With nearly 2 –3% of the population of youngsters and adults (between the ages of 15–59 years) at risk of developing neuropsychiatric diseases, India needs to focus on understanding mental disorders. Now, scientists from the National Centre for Biological Sciences and the Institute for Stem Cell Biology and Regenerative Medicine (NCBS-inStem) in conjunction with the National Institute of Mental Health and Neuro Sciences (NIMHANS) are working on an integrated approach to investigate the genetic and environmental bases of mental disorders through the Accelerator program for Discovery in Brain disorderS (ADBS).
It began simply enough. In his early fifties, Prakash simply though that a period of high-stress at work was leaving him too tired to remember where he left his car keys; even though he always placed them on the shelf near his books as he had for the last twenty years.
Then, he began to misplace other objects, like his spectacles, the remote control, a favorite book. A year later, Prakash began having trouble adding up his bills. “One day, I found him struggling with a page of numbers. My husband, who would usually add up bills mentally, was sitting with a list of bills frowning at them. Even then, we didn’t realize that something was very wrong,” says his wife.
A year later, things did not improve—though physically healthy, Prakash was now struggling to remember his daily routine. He would ask his son about his day, nod and smile at the answer and sit down to read the newspaper; ten minutes later, Prakash would ask his son the same question and listen to the patient answer as if he was hearing it for the first time. “My father has no recollection that he asked me these things just ten minutes ago”, his son sighs, “he also gets confused about what time it is and often bathes several times a day because he has forgotten that he has already done so”.
Prakash is a victim of dementia, a neuropsychiatric disorder that leads to long-term, progressive memory loss that can affect a person’s ability to function normally.
Neuropsychiatric, or mental illnesses such as dementia, Attention Deficit Disorders (ADDs), Obsessive–Compulsive Disorders (OCDs), addictions, and schizophrenia can severely affect the way a person behaves, interacts with others and functions in society. These diseases are non-communicable, but can strike patients at the prime of their lives, and require long-term, often lifelong treatment.
People with such ailments are often unable to comprehend why or how their behavior is not acceptable to society, and are shunned, although what they really require is empathy and medical care. How does one deal with diseases that may leave the body healthy, but take away a part of the mind?
The Accelerator program for Discovery in Brain disorderS (ADBS) is an ambitious project that will integrate clinical medicine with basic research to study mental illnesses. The program, currently in its third year, has recently published its goals and objectives in the journal BMC Psychiatry.
In the long-term, the ADBS program aims to devise novel solutions for the diagnosis and treatment of mental disorders by developing a resource base where different forms of information—clinical, genetic, biochemical, and cellular—are assimilated on a common platform. An important aspect of ADBS is that it brings together three institutions—the clinical expertise of National Institute of Mental Health and Neuro Sciences (NIMHANS) is coupled with the research expertise National Centre for Biological Sciences (NCBS) and the Institute for Stem Cell Biology and Regenerative Medicine (inStem) —to address a very big and challenging issue that none of the institutions could have tackled alone, namely, understanding mental illnesses.
In India, roughly 2–3% of the population of youngsters and adults (between the ages of 15–59 years) are at risk of developing neuropsychiatric diseases. The most recent national mental health survey (2015–2016) indicates that on average, 10% of Indians suffer from mental disorders.
This is an important impetus to drive studies on brain disorders that focus on Indian patients. Another significant reason for studying the genetic basis of mental illnesses in India stems from the observations made by clinicians that patients often brought in other family members for treatment of similar disorders; hinting that mental illnesses are likely to have strong heritable elements.
Director of NCBS and inStem, Prof Satyajit Mayor adds, “what we are creating is an unparalleled global resource for the discovery of drivers of neuropsychiatric disorders. Many elements have had to align for this program to have taken off. Firstly, clinicians at NIMHANS have painstakingly created a cohort of deeply clinically characterized patients where the disease is highly prevalent in families. This is coupled with the high prevalence of kin marriages (consanguinity) amongst the Southern Indian population, providing a unique opportunity for uncovering the heritable basis for such complex disorders. Secondly, and importantly, NIMHANS and NCBS have had more than a decade of collaboration between clinicians and researchers, building trust to function in an inter-institutional effort of this magnitude. Finally, and importantly, recognizing its unique value, ADBS is generously supported by the Department of Biotechnology (DBT) under a larger umbrella for using stem cells as a platform for understanding the biology of chronic diseases. A major donation from Kris and Sudha Gopalakrishnan from the Pratiksha Trust has also ensured a level of flexibility that is necessary to facilitate these partnerships.”
“Although we know that certain mental illnesses run in families, we have no idea how these are caused. Over the last decade, advances in genome sequencing have made it possible to obtain almost the entire genetic profile of a person. Unfortunately, these advances have not translated into new knowledge for neuropsychiatry. This is not just in India—globally, no new insights in neuropsychiatry have emerged over the last 50 years,” says Dr. Sanjeev Jain from NIMHANS, who co-heads the ADBS program along with Dr. Mahendra Rao, a Collaborative Science Chair at inStem, and Dr. Raghu Padinjat from NCBS.
“ADBS is an interdisciplinary, interinstitutional approach to finding a solution for an important social problem, namely, mental illnesses of the young,” says Dr. Raghu Padinjat from NCBS. To do this, clinicians and researchers are using a three-pronged approach involving clinical data, genetic analyses, and cellular studies in an integrated setup that will also serve as a repository of information about mental disorders.
Under the ADBS program, long-term clinical information involving detailed psychiatric evaluations, brain scans, and other parameters are being collected from families with histories of mental illnesses, where, along with patients, family members who do not develop the disorders are also evaluated. In addition, blood samples from each person included in the study not only provide DNA for genetic analyses, but also provide cells for the generation of a “disease in a dish” system.
Central to the “disease in a dish” system, is the ability to derive stem cells from adult cells, called iPSC (induced Pluripotent Stem Cell) technology. Stem cells are undifferentiated cells that are capable of dividing almost indefinitely to form more stem cells and have the remarkable potential to develop into many different cell types. Using iPSC technology, researchers can now grow brain cells in a dish and investigate cellular changes that may occur in patients with mental disorders.
“The ease with which iPSCs can be generated, coupled with their unique ability to grow indefinitely and differentiate into any cell type makes them unique tools which can be used to study the molecular, developmental and genetic aspects of neuropsychiatric diseases,” says Dr. Mahendra Rao. “Stem cell technology provides an unprecedented opportunity to obtain an in vitro culture model of a disease of the nervous system in a reliable and reproducible way and gives investigators access to virtually unlimited amounts of source material. This has been a major roadblock in studying diseases of the brain, unlike say cardiac and other organ disorders,” he adds.
“Unlike other organs such as the liver or muscles, the brain is not accessible to direct evaluation; one cannot take, for example, a biopsy of brain tissues to study a brain-related disorder like neuropsychiatric syndromes. Besides this, mental illnesses often develop and progress slowly, and it may be several years before the disease is fully developed. Because of these factors, there are no clear markers for most neuropsychiatric disorders,” says Dr. Sanjeev Jain.
The ADBS program will provide a platform that functions like an assembly line, where every sample from a patient passes through the hands of psychiatrists, clinicians, geneticists, and cell biologists. In essence, each sample has an amplified information base of patient data unique to India that can be used to address questions at every level.
“Genetic and cellular information from stem cell technology, coupled with data on clinical symptoms and measures of disease progress will allow us to fill many gaps in our knowledge of mental diseases—from developing and testing hypothesis on the cause of a disease to understanding how drugs can be used to treat the disease, and more importantly, how drug combinations may work in one person but not in another,” says Dr. Mahendra Rao.
“The program hopes to facilitate a two-way dialogue between clinical medicine and basic science. In the coming era of personalized medicine, we hope to facilitate rational treatment options tailored to the needs of individual patients. Understanding the brain is a complex scientific challenge and we hope the resources created by ADBS will serve as a focal point to bring together scientists and clinicians with a common interest in neuroscience”, says Dr. Raghu Padinjat of NCBS.
So, what does this mean for people like Prakash and their families? It means that there is hope for better treatment and diagnosis for brain-related maladies. The ADBS program is the first step towards understanding which genes are involved in mental disorders, and which drugs can effectively treat them. In short, this program will build a prospective national resource that will drive crucial advances in science, medicine and our understanding of neurobiology and mental health.
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