“So you’re going to be experimenting on me, doc?” I heard that a fair amount practicing neurology in Montana. There is no guarantee that any drug we use will always work, particularly drugs for epilepsy (anticonvulsants). When one of them didn’t, it was always obvious.
Being honest with patients, I’d always say we’ll try drug X, it has a high chance of working. And that was the (actually quite intelligent) response I sometimes got.
I’d then launch into some sort of explanation, saying that people aren’t cars and not all the same so they don’t respond the medications the same way (cue up rare side effects). Of course in the 70’s and 80’s we had no idea just how different each of us actually is.
Now we do and this is even true for children in which the copies of their parents genomes is far from exact– https://luysii.wordpress.com/wp-admin/post.php?post=3442&action=edit&classic-editor —
From the ENCODE study. Some 2,976 parent child trios had their whole genomes sequenced. There were 200,435 de novo mutations in the group (an average of 67 mutations/child). The number of de novo mutations increases by 1.39% for each year of paternal age and .38% for each year of maternal age at the time of the birth of the child. Earlier work with far less data implied that maternal age at conception was irrelevant to the mutation rate — this is clearly incorrect.
The same variation in genomes is another pitfall in understanding what effects a protein mutation has when studied in animals. Up to now research has been done in very inbred animal strains which all have exactly the same genome, to cancel out the variability in response. Usually just one inbred strain is studied. This is good.
No it’s bad !! [ Neuron vol. 111 pp. 539 – 556 ’23 ] studied one particular mutation in a protein called CHD8 which is associated with autism in man. They put the mutated protein into 1,000 mice from 33 different strains and measured a variety of phenotypes (brain and body weights, cognition, activity, social behavior, exploratory activity in an open field, etc. etc.).
Guess what? The same mutant in the same protein had a wide variety of phenotypes which depended on the strain and sex. Some strains showed no phenotypic effects at all, while others showed many large effects.
So a lot of animal work on disease should be repeated (or at least taken with several grains of salt) on multiple strains.
So experimental animals are just like people responding to drugs that docs experiment with on them
Chemiotics II 