A year or two later I read the first Discworld novel, The Colour of Magic, and Jingo, the latter purely because it was the only other one I could get my hands on. Then, Wyrd Sisters. Then, finally, The Light Fantastic. At some point after that I watched the channel 4 adaptations of Wyrd Sisters and Soul Music, and read all of the other Discworld novels, apart from The Shepherd's Crown. I still haven't read that one.
It would be impossible to list all the things I learned from his books. That all evil starts with treating people as things, that's one. That we should always pay attention to what things are, not what we think they should be or want them to be. To be just.
He introduced me to Esmerelda Weatherwax, a woman cast out of iron, who always did what was good and right, no matter how much it hurt. He introduced me to Samuel Vimes, a man who constantly fought for justice against the darkness inside, because he understood just how terrible he could become if he didn't keep a tight grip on 'the beast'.
He introduced me to Vorbis, an Omnian priest who created the Discworld version of the Spanish inquisition. A "murderer and creator of murderers". Sir Pterry pointed out that "There are hardly any excesses of the most crazed psychopath that cannot easily be duplicated by a normal kindly family man who just comes in to work every day and has a job to do."
And he introduced me to Brutha, a christ-figure who, after death, when faced with a Vorbis who was too terrified to face judgement, took his hand.
He taught me that we are rising apes, not fallen angels. We have to work to be our best and to be better; it isn't ours by right. We defeat evil not by being worse but by being better.
He taught me that people need symbols and stories, but that the truth is better.
"Now we've got a truth to die for!"
"No. Men should die for lies. But the truth is too precious to die for."
He introduced me to Daphne, a girl who thought “Who'd want a pony when you could have the whole universe? It was far more interesting and you didn't have to muck it out once a week.”
Hi books explored the value of truth and the scientific method, and how it can apply to every day life. More practically, his books introduced me to some interesting things about genetics, and they are a strong reason for being here today. That man gave me life, in the sense of being in this trouser-leg-of-time instead of that one.
He embraced new technology, and was active on message boards, engaging with fans. His nickname, Pterry, came from the 7th Discworld novel, Pyramids, which took place in Djelbeybi, where people have an accent that causes them to pronounce 'T' as 'Pt'.
How Alzheimer's Works
"An education was a bit like a communicable sexual disease. It made you unsuitable for a lot of jobs and then you had the urge to pass it on."
Alzheimer's is something many of us are familiar with. It's a form of dementia, with progressive loss of memory and cognitive functions. Approximately 50% of people over the age of 85 are affected.
Alzheimer's is the result of 'plaques' on the brain - clumps of protein which build up and interfere with cognitive processes. We know they are the cause and not a symptom because we can take these plaques from a mouse with Alzheimer's (yes, mice can have a form Alzheimer's), put them into a healthy mouse, and thereby induce the disease.
Incidentally, hedgehogs can develop a form of multiple sclerosis; it's called Wobbly Hedgehog syndrome. Really.
So where do these plaques come from?
We need to go back a little bit to explain that. Here's a diagram I made.
Please note that this is an incredibly simplified, not-to-scale diagram!
The nucleus is where all your DNA lives. The DNA is transcribed - literally, copied - into mRNA, which exits the nucleus. Little things called ribosomes then use this mRNA transcript to make proteins. Some of these are made while the ribosomes are just floating about in the cytosol - the gel stuff that the cell is filled with. These are called cytosolic proteins - simple, right?
Other proteins are made at the endoplasmic reticulum (ER). For now, picture the ribosomes like a pair of knitting needles making a scarf.
Sometimes, when the scarf starts to appear it says "To the ER!" at the bottom (note: sorting signals don't literally say that!). So, the ribosome, helped by a few other proteins, takes the whole operation over the ER. It posts the protein through the ER as it's being made, and from there, the protein is processed and delivered to wherever it needs to be to do its job.
The specific protein we're concerned with is the amyloid precursor protein, or APP. This is a "single spanning membrane-protein", which means it ends up sticking half-in and half-out of the cell, like in the picture above. Some proteins are multi-membrane spanning, so they go in and out like stitches, while others don't span the cell membrane at all!
While APP is at the plasma membrane, two enzymes come along, enzymes being a special type of protein which catalyse reactions. To put it more simply, enzymes help other proteins to do stuff faster.
The first enzyme is alpha-secretase, which snips a bit off the APP. Then gamma-secretase comes along and snips a second bit off. This leaves a short P3 peptide, which isn't harmful, though we don't really know what it's actually for at this point.
Problems occur when alpha-secretase and gamma-secretase are late. If APP hangs about for too long it is put into an 'endosome' - like a little recycling bubble for the cell. Proteins and other molecules are put into endosomes when they need to be destroyed.
If APP ends up in an endosome, it is first snipped by beta-secretase, and then snipped by gamma-secretase. This leaves a slightly longer protein called beta-amyloid, and it is this protein which builds up into plaques. The longer the protein is, the worse it is. We don't know why this happens.
It is suspected that these bits of beta-amyloid can prevent cell-to-cell signalling amongst your neurons - in other words, they can prevent bits of your brain from talking to each other, which we suspect results in those cells being recognised as damaged and destroyed by an immune response.
Tau proteins are also a factor. Cells have transport systems, like little railroad tracks, made of proteins. Tau proteins function kind of like ribbing in corsets; they hold these tracks straight. In brains with alzheimer's, these Tau proteins and therefore the tracks are all tangled up and non-functional.
When we talk of Alzheimer's having a genetic component, we mean that your DNA makes some of these proteins in such a way that these things are more likely to happen.
Knowing all this gives us some ways to treat Alzheimer's. We can give drugs which inhibit gamma or beta-secretase, and we can use monoclonal antibodies to split the plaques apart. We can also look into ways of turning 'off' the APP gene.
What's a Smoking Gnu?
By the 33rd Discworld book, Going Postal, the Clacks have really taken off. They're a form of semaphore towers which play a similar role to that of the early internet in our world, allowing for a great deal of satire (basically what the Discworld books are built on). The smoking GNU is a plotpoint I won't spoil, but a GNU is a code added to messages.
There's a tradition amongst Clacks operators. When someone dies on the towers, they put his or her name in a message with a GNU signal at the end; the GNU code tells the operator at the end of the line to send the message back up. When it gets to the other end, it goes back down. And so on. Forever.
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