Introduction to biological complexity as a missing link in drug discovery

ABSTRACT

Introduction: Despite a burgeoning knowledge of the intricacies and mechanisms responsible for human disease, technological advances in medicinal chemistry, and more efficient assays used for drug screening, it remains difficult to discover novel and effective pharmacologic therapies.

Areas covered: By reference to the primary literature and concepts emerging from academic and industrial drug screening landscapes, the authors propose that this disconnect arises from the inability to scale and integrate responses from simpler model systems to outcomes from more complex and human-based biological systems.

Expert opinion: Further collaborative efforts combining target-based and phenotypic-based screening along with systems-based pharmacology and informatics will be necessary to harness the technological breakthroughs of today to derive the novel drug candidates of tomorrow. New questions must be asked of enabling technologies—while recognizing inherent limitations—in a way that moves drug development forward. Attempts to integrate mechanistic and observational information acquired across multiple scales frequently expose the gap between our knowledge and our understanding as the level of complexity increases. We hope that the thoughts and actionable items highlighted will help to inform the directed evolution of the drug discovery process.

KEYWORDS:

• Drug development
• systems
• complexity
• models
• phenotypic screen
• mechanisms

Article highlights

• A lack of understanding of the complexity of biology in health and disease remains a key issue in limiting the discovery of novel pharmacologic therapeutics.

• Systems-biology approaches and computational models provide alternative frameworks to test drugs (eventually beyond animal models).

• Human stem cell-derived preparations represent an evolving experimental approach to interrogating drug efficacy and drug safety in the proclinical space (preclinical studies using human-derived “clinical-like” cells or tissues). Further work is ongoing to define the minimum systems necessary to recapitulate the critical processes in healthy and diseased states (for safety and efficacy studies, respectively).

• Experimental systems need to be configured and sampled in ways such that data output reflects the dynamic (temporal) changes underpinning disease-linked or drug-toxicity evoked phenotypes.

• The integration of multiple network- and systems-based responses should provide better and more comprehensive assessments of drug effects compared to more traditional target-centric approaches to drug discovery.

Phenotypic screening using human stem cell-derived cells and tissues represent a complementary approach to quantitative systems biology-based studies that include higher levels of integration and complexity for evaluating drug candidates.

Declaration of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

C George receives research funding from the British Heart Foundation, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust.

Notes on contributors

Gary A. Gintant

G Gintant is an employee of AbbVie though the company played no role in the composition of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.