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It requires genetic modification of the cells that researchers want to activate and the intrusive use of a fiber-optic thread in the brain. Using the technology to directly fix malfunctioning brain circuits in humans is not now practical, and it may never be. But as a research technique, it could give drug researchers what they so desperately need: new molecular targets. Researchers like Tye and Feng believe that their optogenetic experiments can help identify specific types of cells in the circuits underlying certain psychiatric symptoms.
Then they will have to spot distinguishing markers on those cells that allow the drug to recognize them. But the research is still in its very early days. One alternative is to try to intervene directly in the circuits, skipping the use of drugs. There might also be ways to directly affect faulty circuits without resorting to surgery.
Amit Etkin, an assistant professor of psychiatry at Stanford, is using a combination of functional magnetic resonance imaging fMRI and noninvasive magnetic stimulation to map the circuitry that goes wrong in patients. The therapy, which is administered using an electromagnetic coil placed against the scalp, uses magnetic pulses to create an electric current that can increase or decrease brain activity. The commercial version of the technique is designed to target the same small part of the prefrontal cortex in all patients, but by combining it with imaging technology, Etkin hopes to aim the stimulation more precisely to where a patient needs it.
The method seems to help only some people. But driving his work, says Etkin, is his frustration at not being able to offer patients more successful options. Etkin, who also works at a clinic at the Palo Alto VA Hospital for veterans suffering from severe anxiety and depression, uses a variety of tools to help patients, including drugs and psychotherapy as well as magnetic stimulation.
The key to making all the approaches more effective, he says, is to learn more about how faulty neural circuits and connections lead to aberrant behavior.
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And sometimes the gap is significant. At Novartis, Ricardo Dolmetsch is responsible for trying to close that gap between the exploding scientific understanding of brain disorders and the availability of more effective drugs. It takes a long time. Dolmetsch is not your typical drug-industry manager. Less than a year ago, he was still running a lab at Stanford and helping to create a library of neurons from autism patients, to be hosted at the Allen Brain Institute in Seattle.
About a decade ago, his research took a dramatic turn. He had started out at Stanford looking into basic questions about the biochemistry in brain cells, work that was impressive enough to gain him an appointment as an assistant professor. But then, in , his son received a diagnosis of autism. Frustrated by the lack of treatment options, Dolmetsch rebuilt his lab around researching the disorder. Since then, he has helped pioneer methods that take skin cells from individuals with autism, reprogram those cells to become stem cells, and then induce them to develop into neurons in which abnormalities can be studied.
Designing drugs to precisely target circuits in the brain remains a more distant opportunity. But that still leaves the daunting challenge of developing a drug that selectively activates or inactivates certain types of cells in certain circuits. Dolmetsch joined the pharmaceutical industry because he realized that the science and technology had advanced far enough to create opportunities for developing new psychiatric drugs.
He also realized after years of academic research that commercializing a new drug requires the resources, money, and patient populations available to a company like Novartis. Still, the failure to find effective new drugs for brain disorders—and the stigma that has grown around the high cost of those failures—is clearly never far from the minds of those in the industry. But at least now, after decades of dead ends, drug researchers finally have some of the tools they need to begin methodically testing strategies for finding and acting on those targets.
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Rewriting Life Shining Light on Madness. But new research is offering renewed hope for better medicines. Scientists can derive such cells from patients and, under the right conditions, prompt them to develop into neurons for research and drug screening. From our advertisers. In association with Intel. Produced in association with IBM. Free download. Book file PDF easily for everyone and every device.
Many of the drugs discovered in the s and s are still the most effective treatments available for schizophrenia, anxiety disorders, and depression. But while these medications have improved the lives of some patients, they are ineffective for others, and they are woefully inadequate in treating many of the worst symptoms. Take schizophrenia, for example. Existing drugs also have no effect on the way schizophrenia can impair concentration, decision-making, and working memory critical in such tasks as language comprehension. These debilitating cognitive problems make it impossible for people to work and difficult for them even to make the seemingly simple logical choices involved in everyday life.
Insidiously, such symptoms can strike high-performing individuals, often in their late teens. And there are no drugs for this. Finally, many people with brain disorders are simply not helped at all by available drugs.
Shining The Light V - Humanity Is Going to Make It!
Antidepressants work well for some people but do nothing for many others, and there are no effective drug treatments for the social disabilities or repetitive behaviors caused by autism. Overall, neuropsychiatric illness is a leading cause of disability. Severe depression, the most common of these disorders, is the leading cause of disability in the U.
Around 1 percent of the American population suffers from schizophrenia; one in 68 American children is diagnosed with an autism spectrum disorder.
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Though the need for better treatments is unquestionable, drug companies had until very recently simply run out of good ideas. The drugs developed in the s and s were discovered by accident, and no one knew how or why they worked. In the subsequent decades, drug researchers reverse-engineered the medications to identify the brain molecules that the drugs acted on, such as dopamine and serotonin.
In retrospect, however, scientists now realize that while tweaking the levels of these chemicals addressed some symptoms of psychiatric disorders, it was a crude strategy that ignored the biological mechanisms underlying the illnesses. Though the swim test has been used for 50 years to test antidepressants and is still widely used, all it probably does is select for drugs that mimic the effects of imipramine in allowing a rodent to swim longer, he says.
Though a number of new psychiatric drugs have been marketed in recent decades, says Richard A. Friedman, a professor of clinical psychiatry and director of the psychopharmacology clinic at Weill Cornell Medical College in New York, they are simply molecular knockoffs of older ones. Indeed, in Novartis announced it was shutting down its center for basic neuroscience research in Basel, Switzerland. Over the last five years, other drug makers, including GlaxoSmithKline and AstraZeneca, have all scaled back efforts and decreased investments in neuroscience and related drug discovery.
And Ciba, another Swiss parent of Novartis, had introduced imipramine in the late s. Now, in Cambridge, Novartis is back on the search. A former professor of neuroscience at Stanford, Dolmetsch joined the company last August and immediately began hiring. Less than a year later, his colleagues are conducting experiments among stacks of plastic moving crates, even as they continue to set up the lab. Faulty genes have a significant role in causing brain disorders. If you have an identical twin with schizophrenia, the likelihood that you will also have the disorder is between 40 and 65 percent; if a sibling has the illness, you have about a 10 percent chance.
Statistics are similar for autism and bipolar disorder. While genes are somewhat less of a factor in depression than in the other disorders, they play a critical role there too. When he was the director of NIMH in the s, Hyman says, it was already clear to him and others that there was no single schizophrenia or autism gene. So far, researchers have identified hundreds of genetic variants associated with increased risk for schizophrenia, and Hyman guesses the number could go as high as a thousand.
Some of the mutations appear to be common, while some rare variants seem to cause the same symptoms as those experienced by individuals with a completely different set of rare mutations. Moreover, different variants seem to confer different degrees of risk, and recent studies have shown that multiple disorders, including schizophrenia and autism, share a number of culpable genes.
Hyman calls it an immensely complicated jigsaw puzzle. The conventional approach to discovering drugs for diseases with a strong genetic component is to identify the gene causing or playing a prominent role in the illness, and then test compounds against the protein it codes for.
That approach is not likely to work for most psychiatric illnesses, given that they are caused by combinations of so many genetic variants. But Sklar obviously leans toward optimism. She suggests that the numerous variants provide more chances to home in on key pathways involved in the disorders, and more opportunities to come up with clever ways to fix them.
The hope is that all those genetic variants will tend to affect common sets of molecular pathways, types of cells, or specific neurocircuits.
Yet Sklar, who specializes in searching for the genetic causes of schizophrenia and bipolar disorder, acknowledges that despite the rapid advances in genetics over the last few years, large gaps in understanding remain. Add to this genetic mystery the fact that the brain has roughly 86 billion neurons and around a quadrillion synapses the connecting points between neurons , and it becomes obvious how overwhelming it will be to understand the causes of brain disorders.
Now they have a way to directly examine how genetic variants have affected the neurons of a patient with an illness.
You still might not know all the details of the genetics, but at least you can see the results. But how do these neurons function in an actual brain, with its immense networks of circuits and connections? How are the genetic mutations implicated in autism and schizophrenia actually affecting those circuits to alter behavior? New research is starting to investigate those questions. Monkeys and people share a highly developed prefrontal cortex, the region near the front of the skull. Later generations of monkeys could have the multiple mutations found in most forms of autism and schizophrenia.
The monkeys could provide a more reliable way to test psychiatric drugs than rodents, whose brain circuitry is much less similar to ours. It becomes a confirmation that we can correct the circuits and that the changes lead to improvements in behavior. The mouse cowers in one corner of the maze. Even in the video of the experiment, its anxiety seems palpable as it presses against a wall. Suddenly, after a burst of blue light through the fiber, the mouse begins scurrying about, exploring the four branches of the maze with new energy and courage.
The invention of optogenetics has revolutionized the study of neurocircuitry. But even among all the impressive studies using the technology, this mouse experiment, which Kay Tye conducted in as a postdoc at Stanford, stands out.