Nobel Laureates in Pharmacology
Short review, or perspective articles, on important topics in pharmacology and therapeutics summarizing the development of knowledge on the topic over the last century.
Rebecca Anderson, Early Development Operations, Amgen, Inc.
On June 15, 1933, Otto Krayer sat down to write the most important letter of his professional career. The thirty-three-year-old clinical scientist had just been offered the chair of pharmacology and toxicology at the Medical Academy of Düsseldorf, and everyone expected Krayer to accept the appointment. He declined. "I will abstain from winning a position that corresponds to my inclinations and abilities," he wrote, "rather than make a decision contrary to my conviction or, by remaining inauspiciously silent, further an opinion about me that is not in accordance with the facts." Krayer saw the removal of the Jewish incumbent chairman, Philipp Ellinger, to be an injustice that he explicitly challenged. "Under these circumstances, assuming such a position as the one in Düsseldorf would impose a great mental burden on me," he explained. Krayer was the sole scientist to decline the "call" (as it is said in German) to a chaired position that, in accordance with Nazi law, could no longer be occupied by a Jew. Krayer’s moral stand, so carefully and thoughtfully considered, enraged the German authorities. The sanctions they imposed, banning him from teaching or even using university libraries, effectively ended his promising academic career in Germany. Contemporaries of Krayer who faced similar censorship were driven to become vocal political dissidents. Otto Krayer, on the other hand, did not enter into external, political discourse, and chose rather to leave his homeland in order to pursue his interests in pharmacology. He went on to lead a highly productive professional life, in the sphere of science, that was always guided by an uncompromising moral compass.
Rebecca Anderson, Technical Writer
One day during my first pharmacology laboratory rotation, my supervising professor challenged me: "Who were the four horsemen of Johns Hopkins University?" Without much hesitation, I replied that Osler, Welsh, Halsted, and Kelly were generally considered the founders of America's first world-class medical school. Ruffled, but not to be outdone by a first-year graduate student, he said, "Ok, then who's the fifth horseman?" I blanked. With panache, the proud Hopkins alum informed me the fifth was John Jacob Abel, the father of American Pharmacology.
Brian M. Cox, Professor, Dept of Pharmacology, Uniformed Services University of the Health Sciences
In 1919, Torald Sollmann published two papers in the on the ability of selected solvents and absorbents to modify the severity of skin lesions induced by mustard gas (1,1'-thiobis[2-chlorethane], or dichloroethyl sulfide). Mustard gas, or sulfur mustard, is a vesicating agent that had recently been used on troops fighting in the First World War. Sollmann’s studies were unusual, at least by today’s standards, in that he chose to study the effects of this highly toxic compound on himself and on students who volunteered for the project. These studies did not provide insights into the mechanism of action of mustard gas or lead to the introduction of a novel antidote, and they certainly do not count among the major contributions to pharmacological research that arose from Sollmann’s long and distinguished career. Nevertheless, the papers are of interest because they shed light on the way that pharmacology was practiced by one of the founding members of the American Society for Pharmacology and Experimental Therapeutics. The willingness of Sollmann to expose both himself and his students to significant personal risk in the search for protective measures against mustard gas may also reflect the sense of fear and concern in the public at the use of chemical warfare in the twentieth century.
The Development of Drug Metabolism Research as Expressed in the Publications of ASPET: Part 1,1909-1958
Drug Metabolism and Disposition, 36: 105 (2008)
Patrick J. Murphy, Butler University
This is the first of three articles covering the development of drug metabolism research in the US during the first 100 years of ASPET. Prior to 1909 the majority of drug metabolism research was performed in Europe. The period from 1909-1958 saw extensive development of the methods required for modern metabolism studies. Examples of trends and specific discoveries are drawn from the archives of ASPET publications.
The Development of Drug Metabolism Research as Expressed in the Publications of ASPET, Part 2 - 1959-1983
Drug Metabolism and Disposition, 36: 981 (2008)
Patrick Murphy, Butler University
In 25 years drug metabolism research went from using sub cellular particles of undefined content to an understanding of metabolism at the molecular level. The discovery of cytochrome P450, enzyme induction, reactive intermediates, and genetic polymorphisms provided milestones in the field. New publications from ASPET chronicled the discoveries and provided communications to advance the science of drug metabolism.
The Development of Drug Metabolism Research as Expressed in the Publications of ASPET, Part 3 - 1984-2008,
Drug Metabolism and Disposition, 36: 1977 (2008)
Patrick Murphy, Butler University
The dramatic changes in drug metabolism research in the last 25 years are well documented in the publications of ASPET. New analytical tools combined with modern molecular biological techniques have provided unprecedented access to the workings of the cell. A field that concentrated on only a handful of primary enzymes now has a list of hundreds in its purview. Genetic variation, environmental impact, and molecular diversity have all come under study in attempts to follow the fate of drugs and chemicals. Examples from ASPET journals will be used to illustrate the dramatic advancements in the field.
James E. Barrett, Drexel Universityand Jack Bergman, Harvard Medical School-McClean Hospital
The publication by Peter B. Dews of a series of five articles in this journal entitled "Studies on Behavior", beginning in 1955 and ending in 1959, were contributions of extraordinary significance in laying a foundation for the emergence of the discipline of behavioral pharmacology. The series of articles were rigorous in their approach, dramatic in terms of the results, and provocative in their implications. Published at the near half-century mark of the founding of the American Society for Pharmacological and Experimental Therapeutics, it is appropriate to now provide a Centennial Perspective on the impact of these studies over the 50 years following their publication and to comment on the way in which they helped to influence the directions in which this discipline has evolved.
Frank J. Gonzalez and Connie Cheung
Cytochrome P450s (P450s) are important enzymes involved in the metabolism of xenobiotics, particularly clinically used drugs, and are also responsible for metabolic activation of chemical carcinogens and toxins. Many xenobiotics can activate nuclear receptors that in turn induce the expression of genes encoding xenobiotic metabolizing enzymes and drug transporters. Marked species differences in the expression and regulation of cytochromes P450 and xenobiotic nuclear receptors exist. Thus obtaining reliable rodent models to accurately reflect human drug and carcinogen metabolism is severely limited. Humanized transgenic mice were developed in an effort to create more reliable in vivo systems to study and predict human responses to xenobiotics. Human P450s or human xenobiotic-activated nuclear receptors were introduced directly or replaced the corresponding mouse gene, thus creating "humanized" transgenic mice. Mice expressing human CYP1A1/CYP1A2, CYP2E1, CYP2D6, CYP3A4, CY3A7, PXR, PPAR were generated and characterized. These humanized mouse models offers a broad utility in the evaluation and prediction of toxicological risk that may aid in the development of safer drugs.