The liver is an almost magical organ. The ancient Greeks knew this. Prometheus’ legendary punishment for stealing fire from the god Zeus was for eagles to feast on his liver daily, only for it to grow back every night.
For tragic demigod Prometheus, this regenerative property made his suffering eternal. For mere mortals, the liver’s ability to heal itself is a biological marvel. The organ can lose nearly half of its mass in a trauma – bird-related or otherwise – and still grow back to full size.
But even this has its limits. The recurrent damage of chronic liver disease leaves scars. The more scarring, the harder it is for the liver to repair itself until, eventually, it is worn out and cirrhosis, or end-stage liver disease, sets in. Transplantation is the only remaining curative option.
Like any expert of the liver, Professor Stuart Forbes is well versed in the Prometheus myth. He is also all too familiar with what happens when livers exhaust their regenerative potential.
“Chronic liver disease is an enormous health burden in the UK,” he says. “There are specific treatments for some causes – like treating viruses or autoimmune diseases, or stopping alcohol – but once the damage is there, there is no specific treatment to help repair the liver.”
The problem is growing. It is the only chronic disease on the rise in western countries and, with 14,000 lives lost each year, is the third leading cause of premature death in the UK. The British Liver Trust describes it as “an epidemic”. Liver transplantation is complex and invasive and is hampered by a shortage of donors.
To counter this grim scenario, Professor Forbes has spent the last decade funded by the Medical Research Council working with another seemingly miraculous part of human biology: macrophages.
Macrophages cells are known primarily for their role in innate immunity, but they also play a part in tissue regeneration. “When any damaged organ tries to repair itself a number of things happen,” says Professor Forbes. “Macrophages are involved in a lot of those processes in terms of breaking down scar tissue, helping repair, and stimulating the regeneration of the organ.”
This is equally true for the liver, but over time the number of macrophages become depleted and unable to function in the face of severe damage.
This has led Prof Forbes and his team at the University’s Centre for Regenerative Medicine to investigate the potential of genetically modifying macrophages to enhance their regenerative features and use them to replace the exhausted cells at the point when the body is healing itself.
It raises the prospect of a treatment that can heal severely damaged livers and reduce the need for transplant.
Professor Forbes is well placed to do that. The University has a strong partnership with Professor John Campbell’s cell therapy group at the Scottish National Blood Transfusion Service. Not only did this collaboration discover the regenerative potential of macrophages as a cell therapy, but it also applied this to the development of novel treatments for chronic liver disease.
Working in the world-class capabilities at BioQuarter, Professor Forbes’ team are close to the region’s liver service and transplant unit. They also have access to a centralised cell culture facility, a state-of-the-art good manufacturing practice cellular therapy facility and all the necessary infrastructure to do imaging and clinical trials.
The work has attracted attention from beyond the University, allowing it to move to the next stage.
Specialist healthcare investment company Syncona Ltd funded a two-year research collaboration to prove the commercial viability of macrophages as a treatment. After filing several foundational patents, in 2020 Professor Forbes co-founded the spin-out company Resolution Therapeutics, which then received £26.6m from Syncona Ltd.
The investment has given the project’s potential a Mount Olympus-sized boost.
“This has enabled us to scale up significantly the number of people working on the project, the equipment and the ambition to really lead in this area,” says Professor Forbes.
Resolution Therapeutics are now genetically modifying macrophages to assist with the repair of severely damaged livers. Phase one trials have proved that the treatment is safe. Phase two, involving a randomised control trial, is happening at the moment.
Should it be successful, there is huge potential for macrophages to be trained on other diseases.
“The fact that we can now engineer cells gives us the potential to target a wider range of diseases,” says Professor Forbes. “For example, people have engineered t-cells to make them active against cancers. So we hope that if we engineer macrophages we can make them more active against chronic organ damage.”
Living without limitations
Research, however, is still at its early stages. That said, Edinburgh is well placed in this developing field. Professor Forbes team are the first in the world to develop macrophage therapies. The thousands of people in the UK suffering from liver disease could be the first beneficiaries.
“Our hope is that they can live their lives outside of hospitals, with no limitations,” he says. “We are some way from that, but that is the dream.”
Image credit: Macrophage cell: Getty/SciePro; Prometheus: Getty/ZU_09