Organic chemistry under assault — II

The winner is Yggdrasil who guessed Parkinsonism and L-DOPA.  First prize: one week in Hoboken N. J.  Wavefunction also got it right on his second attempt. Second prize: two weeks in Hoboken N. J.  If you’re new to the site, please read the previous post before attacking this one.

Parkinsonism has been known since the early 1800s, but there is no mention of it previously (unlike TB, dropsy etc. etc.) which led to the idea that it was in some way due to toxins produced by industrialization.  This may yet to turn out to be true as the drug which can cause severe Parkinsonism by a few (intravenous) injections was made by rogue chemists, as a newer and cheaper demerol (a narcotic) for the addict market.  It is called MPTP (for 1 methyl 4 phenyl , 1, 2, 3, 6 tetrahydropyridine).  It kills dopamine containing neurons in the part of the brain called black stuff (actually it is called the substantia nigra to confuse the laity).  It had been known that this area of the brain was losing cells (which were pigmented) in Parkinsonism long before dopamine was a gleam in anyone’s eye.  Oleh Hornykiewicz found that dopamine levels were quite low in the brain in this disorder, which led to the use of its precursor,  L-DOPA (L-dihydroxyphenylalanine) as treatment.  If ever there was someone who deserved the medicine Nobel prize and didn’t get it, it is this man.  All this happened before the genetics revolution, so we had an effective therapy before we knew anything about the 6 genes described in the previous post.  I was a resident when L-DOPA was released in this country (September 1970) and was assigned to run the (newly created) L-DOPA clinic.  Prior to that, therapy for Parkinsonism was lousy, and I saw a few people get out of wheelchairs, something that always stays with you — definitely a blockbuster drug.

For a time, we thought we were actually curing the disease, as some people in the early stages appeared completely normal on L-DOPA.  In fact, some patients looked so good for so long that I worried that I’d misdiagnosed them.  However, when they got sick from something else and couldn’t take L-DOPA (which could only be taken by mouth), the Parkinsonism became obvious again.

Now we know better.  You begin life with about half a million dopamine containing cells in the substantia nigra, and you lose some of them as you get older.  You don’t become symptomatic until you’ve lost at least half (some say 80%) of them.    So what ever is causing the loss of these neurons continues to do so even while the patient looks normal.  We have a good symptomatic treatment but nothing approaching a cure.

30 years ago a very smart cardiologist told me that despite the marvels of vascular surgery (carotid endarterectomy, valve replacement, aortic grafts, coronary artery bypass) the underlying disease was marching on, and our drug treatments were just (relatively ineffectively) slowing it down.  Consider President Clinton.  A few years ago he had the narrow segments of his coronary arteries removed and replaced with vein grafts from his legs.  The vein grafts were wide open (as they usually are) and pretty free of atherosclerosis (narrowing), yet the disease marched on in just a few years requiring the placement of stents to keep the grafts open.

Now it’s time to look at the 6 genetic causes of Parkinsonism (there are more) and think how we would use them to figure out a way to keep the dopamine neurons in the substantia nigra from continuing to die (e.g. to stop the disease if not exactly cure it).  The first major problem, is the selectivity of the disease.  Mitochondria are found in just about every cell in the body (except red blood cells), so why do 500K of them out of the 10 billion or so cells in the brain get clobbered.   In addition, not all the dopamine neurons in the brain are affected.  There aren’t a lot of brain areas with dopamine containing neurons, but one of them (the hypothalamic arcuate nucleus) doesn’t show any neuronal loss in the disease.  The case of MPTP tells us that there must something different about the susceptible cells. Also it isn’t obvious to me why mutations in any of them should be fatal to a cell. Good luck.

At least in Parkinsonism we knew where (in the brain) the trouble was.  Consider some more prevalent diseases (schizophrenia, syndrome X, atherosclerosis).  We really don’t know the cell (or cells) of origin.  Genome wide association studies (GWAS) have been remarkably uninformative.  All these disease have, to varying degrees, some hereditary component.  No GWAS has accounted for more than 10% of it.

At this point there are two models for the GWAS results.  Docs are like mathematicians, they classify the unknown by the way it behaves.  Look at any of the Linear Algebra Survival Guides for Quantum Mechanics.  The properties of the basis of a vector space were used to prove things without every specifying a particular set of basis vectors (or even one).  Before Pasteur and bacteria, docs classified infections by their fever pattern, or what they did (cholera produced diarrhea, TB caused wasting or phthisis, etc. etc.).   In this model we don’t know enough about say, schizophrenia, to say it is one disease.  It might be hundreds, just as there are hundreds of different infections.  The genome wide association studies have found some suggestive genes which are involved in a very small number of cases.  So there will be hundreds of causes, with hundreds of different treatments. Not an optimistic scenario for a blockbuster drug.

A more hopeful model is — model #1 is true, BUT it doesn’t matter — there is a final common pathway for all these causes which leads to the disease in question.  Parkinsonism again.  This is more hopeful for drug development, as a final common pathway can be attacked.  In the case of Parkinsonism it is the symptom pathway, rather than the causative pathway.

Similarly, it is clear that dopamine is in some way related to schizophrenia.  Too much L-DOPA can produce psychosis (reversible fortunately).  One of the most fascinating things that L-DOPA can produce is hallucinations — the remarkable thing is that patients recognize them as hallucinations, unlike most psychiatric hallucinations.  On the other hand drugs which block dopamine often produce a Parkinsonian-like state.

So the drug industry hasn’t been able to produce as many blockbuster drugs as it would like, and organic chemists are being laid off in droves.  Why?  Well I think, we  are just beginning to see just how hard the problem really is.  Once the target(s) are found it will take organic chemists to make drugs to hit them (assuming there are any left).

One final point.  For a time molecular biology was incredibly protein centric.  Drug development still is.  Have a look at Nature vol. 463 pp. 616, 621 -626 ’10.  Here you will find that what keeps a mouse embryonic stem cell proliferating and not differentiating, or differentiating and not proliferating is the balance not between two proteins, but between various classes of microRNAs.  It’s more grist for the mill of the organic chemist.

Good luck to you all, I hope the carnage stops soon.

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