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Applying induced pluripotent stem cell technology to neurological diseases

Vivi Heine is Associate Professor in Child and Adolescent Psychiatry at Emma Children’s Hospital of Amsterdam UMC, and Associate Professor in Complex Trait Genetics at Vrije Universiteit Amsterdam. Her research in the neuroscience field involves the ground-breaking induced pluripotent stem cell (iPSC) technology. We talk to her about what this means, how iPSC technology contributes to animal-free research, and its applications in neurology and beyond.

Can you tell us more about induced pluripotent stem cell technology?
Induced pluripotent stem cells (iPSCs) were first presented in 2006 – so they’re still very new. Essentially, iPSCs are early stem cells that can be created from any individual. For example, we can take the blood cells or skin cells from a person, transform them in a dish to iPSCs, and then to brain-specific cell types – which gives us the possibility to create a model for the brain. Because we can generate a stem cell model of every patient, we can study the effects of the genetic makeup of each individual. In the case of my team, because we’re primarily studying neurological diseases, we can look at how genetic changes influence brain cells – and ideally intervene if we see brain diseases developing. Eventually, it allows us to test which medication works best for a patient, and to offer “personalised medicine” – this is becoming a realistic possibility for some disorders.

What kind of neurological diseases can this technology be used for?
iPSCs are of particular interest in the case of genetic diseases, because during iPSC generation the cells rejuvenate and lose their built-up experiences. The diseases we’re talking about basically fall into two categories: monogenic disorders and more complex disorders. Typical examples of neurological disorders that could underlie a combination of many changes in the DNA include schizophrenia, depression, migraines and bipolar disorder. Because the genetics in these cases are so complex, traditional model systems were not suitable – but iPSCs now give us tools to make representative disease models. Monogenic disorders often involve more severe, rare disorders that present early in life and lead to epilepsy, motor disorders or behavioural changes such as autism-like symptoms. While typically caused by one disease gene, the clinical spectrum of monogenic disorders is often still very broad, and likely caused by other genetic changes in the patient as well.

But we also use iPSC models to understand human brain development in general. We’re still trying to answer basic biological questions about the human brain, and now we can answer them using these developing human cells. It’s a new tool to understand how brain cells respond on a cellular and physiological level, comparable to cells in the human brain.

Are there are other applications for iPSC?
There are three main applications of iPSC technology. The first is stem-cell therapy: in the past, rejection of stem cell transplants was a major issue, as scientists needed to rely on donor cells – which was very risky for the patient and could lead to cells being rejected. But now we can culture the patient’s own cells ex vivo (in a dish) and then put them back in the patient. In the case of Parkinson’s disease, where patients show a specific brain region of cells degenerating, clinical studies are ongoing. With this new technology, it’s expected that stem cell therapy for other neurological disorders will also be explored soon, to see whether iPSCs can be used to regenerate tissue and treat the patient.

The second application is pre-clinical modelling. The benefit of iPSC models is that they’re human, and are therefore able to capture the genetic profile of the patient and to better mimic the patient’s response to a disease. They allow us to model cell-cell interactions that are simply not present in animals.

And the third application is drug development: iPSC technology allows you to test a lot of different compounds on a lot of different patient groups. For example, you can test whether certain medications are better for a certain group of patients.

Does iPSC replace animal research then?
No – but it can reduce it. iPSCs allow us to study cellular behaviour and cell-cell interactions. But because these models generally mimic early development of the brain, they’re more like a foetal brain structure – and that limits the amount of studies we can use them for. We are getting better at creating more mature and complex brain networks. But at this point, I can’t see how we can fully replace animal research with stem cell research. We can’t incorporate the behavioural studies that we can in a mouse model, for example. There’s a lot of development that still needs to happen.

iPSC technology is an extra tool in the toolbox – it’s an added dimension that enables us to do things that animal studies couldn’t before. For example, we can finally model disease mechanisms that underlie complex genetic disorders that we couldn’t do in an animal. This is providing important new insights and possibilities to develop new drugs.

What do you think are the next developments for this type of technology?
It’s a very young field – only 15 years in the making and still evolving fast. In 2012, two scientists – John B. Gurdon and Shinya Yamanaka – won a Nobel Prize for the discovery that mature cells can be reprogrammed to become pluripotent. And since then, iPSC has been booming. Lots of scientists are developing new protocols – not just in neurology but also in hematology, cardiology and ophthalmology, for instance. Now, we’re at the point where we need to pull all these different protocols together and develop something more standardised. This will allow the models to be used for drug development, because pharmaceutical companies want model systems that are reliable and standardised in order to be able to test the efficacy of their compounds at clinical level.

Things also need to develop at the regulatory level. At the moment, animal testing is required in order to get a drug approved for the market. So we need to improve on a technical level but we also need the regulations to keep up. Plus, there’s societal acceptance to think about: of course, we need consent from the donors of the stem cells. And we need trust from society that scientists are not going to abuse their responsibility for those cells. But scientists are not ethicists. We need to bring society along with us from a communication point of view, and incorporate societal and ethical opinions into our frameworks. 

And all of this needs to move in parallel. There’s huge urgency in the field, and there’s huge scope for the application of iPSC, but we need to bring everything together in order to help patients in the best way possible.

With so many different interested parties, who are you collaborating with?
Indeed, there’s collaboration at every level. To improve the models themselves, we work with our direct peers but also with other biologists to validate the systems we’re creating. We collaborate with other labs to check whether our procedures work the same way in their lab as they do in ours.

We also work with clinicians and disease experts – for example, to check whether the cellular phenotype in a culture dish represents the human disease in question, and to make sure we’re creating good pre-clinical models. Plus, we have alliances with industrial partners to test these model systems – they often know better than scientists how to standardise such models.

And finally at community level, we communicate with ethicists and regulators. This is especially the case with the bigger research consortia, where the aim is to push this research to a higher level.

Where can people go to find more information?
The International Society for Stem Cell Research (ISSCR) is very active at both technical and regulatory level, as well as in informing the public about this type of research. The ISSCR works not only with iPSC technology but also with adult stem cells – for example, using resection or tumour tissue to understand a disease and test medication to treat it. They bring together stem cell biologists in different fields to exchange expertise, but also provide a platform to support scientists in applying advances to new treatment development, such as creating ethical frameworks.

Interview by Vicky Hampton, December 2021