Rebuilding the liver...from the inside

COVID has dominated the headlines for the past year, but important medical research continues apace into a wide range of conditions. Fitzwilliam Fellow and alumnus, Dr Kourosh Saeb-Parsy (Medicine, 1993), is a leading liver transplant surgeon at Addenbrookes, and a Reader in Transplantation in the Department of Clinical Medicine. His team have recently made ground-breaking discoveries in the repair of damaged bile ducts, discoveries which may radically change our capacity to treat a range of conditions. 

The efficient function of the liver is crucial to good health. The liver has multiple metabolic functions, playing a critical role in digestion and nutrient absorption, protein production, and hormonal production and regulation. It is the primary organ involved in the breakdown of every toxic substance our body encounters, preventing the accumulation of waste products. A human adult liver can filter 1.7 litres of blood every minute, and any interruption to this process can have serious consequences for the individual.

Dr Saeb-Parsy's research focuses on the regeneration of bile ducts in the liver, and to understand the importance and application of the research, a snapshot of the bile ducts' function is helpful. As Kourosh explains: "The liver is a complex organ containing lots of different cell types. The bile ducts, or cholangiocytes are a tiny proportion of the total liver, about 2%, but they do a really vital job. They are tiny tree-like networks throughout the liver, lined with epithelial cells which allow bile that's been produced by the liver to drain."

When the network of bile ducts malfunctions, either through deterioration or congenital defects, the liver is unable to function efficiently:

"Gaps occur or can form in these cells that line the tubes. Imagine a cobbled street, where some of the stones have fallen out. If you don't replace the stones, but continue to use the street, the gaps increase until you have serious potholes."

But although the impact of the damage can be huge on the patient, the fact that this damage occurs at a cellular level makes it extremely very difficult to treat:

"Unfortunately leaking occurs within the substance of the liver and we can't do anything about it. Currently we have to wait until this leaking bile causes so much damage to the entire liver that the liver has to be replaced."

The impact of this liver failure can be dramatic and life-threatening. There are significant challenges involved in a liver transplant - both availability and success are far from guaranteed - and many patients endure months and years of poor health. And so, it is by addressing the deterioration of the bile ducts directly, that Kourosh and his team's discoveries will radically improve the treatment of those suffering.

As the Science paper sets out (https://science.sciencemag.org/content/371/6531/839), the technique developed works directly on the bile ducts, infusing them with new cells and plugging the gaps before they cause significant damage. Large numbers of cells can be grown, using a special cocktail of reagents, from a tiny sample taken from a donor.

"Staying with the cobbled street metaphor, we can inject new cells to flow over the cobbles. These cells then grow and fill the gaps and, crucially, repair the damage. In this particular paper, we show that we can do this with the very smallest of tubes in the bile ducts. And we can also use these cells to build (or rebuild) the bigger tubes. This is important because in addition to those who suffer bile duct deterioration, there are some patients - babies - who are born without the full network of bile ducts (biliary atresia) and for whom transplant is currently the only option. In this research, we've shown that we can build the missing parts."

The research took place largely prior to COVID restrictions and was the product a large collaborative network. Dr Saeb-Parsy co-led the project with Dr Ludovic Vallier and Fotis Sampaziotis from the Cambridge Stem Cell Institute, together with a large teach of hepatologists, transplant surgeons, radiologists, molecular biologists, stem cell biologists, physicists and bioinformaticians.

Some of the project required very particular solutions to technical challenges, not least the delicate nature of the organs being scanned. The Fitz community proved helpful in this respect. Fitz Fellow, Dr Steve Sawiak is a co-author on the paper, in recognition of his work on scanning the livers of mice involved in the research. Dr Sawiak, a physicist working on MRI, normally focuses on the preclinical uses of morphometry, with structural imaging, diffusion tensor imaging and spectroscopy and his MRI scanner is generally calibrated to work with much larger samples but, as he explains:

"It's one of the charming things about Cambridge - the spread of expertise is broad, and sometimes you find yourself working on projects quite unrelated to your own research, because you have the expertise on a particular machine. With a few modifications, I was able to build a bespoke facility for the mice, and the results were good. A mouse liver is a challenging subject to work with!"

The impact of this research is hard to overstate. From the patient's perspective, it offers hope and a less risky pathway to health. Rather than more invasive surgery, Kourosh is confident that the treatment could be delivered under sedation:

"Patients would be given an injection of these cells, and then we would monitor improvement in the condition of the bile ducts. We may need to give an injection every five years or maybe we have to give an injection every year, but what is exciting is that the process of giving this injection will be far lower risk and less invasive for the patient."

The process of developing such a treatment is, as Kourosh puts it, "naturally and appropriately arduous". Step one, as represented by the paper, is to show that the science is robust.  The next step will be to demonstrate capacity to manufacture sufficient quantities of the cells required, and to do this Kourosh has co-founded a company, Bilitech (www.bilitech.co.uk), to raise the funds required to do this. Work is underway, and at the time of writing the company is one of four to have been shortlisted to the final stage of the Nature  2021 Spin-Off prize.

Prizes aside, though, it's clear that for Kourosh, much of the reward in this work is the ability to directly impact the lives (and livers) of the patients under his care:

"There is the discovery, and as academics we get excited by making new discoveries and solving problems. It's a given and certainly applies in this case. But first and foremost, I'm a clinician. What really excites me far beyond any high impact publications, is to imagine myself being able to look back, in say ten years’ time and know that we have saved patients who today will most likely die. As today's transplant surgeon, I'm working with these patients and trying help them with clinical intervention.  I know how urgent and transformational this will be."