Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • OUTLOOK

Miniature organs to heal damaged livers

Three people in surgical masks and gowns prepare to inject cells into a liver in an operating theatre

Kourosh Saeb-Parsy and his colleagues prepare to inject cells into a liver.Credit: Teresa Brevini

Bilitech is a spin-off from the University of Cambridge, UK, and one of the final eight for The Spinoff Prize 2021.

Although the human liver can repair itself, everything has its limits. And when this regenerative capacity is exhausted, the best course of action to treat liver disease is a transplant. But it is an expensive procedure. What’s more, the supply of suitable donor livers is inadequate and can vary depending on where a person lives.

Kourosh Saeb-Parsy is a transplant surgeon at Cambridge University Hospitals NHS Trust, UK, and he’s hoping his research will put him out of a job. “If a liver is 2% damaged, then why replace the whole thing if you could just fix the 2%?” he asks.

It was with this question in mind that he founded Bilitech in late 2017, with colleagues at the University of Cambridge. The company wants to use organoids — multicellular in vitro tissues with structures that reflect the intricacies of whole organs — to restore livers, rather than replace them. Its technique could also be used to improve the quality of donor livers before they are transplanted. This could mitigate shortages by allowing more candidate organs to pass quality-control checks.

Bilitech’s technology is focused on the liver’s bile ducts. This intricate network of tubes transports bile — a digestive fluid produced in the liver — to the small intestine, in which it helps to break down fats. Because of bile’s strong digestive capacity, it can kill or injure cells in parts of the body that haven’t developed a suitable protection mechanism. Bile ducts have a layer of epithelial cells known as cholangiocytes to protect against bile’s harsh biochemistry. Biliary disease, however, leads to a loss of these shielding cells. Bilitech is trying to solve this problem.

“Because bile is a digestive fluid, it just starts eating up the liver,” says Fotios Sampaziotis, a hepatologist at the University of Cambridge and a Bilitech co-founder. “It’s a very tough situation.”

Growing a liver

Biliary disease accounts for up to 70% of liver transplants in children and roughly 30% in adults. And the transplant often does not provide a cure — the disease re-emerges in as many as 60% of cases.

To grow their organoids, the Cambridge researchers first extract human cholangiocyctes from a donor through a minimally invasive biopsy or endoscopy. Ideally, organoids would be created from a person’s own cells, which would greatly reduce the chance of the end product being rejected by the immune system. In an emergency, however, there is no time for such a procedure, and scaling-up such a production method to meet the demands of donor waiting lists would be tough. So Bilitech is planning to create a library of organoids from donors.

The 3D, dome-shaped organoids are transferred onto a scaffold, made of both synthetic and biological materials (see ‘Liver repair’). This provides the structure for the organoids to grow into tube shapes akin to bile ducts. The scaffolds contain signalling molecules to encourage the organoid’s cells to grow and mature. The result is a bioengineered organ called BiliDuct, which the researchers hope could replace failing bile ducts. In 2017, they demonstrated that the organoids could replace bile ducts in mice1.

Liver repair: Bilitech’s two liver-regenerating products

The proposed strategy for less-widespread bile-duct deterioration is slightly different. “If the problem is with the little tubes, then they’re too small to replace surgically,” Saeb-Parsy says. That’s where the company’s second product, known as BiliCell, comes in. In a paper published this year, the scientists showed that they can regenerate and repair human bile ducts ex vivo by injecting the livers with cells extracted from the same organoid that BiliDuct is derived from2. “We’ve shown that we can inject BiliCell into these little branches of the tree and they nicely occupy the gaps in the bile duct,” says Saeb-Parsy.

The proposed applications for BiliCell are twofold. First, the cells could be injected into people with declining liver function to prevent them from ever needing a transplant. “This doesn’t have to be a surgical intervention,” Sampaziotis says. “We can access the bile ducts with cameras and put a tube in to inject the ducts.” People would need to be only lightly sedated.

Second, BiliCell could be used to improve the quality of donor livers so that more of them are suitable for transplants. “I’m not aware of anyone else doing anything comparable to this. I’m enthusiastic and impressed by the Bilitech concept,” says Peter Friend, a transplantation researcher at the University of Oxford, UK, who is not involved with the company. Many donor livers end up being rejected because their cholangiocytes are damaged, Friend explains. “Coming up with cell-therapy methods to repopulate the biliary tree is an unmet need,” he says.

The Cell and Gene Therapy Catapult, an independent centre of excellence in London charged with advancing the United Kingdom’s cell-therapy industry, conducted an independent economic analysis of Bilitech in 2020 to determine whether its products are likely to be commercially viable. The centre concluded that the amount Bilitech could reasonably charge for its technology would vary depending on a person’s liver disorder, but could be as high as £632,000 (US$890,000). That figure is driven, in part, by the high (and rising) costs of liver transplants, which are currently the only alternative. The cost of a liver transplant depends on the extent of the pre- and post-surgery costs that need to be included alongside the bill of the procedure itself. But in 2015, it was estimated3 that liver transplants in the United States cost around $1.4 million per person — and the cost is projected to exceed $2 million by 2035. The number reached by the Cell and Gene Therapy Catapult is much greater than Bilitech’s production costs, estimated at $39,000 per person — resulting in a sale price that the company hopes will be acceptable to health-care providers.

The gulf between the price tags of transplants and Bilitech’s products is another string to the company’s bow, says Sue Sundstrom, director of Sundstrom Innovation, a consultancy firm in Clevedon, UK, that specializes in supporting early-stage start-ups in the life sciences. “I do a lot of work with early spin-outs and you wouldn’t believe the number of academics who think they don’t need to think about the commercial side,” says Sundstrom, one of the judges of The Spinoff Prize. “They’ve clearly thought about the economics,” she says.

The company still has hurdles to overcome — not least, the practicalities of manufacturing and storing the product, and delivering it to people. Because there is no other product like it in use, all of the infrastructure needed to get Bilitech’s therapies from production to person will have to be built from scratch. “Getting cells out of patients or donors, prepared and then back into patients sounds easy, but having worked with cell treatments, I can tell you it’s unbelievably difficult,” Sundstrom says. The company will need to work out how to make enough of its product to satisfy demand in a timely manner, without producing so much that it would have to be carefully — and expensively — stored.

doi: https://doi.org/10.1038/d41586-021-01663-y

This article is part of Nature Outlook: The Spinoff Prize 2021, an editorially independent supplement produced with the financial support of third parties. About this content.

References

  1. 1.

    Sampaziotis, F. et al. Nature Med. 23, 954–963 (2017).

    PubMed  Article  Google Scholar 

  2. 2.

    Sampaziotis, F. et al. Science 371, 839–846 (2021).

    PubMed  Article  Google Scholar 

  3. 3.

    Habka, D., Mann, D., Landes, R. & Soto-Gutierrez, A. PloS ONE 10, e0131764 (2015).

    PubMed  Article  Google Scholar 

Download references

Subjects

Nature Careers

Jobs

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing

Search

Quick links