Hot Team: Modern Science Lab Has An Old World Accent

The University of Chicago laboratories of the prolific Richard J. Miller, a 41-year-old British neuropharmacology professor, is a study in cultural contrasts. Animated discussions of neurotransmitters are punctuated with dry British humor; and while classical music permeates Miller's office, rock 'n' roll is king in the labs, where he has attracted many scientists from his native country. In Miller's labs, which are part of the department of pharmacology and physiological sciences, playful, barbed comments are common among British postdoctoral fellows Simon Gibbons and David Bleakman and graduate student Paul Chard. "People who don't know us think we're insulting each other," explains Gibbons. "It's really just the English sense of humor." They really do get along, they say. "There's a group of people who work out together in the gym, and four of us play squash regularly," says Gibbons, "not to mention going out for beers." "If there's one constant, it's going out for beer," agrees Chard. Like the city of Chicago, Miller's neuroscience team is big and his laboratories expansive. With 10 postdoctoral fellows and graduate students, a technician, and a secretary, the group is spread throughout a half-dozen laboratories and offices within the department. "The size of our lab is just right, so that we don't crash into each other," postdoc Steve Glaum says. Says postdoc Ken Scholz, "Although I prefer smaller labs, here I have my own space, which is like my own little empire." "It's a refreshing change from working at a small lab in England," says Gibbons. "There's a lot of expertise at this university, so there's always somebody close by if you have a problem." Bleakman sees the facilities as part of a general contrast between American science and British research, saying, "It's run far more like a business here. The sort of equipment we have here--you'd be hard-pressed to find it in England; it's not there in the same abundance." How does Miller manage his diverse group? "Every person in the lab has a different personality," he says. "Some don't want to be bothered, and some need motivation every day, but every person has something to offer. My job is to find the thing that a person does best and bring it out in them. "I like to feel that I've influenced [graduate students] in a positive way." "To that end, Miller frequently gives out tickets to the Chicago Symphony and encourages his brand of cultural enrichment in his students and researchers. "Science education in this country is a very mixed bag," he says. "While America turns out a lot of top scientists, they don't seem to be very literate or articulate on the whole." Miller laments that traditional academic values have weakened. "Science has become production-like," he argues. "There is no room for scholarship. All the journals care about these days is saving space." Miller stresses, "My job here is to teach students; my hobby is to do research." Some hobby. Miller and his team have experienced consistent success. With four "hot" papers--articles published within the past three years that have a high citation record, according to the Philadelphia- based Institute for Scientific Information's Science Citation Index--to its credit, his group stands out in the field of neuropharmacology. The research focus in Miller's lab is summed up in one word by Canadian postdoc Sylvain Foucart: "Calcium." The team studies how calcium in numerous biochemical pathways in a nerve cell helps regulate the cell's performance. Calcium action in a nerve cell, according to Miller, is analogous to a knock on the door. "We're a cell," he explains, "and we're sitting in this room, and we're not conscious of any message coming in from the outside because of the noise level. If somebody comes along and knocks on the door, and they knock too softly, we won't hear them; but if they knock loudly enough, we'll hear them. In other words, the sound has to be loud enough for us to hear over the baseline sound in this room. "So it is with calcium in a nerve cell. The basal calcium is very low, and calcium has to rise significantly above these levels in order for the effector mechanisms inside the nerve cell to sense it--to release transmitters or for the genome to sense it or whatever is to be done." One of Miller's ground-breaking hot papers (Molecular Pharmacology, 33:581-4, 1988) describes the interaction of the neurotransmitter glutamate with the N-methyl-D-aspartate receptor on the surface of a nerve cell, and how that binding affects calcium influx in the cell. His work provided the basis for a model of drug interaction at that receptor. "A lot of calcium flows in," says Miller. So much so that a long-term electrical potential is observed. He hypothesizes that having so much calcium in the cell for a long time may be a factor in memory. "Glutamate is the brain's most important neurotransmitter," he says. Another pair of hot papers (Proceedings of the National Academy of Sciences, 85:3633-7, 1988 and Neuron, 2:1185-93, 1989) reveals the intricate molecular mechanisms by which two neuropeptides inhibit calcium influx and how that inhibitory ability can be stopped. A fourth hot paper (Journal of Biological Chemistry, 265(14):8243-51, 1990) describes the use of recombinant DNA techniques to purify and study the so-called G-proteins. After a neurotransmitter binds to its receptor, G- proteins often act to open calcium channels. Some of the group's latest projects examine excitotoxicity, the result of the entrance of too much calcium into a nerve cell. Owing to the excess calcium influx, the nerve cell dies; this happens in a stroke or an epileptic seizure. Third-year M.D./Ph.D. candidate Charles Marcuccilli is trying to see if heat shock proteins may preserve a nerve cell experiencing excitotoxicity. Heat shock proteins, also called stress proteins, are normally manufactured by a cell after it is subjected to a mild heat treatment. "Cells that have been heat-treated mildly can then withstand higher heat shocks," says Marcuccilli. But their function is obscure. The researchers think that heat shock proteins active under high levels of calcium might mitigate the effects of excitotoxicity. By Miller's own admission, the work has become "hideously complicated." Originally, when fewer details were known, it was simpler. Miller's early interest while a postdoctoral fellow in 1976 at Burroughs Wellcome Co. in Research Triangle Park, N.C., was in exploring how opiates, like morphine, were able to stop neurotransmitter release. The answer: Opiates stop calcium from entering the cell. From there, Miller continued to study calcium: how nerve cells let it in, keep it out, and chew it up--that is, its homeostatic regulation. Today Miller and his group measure the amount of calcium in a single nerve cell and plot the voltage change that results from the shifting ions as a function of time. Time, in this case, is measured in milliseconds. The result is a diagram of a calcium signal. "We are interested in the mechanism of action at the molecular and cellular level of neurotransmitters," says Miller. In addition to nerve cells' dependence on calcium concentrations for neurotransmitter release, other cell types use internal calcium to perform their duties. "Intracellular calcium is the important determinant of differentiated cell function," asserts Miller. Knowing how calcium gets through the doors into the interior of a cell is only half the story. Intracellular calcium concentration is also regulated on the inside. For example, nerve cells store calcium. "It is very important, if you want to understand how a calcium signal looks, to not only understand the calcium channels, which provide the influx of calcium, but also to understand the calcium homeostatic mechanisms inside the cell," Miller says. "How is it removed again to the outside of the cell? There are organelles inside the cell, the mitochondria, the endoplasmic reticula, that can suck it up. What we then developed in our lab is equipment, which we then built, which enabled us to measure the amount of calcium inside a nerve cell." "My background is in engineering," adds Scholz. "It gives me good problem-solving skills and a good quantitative and technical background that enabled me to build a fair amount of my own equipment." Equipment aside, Scholz identifies perseverance as essential to his and all laboratory work. "Three-quarters of the things I've done that have become successful, at some point along the way someone said wouldn't work." The pace is quick in the department of "pharm-phys," as it is called at the university. Graduate student Heinrich Matthies has been studying the biochemical pathway for adrenal medulla cell secretion. "We know that calcium goes up and then secretion takes place," he says. Details are forthcoming, and, Matthies predicts, "we will have enough data for three papers in the next three months." Commenting on his group's speedy publication rate, Miller says: "I'm very pleased with our work. I can't believe it sometimes." But he writes not only to report research results. His extensive bibliography in the field of neuropharmacology includes review articles, which he writes to put his discipline into an intellectual context. According to Miller, his colleagues often know only their own data, and don't fit their work into the larger picture. "People are completely unaware of what is in the literature," Miller says. "Technical standards in science are high, but scholastic standards have never been lower." Which is part of the reason that, bright and early every Monday morning, Miller can be found with one or two of his team members in the library, scouring the table of contents of every newly arrived journal for articles relevant to their research. "We're the first people to get the journals in the whole University of Chicago," he says. "It's a question of discipline; we're up with the literature." Although the group is a little old-fashioned in its approach to searching the literature (the researchers don't rely on electronic databases), its impressive publication record and pursuit of many projects simultaneously act as a magnet for graduate students and postdocs. Says Gibbons, "Richard has a lot of people writing to him and trying to get into his lab; his name opens doors." Those who have worked here feel lucky to be part of Miller's lab. "There are more big labs in the States--huge labs that work on $1 million or $2 million a year," says Foucart. "We don't have that in Canada. There are a lot more labs in Canada that will work with less than a $100,000 budget." Foucart wrote to Miller from his previous fellowship position in Melbourne, Australia, and shortly thereafter was on a plane bound for Chicago. "I am studying presynaptic junction receptors in rat brain cells, not cultured cells in vitro as I did in Australia," he says. "In the last six months that I've been here, I've been learning a lot." While Miller and his group hail from all over the globe, they are fond of this metropolis in the heartland. "The University of Chicago is a very serious academic environment," says Miller. "It reminds me of Cambridge." Paul Kefalides is freelance writer based in Merion, Pa.

Hot Team: Modern Science Lab Has An Old World Accent

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