Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Abstract

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug–target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent.

Introduction

Pharmacologists typically distinguish two approaches to the development of pharmaceuticals, one termed ‘empirical’, the other ‘rational’, ‘deductive’ or ‘a priori’. The opposition is not, however, about experience or reason being the ultimate source of knowledge, as the terminology could be taken to suggest. Pharmacology, following either of the two methods, is a discipline thoroughly based on experimentation and empirical data. Instead, the distinction is about the role of theoretical understanding in pharmaceutical development. The empirical approach proceeds by testing large numbers of random substances for certain desirable effects in biological test systems or model organisms. Typically, drugs can emerge from this method without their target (receptor, enzyme, and so on), their mode of action or the mechanism of disease being understood. In contrast to this, the rational method usually involves a theoretical understanding of which protein is targeted by the drug, how the drug acts on it, and which mechanisms lead to the desired therapeutic effects.

The rational method, often called ‘rational drug design’, has gradually become more popular in drug development since its first instances in the 1950s. Triggered by a number of impressive successes such as the development of the cholesterol-lowering drug lovastatin or the antihypertensive drug captopril (discussed below) in the 1970s, rational drug design has acquired status as professed methodological ideal in the 1980s (cf. Gambardella, 1995, Ch. 2). This is also evidenced by the awarding of the Nobel Prize for medicine or physiology of 1988 to the pharmacologists Sir James Black, Gertrude B. Elion and George H. Hitchings, three pioneers of rational drug design (Nobel Assembly, 1988).¹

In this paper, three case studies of the rational design of cardiovascular drugs—propranolol, captopril, and losartan—will be presented. Their development histories range from the beginnings of rational drug design in the late 1950s to the mid 1990s. Each of these drugs has been developed in the pharmaceutical industry and has introduced a new pharmacological principle into medicine. Up to the present, they (or their direct descendants) are important therapeutics for various cardiovascular conditions. They are, for instance, the prototype drugs for three of the five classes of therapeutics that are most commonly used in the treatment of hypertension (Brown, Quirk, & Kirkpatrick, 2003). Beyond this impact on clinical practice, the development of the drugs also included research that contributed considerably to the scientific understanding of drug action and of physiological and pathological mechanisms. The studied cases thus closely combined two aims of research and development: on the one hand, the practical aim of developing techniques and tools for the practically useful control of and intervention into a system; and on the other hand the epistemic aim of gaining a theoretical understanding of fundamental features of the natural (or artefactual) world. An analysis of the three cases can therefore test a claim that has been put forward by many authors: that integrated practical and epistemic projects are of growing importance for the overall relationship of science and technology.²

In order to make more precise what is meant by ‘practical’ in this claim, epistemic and non-epistemic domains of practice have to be kept distinct. On the one hand, scientific research of course includes a practice (as opposed to theory) in that, for example, experiments are conducted or research technologies developed. However, this practice can be directed entirely or largely at epistemic aims. As such, it can well be (and regularly is) part of basic research, which I roughly understand as research that is directly and primarily targeted at the fundamental scientific understanding of some area.³ On the other hand, technological practices are often concerned with non-epistemic problems, and the development of novel technologies then aims at devices or procedures that are useful for the solution of these problems. The main field of practical application of pharmacological research in this second sense is of course medicine. The main non-epistemic aims of pharmacological research are therefore the alleviation and the cure of diseases (or the economic profits to be drawn from therapeutic usefulness). The claim about the increasing integration of epistemic and practical work refers to practical utility in this second sense that stands in contrast to epistemic purposes.

With respect to pharmacological research and development, a number of options for the relationship of practical and epistemic projects offer themselves. To start with, there are two basic ways to conceive of the practical and epistemic aims as being pursued separately rather than in an integrated manner. Firstly, as in the theoretically uninformed pharmacological empiricism, development can aim at the empirical establishment of useful causal connections between possible drugs and desirable effects without addressing the precise mechanisms that account for the causal dependency. Even though the development of new drugs can disclose phenomena which are also epistemically important, the elucidation of the underlying mechanisms would be left to subsequent research. Secondly, pharmacology could instantiate the familiar linear model of innovation. In this case, there would be a successive or top-down relationship between epistemic and practical work. Research in physiology, biochemistry, pharmacology or pathology would come first and provide fundamental knowledge of physiological and pathological mechanisms. Only subsequently is this knowledge applied and guides the design of drugs. Even though the practical and the epistemic projects can be linked according to both models, they are not combined in one enterprise, but succeed one another both temporally and logically.

The linear model of innovation has found many critics. They have in general objected that many projects in science and technology have both epistemic and practical aims or implications.⁴ Donald E. Stokes has argued that a type of research that he terms ‘use-inspired basic research’ has been prominent at least since the end of the nineteenth century. He finds in Pasteur a paradigmatic researcher of this type. Such researchers choose their subjects in direct response to practical needs that they aim to solve. However, they also strive for a fundamental understanding of the phenomena (Stokes, 1997). Other authors make out more recent transformations in the combination of epistemic and practical projects. Philippe Larédo and Philippe Mustar, for instance, stress organizational characteristics of what they call ‘basic technological research’. They observe the formation of ‘techno-economic networks’ that include academic and industrial researchers, but also public and financial institutions, and which are engaged both in the development of new products and the gain of scientific knowledge (Larédo & Mustar, 1996; cf. Walsh, 1998). Michael Gibbons and co-authors capture further novel features of research in the context of the development of specific applications under the heading of ‘mode 2 knowledge production’. According to them, such integrated activities often take place in a framework that includes the resources from various disciplines and combines them into a new capability for problem solving. In addition, they see a transformation in the procedures for validating scientific knowledge, since the users of this knowledge (in politics, economy, or society) get included in its establishment (Gibbons, Limoges, Nowotny et al., 1994).

The aim of this paper is to contribute in two major respects to the understanding of the integrated model of innovation. Firstly, it intends to elucidate epistemic characteristics and conditions of combined practical and epistemic projects. The investigation of the three consecutive cases shows that the emergence of the integrated method of rational drug design is closely connected to specific progress both in theory and experimental techniques. The theoretical modeling of the chemical interactions between drugs and targets together with a mechanistic interpretation of experimental test systems enabled the close combination of theory and practice in cycles of mutual advancement.

Secondly, the paper aims to improve the broader understanding of the relation between research and development by elucidating the role of basic research in rational drug design. It will turn out that the integrated epistemic and practical work presupposes input from basic research, while basic results gain practical importance only through additional investigations within the contexts of development. Contrary to the initial impression, the linear and the integrated modes of innovation do therefore not exclude each other. Instead, rational drug design shows how the operation of each can be dependent on the other.