Pharmacology is Murder, by Dirk Wyle, Chapter 14, Free HTML download
Neurotoxins Galore

Margo was all smiles. "Today Dr. Ashton will assign you a project."

      "Thanks for finally telling Dr. Ashton that Iím a reliable pair of hands," I replied half-seriously.

     "Oh, theyíre reliable. And you just keep them to yourself!"

     I blew her a raspberry. We both liked to joke around.

     Margo knocked on Ashtonís permanently closed door, went in and told him something in sotto voce. Then Dr. Ashton beckoned aristocratically and received me. I would study a "muscarinic" receptor for the neurotransmitter acetylcholine from the brain. It binds the hallucinogen muscarine. It is a cousin of the "nicotinic" receptor which binds nicotine.

     My job would be to study the muscarine receptor #5, the "M-5" receptor, from mouse brain. Ashton gave me a scientific paper showing a complicated twisted ribbon picture of how the M-5 receptor was supposed to nestle in the membrane. Margo gave me a sample of a decapeptide, a short piece of protein consisting of ten amino acids in a specific sequence. Against the diagram of the M-5 receptor, my decapeptide would look like a short snip of ribbon. It was supposed to bind in a crevice of the M-5 receptor, fitting like a key in a lock, and activating the receptor.

     Ashton said that my decapeptide was a candidate anti-Parkinson drug. I didnít believe him but kept my opinion to myself. It canít be taken orally because it canít cross the intestinal lining. And it wouldnít be practical to inject the patient every day.

     Dr. Ashton wanted data on how tight my decapeptide bound to the M-5 receptor. After spending a few crisp and efficient minutes with me, he sent me to Margo to "get set up in the assay." It would be some variation on the Bind íní Grind. It was okay that he didnít pay more attention to me. That way I wouldnít feel so bad about turning him in to Westley.

     Half an hour later, Margo was free. She gave me a radiolabelled ligand for the M-5 receptor and some general instructions to get me started. Another half an hour later, I was standing in front of an array of test tubes and manifolded filter-holders that looked like a miniature organ, merrily adding the radio-ligand to homogenized mouse brains.

     I tried to get excited about reactions in the first row of test tubes, thinking about how the radio-ligand molecules were swimming around in the brain soup, in and about the membrane fragments, until they found an M-5 receptor, binding tightly and staying bound for a long time.

     The reactions in the other rows of test tubes were competitions between the decapeptide and the radio-ligand for binding to the M-5 receptor. It was like the competition between two guys for one girl. If the decapeptide bound, then the radio-ligand couldnít. In fact, that was how I measured binding of the decapeptide, which didnít have its own radioactivity.

     But the Grind íní Bind wasnít very exciting. It left me plenty of time to worry about the large wall chart from Eta Biochemical Company. It listed hundreds of lethal neurotoxins:

     omega-agatoxin IVA from Agelenopsis aperta venom, calcisptine toxin, conotoxin, TaiCatoxin, dendrotoxin, apamin toxin, charybdotoxin, iberiotoxin, leiurotoxin, brevetoxin, imperatoxin, imperialine, argiotoxin, bicuculline, fasciculine, ammodytoxin, totexin, liquorine, heliotrine, cardiotoxin, tetrodotoxin, saxitoxin, separateline ó just to name a few.

     They had toxins from snakes, spiders, lizards, fish, snails, frogs, toads, sponges and microorganisms. Half of them were non-protein, and many of them actually worked on the acetylcholine receptor. So the aristocratic George Ashton, M.D. didnít have to stray out of his own field to find the perfect poison.

     During the next two weeks, I spent every spare moment in Ashtonís lab. During dead time, when the scintillation counter was backed up, I kept my eyes and ears open for clues.

     The simple principles of experiments were delightfully similar to Ashtonís poisoning of Cooper. My decapeptide toxin bound to the M-5 receptor in a cell membrane fragment; Ashtonís unknown toxin bound to receptors in a living man. The binding of my decapeptide to its receptor was extremely tight; Ashtonís poison had to bind tight. The decapeptide/M-5 receptor complex had a so-called "dissociation constant" of 10**(-10) molar. The lower the dissociation constant the tighter the binding. Using Avogadroís Number, a 10**(-10) molar blood concentration and the weight of a grown man, I calculated that 14 milligrams of this peptide could kill a man. Fourteen milligrams is the weight of 30 grains of sugar. It takes a big puncture to put that much material under the skin. So here was another reason to forget about protein and polypeptide toxins.

     Now, many orally active toxins could bind just as tight. And 14 milligrams would be easy to slip into Cooperís food. And it could have easily escaped detection by my HPLC machine back at the M.E.ís lab. The problem was beginning to get interesting.

     The next day, long-absent Dr. Manson generated his own fanfare when he drove his van to the loading dock, returning from Woods Hole. It was impossible to miss him. He and his technician spent most of the morning unloading and hauling his gear to his lab.

     Manson was a sight to see, with a baseball cap advertising "Caterpillar Power," a curly red beard and shoulder-length hair. He wore a heavy, oversized, plaid lumberjack shirt and naturally faded jeans. Completing the picture were thick, loose-fitting white socks and Japanese sandals. The thong indented the sock between the big toe and adjoining toe, but there was plenty of slack to go around. Manson slipped all over the place while pushing the wheel-mounted electronics rack, in a whimsically distracted manner, as if he didnít care if the task would take 10 minutes or 10 hours.

     His technician, a bookish-looking woman in her late twenties, did most of the work. Manson stopped at the elevator and got into a conversation with a Chinese graduate student ó speaking fairly fluent Chinese! He was a colorful, unforgettable character. I scratched his name off the list of suspects.

     Post-seminar lunch with Rob McGregor had become a regular thing. After Dr. Sturtzí seminar, I learned that Dr. Cooper had tampered with the recruiting process to hire Sturz. For five years Sturtz had worked exclusively on molecular genetic experiments for Cooper, who paid him with Departmental "hard money."

     The molecular geneticists had become the fair-haired boys of biomedical science because they could manipulate genes. They had indirect methods for finding a specific gene, isolating the gene, reproducing it in bacteria and mutating it at the exact point where they wanted. It was like being able to search a whole library for a certain quote ó then being able to change the quote and put the book back on the shelf. You could learn a lot with the technique, but you could also create a lot of nonsense with it.

     But there were still greater wonders: Like putting the mutated gene back into the right spot in a fertilized mouse egg, producing a daughter mouse with cystic fibrosis or orange fur.

     But the most wondrous story was told by Dr. Mary Pennington.



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