Ronald Buijsen, Senior Researcher specialising in human genetics, RNA therapy and 3D brain models (LUMC)
Using human 3D brain models to tackle genetic brain disorders
Having a better understanding of how genetic brain disorders work and offering patient-specific treatment is a dream that is gradually coming true for Dr Ronald Buijsen, a Senior Researcher specialising in human genetics, RNA therapy and 3D brain models. Together with his team, he recently developed a technology to study so-called 3D brain models using patient cells. This offers a wealth of opportunities for improved predictions, smarter treatment options and animal-free and more effective therapies. ‘One and the same DNA abnormality results in a different disease progression in each person, which is why brain research requires a tailored approach.’
For several years now, Ronald and his team have been researching genetic brain disorders for which no medication is usually available. In their ‘brain lab’ at LUMC in Leiden, they are developing such things as 2D models (small groups of stem cells). These stem cells are made from blood, skin or urine from people with a genetic brain disorder and are then converted into brain cells. Comparing models with and without the abnormality (aka ‘mutation’) that is associated with a particular brain disorder, enables the researchers to study the effect of that abnormality in a very targeted way. For example, how the brain deteriorates in Spinocerebellar ataxia (SCA), a genetic brain disorder that mainly affects the cerebellum.
The latest improvements in brain research
Ronald explained that cell research into genetic brain disorders has already seen significant improvements in recent years. ‘We used to use only skin cells from the thigh or armpit for brain disorder research. That’s far from ideal because the function of skin cells is completely different from that of brain cells. Usually, the tested cells were also from a random person, i.e. without the DNA error associated with the brain disorder being studied. These days, we use cells from patients who do have this DNA error. And we always work with brain cells.’
Human cells versus animal testing
According to Ronald, the use of human cells is already an advancement. ‘Cells from mice were and are still used in many brain disorder studies. That can lead to distorted results, because even if you study the exact DNA error of a human brain disorder in mouse cells, this rarely leads to the same brain abnormalities as in humans. The precise explanation for this is technical, but it essentially boils down to the fact that you’re studying a mouse, and the effect of DNA abnormalities is different in mice than in humans. Symptoms cannot, therefore, be simply translated to a human being. I’d also like to emphasise the fact that research involving mouse cells does provide sound valuable insights, so it’s not something we can jettison completely just yet.’
Human mini brains
Back to the breakthrough that Ronald and his colleagues recently achieved. What techniques are involved in this? Ronald: ‘As well as the 2D models that we’d already developed, we can now also create and study models with a 3D structure. These are like human mini brains of a few millimetres to half a centimetre in diameter that are unable to think for themselves. We can use these models to mimic certain brain regions. For example, we’re mainly researching diseases that result in cerebellum malfunctions, such as SCA. The cerebellum controls our movements, so abnormalities there often lead to abnormal movements in a patient, making them move like someone leaving a bar drunk.’
Brain-on-a-chip
According to Ronald, what is ground-breaking about the innovation is particularly the ‘brain-on-a-chip’ concept. ‘We were already able to cut the brain into thin slices to see exactly what is wrong with it, such as which cell types are missing and how many of each type are present. But when you cut, you also destroy tissue structures and cells’, he explained. ‘Using chips enables us to study the brains “from within” and without cutting. We can conduct even better standardised studies by comparing dozens of homogeneous brains of control subjects and patients in this way. Basically, the innovation results in much improved human and patient-specific brain disorder research.’
Personalised treatment process
Why does brain research actually require a patient-centred strategy? Ronald: ‘When a brain disease starts and how the abnormality develops in the brain is very complicated. You’d expect patients with a particular brain disorder to all have the same disease progression, but in practice there are major differences. There is no standard timeline of deterioration that a patient can use to make such things as family planning and career choices. As the disease progression differs per individual, you actually need to develop a treatment process for each patient, in which you also determine when treatment is actually useful and when it’s not (or no longer) useful. We desperately need to have a better understanding of how brain disorders work and progress in each individual.’
Wish list
Although he is proud of his innovation, Ronald also sees areas for improvement. ‘A disadvantage of the current mini brains is that they only have the “level” of embryos, while we’re studying disorders in which the first symptoms appear around the age of 30. The abnormality being studied is not readily apparent in those very young mini brains. Another difficulty is that we are, as yet, unable to effectively recreate the circulatory system in those mini brains, which means they die off relatively quickly. Time is always an obstacle in research into degenerative brain disorders, which tend to develop slowly. Finally, we’d like to be able to explore even better how the brain cells in these mini brains communicate with each other. Indeed, this communication is exactly where a lot goes wrong in brain disorders, rather like in a cluttered WhatsApp group. We’re working hard to improve this.’
A focus on ‘unique’ mutations
Fortunately, the technological possibilities are increasing all the time, which is why Ronald is finding his work increasingly rewarding. ‘I’ve been working with the very latest medical devices for years now but I’m still fascinated by everything we can achieve these days. A few years ago it was unimaginable that we’d be able to recreate brain cells from skin cells and even mimic mini brains. First from mice and now also from people. The fact that we can now really target our research on brain regions in specific individuals is also great news for patients who have “unique” mutations that had previously been overlooked. This means that increasing numbers of researchers and companies worldwide will now be conducting research on this to find treatments, which is why I’m predicting an acceleration in the overall knowledge of brain disorders as well as in the therapies to treat them.’
Preferably more animal-free research
Ronald also sees possibilities for even more animal-free research. ‘High-quality research and effective treatment methods are, of course, paramount for us as researchers, but it’s good that groups like Proefdiervrij are raising critical questions about our working methods. It opens our eyes and results in more grants becoming available for research into alternative research methods. For me, working towards animal-free innovations has become more of an endeavour in itself. For example, we’re also trying to get more and more out of the animal materials we currently use as nutrition or culture plates for our cell culture models. If we succeed, we’ll have developed a completely animal-free innovation. Here, too, the rapid growth in technological possibilities offers increasing opportunities. If we can conduct animal-free research, we should certainly do that. Fortunately, human models like ours almost always provide the best answers anyway.’
Intrinsically motivated researchers
Ronald is proud of his research team, which largely comprises trainee researchers. ‘They are all intrinsically motivated people who, despite their relatively young age, are very aware of what they’re working on. Together, we have a huge amount of knowledge and a great diversity of nationalities, cultures and languages. We work on innovations largely in sub-studies, with a few colleagues being responsible for the chip, while another sub-team works on culturing the cells. We’re also working a lot with external parties including research centres, international companies and knowledge institutes. It’s a really cool dynamic.’
Growing focus on genetic brain disorders
By the end of his career, Ronald would like to see much more research being conducted into genetic brain disorders. ‘I notice from the feedback from patient associations that the growing focus on brain disorders is in itself much appreciated. I’m hoping that the models we’re creating now and the therapies we’re developing will lay a foundation for more follow-up research and for all the innovations that will flow from that. There’s still a long way to go in the fight against brain disorders, but any improvement is welcome and is something to celebrate.’
More information
Interview: Bard Borger
Photo: LUMC