Insights from Matthew Dalby, Professor of Cell Engineering, University of Glasgow

While emerging non-animal technologies and regenerative medicines present exciting opportunities to improve the drug discovery process, technological adoption challenges are slowing their development, deployment, and wider implementation.

This article explores the work undertaken by Professor Matthew Dalby and the lifETIME Centre for Doctoral Training (CDT) to address these bottlenecks and facilitate innovation in drug discovery. The lifETIME CDT is a partnership between the Universities of Glasgow, Birmingham, Aston, and Galway that trains PhD 'innovation leaders' with multidisciplinary, high-value skills in creating and applying new knowledge to accelerate therapeutic discovery.

Current scientific challenges in drug discovery and regenerative medicine

Despite a cost of approximately £1.5 billion to develop a new drug, about 60% of small molecule drug projects ultimately fail. But critically, the majority of them fail during clinical trials due to toxicity or efficacy effects on humans. These later stage drug development failures are a significant issue, costing companies hundreds of millions of dollars. One principal cause is that the conventional cell cultures and non-human systems used for research do not adequately represent human physiology.

In recent years, humanized, non-animal technologies (NATs) built using regenerative medicine principles have started to emerge. NATs represent more complex in vitro biological systems and provide more predictive power than conventional in vitro systems. Therefore, they may have the potential to replace animal studies to improve drug safety and efficacy prediction before human clinical trials.

However, technological acceptance and resistance are some of the biggest challenges we face in these fields. For example, in drug discovery, most biopharmaceutical companies follow conventional methods because they are familiar and well established. Similarly, in regenerative medicine, driving the acceptance of new cell therapies, new biomaterials, and new approaches in a traditionally conservative industry can be slow.

Drug companies are starting to look at novel technologies and microphysiological systems, but this work is gradual and often limited to a small department. There needs to be more emphasis on these platforms, and greater collaboration between academics and industrialists to improve the research, development, and adoption pipeline. Ultimately, this comes down to the willingness of large companies, SMEs, and academics to engage with each other and understand their roles in driving this change. It will also be necessary to work with regulators throughout the process to ensure that information on how new techniques benchmark to in vivo tests is easily accessible.

Overcoming bottlenecks in drug discovery and regenerative medicine

When discussing drug discovery or regenerative medicine, it is first important to understand that challenges stem from a combination of problems across engineering, physics, chemistry, mathematics, clinical research, and biology. In response, the lifETIME CDT is training world-class PhD's in the skills for cross-disciplinary research. 84 PhD students will complete the program over five cohort intakes, creating a sizable pool of talent in the UK with the right skills to tackle complex drug discovery problems and cohort-based training is fundamental to the program. With each cohort intake, the CDT builds a connected network of talented researchers and 'innovation leaders,' with the necessary mindset to be able to promote closer collaboration across biology, engineering, chemistry, physics, and mathematics disciplines.

Business and entrepreneurial skills are given just as much attention through schemes such as a "Dragons Den" style business planning and pitching competition, judged by our industry partners, to foster their leadership potential. As a result, students are well equipped to fill all of the requirements in this sector, whether they want to pursue a career in research, business management, consultancy, regulation, or charity.

Industry partners provide in-kind support by contributing projects and providing mentorship throughout the program. In doing so, they help students develop skills they are looking for in their future leaders. Our vision is that students graduate with academic and real-world experience and work with industry partners permanently, so together, we can continue building the environment we need to flourish. Overall, the CDT is an opportunity for companies, students, and academics to collaborate, encourage cross-disciplinary innovation, and shape this sector in the UK.

CDT projects span several sectors, including microfluidic technology projects, lab-on-a-chip projects, and detection and characterization projects using Raman Spectroscopy for neurodegenerative disease research. There are also soft material-based projects using hydrogels (soft material) and scaffolds (hard materials) looking at bioengineering a range of tissues, for example, different cancer environments, bone, vascular tissues etc. Furthermore, there are bioinspired micro-robotics projects on responsive cell changing materials. These are the breadth of projects we are going to need to improve drug discovery and lead the development of non-animal technologies.

Leveraging novel droplet-based microfluidics technologies in drug discovery

 High-throughput screening capabilities are crucial to accelerating therapeutic discovery. But when you combine high-throughput screening with the ability to rapidly encapsulate single cells in picolitre volume droplets (picodroplets) and perform highly sensitive assays, you now have a powerful tool to run experiments beyond only screening cells. These capabilities are just some of the beneficial features provided by picodroplet-based microfluidic technologies.

 The development of high-throughput picodroplet-based microfluidics are transforming our understanding of complex biological processes and our ability to discover new antibiotics. By compartmentalizing individual cells in picodroplets, we can now accurately analyze the mechanical properties of cells, to better understand cell potency and growth, and enable the development of drugs against hard-to-target cells. For these studies, streamlined systems like Sphere Fluidics' Cyto-Mine® are useful. Companies like Sphere Fluidics can also help academics define the best protocols and assays to use to interrogate mechanosensitivity in the pipeline and accelerate the discovery of new drugs.

 One of our current projects, run by Dr. Jonathan Cox, a Lecturer in Microbiology and Director of the Mycobacterial Research Group at Aston University, and Dr. Marian Rehak, VP of Research and Development at Sphere Fluidics, is using picodroplet technology to accelerate the discovery of novel antibiotics against Mycobacterium tuberculosis. Mycobacterium tuberculosis is a bacterium that causes tuberculosis (TB). This is an important area of research because people are worried about the post-antibiotic era, and TB is one such example of a disease that is becoming difficult to treat due to antibiotic-resistance. Dr. Cox is doing outstanding work in this area. But teaming up with Sphere Fluidics has helped catalyze this research and speed up the discovery pipeline with their novel picodroplet-based microfluidic technologies. During this project, our CDT student will produce a physiologically relevant and suitable platform for high-throughput drug discovery. They will then apply this platform to screen a highly valuable set of anti-TB drugs to discover their activity and investigate their mechanisms of action.

The future of drug discovery and regenerative medicine

 Over the next five to ten years, we aim to encourage the prioritization of non-animal technologies through building partnerships, supporting scientific publications, and producing the next generation of talent.

Partnerships: More rapid progress will arise from closer collaboration between academia and industry. We have begun the process through CDT projects, but new and expanded partnerships will help drive the research, development, and acceptance of new products.

Publications: Producing literature and publications is also vital to demonstrate the equivalence of these new techniques with conventional in vivo models and evaluate the performance of regenerative medicine approaches when taken through the phases of preclinical and clinical trials.

Talent: Most importantly, our long-term vision centers on developing a network of 84 CDT graduates from different backgrounds who will be progressing in their careers and uniquely positioned to shape change. The CDT will then focus on producing subsequent cohorts to add to the talent pool continuously.

This industry/academic collaboration will have a considerable impact on the environment and guide the change needed to help all players in the ecosystem flourish. Companies will see market growth, patients will access better drugs and better regenerative medicines, and students will progress into dynamic careers. To find out more, visit the lifETIME CDT website.