Proc. West. Pharmacol. Soc. 42: 153-159 (1999) Special Supplement: Pharmacology at the Millennium Pharmacology - A Unique Discipline for Unique Questions? M.I.A. WALKER Deparment of Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada SUMMARY .. PREAMBLE.... DEFINITION OF PHARMACOLOGY Depth and Width of PharmacolOgy wcnvmon Special and Unique Features of Pharmacology... THE FUTURE FOR PHARMACOLOGY .. Dangers.. Opportunities VISION FOR THE FUTURE OF PHARMACOLOGY. This article discusses the nature and responsibilities of the biomedi- cal subject known as pharmacology. It will attempt to show how phar- macology is a very special subject that is uniquely positioned to ask fundamental questions about drugs, such as how they produce their ac- tions, and how they may be used more effectively in man, Further- more, pharmacology is a most im- Portant subject to the pharmaceuti- cal industry as it is pharmacology, combined with medicinal chemistry and toxicology, that is responsible for the introduction of the vast ma- jority of new drugs. Thus, pharma- cologists are to be found in univers ties, research institutes and industry. In universities, pharmacologists are concerned more with discovering new drug-like entities in the body SUMMARY Pharmacology: That branch of medical science which relates to drugs, their preparation, uses and effects Dmg: An original, simple, medicinal substance, organic or inorganic, whether used by itself in its natural condi- tion or prepared by art, or as an ingredient in a medicine ot medicament Oxford English Dictionary PREAMBLE 153 153 154 155 156 157 157 157 158 and natural world and in understand- ing how current drugs work. In in- dustry, pharmacologists seek new drugs. Over the last decade there have been many discoveries in mo- lecular biology, the new biology. The enthusiasm and revolutionary spirit which greets such discoveries leads to an assumption by some that pharmacology in its present form has been rendered redundant. This arti- cle refutes such a conclusion and shows how pharmacology has unique attributes and approaches that are as important now as they always were. Indeed, it argues for improve- ments in the understanding of phar- macology and how it remains a unique and special subject that should be nurtured ‘The following is one person's view of pharmacology. Itis a very personal view with all the faults of such. Many will find it too philosophical and complain of a lack of substantiating data. Unfortunately, it is hard to find real data but it is harder stil to think without conscious refer- ence to an underlying philosophy. Thus the way we view and understand pharmacology colors all our thinking on the subject. The author makes only token apologies for the lengthy discussion of reductionism versus functionalism, as this may be at the root of people's perception of phar- macology. The initial premise of this article is that the discipline of pharmacology is at risk, if not under direct attack. If the reader does not believe that this is the case, read no more. 153If we accept that that there are risks to the discipline, then we must ask why this is, and what may we do to lessen the risk? With this in mind, what follows is a considera- tion of the nature and goals of pharmacology while trying Special Supplement: Pharmacology at the Millennium. to identify the strength and weaknesses of the discipline ‘The aim of this article is to get both existing and would-be pharmacologists to think more about the discipline of pharmacology. DEFINITION OF PHARMACOLOGY There have been many definitions of pharmacology, ‘no one of which is complete, At times it seems as that any definition of pharmacology cannot be agreed upon by more than two people at any one time. An often quoted quip, "pharmacology is what pharmacologists do" lies at the heart of the issue. Such a definition can be tautological since one defines a pharmacologist as a person who works in a department of pirarmacology. There are, of course, ‘other pharmacologists who define themselves on the basis of education or interest and who work in other biomedical sciences. Sadly the above state of affairs does not compare fi vourably with the replies (o questions such as, what is anatomy, or what is physiology? Answers to the latter tend to be uniform and structurally similar. The natures and directions of such disciplines are defined with reason- able clarity although the borders of the answer may be fuzzy and irregular. The same question asked of pharma- cology brings answers which depend upon who is asking the question of whom. Most commonly, answers center around the study of drugs with immediate confusion with pharmacy, physiology and other biomedical disciplines. Such confusion, relative to that seen for other closely re- lated biomedical disciplines, is cither at the root of the problem, or is merely a symptom. If the very meaning of the word pharmacology is confused, is it any wonder that the directions and goals of the discipline of pharmacology are sometimes confused and ill-defined? What other dis- cipline would bother to ask of itself the question "Wither, whether and whither pharmacology” [1]. ‘The reasons for the existence of disciplines such as physiology, anatomy, pathology and biochemistry are of- ten self-explanatory in that as biological science grew, and medicine became more scientific, it became useful to di- vide the rapidly growing knowledge into obvious divi sions based upon how bodies were constructed (anatomy), how they worked in health (physiology), and disease (pa- thology), the underlying chemistry of life (biochemistry), the general biology of animals (zoology), plants (botany) or microbes (microbiology). All of these disciplines are natural divisions in the study of life (biology). The existence of pharmacology arises from a conun- drum, Pharmacology is not centred on the study of a par- ticular aspect of nature, but only exists because man take: or gives, medicines to himself, and other animals, in at- tempts to cure or alleviate the diseases that man, and other animals, are heir to. Lohse [2] described it as follows, “other biomedical sciences are trying to explain the world, pharmacologists try to alter it”. Pharmacology is less about determining how the biology works, and more about how to manipulate biology. The roots of this ma- nipulation, and pharmacology itself, stretch back into an- tiquity since man (and other animals) have constantly used biological material, other than food, to alleviate dis- ease and discomfort. In such ways pharmacology is dif- ferent from the usual biomedical disciplines. It appears less likely to be asking fundamental scientific questions and more likely to be concerned with technologically di- rected questions related to the analysis of the actions and uses of drugs. As a result pharmacology has the attributes of a technology rather than of a science, in much the same manner as engineering stands to physics. To some this appears to be a fail from the pantheon of “real sciences" Powerful factors are at play. One of these factors is how pharmacologists, and others, view science in general, and pharmacology in particular. We live in an era of re- ductionism and the worship of technique. Reductionism is an all powerful approach to the model building and prob- lem solving of science. With specific respect to pharma- cology, "There are two ways that pharmacology has de- veloped that are both independent and interactive. The first is exploratory and pragmatic, the second accords with the philosophic approach of physics - that of reducing complex phenomena to their simplest - what is usually termed reductionist.” [3]. In the world of physics (the pin- nacle of reductionism), there is talk of "theories of every- thing”. In an analogous manner, molecular biology holds out the promise of giving a complete understanding to all aspects of biology, including Homo sapiens. Thus, in the biomedical sciences the hope is that the physiology and diseases of humans and animals will be understood as long as the details of the appropriate genomes are known. While reductionism has been fundamental to the prog- ress of science, and is underpinned by a powerful philoso- phy, it carries its own problems. It encourages the suspect belief chat the whole is merely the sum of the parts and ignores the fact that the whole can be much greater that that of its parts. Thus DNA does not offer a blueprint for life in the way that blueprints describe man-made objects. Rather it is a blueprint for the tools of life and how these interact by as yet unknown laws to make functional life possible. Thus the laws governing how biological parts interact have yet to be fully understood, because those laws are difficult to analyse. These interactive or func- 154tional laws are just beginning to be untangled by such as the mathematics of chaos. To believe that reductionism opens all doors is overly simple. We have to remember that, despite all of our deep knowledge of quantum mechanics, it is very hard to even derive an empirical (functional) law such as Ohms law from first principles and the laws of quantum mechanics. ‘And yet Ohm's law has been of inestimable value. Reduc- tionist theories of everything were dealt a harsh lessons with the discovery of chaos mathematics with its odd ap- parently non-deterministic parameters, such as strange attractors, and the realization that functionalism has its ‘own laws. Thus function has as much importance as form while function does not always follow form in the way that the machines of man follow the blueprints of man. The whole can be very much more than the sum of the parts. However, many of our views about science have been contaminated by the “success” of atomic explosions where a clear path leads from superb reductionist analyses in atomic theory to the chain reaction, and the subsequent undeniable power generated by that reaction. We have to be carefu) that we do not assume that the analogous bio- logical applications of a reductionist approach will yield all the information required for understanding and produc- ing drugs. We are far from a "theory of everything” for drugs. The above diversion into the philosophy of science does not help define the discipline of pharmacology. The semantic roots of the word pharmacology have often been discussed, but they are difficult to encapsulate simply. In the following we will provide information to allow the reader to form his or her oWn definition. In the meantime the following definition is offered: pharmacology is the biological study of drugs, where a drug is a chemical which is taken into or onto the body, by whatever means, for a purpose other than as food. This study ranges from the basic molecular interaction of drugs with the biologi- cal macromolecules that are their targets, to the actions of drugs in populations of man or animals. Thus the pharma- cologist is charged with understanding the actions of rugs at all levels of biology. In a trivial sense it is what drugs do to the body, and what biological bodies do to drugs. It is not the study of the chemical nature of drugs, the manufacture, source nor care of drugs, nor is it the chemistry of biological tissue. In the past pharmacology also covered the toxic actions of drugs and toxic sub- stances, but a growing separation has led to the formation of a sister discipline, toxicology. Toxicology centers on how drugs and toxins produce their adverse actions, but this is a separate top DEPTH AND WIDTH OF PHARMACOLOGY: It is often forgotten that pharmacology is all-encompassing in its interests from microscopic to macroscopic phenomena, Special Supplement: Pharmacology at the Millennium It is equally valuable to investigate drug action at the mo- lecular level as it is at the level of whole populations of organisms, usually man. However, any complete biologi- cal analysis of a drug starts at the level of the biomolecule with which the drug first interacts. In the classic view, beginning with Paul Ehrlich, this biomolecule is known as the receptor for the drug. Thus nature either thoughtfully provides receptors for drugs or drugs happen, by chance, to bind to a particular biomolecule in a manner that would lead us to identify a biomolecule as a receptor for a drug. As with all biological truisms, there are exceptions. Some drugs may not act by first binding to a receptor; i.e. a spe- cific biomolecule site or a biomolecule. Regardless of whether all drugs have first to bind with a receptor in or- der to produce their actions, the initial logical step in an analysis of a drug's action concentrates on the drug’s in- teraction at the interface of the responding biological sys- tem. This area of pharmacology, known conventionally as molecular pharmacology, is content at present (© investi- gate imeractions at a relatively macroscopic level in the sense of the whole receptor molecule and then the specific binding domain. Will reductionism proceed further such that in the future we will talk of quantum mechanical pharmacology? Probably not, as such a depth of analysis will fall into the province of medicinal and other chemists, or even physicists. Where will the search for the molecu- lar actions of drugs lead? Presumably, in essence, to a specific solution of Schrodinger equations for the interac- tion of an endogenous or exogenous molecule (the drug) with a macromolecule (biological target). Following the interaction of a drug with its receptor, the information generated by binding of the drug to the receptor has to be transduced in some manner to lead to cellular actions. For a classical agonist drug this involves changes ip az ion channel, or activation of a second mes- senger system, Such interactions fall within the general auspices of biochemistry as is the case when the receptor is an enzyme, transporter, or any one of the many macro- molecular biochemical systems to be found in a cell. In view of the current interest in second messengers and ion channels, can we expect to see channel and second mes- senger pharmacology or are they already here? The next step in the progressive analysis of responses to drugs is at the cellular level. We have yet to see cellular pharmacology described as a separate section of pharma- cology. However, in vitro analyses of drug action at a cel- lular level is of prime and classic concern to pharmacolo- gists. Cellular responses become integrated at organ or systems level where we recognize the existence of auto- nomic, neural, cardiovascular, renal, or other pharmacol- ogy. In those cases where the pharmacological study is made on isolated tissue we have in vitro pharmacology; the "in glass" home of the pharmacologists interested in functional analyses of drug actions. 155