Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery

Abstract

Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies as well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between (empirical and/or rational) development methodology and actual therapeutic success. An obstinate dilemma in early drug developmentFor the successful development of technology, it is often crucial to pay close attention to a number of different complex circumstances. Development can be particularly demanding if the complexities lie on different levels of a system. For instance, the design of a technology can require, first, that the technological artifact intervenes in a highly sophisticated way on a specific part of a system. Second, this intervention might have to produce effects in the system as a whole that are mediated by complex systems mechanisms. In such a case, complexities on two levels have to be dealt with: complexity of (local) intervention and complexity of systems effects (or systems complexity).For drug development, both types of complexity play a major role. Pharmaceuticals typically act on target proteins, such as enzymes, receptors or ion channels. The interaction between (potential) drugs and these molecular targets is often highly complex and subject to comprehensive theoretical modeling, chemical design and empirical testing in drug development. This problem is local in nature, being associated with specific proteins and their manipulation by drug molecules. At the same time, the intended and unintended effects of pharmacological interventions lie on the level of entire systems such as cells, organs or the organism

Synthetic Biology at the Limits of Science

“…Thus, the idea of "rational drug design" was advanced in the 1970s by biomedical researchers who were scandalized by the notion that in this day and age drug discovery should proceed by way of randomized search procedures. And after trial and error -in the form of automated high-throughput methods -triumphed over rational drug design (Adam 2010), the scientific community came back with nanomedicine and visions of targeted drug-delivery ("this…”