Chapter 13

Zeroing In

"Hodgkin and Huxley discovered nerve action potential right after the war," the Old Boy exclaimed in a cadence that matched the Bach fugue spinning on his ancient turntable. I sensed a mini-lecture coming on. "Brilliant Cambridge chaps! Worked with squid axon. Seems that the fishing boats brought back an abundant supply of squid. You may not know, but Hodgkin and Huxley worked on perfecting radar during the war. Then they used their special knowledge of electronics to analyze the signals from nerve. Of course, they were awarded the Nobel Prize in 1963 for their efforts, along with John Eccles, an Australian who picked up on their singular demonstrations."

     The Old Boy should have tried his hand at television quiz shows ó preferably the slow-paced BBC variety, which allowed long-winded answers. My mention of the protein structure lectures triggered another historical monologue.

     "Yes. Of course, protein structure was a murky business until Perutz ó who put it on a rational basis. Used x-ray crystallography with Germanic persistence to study hemoglobin, but made his contribution in England, of course."

     I told him about Kozinskiís molecular graphics lecture, with oxygen binding to hemoglobin. He told me that Roughton (an Englishman, of course) had studied the reaction on a millisecond time scale using his specially designed rapid-mixing apparatus. To hear him talk, every major discovery was made by an Englishman.

     I shifted the conversation to Wongís seminar, but Westley stopped me when I began to describe the argument.

     "You know, these Chinese are so dreary! And it is so sad when work is misdirected. We must find something more positive."

     He also rejected Rob McGregorís diatribe on Cooper.

     "Well, I suppose that every place has its juicy little items of gossip. This McGregor chap seems to be a good one to carry it on. Good Scottish name. The Scots seem to gossip only two-thirds as much as the Irish ó to the detriment of both, mind you. But the Scots do manage to put in a good dayís work, unlike their Gaelic brethren. And Scottish gossip tends to be more concise, although this McGregor seems to be the exception which proves the rule."

     So, what the hell, Iíd let the Old Boy get it off his chest.

     "Is Scottish gossip easier to forgive than Irish gossip? Why do the Scots gossip?"

     "I have often thought that the Scotsí proclivities for gossip come from a certain sense of justice. They do have a very pronounced sense of justice, they do. Although they havenít quite forgiven us for civilizing them. A century longer in The Empire and we will be able to call them English. Of course, with the Irish there was absolutely no hope. We began the actual process too late."

     I tried to restart the subject of Cooperís crimes, but the Old Man would have none of it.

     "Gossip and idleness are the devilís playground. You will find, Ben, that there are certain things which one learns, but does not communicate. McGregor may be an interesting fellow, but Ďa dog which will bring a bone will also carry one away.í We shouldnít want you carried away, so to speak."

     At this moment, Margaret announced that dinner was served. And they both served me large portions of delightful Anglophile conversation. Afterward, Westley and I took our places on the balcony. I expressed interest in learning more about orally active toxins, and the Old Man proved happy to provide a mini-dissertation.

     "The general principles are quite easy, Ben. If you are a snail or lizard or some other helpless creature without massive teeth and claws to defend yourself, you may want to incorporate into your flesh some sort of toxin which would persuade your larger predators not to eat you. Usually these animals are brightly colored. It would not do, in the general scheme of things, to have the predators die without knowing why."

     "And bright coloring is a way of advertising that they are poisonous?"

     "Quite. All manner of reptiles do it. In fact, I have read of the recent discovery of a poisonous bird . . . in New Guinea. It is called the pitohui, and it has distinctive orange-and-black plumage. Ingestion of only 100 milligrams of itís breast flesh is sufficient to kill a mouse in twenty minutes, the article said. The toxic principle is called homobatrachotoxin. Itís a steroid alkaloid, a nonprotein toxin."

     "What about plant toxins?"

     "Yes, there are more numerous examples and many examples of weak toxins. Of course, half of the molecules made by plants are poisons of one sort or other. Plants, being passive, had to find some way to keep from being eaten out of existence by the animals. So they produce molecules which made the animals sick to serve as a deterrent. The turpentine in pine sap and tetrahydrocanabinol in marijuana are two such examples. Of course, there are spruce hens in Alaska which will eat pine needles, and a starving goat would probably eat hemp. But the point is that these stout little molecules are created by the plants to make the herbivorous animals sick by interfering with one or more bodily function."

     The Old Boy radiated such warmth when delivering these monologues.

     "So thatís why you canít keep yourself alive in the woods by eating leaves," I summarized.

     "Quite true. Youíd make yourself quite sick. Even grass, you really canít eat, even if it were cooked. On the other hand, the cow has an excellent liver which is well-designed to detoxify itself, so she can subsist on a steady diet of these things. Of course they are just low grade toxins. Nothing so horrible that a few mouths-full will kill you. No poisonous molecules which are strong or specific enough to kill the animal. That would not do! It is not in Our Makerís scheme of things to have animals dropping dead all over the landscape. No, the Good Lord has only allowed his creatures to do a little prodding, in the right direction ó unpleasant consequences after fair warning. It is a bit like the border collie nipping at the sheepís heels, getting it to go in the right direction without hurting it."

     His voice softened and his face seemed to glow as he talked about Our Makerís Scheme of Things. He must have found comfort, believing in a benevolent universe after so many years of examining murder victims. Thatís what the human flock needs: A gentle British sheepdog to keep them from going astray.

     "Understandably, these low-grade, orally-active toxins are small molecules. They are not carbohydrates, proteins or fats, which are easily digested. Their chemical bonds are a little more stout. Rugged molecules, so to speak. They arenít digested by the saliva, stomach acid or by the bile juice. And they are sufficiently hydrophobic to cross membranes and transit the gut lining unchanged. So they can get into the bloodstream. Itís the liver that has the job of digesting them."

     He reaffirmed an important working principle: The nonprotein toxins work by mouth.

     Next, the Old Man told me a heartwarming story of the old Cornish doctor who discovered the heart medicine digitalis when he noticed that cows dropped dead after eating an innocent-looking flower called foxglove. He prescribed it for his patients ó as a fine medicinal English tea, of course. "Today, this simple toxin is keeping hundreds of thousands of geriatric souls in their decrepit bodies," he concluded.

     Rejoice! Both the British sheepdog and the English doctor are on our side!

      I told him that digitalis works on the sodium pump discovered by Dr. Fleischman, and he cut me off. "Of course, it would be possible to kill a man by giving him a large dose of digitalis, just like the poor cow. And this is indeed what many doctors unwittingly do to thousands of patients each year. But digitalis is rather old-hat. A death from digitalis overdose would present no great mystery to us. Hospital laboratories have antibody-based radioimmunoassays to monitor digitalis blood levels in their patients."

     I made him confirm that he also had assays for well-known toxins like the puffer fish poison, tetrodotoxin. He agreed that I should deliver a short list of Ashtonís nonprotein toxins. He didnít seem to be interested in protein toxins, which are produced by snakes and other animals that can bite it in.

     "Thank you, Dr. Westley. Iím clear on what I have to do."

     A few minutes later, Westley was shaking my hand warmly and wishing me well with my "endeavours."

     Rowing home, I felt satisfied to give Westley a short list of Ashtonís nonprotein toxins. But I still worried about how to decide which neurotoxins to put on the list ó and which ones to leave out.



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