Organ-on-a-chip: transforming drug development

When we are ill, most of us will rely on medicine to help us get better. But behind every drug is many years of thorough research – it takes an average of 12 years for a drug to travel from the laboratory to your medicine cabinet [1]. 

Before any new drug can be approved, it must undergo extensive testing – both in the laboratory and in clinical trials – to ensure that it is safe and effective for patients. Despite this, an estimated 86% of drug candidates entering clinical trials will never reach the market [2].

The crux of the problem lies with traditional pre-clinical testing models – which involve human cells or animals – as these can only go so far towards predicting the effects of an experimental medicine on the human body. Another layer of complexity comes from the genetic variations between patients that can influence the way the body reacts to a drug. 

The development of advanced cell culture models, such as ‘organ-on-a-chip’ technologies, can more accurately reflect human physiology and could potentially revolutionize the future of drug development.

“The hope is that these organ-on-a-chip technologies can one day help accelerate the development of new drugs and advance personalized medicine,” says Philip Hewitt, our Head of Early Investigative Toxicology.

In the early stages of drug discovery, researchers will carry out many of their experiments on cells grown in laboratory dishes (in vitro testing).

“At these stages, we have a lot of open questions and uncertainties and the chemists can’t manufacture kilos of the compound – so it’s more about fine-tuning the chemical to make sure we have the right candidate,” explains Hewitt. 

Traditionally, these experiments are carried out on a single type of cell grown in a 2D monolayer on the surface of a plastic dish. But this does not represent how cells normally grow and function in the body where they are surrounded by other types of cells in three dimensions and bathed in bodily fluids that contain a complex milieu of hormones and other molecules that can influence their activities.

“A cell in a dish is not anything like a cell you have in your body,” says Hewitt.

If the results from in vitro testing are promising, the experimental drug will then move onto the next stage. It is a strict regulatory requirement, enforced by law, that all new medicines must first be assessed in animals (in vivo testing). This will provide important evidence about the safety and effectiveness of an experimental drug before authorities can approve it for human trials.

“The tests in animals are required to evaluate the drugs as this provides a fully integrated organism which metabolizes, distributes and exhibitsall effects and side-effects of the compound,” says Paul Germann, our Global Head of Chemical and Preclinical Safety. 

While differences between species may help explain why some promising experimental medicines fail in clinical trials, genetic variations or disease phenotypes between patients offer another explanation. For example, a drug can ultimately fail in clinical trials if it is only effective in a subgroup of individuals who have a specific genetic profile.

In recent years, scientists have turned towards the use of advanced 3D cell models for drug testing, which better reflect the real-life human context. For example, our researchers are at the forefront of work investigating the potential  of organ-on-a-chip technologies to advance drug development.

“Organ-on-a-chip technologies aim to create miniaturized physiologically-relevant biological testing systems,” explains Hewitt. “You’re effectively trying to mimic the human situation by a mini-organ on a small chip.” 

As well as incorporating multiple cell types, these devices contain hollow microfluidic channels – and so researchers can apply mechanical forces to create a fluidic flow to mimic the physiological conditions of the real organ.

“In traditional cell culture, you will put the drug compound on top of the cells and it just sits there,” explains Hewitt. “Whereas in a more sophisticated flow model, you can control the concentration of the drug that the mini-organ is exposed to.”

But in the longer term, the ultimate prize will come from interconnecting these mini-organs – delivering physiologically relevant in vitro testing systems. Adopting these sophisticated new models could ultimately help deliver better medicines for patients – and contribute to the ‘3Rs’ principles (Replacement, Reduction, and Refinement) by reducing the use of animals in research [3].

“If we can filter out more of the drug candidates that are unlikely to succeed at the earliest stages of drug development, this will help boost the success rate of medicines that enter clinical trials,” says Hewitt.

In the future, it may even be possible to use a person’s stem cells to create their own organ-on-a-chip, offering important new opportunities for realizing the benefits of personalized medicine.

“We’d be able to use these models to identify key genetic differences between people who are sensitive to the effects of an experimental drug and those who aren’t,” explains Hewitt.

This could lead to the development of tests that can help target a new medicine to the right patients, potentially improving the chance of success in clinical trials.

The organ-on-a-chip technology is very complex, is constantly developing, and is being used by multiple industries for many different purposes. And so, collaboration is a key aspect for its success, requiring input from scientists working across several areas of research.

We have already established a very tight network across all areas of our company, including joint research projects, and general information exchange. This has been consistently expanding, with new connections being established - for example, through our internal Science Network.

“Our Life Science and Electronics colleagues have expertise in technologies that can drive the structure of the chips, drive the integration of biosensors – and importantly, in developing the cells and growth media to use,” says Hewitt. “We also have access to the pharmacologists, biologists, drug metabolism and pharmacokinetics (DMPK) experts with the necessary knowledge in the testing, assessing and validation of models for future implementation into routine preclinical testing.”

Our team is currently focusing on using liver and intestine organ-on-a-chip models to improve the in vitro safety testing of experimental drugs.

“Liver toxicity is one of the main reasons that drugs fail or get withdrawn from the market,” explains Hewitt. “And the gut is also important for the absorption of orally-delivered drugs and a common target for novel anti-cancer treatments.”

But there are still some major challenges that will need to be overcome to realize the full potential of organ-on-a-chip technologies. These include accessing and combining different cells. The next step, combining multiple organs to mimic their interconnectedness within the body, is even more complex. To help address this challenge, we are participating in a large EU-funded consortium (imSAVAR) [4].

“One of the aspects of this collaborative project is the development of organ-on-a-chip models to understand the impact of the human immune system on the safety of new drugs”, adds Hewitt.

We are also running and setting up multiple other external collaborations, including our participation in the IQ Microphysiological Systems (MPS) Affiliate, which brings together pharmaceutical and biotechnology companies working on these models [5].

“These collaborations will lead to greater success, additional innovation - and more robust and predictive tools in the future,” says Hewitt.

Developing organ-on-a-chip technologies offers the potential to have a huge impact on patients in the longer term.

“Over the next 1-2 years organ-on-a-chip will be used to answer specific questions, data is already being used as part of submission documents. The real power to potentially replace well established in vitro and in vivo models will take longer, but within 5-10 years this could start to become a reality,” says Hewitt.

In the future, it might be possible to use these micro devices to dramatically improve the accuracy and efficiency of preclinical drug testing – meaning that more experimental medicines succeed in clinical trials. Looking even further ahead, it might be possible to create personalized drug testing systems that could help identify the ideal drug combination and dose for treating that individual’s disease.

“It is a very exciting technology – it’s like having a miniaturized human body on a small chip,” enthuses Hewitt.

Organ-on-a-chip is one of the innovations where our company is coming together with others to push the boundaries of what’s possible. We want to reinvent tomorrow so that we make a difference to millions of people’s lives every day - and to do whatever we can towards reducing or replacing the use of animals in drug testing.

_{[1] https://www.medicinenet.com/script/main/art.asp?articlekey=9877
[2] https://www.centerwatch.com/articles/12702-new-mit-study-puts-clinical-research-success-rate-at-14-percent 
[3] https://www.nc3rs.org.uk/the-3rs 
[4] https://www.ime.fraunhofer.de/en/press/imSAVAR.html
[5] https://iqconsortium.org/news/iq-mps-affiliate}