Unravelling psychiatric disorders down to the cellular level

Case

Unravelling psychiatric disorders down to the cellular level

Headlines such as "Six new schizophrenia genes discovered", or "Extra Alzheimer gene found" regularly appear in newspapers. However, this rapid discovery of genes that play a role in the development of brain disorders does not mean that we know what goes wrong in patients' brain cells. An interdisciplinary consortium of researchers will investigate this within the Gravitation project BRAINSCAPES.

Danielle PosthumaDanielle Posthuma

'We have known for a long time that several disorders such as depression, schizophrenia or addiction are hereditary. And now we can also identify the genes involved. However, until about two years ago it was almost impossible to translate that information into the biological mechanisms that take place in the brain,' says main applicant Danielle Posthuma from VU Amsterdam. 'If you only have a single defective gene, such as in Huntington's disease, then you can manipulate that gene in an animal model and see how those changes influence the disorder. Unfortunately, there is not just a single gene for depression or an eating disorder. Instead, there are hundreds and sometimes even thousands of genes.'

Describe the complete network of cells that determines the disease progression of each specific disorder.
- Danielle Posthuma

Addicted smoker smokes a cigarette

From gene to cell network

In the Gravitation programme BRAINSCAPES, geneticist Posthuma is joining forces with neurobiologist Guus Smit, neurophysiologist Huib Mansvelder, biologist Elly Hol, translational neuroscientist Jeroen Pasterkamp and computational biologist Boudewijn Lelieveldt. 'As a result of several recent, major revolutions in genetics and neurobiology, we now know which genes are involved in which characteristics and we can at last map the effects of gene expression on individual cells. So this is the ideal moment to bring the various disciplines together. Based on genetics and with the help of bioinformatics, we will formulate a hypothesis about which types of cells are influenced by which genes. Subsequently, we will examine brain tissue to see whether we can observe differences in gene expression in those different cell types. We will also describe the role of specific cell types in the brain. Where exactly are these located? How do they communicate? Which network of cells are they part of? With this information, we will describe the complete network of cells that determines the disease progression of each specific disorder. And then finally, we will study this in animal models. Take obesity, for example. If you modify the cell network that is responsible for that in obese mice, then do they become slimmer?'

Did you know? During the first five years of the ten-year programme, the researchers will focus on disorders within three focus areas, namely addiction, eating behaviour and mood-related disorders, such as depression and anxiety disorders.

Woman with eating disorder cuts a slice of cucumber

During the first five years of the ten-year programme, the researchers will focus on disorders within three focus areas, namely addiction, eating behaviour and mood-related disorders, such as depression and anxiety disorders. 'Within these focus areas, there are already enough indications about the genes and cell types involved, and we have good animal models for these. That allows us to start our research immediately without somebody having to wait for the results of someone else.'

Millions of participants

The scientists have a wealth of data available for their research, says Posthuma. 'We are collaborating with a large number of cohort studies, which allows us to compare the characteristics of millions of participants.' For example, there is a biobank in the United Kingdom that contains the genetic and medical details of half a million healthy and ill British people. 'And we are collaborating with the company 23andMe, which private individuals can send a pot of saliva to, and from this receive a complete DNA profile. If participants have stated that they are willing to contribute to scientific research, then we can analyse the data. For example, we have previously used this data to carry out a study into the genetic disposition for insomnia.' In the field of addiction, there are large consortia in which, among others, clinicians collaborate with geneticists, she says. 'This allows us to compare patients who are officially diagnosed with, for example, moderate smokers or drinkers or people who use no addictive substances whatsoever.'

Box of pills fallen over on a table

Legacy

Posthuma and her fellow applicants hope that BRAINSCAPES will lead to a paradigm shift. 'At the cellular level, we must close the entire chain from genetics to biological processes, as then we will be able to eventually develop new treatments for brain disorders.' The consortium is explicitly looking towards the future: 'We have a workgroup that monitors all of the research so that highly promising findings can be transferred to the pharmaceutical industry at an early stage. And we have set up a scheme for talented young researchers. The first group will soon start work, and the second group will follow in five years. With this approach, we will not just acquire knowledge within this programme, but we will also provide a strong foundation of new talent. In 10 to 15 years, the applicants for this programme will be approaching retirement. We therefore want to ensure that a new generation is ready to continue this work.'

BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology

Applicants: Prof. D. Posthuma (VU Amsterdam), Prof. A.B. Smit (VU Amsterdam), Prof. H.D. Mansvelder (VU Amsterdam), Prof. E. Hol (Utrecht University), Prof. R.J. Pasterkamp (Utrecht University), Prof. B. Lelieveldt (Leiden University)

Grant size: 19.6 million euros for ten years, 21 researchers involved from 7 Dutch research institutes

Text: Sonja Knols (Ingenieuse)

Banner: Digital illustration of brain cells in action.