Chapter 8

Second Class

Covered by white, red and blue beads, it resembled a coral snake coiled and twisted on itself. Maria Mendez, sitting close to me, shuddered. We all peered at the screen, spellbound. The keyboard clicked and the protein molecule turned slowly on the unseen spit of a rotisserie.

     "Looks ugly enough to make you sick, doesnít it?" said Dr. Al Kozinski, Professor of Pharmacology. He stood at the side of the computer screen, surveying the class through thick, heavy-framed glasses. He was small but of muscular build, particularly in the shoulders and forearms. "I still canít get used to looking at molecules. This is a single subunit of the hemoglobin molecule. Of course, the little white balls are hydrogen, the blues are nitrogen and the reds are oxygen. Carbons are black, but you canít see them well. Now, you will remember the hydrogens, carbons, nitrogens and oxygens are combined to make amino acids. There are twenty types of amino acid, and they are linked into chains to form proteins."

     Dr. Kozinski related this in a quiet and friendly voice, with a strong Brooklyn accent. He must have been approaching 60, and it was very clear that years of experience had made him master of the situation.

     "Each amino acid has subtle differences in shape which affect how the protein chains fold. How the chains fold is important, because it determines its overall shape and what the protein does. Dr. Alverez, could you change to Ďribbon formatí."

     Two clicks, and the snakeís body changed to spiral twists and loops of green ribbon.

     "Ribbon format is better to see the backbone of the protein. Notice where the ribbon is thicker, itís twisted in an alpha helix. It looks like a spiral staircase and itís stiff. Where the ribbon is thinner, there are flexible loops. But to appreciate the subtle twisting and folding of this molecule, you have to look at its carbon backbone. Of course, to really appreciate protein architecture, you need a master of molecular modelling, like Dr. Alverez. Juan, could you give me the stick representation?"

     Dr. Alverez, a handsome man about my age, typed in some instructions that turned the ribbon into a skeleton of sticks, showing tight spiral staircases and wide loops.

     "In this representation itís easy to see the heme group which contains the iron atom and which binds the oxygen."

     The "heme" looked a little like a trampoline suspended between four mangled New York fire escapes. Then Kozinski showed us what happens when the oxygen binds. A stubby dumbbell representing an oxygen molecule came down from the top of the screen, and sat on the "heme" trampoline. As the dumbbell and trampoline touched, one of the fire escapes twisted subtly. Hopefully, I wouldnít have to understand all this perfectly to solve the murder, because it was getting pretty darn complicated.

     "Wow," said Maria.

     Dr. Kozinski lectured from a personal viewpoint that made us more comfortable while being force-fed with protein structure. He told how, back in the 1950s when he was at Brooklyn Polyscience High School, biochemists broke up red cells, purified the hemoglobin and crystallized it. Back when he was an undergrad at NYU, they were just beginning to solve the structures of simple proteins using a method called x-ray crystallography. A few years later, while a grad student at Columbia, the structure of hemoglobin was published. The computer picture was a playback of this data.

     Smoothly and patiently, he went on to describe how four hemoglobin molecules bind together in so-called allosteric interactions, so that either four oxygens bind simultaneously, or none at all. He told us that this was Natureís way of making every breath count.

     "When the hemoglobin molecules pass through the lung, all of them bind a full load of oxygen. When the hemoglobin molecules pass through oxygen-starved tissue, all of them give up all their oxygens. If allosteric interaction were missing, some of the hemoglobins wouldnít give up their oxygen to the oxygen-starved tissue ó which wouldnít be good."

     We had a lot of questions on this. Kozinski told us that we would first have to learn the mathematics of binding and molecular affinity, which would be taught later by a biochemist.

     "Let me show you what happens to hemoglobin in sickle cell anemia. Watch these four hemoglobin molecules closely, while Juan mutates only one amino acid in the chain."

     Juan clicked the keyboard and at least two of the four molecules moved subtly.

     Dr. Kozinski said, "This small change, when you have it from both your mother and your father, can give you painful and damaging circulatory crises, which will reduce your life expectancy to less than fifty years."

     We were all very impressed.

     "The subtle change in these hemoglobin molecules disturbs their packaging in the red cell. So the cell canít change shape easily when it has to squeeze through the blood capillary. And the cells break easily, and this starts painful blood clotting in the small blood vessels ó all because of one bad link in the chain of amino acids."

     Dr. Kozinski told us how there are thousands of different "receptor" molecules in the body, and how each receptor has a specific molecule, like a "neurotransmitter" or hormone, that binds to it ó just like oxygen binds to hemoglobin ó fitting just like a key fits into a lock ó to unlock cellular functions. He told us how drugs bind to these receptors and change all this.

     "The tighter and more specific the binding, the better the drug. Tetrodotoxin, the puffer fish poison which plugs up the sodium channel, is an example of this. Of course, tetrodotoxin is too effective, so it isnít a good drug."

     Grant Shipley had a gem of a question.

     "Dr. Kozinski, I read about all these biotechnology companies that are making these short pieces of protein . . . uh . . . polypeptides. The article said that they bind tightly to specific receptors. But then I read thereís some reason why most of them canít be used as drugs. But I donít see why they couldnít, if the polypeptide could bind tightly to a specific receptor and change its function. So why canít polypeptides be used as drugs?"

     "They can," Kozinski answered. "The companies are making all sorts of polypeptides ó strings of amino acids linked together. They would look like little strips of ribbon in the pictures I have been showing you. If the drug company finds the right little strips of ribbon, it could have a very powerful drug. But Dr. Johnson probably told you, yesterday, that they canít cross membranes. And, unfortunately, thereís no way of getting these polypeptides into the bloodstream without injecting them. People donít like to inject themselves. And doctors donít want them to do it either. Especially intravenous injections."

     I nodded in agreement. This confirmed the information from Dr. Westley and the Scientific American article.

     "Well, class, Iíve talked enough. You have your reading assignments. Study hard and take care."

     When the students were finished with their informal questions, I followed Dr. Kozinski back to his office and he granted me a get-acquainted interview. Over his desk was a photograph of him as a curly-headed young man in a white lab jacket and standing in a hospital parking lot by a 1956 Chevy, staring into the camera intensely through thick glasses. Today, his light brown hair was so thin that I could see his scalp.

     Kozinskiís lecture identified him as a mensch who was probably incapable of killing anyone. He immediately took me under his wing, offering encouraging advice on how to deal with graduate study. I asked about his research. He told me that he studied "regulatory phosphorylation" ó how one enzyme kicks another into high gear by tagging it with a phosphate.

     As I started to ask a question, Kozinski gave me a pat on the shoulder.

     "Donít feel that you have to learn it all in the first week. You will just get frustrated. And the longer you are around here the more Kafkaesque it is going to seem. Sometimes things get pretty surreal around here, even for me."

     "Do you mean that I made a wrong choice in coming to this department?"

     "No. Things are crazy in every department, everywhere. They are crazy in academic science in general. But I hope you knew what you were getting into when you chose science for a career. There arenít many real jobs out there in academia." He glanced at the door, indicating it was the end of the interview. "Take care," he said, patting me gently on the back as I got up. I checked him off the list.

     I went to lunch with Maria Mendez and Grant Shipley. He had a lot to say about pharmacy school in Georgia and little good to say about drugstore pharmacy. I expressed similar feelings about the M.E. lab. Maria was 23 and had always been studying full time. She lived with her extended family in Kendall, in the "Southwest."

     That afternoon, I was back at work with the list of suspects. Sturtz and Gunnison, who interviewed me before acceptance, were not suspects. They were New Guard and didnít have any murderous pharmacology. Neither did Taylor. The remaining profs were Drs. Fleischman, Ledbetter, Manson, and, of course, Ashton.

     Dr. Donald Fleischman, Professor of Pharmacology seemed least suspect and the easiest to start with. Reference to the brochure identified him as the oldest member of the Department, having received his Ph.D. in 1961 at the University of Wisconsin and coming to Bryan Medical School in 1965.

     It was surprising to find the discoverer of the sodium pump in a tiny lab with a single technician. He was working on a manuscript at a cluttered desk, writing in longhand in large rounded letters on a pad of paper with blue gridlines. As I approached, he turned his large head and looked up over his large, rimless glasses.

     Speaking in a nasal voice, high-pitched but friendly, he asked me about Swarthmore. Then he rambled on about his graduate student days at the University of Wisconsin and the intellectual ferment of yesteryear.

     How had he discovered the sodium pump?

     "Oh, it just all came together one afternoon while I was a post-doctoral, sitting on a canal bank in Amsterdam." He leaned back in his chair and recited a number of present-day textbook facts ó how each enzyme has a specific purpose, how cells are finicky about sodium and potassium, and how ATP functions as the dollar bill of the cell. "So I just put two and two together and guessed that there was an ATP-splitting enzyme that pumps sodium out and potassium into the cell."

     "So your discovery was putting different unexplained facts together."

     "Exactly. Plus a little pinch of teleology. The cell couldnít go around wasting its valuable ATP like this department has been wasting money." Dr. Fleischman hesitated for a second, as if he had said too much.

     "You make your discovery sound so simple."

     "All significant discoveries are simple, once they are made. Just donít be too bothered by lack of precedent."

     He was so engaging when talking about science. I said something about him being illustrious.

     "Illustrious?" His face clouded over. He shifted his short, ovoid body in his chair and ran his hand through his big head of graying brown hair. "Well, Mr. Candidi, quite a few years have passed since my initial discoveries . . . and Miami has plenty of ways to remove oneís luster. And I donít mean tarnish from the salt air." He spoke with a trace of anger and a touch of resignation.

     Not knowing what to say, I stared at the poster of a European castle over his desk.

      "Neuschwanstein," he said. "One of Ludwig the Secondís Castles. Of course, thereís a plastic version of it in Orlando. Plastic replicas seem to be the norm in Florida, even in science. Some people treat science like a hobby, others treat it like a business, and others treat it like a game. For me, science has been a religion."

     Obviously, Cooper had not treated him well. But why was he telling me this? I asked about his present research and he showed me a giant chart on the opposite wall, covered by small penciled-in squares, circles and triangles labelled with terms like "cAMP," "cGMP," "protein kinase," and "protein phosphatase," connected with arrows. Some arrows were thick; others were drawn with thin dotted lines, noted with question marks.

     He waved his hand at the chart. "Iím working out a rigorous and systematic approach to the problem of Ďsecond messenger regulation.í I still have some tricks up my sleeve," he said pugnaciously. "I recently discovered that the body produces its own circulating digitalis-like compounds which regulate the strength of heart beats. But I made the mistake of presenting it at a departmental seminar. By some sort of magic, one of the late Dr. Cooperís friends from another institution managed to come up with the same thing a short time later."

     He noted that I looked older than most students. I told him I was 28 and had worked for six years in the laboratories at the Medical Examinerís Office. He took this without batting an eye, and asked, "Is that outfit still run by Westley?"

     "Yes."

     "Well, I used to know him before he became famous. I read about him in the newspaper every so often. Back in the middle 1960s I helped him with some biochemistry. In those days there was a great spirit of cooperation around here. But many things have changed."

     He told me that Cooper had run the Department like an "East-Block Managed Economy" and that he hoped it would now "revert to a community of scholars." Although it was too late for him to learn the "new molecular genetic approaches" and keep up with the younger scientists who were "marching through biomedical science with Seven League Boots," he assured me he still had a few tricks up his sleeve.

     What a strange interview! Although he had the motive for murder and at least fifty compounds at his disposal, I couldnít imagine him doing it. He didnít seem sufficiently devious.

     I could not check off two suspects because they were unavailable. Both were Old Guard, but a quick check of their publications did not reveal any super poisons. Dr. Howard Manson was "still up in Woods Hole." They said heíd packed his whole laboratory into a van last June, drove up to Woods Hole and worked like a fiend the whole summer. Dr. John Ledbetter had also been out of town for a long time. His Chinese post-doctoral fellow wasnít very communicative about his date of return. Dr. Westley would have to tell me if Manson and Ledbetter were absent on the day Cooper was poisoned.

     So I had checked everyone off and was now ready for my prime suspect, George Ashton, M.D., the guy who worked with neurotoxins ó the guy whose papers Westley had found interesting enough to have Doris order them. The brochure informed me that Dr. Ashton had an M.D. from Harvard Medical School, 1967. He worked on "neurotransmitters" in relation to Parkinsonís and Alzheimerís disease, using neurotoxins as tools. One of his earliest studies showed how a deadly scorpion toxin binds to a neurotransmitter receptor in nerves.

     I had already observed the aristocratic Dr. Ashton in the hallway a number of times. He was tall, with a large-boned muscular frame and dirty-blond hair. He walked around with proud, self-absorbed aloofness, accentuated by his thin-rimmed, thick-lensed glasses and by his hand-tied yellow bow tie, fluffed stylishly under his chin. He reminded me of a movie in which a Providence, Rhode Island, aristocrat put his wife into a coma with an overdose of insulin.

     Ashtonís office was entered through his lab. Outside his door were reproductions of paintings by Monet. Or was it Manet? As I stepped over his threshold, he looked up from his tidy desk, slowly and curiously, offering no greeting.

     "Hello, Dr. Ashton. Iím Ben Candidi, first-year graduate student. We are supposed to talk to . . . that is . . . to have an interview with each faculty member."

     After letting me dangle a while, he said, "Yes. Iím in perfect agreement. In fact, I am the author of that policy. We initiated it back in 1969. So please sit down. Tell me a little about yourself."

     "I graduated from Swarthmore in chemistry six years ago, and I have worked in the clinical laboratory of the Dade County Medical Examiner."

     Did I detect mild surprise?

     "Is . . . Westley still there?" he asked, gazing at the window.

     "Yes, but I hardly ever saw him."

     "I guess heís getting up there in age. About to retire, maybe?" he asked smoothly. He might have seen my application and mentally rehearsed for this interview.

     "There were several layers of bureaucracy between him and me," I answered. "I hardly knew him. Did you know him?"

     "We exchanged notes on snake venoms back in the early days. Miami was a lot smaller place back then. Not many scientists. Everyone knew everyone."

     He delivered this information in a bored, cocktail-party voice. Was this an Ivy League reflex or a calculated move to throw me off his track? Where would he steer the conversation at this point? Ashtonís gaze drifted from the window to me, and he said, "And you, Mr. Candidi. What do you want to do, now that you are getting back on track with science?"

     "I want to do research, either in academia or in industry. Iím not sure what I want to specialize in."

     "Well neuroscience, my field, is quite specialized, but also quite rewarding, and certainly well-funded. If you consider it, we could talk again."

     "Would it be possible for me to have a few selected reprints of your work?"

     "Most certainly. Help yourself to anything in my collection," he said, pointing to an expanse of shelves, just outside the door. "Browse to your heartís content."

     He resumed work at his clean, well-organized desk. What a phony. If Iíd said neuroscience is the science of the future, heíd probably tell me I was the smartest graduate student to come through since 1969.

      The shelves held multiple copies of over ninety-some papers, some dating back to 1965. Yes, he had published as a Junior in medical school. Heíd used cobra toxins to characterize the acetylcholine-activated sodium channel in nerve cell membranes. It was the same sodium channel that the wife-murdering anesthesiologist had targeted with succinylcholine.

     The reprints revealed that Ashton had worked with dozens and dozens of potent toxins. He had toxins that could stop you from breathing, stop your heart, drop your blood pressure, throw you into convulsions or to make you hallucinate. Some were natural toxins and some were man-made.

     My heart raced as I turned his papers over in my hands. Out of the corner of my eye, I noticed that Ashton was observing me. The deeper I dug into his collection, the longer his glances became. At the end of my dig, I looked up and caught his eye. He pretended to be looking up from his work, as if for inspiration. Did I detect curiosity, pride, suspicion or fear? With 10 papers under my arm, I returned to his office, thanked him again for the interview and told him Iíd like to come back.

     "Please do."

     That evening on the Diogenes, I went through Ashtonís poison papers. Yes, he had a lot of ways to poison Cooper. Many of the marine toxins in his early work seemed to be simple molecules that would be effective when taken by mouth. But his later work seemed to concentrate on proteins and peptides that would have to be injected.

     I opened the brochure and revisited my Old Guard/New Guard theory. It checked out. All the full professors had received their Ph.D.s in the 1961-1968 period and were well-established at Bryan before Cooper came. Those older profs must have resented him. Cooper received his Ph.D. in 1971 from the University of Delaware, making him the youngest of the old ones. All the assistant professors received their Ph.D.s in the 1985-1988 period, were obviously hired by Cooper and were undoubtedly beholden to him.

     In an attempt to remain objective, I made a little chart listing the personality characteristics and possible motives and means of each of the suspects. I didnít know much about Manson and Ledbetter, but their publications contained no examples of potent toxins. The more I stared at the chart, the more I became convinced of my initial impression and Westleyís inadvertent hint: It had to be Ashton.

     Now to get the Old Boy to confirm it.



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