Living dangerously

I wrote a couple of years ago about a drug-trial carried out in Northwick Park in England that went horribly wrong.  Researcher felt that they knew how a certain section of the immune and inflammation system worked and thought they had a clever way of nobbling it when it went wrong - in the Northwich Park debacle they were hoping for a cure to rheumatoid arthritis and/or leukemia. That's suspect immediately: it is hard to think of two diseases, not caused by microbes, that are more different in their causes or symptoms. Any therapy that has the possibility of curing them both is likely to lie quite deeply embedded in the body's defence system so it might well be expected to have unexpected effects elsewhere.

These last tuthree years I've been teaching two days on/for the TCD MSc in Immunology.  My angle is comparative immunology - how the immune system varies among organisms because they are subject to different pathogenic assaults.  Humans tend not to get viral diseases that are spread by bird lice.  The research the Masters of Imm I - II carried out was asking the underlying question "Is the mouse Mus musculus a good model for this disease or its cure?".  If the relevant genes are present in both species, in the equivalent part of the genome, and have the same exon structure and similar upstream control regions then we are more confident that the rodent will inform us about how the disease works.  If not, then not-so-much.  The catastrophe in Northwick Park was blown up - like the heads of the unfortunate experimental participants - by the fact that, for this system the mouse is a poor model for what happens in humans. Yes, they'd carried out the expriment safely on a large sample of lab-mice.

Over the last week, we are getting a story, which is being given out by the teaspoon, about a Northwick-like story from Rennes in Brittany.  Science can be trusted not to overstate the Rennes story and give a reasonable take on the scientific background.  The drug being tested seems to be a psychoactive compound based on one or other of the molecules concentrated by Indian hemp Cannabis sativa. Like with Northwick's aspiration to cure both RA and cancer, the Rennes experiment aims at multiple targets incluing 'anxiety' and 'neurodegenerative diseases' - the latter could be anything at all - multiple sclerosis, Alzheimer's, Motor Neurone Disease.Whatever little we know about how the immune system works we know bugger-all about the subtleties of the nervous system.  I'm teaching it currently at The Institute in Human Physiology class.  A key problem with understanding the nervous system is that there a couple of handfuls of known neurotransmitters: dopamine, adrenalin, GABA and acetylcholine, serotonin, and some others. The thing is that each of the neurotransmitters must be double-jobbing and capable of reacting with lots of different receptors in a variety of different cell types.  Many of these are also hormones which act-at-a-distance so if you flood the system with neurotransmitter X it is a racing certainty to have lots of side-effects. The target in Rennes is an endocannibinoid receptor, so named because it reacts to the presence of the active compound in cannabis. We know that, but we have no idea what other compounds it reacts to although we are reasonably confident that the 'natural' stimulus is Anandamide, aka N-arachidonoylethanolamine or AEA. None of this complexity appears in biochemistry text-books - there everything is represented by a set of labelled blobs connected with confident arrows.  These cartoons represent what has been painstakingly won from controlled experiments in an wholly artificial system that can be run in a glass test-tube to generate a response that can be picked up by a laboratory instrument.  Clearly the endocannibinoid receptor has functions that we didn't know about!

It's a wonder that so many drug trials go off without a hitch or at least without killing people. One chap has just died in Rennes and three others are likely to be quality-of-life-impaired indefinitely. Getting paid to hang out in a government approved testing centre must have seemed like easy money . . . until it didn't.