Psychiatric and neurological disorders such as schizophrenia can cause complex molecular changes in the brain that result in myriad behavioral symptoms. This has made creating a single, comprehensive pharmacological treatment for such diseases challenging.
Now researchers at the University of California at San Diego (UCSD) have created a biosensor—a genetically engineered cell that can measure chemical messages in the brain—that may help direct future drug development for such conditions. The sensor has already revealed that at least one current approach to treating schizophrenia is likely to produce lackluster results.
A complex disorder
Schizophrenia is a far more complex disease than most people realize. It has not one but three specific and distinct types of symptoms: positive, negative, and cognitive.
“The most commonly associated type of symptoms in schizophrenia are the positive or psychotic symptoms—the delusions, the false beliefs and perceptions, the disorganized thinking,” says Jeffrey Lieberman, chairman of psychiatry at the Columbia University College of Physicians and Surgeons in New York. “They are called positive because it’s thought they are the result of some over-increased activity in certain brain regions.”
Similarly, other symptoms, including loss of interest in life, loss of emotional vibrancy, and an inability to experience pleasure, are referred to as negative because they are thought to reflect a reduction of brain activity. Cognitive symptoms, on the other hand, are those that detrimentally influence performance in memory, attention, and decision-making.
Drug manufacturers have aspired—unsuccessfully, thus far—to develop a single compound that can treat all three of these dimensions. A well-publicized 2005 study testing the efficacy of second-generation, or atypical, anti-psychotic medications, which had been thought to handle all symptoms and decrease side effects, showed they were less effective than their predecessors. (See our coverage of this and other schizophrenia developments here and here.) Researchers are still working to find better and safer drugs against the disease.
“We’ve learned there are different pathophysiological mechanisms that underlie the different dimensions of this illness,” Lieberman says. “And we’re trying to identify and develop targets for those different dimensions that can work together in a single drug.”
Advantages of biosensors
Biosensors, or genetically engineered monitoring cells, may help with that quest. UCSD researchers have developed a biosensing molecule called a CNiFER (pronounced “sniffer”) that can help scientists and drug developers see how drugs influence molecular signaling in living brain tissue.
“The CNiFER is just an engineered cell that has natural receptors for a specific neurotransmitter on its surface and a fluorescent protein,” says Quoc-Thang Nguyen, a former research scientist at UCSD. “Nothing senses a neurotransmitter better than a natural receptor. And here, when the CNiFER’s receptors are activated by the neurotransmitter molecules in the brain, it induces a change of color, letting us know there’s been some kind of change.”
In the new study, which appears in the Dec. 13, 2009, issue of Nature Neuroscience, Nguyen and colleagues used the CNiFER to monitor changes in acetylcholine (ACH), a neurotransmitter critical to proper cognitive function, both before and after administration of clozapine to anesthetized rats. An atypical anti-psychotic medication, clozapine is one of the most commonly prescribed drugs for schizophrenic patients.
“Clozapine causes a huge release of ACH into the brain. And because of that, it was thought it might treat the cognitive symptoms as well as the positive symptoms of schizophrenia—that release of ACH could be assisting attention and other cognitive behaviors,” says Lee Schroeder, a co-author of the study. “But at the same time, clozapine also blocks out some of the ACH receptors. So it’s been unclear which wins out—does that ACH release activate cognitive pathways with extra neurotransmitter or does the drug instead block the receptors?”
The results came back supporting the latter. “[The CNiFER] can shine light back in one of two different colors,” says David Kleinfeld, the lead author of the study. “It comes back yellow when ACH has bound to the cells—and if the drug causes more ACH to be given off, it gets brighter. But once we added the drug, we saw that it bound to the cell’s receptors, blocking them, and saw instead a red signal.” That change in color indicated that the drug was inhibiting the receptors—and thus could not mitigate the cognitive symptoms of the disease.
“Seeing how these different molecules bind or don’t bind has a deep impact on drug development,” Nguyen says. “If you want to design new drugs to help specific symptoms, you need to understand the specific mechanism of action on the different receptors.”
“Biosensors can help a lot in the context of drug discovery,” Nguyen says. “We can use them to weed out non-performing compounds, for one. We can use them to accelerate drug development and select only the best-of-class candidates. And, of course, they can also help us understand how new compounds work in the living brain.” This last point is particularly important, he says, because current technologies looking at the molecular mechanisms of drug action usually do so in a Petri dish or other limited setting—not in the more complex brains of living animals.
Lieberman also sees great promise in CNiFER technology for the development of more effective schizophrenia drugs.“It’s a new technology that can allow us to measure the effects of neurotransmitter release in a more precise way,” he says. “It’s highly valuable and a significant innovation in pharmacologic technology—it really will be invaluable in helping us characterize the mechanism of action of specific drugs.” -30-