Human-based Systems for Translational Research

One of the main challenges we all face working as medicinal chemists or other scientists in drug discovery project teams is the relevance and interpretation of the data we generate. Specifically, we aspire to test hypotheses and advance molecules into patients to address a multitude of diseases, but obvious practical and ethical considerations require us to first characterise our molecules in various artificial and approximate systems. All project teams worry (quite rightly) about the relevance of the assays in the screening cascades to appropriately drive medicinal chemistry, and all teams openly acknowledge (quite rightly again) the limitations of the use of animal models for both efficacy and toxicity testing. However, whilst criticising the various animal disease models available, we nearly always choose to use them to generate data to support onward progression and furthermore are required by current legislation to perform specific toxicology studies in rodent and non- rodent species prior to evaluation in humans. Few models outside those for infection and diabetes studies have full validity for assessing the human disease state, and over-reliance on the current battery of models validated by the currently approved drugs creates an inherent limitation in our ability to prosecute drug development for novel mechanisms, or to tackle currently untreated diseases. The stated intent of this book is to provide a summary of the opportunities and challenges to overcome these limitations by working directly with human-derived materials, both in terms of alternative means of assessing efficacy in targeted disease states and the far slower push to move regulatory toxicology towards systems of greater relevance and predictivity.

The book provides a very interesting historical perspective on the use of animal models, with the foreword focussing on the current limitations of animal toxicology as a means of assessing likely safety in humans, whilst acknowledging that a desire to always understand the systemic response to administration of a drug means that animal toxicology studies are likely to be important for the foreseeable future. The early chapters provide some clear arguments of why we should be striving to generate more data in human-derived test systems as well as the current barriers to doing so. In particular, the point is well made that whilst in the UK an estimated two million animals are used annually in various studies, only a few thousand studies are conducted on material derived from people, despite the fact that there are over 600 000 surgical tissue samples obtained annually that could enable this, coupled with a 95% consent rate from the putative donor. Subsequent chapters highlight the need for tissue banks, standardised processes and hospital staff able to work to the required standards to ensure high fidelity, viable tissue samples with low risk of contamination, and detail the particular challenges and technical specifications required to enable this. Later chapters develop the alternatives to current animal toxicology studies, with emphasis on various tissue types, in particular developing an understanding of the pros and cons of cells lines and different primary tissue samples, and reinforce the difficulties of tissue culturing and the common lack of confidence in data currently generated using primary tissue given the technical complexities involved. Chapter 5 overviews an interesting complementary technique to the usual biochemical selectivity panels, highlighting the example of certain kinase families such as the Janus kinases (JAKs), for which the complexities of pairs/multimers in functional cascades renders simple isolated bio- chemical selectivity inadequate for assessing downstream safety risks. The commercial opportunity outlined offers an alternative screening method against panels of standardised primary human cells and co-cultures focussed around specific disease readouts.

Whilst I enjoyed reading this book, I found that some of the chapters do not align with the overall stated aims of the book, which is to provide discussion on the use of and access to human-derived tissues. In particular, the chapters on computational methods of toxicology prediction and on the general pharmacokinetics overview, whilst interesting, did not add to the knowledge I was looking to gain from this book. Furthermore, the early chapters stated strongly that engineered 3D tissues, stem cell- derived materials or reconstructed organoids are themselves approximations and are not equivalent to primary human tissue, and argued eloquently for the provision and access to more patient-derived materials to enable improved drug discovery and development. However, due to current limitations in this access and, in particular for diseases of the central nervous system, it is apparent that there is no easy way to ever change this situation, and as such, the majority of the book chapters focus on these other approximative tools. That being said, Chapter 8 dedicated to stem cells gave an informed and balanced view of the technical challenges and opportunities of these often over-hyped ‘patient in a dish’ cells, and provided useful summaries of the current cell types and their successes and failures.

Overall, the book is a useful read for anyone engaged in translational drug discovery to consolidate their understanding of the inherent technical difficulties of accessing primary human tissue and the advantages of doing so in the context of the disadvantages of the current animal models. The main theme of the book advocates the move to toxicology systems of greater human relevance, which, although we remain constrained in our current working practices by current regulatory safety requirements, nonetheless broadens our aware- ness of the key issues involved.

* ChemMedChem July 2015 *

"The book provides a very interesting historical perspective on the use of animal models."

"...the book is a useful read for anyone engaged in translational drug discovery to consolidate their understanding of the inherent technical difficulties of accessing primary human tissue and the advantages of doing so in the context of the disadvantages of the current animal models."

* ChemMedChem July 20