One (cell) to rule them all

Listen to this blog story:
Listen to "One cell to rule them all" on Spreaker.

Pluripotent stem cells, primary cells that can turn into any body cell type, have revolutionised how we conduct basic biological research. Since human pluripotent stem cells were first grown in the laboratory in 1998 by Professor James Alexander Thomson and his team at the University of Wisconsin–Madison, stem cell research has come a long way. Pluripotent stem cells are found in the earliest stages of human development - when we’re embryos. They form part of our very first cells, which then will divide, diversify and specialise into the millions of cells that form the different organs and tissues in our body.

Over the last few decades, scientists have learnt how to leverage this superpower of stem cells and are now able to turn them into many different types of cells of interest as needed for their experiments. These modified cells can help scientists work on different tissue types and allow them to test drugs against diseases such as cancer, Alzheimer’s or Cystic Fibrosis.

But the story gets more interesting. In 2007, Shinya Yamanaka, from Kyoto University, and his team found a way to reprogram adult cells to act like embryonic stem cells. These reprogrammed cells are called induced pluripotent stem cells. They provide expanded opportunities for translational research that looks into future cell therapies and a range of other studies such as human development, disease replication, and drug discovery.

Skin cells can be reprogrammed into iPS cells that can then develop into different types of cells. Image credit: Laura Olivares Boldú / Wellcome Connecting Science

This advance removed an ethical quandary, as pluripotent stem cells can only be found in embryos during the first fortnight of their development. It also tackled a technical challenge - embryonic stem cells could never be genetically identical to a patient, therefore their potential use in regenerative medicine faced a significant challenge.

Producing one line of induced pluripotent stem cells isn’t too difficult - you just need a lab with the right equipment, expertise and importantly, consent from the donor. However, one cell line will not be able to give researchers the necessary information on how humans of diverse genetic backgrounds react to a certain drug, as we are all different, and reactions can differ notably. To obtain robust data that can safely validate if a new treatment works or not, researchers ideally need to be able to run tests on a wide variety of genetic backgrounds, and that’s the tricky bit - it requires multiple cells from multiple individuals to be produced using the same methods and that are comparable with each other.

In 2012, the Wellcome Sanger Institute and five other institutes came together to  develop a unique resource: a global portal with induced pluripotent stem cells containing information from hundreds of individuals. This crystalised into the Human Induced Pluripotent Stem Cell Initiative (HipSci) project, which generated what is still today the largest induced pluripotent stem cell resource available worldwide and was made possible by a grant from Wellcome and the Medical Research Council (MRC). HipSci built on Yamanaka’s innovations to make pluripotent stem cells consistently from both healthy people and those with known genetic diseases.

Richard Durbin, Associate Faculty at the Wellcome Sanger Institute and Professor of Genetics at the University of Cambridge, was co-director of the project. He says: “We were able to develop HipSci at the Sanger Institute because of our ability to carry out research at scale. But we did not do it alone.”

As with any great endeavour, HipSci was a team effort, with collaborators at King’s College London, the Cambridge Stem Cell Institute, the University of Dundee and EMBL’s European Bioinformatics Institute, among others.

The resource now contains over 700 induced pluripotent stem cell lines which are valuable for many reasons. Firstly, the number itself. Secondly, they include two cohorts of donors: a set of individuals with an inherited genetic disease, and another set who were healthy at the time, for which the genomic data are open access. Healthy donors provide a set of cells that allow geneticists to generate disease-driving mutations and test specific drugs. They are also used as control cells.

A laboratory technician viewing cells using a microscope. Image credit: Greg Moss / Wellcome Sanger Institute

On the other hand, donors with an inherited genetic disease allow researchers to study the developments that have led to that specific pathology - how the cell reached that point, but most importantly, how could that be avoided or compensated - potentially leading to new therapeutics.

Thirdly, the fact that all cell lines were created following a standardised process. Researchers can use these cells and compare experiments knowing they were all developed in the same way. This normally leads to significantly more robust conclusions. Ludovic Vallier, who also spearheaded the project, now Honorary Faculty at the Sanger Institute and member of the Berlin Institute of Health, recalls the project was a veritable challenge. “The great question was how to turn a process that was mainly ‘artisan,’ hands-on, into an industrialised process,” Ludovic states.

How did they do this? Most of the process couldn’t be automated, so talent was key.

“We recruited a new team and technical staff dedicated to the production, we also took on board people with expertise in industrialisation, or with a pharma industry background. We had to invest in leading-edge technology and massive incubators to make sure we could deliver the project at the scale we had initially proposed.”

Ludovic Vallier,
Honorary Faculty, Wellcome Sanger Institute and member of the Berlin Institute of Health

Data was another important, if not crucial, component that added to the project’s remit. The cell lines developed within the Hipsci project have a huge amount of associated data that add to the reliability and utility of the experiments undertaken with these cells.

The team put together four sets of exhaustive analytical data that contributed to the full understanding of the cell lines and how they had been developed. This includes data on quality control, genetic testing, cellular phenotyping, proteomics and patient consent forms.

But what does each set of data tell us? The quality control data explain how the cells have been obtained from the primary adult cell, laying out the process to understand what was involved - what procedures, chemicals or protocols were followed. Then, the assay data give us information from a genetic point of view - a breakdown of the DNA and RNA in the cell. Cellular phenotyping then looks into the way genes are expressed. Thinking of it graphically, genes contain the information of what we look like (the genotype) but how this information is then expressed, what can be seen under a microscope, that’s the phenotype.

Last but not least, the cell lines in the project also underwent a proteomics analysis - the study of the combination of proteins that are contained within a cell at a given time. A proteomics study is yet another indicator of a cell’s health.

In short, these four sets of data allow researchers using these cells to perform a wide variety of large-scale experiments they would not be able to carry out otherwise. Additionally, ethics was at the heart of the project, and all volunteers in the project expressed their consent to participate, the consent forms being available when using the cell lines.

Cells generated by Sanger scientists are being picked up by different laboratories worldwide to progress genetic therapeutic discovery for a wide range of diseases. The Jackson Laboratory, for example, is a non-profit institution with headquarters in Maine, USA, and specialises in genomic solutions for disease. It has recently launched a HUMAN iPS CELLS portal with the aim of providing a comprehensive resource for scientists to study the genes behind neurodegenerative diseases, such as Alzheimer’s. The engineered cell lines present in the portal are derived from an induced pluripotent cell line, created at the Sanger Institute and selected for its favourable characteristics including ease of genomic editing.

“We are excited to see how Sanger science can lead to real-world applications, specifically in diseases that have traditionally been difficult to tackle, such as Alzheimer’s. This comes to show the importance of the science at scale that we carry out at the Institute, and is a major achievement of our translational efforts.”

Mariya Chhatriwala,
Business Development Manager, Wellcome Sanger Institute 

Mariya and the Business Development team are actively seeking new partnerships all around the world with Contract Research Organisations, Biotech, and Pharma who are interested in using these cell lines for activities such as the provision of services, internal research development, or the creation of derived products. They are also interested in working with organisations interested in distributing these materials. The HipSci lines are consented to for broad commercial use and Sanger would like to ensure that they are easily accessible to the wider scientific community.