Genetic alchemy: How Yichen Shi at Axol Bioscience takes blood cells and turns them into brain cells

Using Nobel Prize-winning technology, Axol Bioscience is reprogramming cells to help researchers develop drugs.

In 1962, John Gurdon removed the nucleus of a fertilised egg cell from a frog.

He replaced it with the nucleus of a cell taken from a tadpole’s intestine. The modified egg cell grew into a new frog – a result that proved mature cells still contained the genetic information required to form all cell types.

The same year, Shinya Yamanaka was born in Higashiōsaka, Japan.

After an unsuccessful spell as a surgeon, he went into stem cell research and proved that an intact cell could be programmed back into an embryonic state, from which it could form any type of cell – a quality known as pluripotency.

In 2012, Sir John B Gurdon and Shinya Yamanaka shared the Nobel Prize in Physiology or Medicine for the discovery that “mature cells can be reprogrammed to become pluripotent”.

That year, Yichen Shi was completing his PhD in neuroscience/stem cell technology at the Gurdon Institute in Cambridge – named after the Nobel laureate, who has been associated with Cambridge University since 1971.

Biotech star Jonathan Milner, founder of Cambridge antibody company Abcam, studied there as a post-doc and Yichen recalls how he came back to give a career talk.

“He said there were other routes. You don’t have to do a post-doc or become a research group leader, you can go into industry or start a company,” says Yichen, who developed an efficient method for producing brain cells from stem cells during his PhD.

“I met Jonathan and told him about my idea of creating the world’s biggest human cell ecommerce company.

“His vision was creating the world’s largest high quality antibody company. So we had similar ideas but different products: He was working on antibodies, whereas I had the vision of a creating a great cell catalogue.

“I asked him, ‘Could you teach me how to do business and could you invest?’”

Milner became mentor and chairman of Axol Bioscience, which Yichen set up in 2013, straight after his PhD.

“He taught me how to do business,” says Yichen. “He taught me how to deal with customers, marketing and a lot of concepts. I didn’t go to business school – I pretty much learnt it all from Jonathan.

“A lot of entrepreneurs are really grateful that Cambridge has this group of business angels. They are not just putting in money, they are teaching us how to do business.

“I started the company with a rented bench at Babraham Research Campus. My wife was at the desk working on the administration and she is still working with me. I was at the bench creating cells.

“In the first year, we got our first customer – a large European pharma company placed a big order.

“That sparked a lot of interest from other business angels.”

Milner helped bring in other investors and further funding rounds followed. Most recently, the firm – which has grown from two people to 20 - secured venture capitalist funding of £2.5million from Calculus Capital, which is enabling it to add equipment, occupy more space at Chesterford Research Park and strengthen its scientific team.

What Axol Bioscience sells would have been the stuff of science fiction just a few years ago.

“We are using Nobel Prize-winning technology and introducing some special stem-cell related genes into very easily accessible cells, such as blood cells, skins cells and now urine-derived cells and kidney cells,” says Yichen.

“We convert these easily accessible cells into embryonic stem cell-like cells. We call them induced pluripotent stem cells (iPSCs).

“This is licensed technology – any company with money can do the work but what’s special about us is that we have developed know-how in making high quality neural cells, or brain cells, and also cardiac muscle cells - blood vessel cells – from these embryonic stem cell-like cells.

“We sell the functional cells – the heart cells or the brain cells.”

Axol also works with Horizon Discovery, the Waterbeach gene editing firm where Milner is a non-executive director.

“They introduce mutations and genetic modifications into the genome of these cells to mimic the Alzheimer’s condition,” explains Yichen.

“It’s a fantastic place to be in with all these sister companies supporting each other doing joint venture projects.

“The ultimate use of these cells is to make cell-based assays for testing drugs.”

There are ethical and medical benefits to this approach. Using human cells prevents the need for animal research and offers pharma companies a more accurate picture of how their drugs will impact us.

The raw material for the work – the cell lines – were initially brought in from the National Institutes of Health in the US, and other providers in the US and Europe followed.

“They acquire the cell lines from blood banks and donors with commercial consent,” says Yichen.

Axol’s customers can also supply cells from particular donor patients if they wish to test drugs against specific conditions. Then the alchemy begins…

“Imagine a computer running a specific programme, just like your blood cells are doing a specific job,” says Yichen. “There are a set of genes expressed to do the blood cell job, which is delivering oxygen. What we do is wipe off all these programmes – like resetting the computer to its original state, which we call the embryonic stem cell state. This cell is not doing anything – just proliferating: it’s self-renewal.

“When we make specific cell types, like neural cells or cardiac cells, we launch specific programmes into the cells and drive the embryonic stem cell-like cells to become specific functional cells.”

The scientists must apply very precise conditions.

“A lot of things were learnt from developmental biology,” says Yichen. “For the last 20-30 years, people have mapped out how the brain is developed over time in the embryo and what signals, hormones and growth factors are needed.

“We are doing an engineering jobs: applying this to the cells to become a specific cell type using this knowledge.

“It’s precise in terms of the concentration of growth factors to use and the timing of when to edit. These are the know-hows we have developed to make sure the cell population is pure enough. We are trying to aim for one pure cell type in a dish.”

Some cell types prove more challenging than others.

“Certain brain cell types are very difficult to create,” says Yichen. “Muscle cells are relatively easy. But to other people maybe it’s different.”

Despite the difficulty, Yichen chose to focus on neural cells initially.

“I did a PhD in neuroscience and stem cells so I was applying my PhD knowledge,” he explains. “The other reason is there is a huge demand for high quality human brain cells in research, especially cells with a patient’s genetic background.

“You or me wouldn’t want to donate any of our live brain cells for research because we still use them! So a lot of material researchers are getting are from dead people so they are not functional any more and you can’t test drugs with them.

“There is a huge need for neural cells, brain cells and spinal cord cells for drug discovery and for tissue engineering for cell therapy research.”

The modification of cells is carried out at the stem cell stage, he added.

“We create these iPS cells because they can proliferate indefinitely… they grow like weeds. It’s better to do genetic modification at this stage.

“Once you introduce an Alzheimer’s specific mutation and make these cells into the type affected – cerebral corticol neurons – then you have a better chance to model Alzheimer’s. It’s the right cell type and the right genetic mutation, so you can study how Alzheimer’s occurs in a dish and do some screening.

“We want to be the place that researchers go to whenever they want to buy cells,” says Yichen.

“There are other companies focused on one or two cell types. We want to do everything and that requires a special business model. So we work with professors around the globe – Japanese, America and UK-based – and license their technology.”

Paying a consultancy or licensing fee, Axol brings in the technology it needs, produces cells and then sends them out for validation before they go on sale. It’s a model that has enabled to grow quickly.

A future market for Axol’s products is cell therapy – by which healthy engineered cells are reintroduced to the body.

“There is huge potential,” says Yichen. “The hurdle is the scientific community has to test it thoroughly making sure these cells do not become tumourigenic.

“The idea is to make functional cells like pancreatic cells for generating insulin or cardiac muscles as pure as possible so you can transplant these cells back to the patient and they can do their job without turning into tumour cells. There is at least five to 10 years of work that needs to be done in terms of validating IPS-derived cells.

“That’s why so many companies are trying to get into this space – and why it’s a Nobel Prize-winning technology.”

Building a 3D brain with live cells and nano-electrodes

Axol Bioscience is part of the extraordinary MESO-BRAIN Consortium, creating a 3D structure with multiple layers of live neural cells and nano-electrodes designed to emulate the brain’s activity.

“As a 3D structure it is more physiologically relevant testing platform,” says Yichen. “You can measure a real-time response with different drugs. It’s a European-funded project and we are one of the participants responsible for supplying human brain cells.”

The structure will be based on a brain cortical module and will be designed and produced using nanoscale 3D-laser-printed structures incorporating nano-electrodes to enable downstream electrophysiological analysis of neural network function.

Prof Edik Rafailov, head of the MESO-BRAIN project at Aston University, said: “What we’re proposing to achieve with this project has, until recently, been the stuff of science fiction. Being able to extract and replicate neural networks from the brain through 3D nanoprinting promises to change this.

“The MESO-BRAIN project has the potential to revolutionise the way we are able to understand the onset and development of disease and discover treatments for those with dementia or brain injuries.”

Yichen added: “There are other applications we are supporting such as making a 3D heart structure for testing new drugs. Cardiac toxicity is very important subject for developing new drugs.”

How much for 1.5 million brain cells please?

It’s easy to buy from Axol Bioscience’s online catalogue.

Want to purchase 1.5 million neural cells? That’ll be £350 please. It’s the same charge should you want to purchase some from a patient with Alzheimer’s.

Axol also sells all the media and reagents needed by researchers. And it handily packages them into starter kits.

An uncultured hepatocyte starter kit, for example, including five million liver cells, plus mediums and multi-well plates, will set you back £1,000.

Meanwhile, one million Tamoxifen-resistant breast cancer cells are priced at £800.

Axol aims for next-day delivery in Europe and worldwide shipping in two to three days. It accepts Visa and Mastercard.

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