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How Stemnovate will change drug development with its liver-on-a-chip technology

Stemnovate CEO Dr Ruchi Sharma. Picture: Keith Heppell
Stemnovate CEO Dr Ruchi Sharma. Picture: Keith Heppell

Cambridge start-up aims to reduce need for animal testing - but it needs your help

Stemnovate using cell reprogramming technology. In this image, iPSC cells are in grey, skin cells are in red and liver cells are in green. Image: Stemnovate
Stemnovate using cell reprogramming technology. In this image, iPSC cells are in grey, skin cells are in red and liver cells are in green. Image: Stemnovate

It takes, on average, about 12 years for a new medicine to reach the market – and the typical cost is an eye-watering £1.2billion.

Only one in 5,000 drugs ever makes it that far. Most of those that reach preclinical testing fail at that stage – 99.9 per cent of them in fact. Of the few that go forward to human testing, only one in five is eventually approved.

Little wonder, then, that there is huge demand for improvements to the drug discovery process.

One of the biggest challenges for pharmaceutical companies is working out which drugs are going to be toxic to the human liver.

In addition to laboratory testing, mandatory studies in animals are carried out to help predict this at the pre-clinical stage. But in addition to the ethical concerns this raises, there is the question of physiological differences between the animal models and humans.

One Cambridge company seeking to do something about this is Stemnovate, which is shortlisted in the One to Watch category of the Cambridge Independent Science and Technology Awards due to be announced on November 1.

It is developing a ‘liver-on-a-chip’ system, which uses human liver cells on microchips as a testbed for drug toxicity.

Induced pluripotent stem cells. Image: Stemnovate
Induced pluripotent stem cells. Image: Stemnovate

Co-founder and CEO Dr Ruchi Sharma told the Cambridge Independent: “Organs-on-chips are micro-engineered systems. Cells are cultured on miniature chips which are similar to glass slides and perfused with nutrients and media, mimicking organ systems on a microscale.

“The organs-on-chips system could be used to recreate mini-livers, kidneys and cancer models and therefore can be used as an alternative to animal testing.

“The advantage of such in vitro models is species-specific physiological systems that could benefit humans through better disease modelling, safety testing and targeted therapies.”

The most common cause of adverse drug reactions, according to the US Food and Drug Administration (FDA), is toxicity resulting from drug-induced liver injury.

“The liver is a prime site for drug metabolism, so liver toxicity testing and safety studies are mandatory for all new drug applications,” explains Dr Sharma.

“The drugs are tested in the laboratory and then on mice or other animal models, but such models are suboptimal in predicting adverse drug reactions due to drug-induced liver injury, and hence drugs fail during clinical trials or have to be removed from the market post-licensing.”

With differences in liver pathways between species, and limited physiologically relevant information from in vitro models, so-called ‘silent’ hepatotoxic drugs are often introduced into clinical trials.

Dr Ruchi Sharma at Stemnovate
Dr Ruchi Sharma at Stemnovate

Stemnovate and sensor company ANB Sensors – another finalist in the Cambridge Independent awards – secured a $1million funding boost in September 2017 from Innovate UK to develop the liver-on-a-chip technology that could tackle this problem. But Dr Sharma says it will also help progress the drive for personalised medicine.

The company, which has offices at IdeaSpace West on Charles Babbage Road in Cambridge and lab space at Babraham Research Campus, recently secured a licence from the Human Tissue Authority that enables it to procure, test and store human cells.

It wants skin cells and blood from patients who had drug-induced liver injury, but also from the general population.

“To build a robust platform we have to analyse genetic and physiological information of people from different ethnicity, gender and age,” says Dr Sharma.

“We will be doing this through our partners at various hospitals and clinics that also have HTA licences in England and Scotland. We need to identify patients who have drug-induced liver injury and we will ask them for the sample. But we also need the general public, to compare what’s different.”

Standard sources of human cells cannot provide the detail Stemnovate requires.

“It’s really difficult to get information on age or particular ethnicity from commercial providers. There is no traceability,” says Dr Sharma. “All the lines conventionally used are male lines, but these miss gender-specific information that may be relevant for female patients.

Stemnovate and ANB Sensors received £1m in funding from Innovate UK to progress the liver on a chip technology. From left, Nathan Lawrence, from ANB Sensors, Dr Ruchi Sharma, CEO of Stemnovate, and Adrian Fisher, from ANB Sensors. Picture: Keith Heppell
Stemnovate and ANB Sensors received £1m in funding from Innovate UK to progress the liver on a chip technology. From left, Nathan Lawrence, from ANB Sensors, Dr Ruchi Sharma, CEO of Stemnovate, and Adrian Fisher, from ANB Sensors. Picture: Keith Heppell

Using technology licensed from iPS Academia Japan earlier this year, Stemnovate can reprogramme donated adult human cells back to a state similar to that of embryonic stem cells using an induction of genes known to play an essential role in the early embryonic development or cell proliferation.

It is astonishing technology – and earned its creator, Japanese stem cell researcher Professor Shinya Yamanaka, a Nobel Prize in 2012. He shared it with Cambridge’s own Sir John Gurdon, who in 1962 was the first to discover that mature cells contain the genetic information required to form all cell types.

Once in an embryonic-like state, the cells are differentiated to liver cells – using further technology licensed from the University of Edinburgh – and integrated on microfluidic devices, creating physiologically relevant liver tissue at a microscale level.

Stemnovate co-founder Prof David Hay, based at the MRC Centre for Regenerative Medicine in Edinburgh, is a world expert in liver stem cell research and the process of generating hepatocytes from pluripotent stem cells in the lab.

“The technique offers an ethical solution to obtain multiple cell types and has enormous potential for both regenerative medicine and drug development,” says Dr Sharma.

Stemnovate intends to use its new cell bank to help pharmaceutical companies ensure they can get the right drugs to the right patients.

“We can expose these cells to a particular drug repeatedly,” explains Dr Sharma. “We are building towards a data platform within four or five years.

“You won’t even have to do all the testing because we’ll have done it so many times we’ll have a predictive model in silico, using deep learning and machine learning.”

The liver-on-a-chip system will enable Stemnovate to carry out testing more likely to identify toxicity. In standard lab tests, primary hepatocytes – or liver cells – last only days.

“Our purpose with this organ-on-a-chip technology is to do long-term studies because in the liver toxicity happens over a period of time,” says Dr Sharma. “In future, we hope the perfusion system we are using will increase the timescale to months. It gives you the opportunity to see how different cell lines interact.”

While Stemnovate has focused on the liver due to its significance in drug toxicity, it has a pipeline of other tissue and cell types. In the longer-term, this could enable some quite remarkable studies, in which multiple organs-on-chips can be linked.

“Once we have the system integrated on the devices you can put a series together. It’s the concept of a ‘human-on-a-chip’.

“In our body, from the intestine, the blood flow goes to the liver, then it comes back and leads to a cycle where drug molecules and food particles are absorbed and processed. We can recreate that kind of system outside the body,” said Dr Sharma.

Even a brain-on-a-chip is feasible, depending on what it is you are seeking to test.

Dr Sharma hopes the progress of the technology will help reduce the reliance on animal testing, which is required by law at the moment, and help change the approach of developing drugs for the ‘average’ person by developing better models for diseases.

“The regulators like FDA already have a strategy for organ-on-a-chip technology to help make better decisions,” noted Dr Sharma. “They have even given grants to support this kind of work because they want to promote personalised drug development from the beginning.”

How you can help

Stemnovate needs small skin biopsies or a few drops of blood.

Volunteers will fill in a consent form after reading details on how the cells will be used.

The tissue sample will be collected and from that DNA and RNA will be harvested for understanding the genetic variability.

The cells will be cultured for developing iPSC (induced pluripotent stem cell) lines. The assays and cell lines will be used by research groups to study diseases, pharmaceutical companies developing new drugs and researchers in future for deciding the best treatment.

This will help develop better models for diseases like cancer, arthritis and diabetes and could help ultimately lead to the reduction in the use of animals for research.

Volunteers will remain anonymous.

Get in touch to help by emailing info@stemnovate.co.uk. Stemnovate will also be organising public lectures where its experts will be on hand to answer questions.

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