A platform facilitating research on human organs maintained ex-vivo.

Much of the research on human disease and how our body works is performed in the laboratory or using animal models. Although these systems are very useful, they demonstrate some inherent differences from human organs. Consequently, only a small proportion of drugs developed in the laboratory are shown to be effective in human in clinical trials. This results in significant burdens in terms of money, time and effort for UK research and healthcare, and prolongs the period required to deliver effective therapies to patients.

We recently demonstrated that we could overcome this barrier by performing studies directly on human organs. These organs were kept 'alive' outside the body using machines called ex-situ normothermic perfusion (NMP) devices. NMP devices are used in clinical practice to preserve donor organs outside the body during the period leading up to a transplantation. Organs not used for transplantation are offered for research. In our most recent work we used these organs to trial experimental treatments, such as injecting cells to repair damaged organs (cell-based therapy) or testing new COVID-19 drugs. Importantly, our results provide proof-of-principle for the feasibility of this approach. The same method could be used to perform a broad variety of studies which were not possible until now, such as testing new therapeutics in human tissue.

Following publication of our findings, we were approached by multiple groups within the University of Cambridge and beyond requesting to collaborate and use this technology; while we secured UKRI funding to continue our work on cellular therapy. However, the clinical device we used for our initial experiments could not meet the increased demands for research studies, as it is extensively used in day-to-day clinical practice. To overcome this restriction, we are requesting funding to purchase a dedicated NMP device for research which will be hosted in Cambridge Stem Cell Institute (CSCI). The Institute is located within the Cambridge Biomedical Research Campus (BRC) making it easily accessible to any group within the University. The BRC combines cutting edge research facilities with two major organ transplantation centres (Addenbrooke's Hospital and Royal Papworth).

The device will enable for the first time multidisciplinary research in human organs. Some of the initial studies planned using this equipment include:
1. Using cell transplantation to repair human organs as a treatment for liver disorders
2. Developing and testing drugs for a multitude of diseases including COVID-19
3. Infecting organs with viruses or bacteria to better understand how our immune system works and how infectious organisms develop resistance to treatment
4. Explore how organs regenerate after damage
5. Developing new tests which predict how donor organs will behave after transplantation.
6. Developing new biosensors to monitor human organs in real-time

These studies will be performed by diverse groups within and beyond the University of Cambridge including the CSCI, the Cambridge Institute of Therapeutic Immunology and Infectious Diseases (CITIID), the Wellcome Sanger Institute and the Catholic University of Louvain (Belgium) promoting national and international collaborations. Importantly, this equipment will provide the foundation for developing one of the first facilities for basic research using NMP organs in the UK contributing to the advancing the national research infrastructure.

Clinical translation is limited by lack of optimal systems for validating basic research. The complexity of human organs cannot be reproduced in vitro; animal models are restricted by interspecies variation, while patient recruitment and regulatory requirements limit human trials.

We recently showed proof-of-principle that we can overcome this barrier by performing experiments in human organs using ex-situ normothermic perfusion (NMP) devices. These devices maintain donor organs in physiological conditions ex vivo, in anticipation of transplantation. We injected cholangiocyte organoids in NMP livers and validated their capacity to repair human tissue. Since then, multiple groups requested access to this system for studies that can only be performed in human organs. To meet this demand, we are requesting an NMP device dedicated to research.

The device will be used for multidisciplinary research by groups in the University of Cambridge and beyond, including, but not limited to:

1. Regenerative medicine. Different cell types will be transplanted in NMP liver to repair the organs.
2. Infection and immunity. Pathogens, immune modulating agents and drugs will be injected in the circulating blood (perfusate) of NMP organs to study host-immune system or host-pathogen interactions and test new therapeutics.
3. Molecular mechanisms controlling cell identity and organ regeneration. Small molecules or therapeutic agents (e.g. bile acids) perturbing the organ microenvironment will be administered to NMP organs to characterise how changes in the cells' niche affect cell fate decisions and organ regeneration.
4. Precision medicine/biomarkers. Transcriptomic characterization of NMP organs will be correlated with clinical outcomes to identify predictors of graft quality.
5. Bioengineering. Testing implantable organ biosensors

An NMP device will set the foundation for one of the first UK platforms to perform studies in human organs and accelerate clinical translation.