From genes to brain function in health and disease
New knowledge on how genes are linked to diseases such as schizophrenia and bipolar disorder, will enable easier diagnostics and better choice of optimal treatment.
In contrast to familial diseases, like cancer and the seasonal flue, we know much less about the molecular and cellular processes underlying mental illnesses and potential molecules that could act as diagnostic markers. Today, these conditions are diagnosed by observations and various test performed by experienced psychiatrists.
A major challenge in the DigiBrain project is to connect specific gene variants to different brain functions and disorders. As a starting point, part of the project group has contributed to a vast study collecting and analyzing the genes from close to a 100 000 schizophrenia patients, revealing that certain gene variants are more common among the patients than the normal healthy population. Several of the genes identified, are expressed in the brain, but what are their function and relation to the disease?
As several genes are involved, something which varies depending on the type of illness, the amount of experiments needed to test all the different combinations are not feasible to carry out. Instead, the researchers construct detailed mathematical models of neurons and the network in the brain to predict the most likely gene variants that have an effect. These genes are then selected and tested experimentally in animal models.
Patients with neurological disorders may display altered brain activity that can be recorded by electroencephalography (EEG). This non-invasive technique measure whole brain activity by placing electrodes on the skull. Alteration in whole brain activity probably relates to alterations in activity at the level of individual neurons. The researchers try to understand the connection between neuronal activity at the cellular level and the activity in large networks of cells, like the brain.
Medical doctors, biologists, mathematicians, physicists and data engineers work together to reveal how mechanisms of disease operate.
The project consortium is headed by Department of Biosciences, UiO, with partners from UiO; Department of Physics and Norwegian Centre for Molecular Medicine (NCMM), Oslo University Hospital (OUS), Simula Research Laboratory, Norwegian University of Life Sciences (NMBU), Kavli Institute for Systems Neuroscience, Pharmasum Therapeutics AS, and Holberg EEG AS.
Oslo universitetssykehus (SFF Norment), Simula Research Laboratory, NMBU, Kavli Institute for Systems Neuroscience, Pharmasum Therapeutics AS og Holberg EEG AS
In the project DigiBrain: From genes to brain function in health and disease the researchers will study mechanisms of disease in the brain and how these are coupled to different gene variants in patients. This knowledge can contribute to development of new drugs and novel treatments of patients with schizophrenia or bipolar disorder.
Today you are not able to diagnose schizophrenia based on a blood test. The diagnose is based on a psychiatrist judges the patient according to a set of given subjective and objective criteria. This allows for variation, and the diagnose will depend on the person conducting the examination. One of the goals in the project is to understand the mechanisms to such an extend that measurement of physiological parameters can replace current diagnostic practice. Allowing a more objective and reliable method than today.
The researcher in the project employ data from a large global study which has analyzed samples from almost 100 000 schizophrenia patients and an equal number of control individuals. The study revealed that 120-150 gene variants are more common among patients than in the regular population. The project will especially focus on gene variants that are involved in communications between neurons and other brain cells.
But where to start? There are so many gene variants and possible combinations of them that a traditional experimental approach to try out all of them is impossible. Instead, the researchers use mathematical models. At the University of Oslo the researcher have made a detailed mathematical model of the how the individual neuron and communication between neurons in a network works. By altering the model adjusting for different gene variants, the effects can be tested by running simulations.
These simulations will then separate out the gene variants with the most impact, which then can be tested out in animal experiments to investigate functions in live neurons and neuronal networks.
As part of the investigation to reveal connection between gene variants and brain function, the researchers will utilize behavioral tests. In schizophrenia a certain behavior is associated with the certain disorder in humans, called “Pre-pulse inhibition”. This behavior exists in many other species as well, such as zebra fish and mice, and works in the following way: If you are exposed to a sharp sound, you startle. However, if you are exposed to weak sound immediately before the sharp sound, you are less startled. The effect is called pre-pulse inhibition. Schizophrenia patient do not display this, and will startle equally in both conditions. This can then be used as a read out on schizophrenia related effects in the experiments.
By combining the approaches the researcerh aim to identify connections between gene variants that have a large impact on neuronal function and also alters the behavior.
Brain activityThe researchers will first find out how single genes affect a single neuron. Then, it gets really exciting when this approach is scaled up to investigate several hundred thousands of neurons connected in a large network. The network activity is measured by EEG, but there is still a challenge to relate the signal recordings at whole brain level to what goes on at the individual neuronal level. One part of the project is therefore to decipher the EEG signals using different network models to establish connection between activity changes at the cellular level, network and finally whole brain level.
In the project medical doctors, biologists, mathematicians and physicists, as well as data engineers collaborate.
The mathematicians and physicists in the project utilize their computational background, and are also role models in their way of employing expert skills in another scientific field and pursuing a carrier within the life sciences. Although many of the project partners have a common natural science foundation, there is challenge to translate from mathematics and physics to medical and biological science.
Extra measures are in place to bridge the different disciplines. Among these are co-localization, sharing office space and working together to create a common vocabulary and more thorough understanding of each other’s disciplines. But also integration to the social and scientific environment at the Department of Biosciences developing a through transdisciplinary project group.To integrate the external partners in the project, located at NBMU or OUS, as well as collaborators abroad, regular meetings physically or by Skype are arranged. Also, extra office space is available, allowing external partner to have shorter stays at the Department of Biosciences. Altogether, nine persons are employed on the project.
The project draws on experience gathered by the Norwegian Centre for Mental Disorders Research (NORMENT) to ensure justifiable treatment of patients. The centre has a user-group that represents the patient organisations and the patients. As the project proceeds, the group is involved and asked for their opinion and advice.
An event together with the Norwegian Biotechnology Advisory Board about gene mapping and patients are in planning.
In this project the innovation lays in creating knowledge about what happens in the brain when something goes wrong, a knowledge that is important for mental health services. A major part of the project is basic science, but the goal is to create a platform for studying disease mechanisms and genes that can be utilized for studying other diseases as well.
A large part of the project is to establish methods for measuring, among others EEG signals. The company Holberg EEG in Bergen has specialized in EEG-measurements, and the project will contribute to improve their product.The partner Pharmasum Therapeutics works on therapeutic strategies for neurological diseases, but not mental illnesses. However, they are searching for new biomarkers as starting points for development of new drugs. However, this part is more distant, and will probably occur more as a result of the project.
Dr. Esguerra is a Partner Principal Investigator on the DigiBrain project responsible for leading the work involved in generating and characterizing novel genetic schizophrenia models in zebrafish. Newly identified genes linked to schizophrenia will serve as the starting point for investigating the functional consequences of these risk variants, with a particular focus on determining how they affect neuronal excitability and behavior. These new zebrafish schizophrenia models will be used for carrying out small-molecule compound screens in order to identify chemical modifiers of the disease towards the development of therapeutic drug leads.
PI in the DigiBrain project.
Partner in the DigiBrain project
Project leader - DigiBrain
PhD student on the Digibrain project
Partner in the DigiBrain project
PhD student DigiBrain
PI WP2.task 2
PI in the DigiBrain project (on Workpages 2 and 3)
Working on modeling of neurons and heart cells, studying the contribution of schizophrenia-associated genes, and building of new models