A cure for schizophrenia may be possible – by Karen Lankford, PhD, Neuroscientist Researcher at Yale University

Note: The author of this article works in neuroscience research, but not in the area of mental illness research.  Her opinion is based on articles and opinion pieces published by other scientists.

Understanding the biological nature and cause of schizophrenia has frustrated researches for decades.   Only subtle differences could be detected between the brains of patients diagnosed with schizophrenia and their age matched peers.  There seemed to be slight decreases in neural connections within regions of the brain involved in the initial processing of raw sensory data in individuals with schizophrenia, while slight increases in connectivity were apparent in the regions involved in ascribing meaning to visual and auditory information. These differences in wiring patterns were thought to be responsible for the hallucinations experienced by individuals with schizophrenia.  It seemed that the background noise within sensory processing systems was not being filtered out at the early processing level, but was instead being enhanced, stretched, extrapolated, interpreted, and ascribed meaning based on each individual’s belief system.  Instead of simply disappearing from consciousness, the person’s heartbeat, breathing, and stomach rumblings became the whisperings of angels or mutterings of demons.  While these wiring differences could explain some of the key symptoms of schizophrenia, it was not clear how or why such abnormal wiring patterns occurred.

It has long been known that schizophrenia had a strong genetic component, being much more common in individuals who have family members with the disease.  Comparing genetic profiles of individuals with schizophrenia and those without any diagnosed mental illness however did not reveal a single genetic mutation causing schizophrenia, or even a small number of genes associated with increased risk of schizophrenia.  Rather they found that there were hundreds of genes for which specific mutations or epigenetic modifications (changes not in the genetic information itself, but in the relative ease with which the gene could be expressed, and hence the amount of the gene product produced) increased the risk of schizophrenia by only a few percent.   Overall, as the sample sizes of DNA from schizophrenia patients and their unaffected family members increased, something like 1,200 genetic mutations or epigenetic modifications that were associated with small increases in schizophrenia risk was increased.

Making sense out of all of this data was a dauting task, but researchers did not give up.  As they started looking at what each of the genes linked to increased schizophrenia risk did and how their gene products interacted with other molecules, a common thread seemed to emerge.  The genes affecting schizophrenia risk all seemed to directly or indirectly participate in the process of stabilizing or removing synaptic connections.

During the development of the nervous system, approximately 86 billion neurons in the human brain make tens of trillions of individual connections.  (It has been estimated that there are more synaptic connections in the human brain than there are stars in the known universe.)  Not surprisingly, some of these connections are made in error, and even a very low error rate would result in millions of bad connections.  After the connections are formed therefore, the system runs tests on the circuitry.  It then prunes inappropriate connections and stabilizes those which have made correct connections.  This process is very similar to that which occurs during learning, either of a new fact or a new skill.  Useful connections are stabilized and enlarged, while connections which tend to interfere with useful functions are removed.  Since this type of activity dependent synaptic remodeling is ongoing throughout a person’s life, the basic machinery necessary for correcting the developmental errors remain present in the mature brain.

It is important that the key developmental defect in individuals with schizophrenia appears to occur so late in the developmental process.  Trying to reverse a problem that occurred during the early stages of brain development, when neurons are migrating into the correct positions or extending long distance processes to connect different brain regions, would be like trying to unbake a cake after forgetting to add a key ingredient.  Fixing a problem occurring at this final stage in development would be more like scraping some of the icing off the cake and correcting the spelling of “Happy Birthday”.  It is doable with the right skill set and tools.

If this current theory about the developmental origin of schizophrenia is correct, it should be possible to transiently infect the affected parts of the brain with corrected versions of the abnormal genes and then reactivate the test program.  The brain could then correct the wiring errors and permanently eliminate the symptoms.  Permanently inserting a corrected gene into mature cells is very difficult.  However, getting cells to take up and express a gene for the few weeks, which is all that would be required to prune or stabilize synapses, is comparatively easy.

For the first time therefore, researchers are talking about the possibility of a cure for schizophrenia.  They believe that we may be able to permanently correct the cause of schizophrenia symptoms.  It will take several years to properly test this new theory and determine if is correct, and even if it is correct, it will take many more years to develop and test a vector for delivering the proper instructions to brain cells.  But there is real excitement in the field today.  It may well be that in my lifetime, I will hear someone say that they used to have schizophrenia.  What a wonderful day that would be.

 


About the Author:

Karen Lankford has a broadly based background in biology and over thirty years of experience with cell culture and quantitative morphometric analysis techniques using a wide variety of light and electron microscopic procedures. She is philosophically committed to following the data wherever it may lead, even when it involves shifting the direction and learning new techniques.

In addition to her research activities, she is the co-founder of a nonprofit website called Simply Gray Matters which provides basic brain science information to patients and families dealing with serious neurological or neuropsychiatric disorders. The site provides this information in a layman friendly conversational tone with the goal of helping patients and family members understand what their doctor is trying to explain to them and participate in a more meaningful way in treatment decision.

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