Stephen Hawking, brilliant mathematician and physicist has died. Forget all that. He did something for my patients with motor neuron disease that I, as a neurologist, could not do. He gave them hope.
What has chemistry done for them? Quite a bit, but there’s so much left.
Chemistry, when successful, just becomes part of the wallpaper and ignored. All genome sequencing depends on what some chemist did.
For one spectacular example of what, without chemistry, would be impossible is Infantile Spinal Muscular Atrophy (Werdnig Hoffmann disease). For the actual molecular biology behind it — please see — https://luysii.wordpress.com/2016/12/25/tidings-of-great-joy/. Knowing the cause has led to not one but two specific therapies — an antisense oligonucleotide and a virus which infects neurons and actually changes the gene.
So knowing what the cause of a disease is should lead to a treatment, shouldn’t it? Hold that thought. Sometimes one form of motor neuron disease (amyotrophic lateral sclerosis or ALS) can be hereditary. Find out what is being inherited to find how ALS is caused.
Well, the first protein in which a mutation is associated with familial ALS (FALS) was found exactly 25 years ago. It is called superoxide dismutase (SOD1). Over 150 mutations have been found in the protein associated with FALS, and yet despite literally thousands of papers on the subject we don’t know if the mutations cause a loss of function, a gain of function (and if so what that function is), an increased tendency to fold incorrectly, and on and on and on. It’s a fascinating puzzle for the protein chemist and over the years my notes on the papers I’ve read about SOD1 have ballooned to some 25,000 words.
If you’re tired of working on SOD1, try a few of the other proteins in which mutations have been associated with FALS — Alsin, TAF15, Ubiquilin, Optineurin, TBK1 etc. etc. The list is long.
Now it’s biology’s turn. Motor neurons go from the spinal cord (mostly) and brain to produce muscle contraction. Why should only this tiny (but crucial) minority of cells be affected. The nerve fibers leave the spinal cord and travel to muscle in nerves which contain sensory nerve fibers making the same long trip, yet somehow these nerves are spared.
More than that, why should these mutations affect only these neurons, and that often after decades. Also why should great athletes (Lou Gehrig, Ezzard Charles, etc. etc. ) get the disease.
One closing point. Hawking shows why, in any disease median survival (when 50% of those afflicted die) is much a more meaningful statistic than average duration of survival. Although he gave my patients great hope, they all died within a few years even as he mightily extended average survival.
Chemiotics II 