Schizophrenia research breakthrough

Researchers can now study the causes of schizophrenia and the effects of medication on specific patients using little more than a few cells in a dish

A CENTURY of medical study has been unable to reveal exactly what causes schizophrenia. Yet as a result of a remarkable piece of new research, scientists can now watch in detail what is happening inside individual brain cells of patients with the disorder.

The work is based on taking adult cells from a patient, converting them into a form of stem cells and then transforming these into neurons.

Because the original cells came from a person with schizophrenia they behave like the patient’s own neurons, displaying the subtle differences associated with the disorder. This means that the effects of antipsychotic drugs can be tested on that patient’s own cells, and scientists can gauge how these drugs will perform.

The work also reveals that almost 600 genes do not function normally in patients with schizophrenia. After years of comparative genome studies only 25 per cent of these genes had been associated with the disorder before now. This will give researchers many more targets to chase in trying to understand the disease.

“This is the first time that a complex mental disease has been modelled in live human cells,” says Prof Fred Gage of the Salk Institute in California. “This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also to screen for drugs that may be effective in reversing it.”

The work is published this morning in the online issue of the journal Nature and involves collaborators in other labs in Pennsylvania, New York and in California.

Schizophrenia is a very common disorder, affecting one in 100 people. It is a highly complex disease which practitioners in the past put down to upbringing or environment.

More and more, however, researchers are identifying genetic changes that are associated with schizophrenia, leading them to understand that it comes down to your genes and not your upbringing.

So complex is the disorder and with so much variation in the way it affects individuals, it has proved a tremendous challenge, Gage says. “Without a basic understanding of the causes and the pathophysiology of the disorder, we lack the tools to develop effective treatments or take preventative measures.”

This research greatly advances the ability to study the disease, however and to do so with complete safety. The patient’s own cells can be used so drugs and other interventions can be assessed before they are actually given to the patient.

The work depended initially on the ability to take adult cells from the skin and turn them into induced pluripotent stem cells. These in turn can be turned into a range of cell types but in this case, they were converted into neurons.

Neurons in the brain make connections between one another, a vital process that enables the brain to work.

Because the initial cells came from a schizophrenic, the DNA they contained carried along the genetic changes that were responsible for the disorder. When the neurons were produced they were found to have similar characteristics to tissues from schizophrenics examined post mortem.

The schizophrenic-derived cells made fewer connections with each other than normal cells. The researchers were also able to do DNA comparisons and identify differences between the two groups of cells.

Postdoctoral researcher and first author Dr Kristen Brennand of Salk then tested a range of frequently prescribed medications to see what effect these had on the neurons. She found that one of the drugs, Loxapine, improved the numbers of connections made between neurons. The drug also altered the activity of hundreds of genes which must have contributed to the neurons’ ability to interconnect.

“These drugs were doing a lot more than we thought they were doing,” she says. The technique now provides the researchers with a model system to see how these drugs work “in live, genetically identical neurons from patients with known clinical outcomes”, she adds. This will allow the researchers to match up the effect of the drugs with the symptoms.

The work also allows the researchers to rule a person’s environment out of the situation. The researchers can see actual biological malfunctions in neurons, without any of the supposed influences associated with how a person was brought up.