Stem cell research: meet the scientist growing ‘mini guts’ in her lab

Cancer

Vivian Li, group leader of the stem cell and cancer biology lab at the Francis Crick Institute, talks tumours, how she aims to target them – and why female researchers need to aim big.

Written by Natalie Grover for The Guardian

Vivian Li from the Francis Crick Institute. Credit: Dave Guttridge

Vivian Li likes to grow things. Apart from cultivating vegetables and caring for her chickens, she’s been nurturing “mini-organs” – tiny versions of organs derived from a patient’s own stem cells – in her lab at the Francis Crick Institute in London.

These cultures, known as organoids, mimic the way the tissues of a specific organ behave so that scientists can try to unravel the evolution of diseases, carry out drug research and refine personalised medicine.

A lab grown gut organoid

Gut organoids, labelled with markers that show dividing stem cells (green) and matured cells (red), with cells’ nuclei shown in blue. Credit: Vivian Li

Starting with stem cells

Crucial to the field of organoids is the ability of stem cells to develop into almost any kind of cell in the body, becoming muscle cells, brain cells or a variety of other cells. Using these, researchers can grow tissues and organ structures – organoids – giving them the ability to study how the organs actually function.

Li, a stem cell scientist investigating the healthy gut and bowel cancer, first worked on organoids in the Netherlands at the Hubrecht Institute for Developmental Biology and Stem Cell Research under Prof Hans Clevers, one of the original architects of the diminutive structures.

She had made a beeline for the Clevers Lab in 2008 after wrapping up a PhD focused on bowel cancer in her native Hong Kong. The following year, the (levers Lab, in Utrecht, created its first Iteration of an organoid: a mini-gut.

The advances came thick and fast after that, with researchers crafting a range of other mini-organs, including a liver, pancreas, bladder, and tear glands capable of “crying”. The Clevers team even graduated from mammals to reptiles, successfully growing snake venom glands.

This film is taken from Outwitting Cancer: Making Sense of Nature’s Enigma, a free in-person and online exhibition at The Francis Crick Institute in London. Visit crick.ac.uk for further details

Going with your gut

But given her previous work on cancer, Li was especially interested in the bowel, and eager to take this strand of work forward. So, in 2013, she moved to the UK and set up her own lab at the Francis Crick Institute, growing mini-guts with the ability to digest nutrients and secrete mucus in a bid to solve an assortment of medical challenges.

The Crick is the ideal environment for this – collaborative, multidisciplinary, open. Along with other key funders, we support more than 90 research groups, including Li’s lab, at the Crick- the largest biomedical research institute under one roof in Europe. As well as having raised £100m through our “Create the Change” campaign to help build the institute, we invest around £50m each year so that the Crick can offer researchers such as Li reliable, ongoing core funding. This mitigates some of the pressure of applying for grants, allowing them to make ambitious long-term plans and pursue demanding research that will shape the future of human health.

One of Li’s projects – in collaboration with the Great Ormond Street children’s hospital – involves work that could one day lead to the generation of organs for children with small-intestine failure who require transplants; at present this procedure is limited by a scarcity of donors, the risk of rejection and other complications, Early research has demonstrated that it is possible to grow a small piece of functional gut in the lab using a sick child’s own stem cells, raising the possibility of eventually scaling up to grow a larger segment of functional intestine.

A scientist pipetting a sample into a tube

By growing mini-tumours in the lab, Li’s team are able to screen drugs the tumour might be sensitive to. Credit: Getty Images

The potential of mini-organs

But it’s not only healthy tissue that can be grown into mini-organs. A tumour surgically removed from a cancer patient can provide the raw material to grow a mini-tumour in a dish. This can then be used to screen drugs to which the mini­ tumour – and thus, in theory, the patient it came from – might be sensitive, says Li. The hope is that, one day, this might be used in real time, to find personalised treatment strategies for individual patients.

A key longer-term avenue of research is an internal network of proteins that signal inside stem cells, keeping them growing and multiplying, known as the Wnt signalling pathway. Overzealous Wnt signals are thought to be responsible for many bowel cancers, triggering stem cells to proliferate furiously and form tumours.

However, as the pathway is also integral to a healthy stem cell population, broadly targeting it would create new problems. Instead, Li’s lab has honed in on what appear to be tumour-specific targets on the pathway. “It usually takes decades to develop a drug. We’re nowhere near that, but finding a target is already a big step,” says Li.

This research all came to a standstill when the pandemic hit, with the lab being forced to pause all activity. Undeterred, by day Li locked down with her young children (aged three and five), growing chillies, broccoli, tomatoes and courgettes. At night, between 10pm and 2am, she worked on papers chronicling insights from her work.

The thing about starting her own lab, she says, is that much of her work is now computer based, with her time taken up reviewing grants and fellowship applications as well as writing papers. “You actually have to suddenly tum from a lab bench scientist to a manager … and an accountant as well because you have to manage your own budget.”

As it happens, mathematical alchemy comes easy to Li. Her PhD experience in bioinformatics (computational tools employed to analyse swathes of biological data) was a key skill that made Li a strong candidate for the Clevers Lab. When she arrived there, Li met a cohort of confident male scientists who believed they were proficient at these complex mathematical calculations. She was better than them, says Clevers, and she felt she had to make that dear. “At one point, she basically told all of us that she was the one who knew bioinformatics and we’d better listen to her,” he says. “I remember that lab meeting, it essentially was more like a lecture … she went through the whole mathematical analysis. I think that was an interesting eye­ opener for a few people in the lab.”

Don’t hesitate – the time is now

Having just given birth to her third child, Li’s drive is undiminished. The one rule she lives by- and wants others, especially female scientists, to internalise – is to aim big, because waiting for the “right time” in terms of career and/or family goals can result in missed opportunities.

In her experience of recruiting scientists, women are missing out on opportunities to take leadership roles because fewer put themselves forward, “yet at the PhD or postdoctoral level, applications are kind of evenly split, if not more women sometimes”.

She adds: “You can always say: ‘Oh, I’ll do it after I’ve met this deadline, or maybe I’ll get to it next year,’ but, in fact, it will never be the right time – that’s what I’ve learned over the years. So do it now.”

To find out more about the researchers we fund visit our research pages or to donate to this life-saving work go to cruk.org

Written by Natalie Grover for The Guardian

This article was originally published on theguardian.com as part of the Cancer Research UK and Guardian Labs Cancer revolutionaries campaign.

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