* ITEH and Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616; and
AstraZeneca Ltd., Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom
The United Kingdom Medical Research Council Toxicology Research Unit, located about 15 miles south of London in the suburb of Carshalton, was one of the most exciting places for mechanistic research in toxicology during the 1960's. The unit occupied most of the space in a large building, located on a few dozen acres of open ground. It was not isolated; 3 more MRC Units (neurobiology, virus research, and animal sciences) occupied part of the same facility and across the meadow was the newly built BIBRA laboratories (British Industrial Biological Research Association), a research institute founded and directed by Leon Golberg. But by far the largest unit in this set-up was the Toxicology Research Unit, directed by John Morrison Barnes.
It was a most stimulating environment in which to conduct research. John Barnes was an acknowledged authority in toxicology and much sought after as a consultant by the World Health Organization and other international bodies. He deeply believed in the value of basic research and imposed practically no restrictions on what was to be pursued, although on occasion he grumbled that some of the research in biochemistry and molecular biology was a bit too esoteric to be practical for what now would be called "hazard identification." He once complained that a young postdoctoral fellow who studied biochemical changes caused by beryllium should rather have done some more mundane toxicity studiesso we would know more about beryllium toxicity. The fellow's supervisor immediately retorted: "If he had not done biochemistry, he still would not know what he is doing," and the matter was settled.
John Barnes also had some very strong views on how to study the effects of toxic agents. He believed in experiments involving animals and particularly he viewed cancer as a disease of the whole animal. As a trained pathologist, it was quite natural that he emphasized the need to analyze early structural changes when studying toxicity. In an essay on nitrosamines, he also raised some caveats that make interesting reading even today: "What is to be avoided is the error of many pathologists who followed Virchow and believed that they helped the understanding of disease simply by elaborating on the minutiae of structural changes and the responses of various cell constituents to an exposure to aniline dyes and complicating the nomenclature. These techniques have a place, but only a place, in research on disease. It seems possible that in the next generation the molecular biologist will fall into the same trap of believing, like the cellular pathologists of 100 years ago, that his subject alone holds the key to an understanding of disease. It may play a very valuable partbut only a small part, for the understanding of disease can only be derived from more studies on the whole animal" (1974, Essays Toxicol. 5, 115).
Many of the founding members of the unit were working at the Chemical Defence Establishment at Porton Down during wartime and then moved to Carshalton. John Barnes had assembled an impressive team of senior and junior investigators. There was Peter N. Magee. About 10 years earlier, the unit was approached because there was a problem in a certain chemical plant: Workers developed jaundice when working with a particular agent. It was dimethylnitrosamine (DMN) and acute toxicity studies soon showed its necrogenic action in the liver. However, Magee also carried out a long-term experiment with DMN and discovered its carcinogenic action. This led to a series of investigations into nitrosamines, their organ specificity, and above all their molecular mechanisms of action as alkylating agents. Many scientists who became widely known for their work on nitrosamines were at one time or another associated with work in Carshalton: Emmanuel Farber, Willy Lijinsky, William Butler, Peter Swan, Ron Shank, and Saul Villa Trevino, to name just a few.
W. Norman Aldridge, a later Merit Award winner of the SOT, had been associated with the unit practically from the beginning. His interests were mainly the organophosphorus pesticides and their inhibitory action on acetylcholinesterase. His investigations on the kinetics of enzyme inhibition are by now classics in the field. However, he had other interests that he shared with some of his junior associates: the toxicity of organotin compounds and their effect on oxidative phosphorylation and the hepatotoxic effects of soluble beryllium salts. The studies with organotin compounds were stimulated by a large outbreak of poisonings in France where mixtures of diethyl and triethyltin had been used to treat boils, with a fatal outcome in some cases. This stimulated extensive studies on the metabolism of organotin and organolead compounds and their effects on the nervous system. He was a great teachercritical, objective, always questioning, and always helpful. Whenever presented with results, and after having assured himself that the results were real and reproducible, he would ask: "And what are you planning to do next?" Particularly worthy to remember is a laboratory meeting, in 1966, when Martin Johnson presented his newest project: as he put it, he and Dr. Aldridge were convincedor believedthat in order for something to be toxic it had to bind to something. Therefore, he was going to treat hens with a radiolabeled organophosphate compound and examine to which protein in the nervous system the molecule would bind. Thus was conceived neurotoxic esterase or NTE, a concept that led to much fruitful research and deeper insights into the delayed neurotoxic effects of certain pesticides. Aldridge also trainededucated might be a better wordmany students and postdoctoral fellows, many of whom made their mark in mechanistic toxicology: Michael Rose, Ted Lock, Robert Lauwerys, Marcello Lotti, Elsa Reiner, and Lewis L. Smith who many years later became the director of the unit. Closely associated with Dr. Aldridge's group, but working independently, were Jill Cremer, who examined the biochemical basis of brain damage induced by chemicals, and Francesco de Matteis, who had gained his Ph.D. in Charles Rimington's laboratory, studying mechanisms of porphyria. He turned his attention to a then comparatively new field, mixed function oxidases and became well known for his elegant work on liver hemesynthesis and turnover. A number of visiting scientists spent time in Francesco's laboratory, such as Alan Seawright from Brisbane, who became a regular visitor to the unit and later was actively involved in setting up the MRC Toxicology Unit in Australia. At that time, Victor Parker, Bendeno Terracini, and Michael Stonard were studying the recently identified amino acid analogues found in animal feed treated with trichloroethylene that cause aplastic anaemia and renal injury in cattle. This founding work provided a basis for much of the work during the 19701980's on the ß-lyase mechanism of nephrotoxicity.
The unit was not really structured in departments or groups, and many investigators worked on their own projects. H. Berry Stoner was deeply interested in the biochemistry of shock and how adaptation to cold could modify it. Dennis Heath was the resident guru in statistics and taught how to use ANOVA before the advent of computers; to analyze an experiment took hours or days. A small paper he wrote on the criteria when to assume log normal distributions in toxicology was published in Nature. A. Robin Mattocks examined the toxicology of natural compounds, e.g., pyrrolizidine alkaloids, and André E. M. McLean, who had initially worked in the laboratory of Jack Judah, was a pioneer in the study of mechanisms of toxic liver damage. André McLean then left for a sojourn in the United States and then in Jamaica where he got first-hand experience of the toxic effects of "bush teas" made from plants containing pyrrolizidine alkaloids. When he returned to the unit, he established that the nutritional status of animals could markedly modulate hepatotoxicity. Tom Clarkson did work on the toxicity of inorganic and organic mercury; after he left for the United States, mercury work continued to be done by Laszlo Magos.
It was always exciting to talk to Regina Schoenthal, because she was so enthusiastic about her work and her discoveries. She was interested in the toxicology and carcinogenicity of natural compounds and her work on the toxicity of pyrrolizidine alkaloids became widely recognized and is often quoted today. Valda Craddock, who initially joined Peter Magee, studied molecular mechanisms of hepatocarcinogenesis and conceived of the idea that a regenerating liver might be more sensitive to carcinogens because of increased cell turnover. Her prediction would be verified experimentally and so the foundation was laid for the crucial role of cell proliferation in carcinogenesis.
Life at the unit was relaxed, yet immensely productive, although it must be said that criteria for productivity at that timeand thus, professional advancement and successwere different from today. Norman Aldridge, when asked what he considered to be good productivity, thought that 1 paper per year would be very good. Of course, scientific papers in those days were much more substantial and contained much more information than do most of today's "least publishable units." Internal review of manuscripts was rigorous, but then most were invariably published in the highest quality journals. Regular seminars formed an important part of the life in the unit, with international visitors regularly stopping by to talk to John Barnes, Norman Aldridge, Berry Stoner, or Peter Magee and at the same time enlighten the unit of their problems and findings. A cafeteria was located across from the main building and lunches were taken together. The presence of several others units at the same location made exchange of ideas with other disciplines easy. Twice a day, in the morning and in the afternoon, there was tea time, again a time for exchange of ideas, but also quite often for intense discussions, often on pesticides on the international scene. Barnes, Aldridge, Stoner, and Magee all played leading roles in setting standards for pesticide safety at the international committees, so there were conversations about the reports from the field workers in South America that were never published, about pesticide misuse and toxicity. But there were also lively discussions on books, theater and, of course, current politics. The new budget, as suggested by the Chancellor of the Exchequer, was always intensely analyzednot because it would impact the unit (money was plentiful in those days), but rather because of the impact it might have on one's personal income taxes!
NOTES
1 To whom correspondence should be addressed. Fax: (530) 752-5300. E-mail: hrwitschi{at}ucdavis.edu.