My grandmother was diagnosed with Schizophrenia in her 40s, which is really late for most people who suffer from this mental illness. Convincing my grandma to take her pills is extremely hard because she feels they distort her perception. Her reaction is not at all surprising, considering that most people with this illness feel this way. I sometimes find myself thinking that a mental illness is like a broken bone whose fissure doctors are unable to find and so, cannot put a cast in it. The best they can do is give you pills. This is one of the reasons why I did not want to pursue psychiatry. Seeing my grandma enslaved by medication made me realize that I would much rather find a cure than provide a remedy. Brain disease is but the last frontier that scientists have yet to conquer.
When reading "Retroviruses and Amyotrophic Lateral Sclerosis" by Vincent Rancaniello in his Virology Blog, I came across the term HERV-K. Naturally, I did what every science student would have done when faced with a term he/she does not recognize: I looked it up in Wikipedia. HERV-K stands for "Human Endogenous Retrovirus K." I was not entirely surprised by the idea that ALS could be linked to retroviruses because I had been exposed before to papers discussing the possibility of prions being shuttled into the brain by retroviruses. But as one link led me to another, I found one which talked about HERV-W, an endogenous retrovirus which has been linked to Multiple Sclerosis and Schizophrenia. Naturally, this caught my attention, and decided that I should write a bit about it. Hopefully, this will spark your interest too and get you to read more papers related to this!
Schizophrenia is a chronic mental illness with a variety of psychological symptoms such as paranoid delusions, auditory hallucinations, speech disorganization, lethargy and social withdrawal as well as physical symptoms like gradual grey matter decay, brain structural disruptions and a marked alteration in the dopamine pathways. Schizophrenia is thought to arise due to different risk factors, the most apparent of which is a genetic predisposition, but which also include environmental conditions like growing up in an urbanized area. There also seems to be a gender-associated predisposition since from those at risk, men are more likely to develop Schizophrenia and with more aggressive symptoms than women.
Some men and women who develop Schizophrenia encounter problems during their fetal life like hypoxia, infection, malnutrition and stress. Moreover, individuals who are born during the Winter or early Spring months, are 5-8% more likely to eventually develop Schizophrenia in their adulthood. This is also the case for Multiple Sclerosis (MS) and Bipolar Disorder (BD). Drs. Torrey and Yolken are two scientists that argue that the answer to Schizophrenia lies in infection. They think that a pathogen could have gained entry to the body and managed to cross the blood brain barrier when these individuals were infants. And interestingly enough, despite the fact that genetic predisposition plays a major role in the onset of Schizophrenia, the genes thought to be responsible for this illness have yet to be identified. But, in 2009, 3 studies were published in Nature, claiming that susceptibility to Schizophrenia could lie within certain immune system genes, specifically those of human leukocyte antigens. If these individuals’ immune systems are weaker compared to those of healthy people, genetic predisposition would tie in to the observed birth-month effect since people are usually more likely to get sick from flus and colds during the Winter and early Spring.
Dr. Perron was the first scientist to state that the pathogen responsible for this disease was part of our own genome. He linked the presence of endogenous retroviruses, specifically HERV-W, to the development of Schizophrenia and MS, the focus of his research. Endogenous retroviruses are RNA viruses that infected the human germ line at some point in time and have been transferred from parent to offspring ever since. Some of these retroviruses have been found to be active during gestation, and there is evidence of their activity in the placenta of humans and other animals. What is even more compelling is the fact that some studies, like that of Karlsson et al. published in 2000 in PNAS, showed the presence of retroviral sequences in the cerebrospinal fluids and the brains of Schizophrenics. Furtheremore, Huang et al. in 2010 linked the retrovirus HERV-W to Schizophrenia when they found env gene sequences of this gene in the blood of patients suffering from this illness. The same group had previously identified pol RNA in the blood of patients but not in the healthy controls.
In vivo studies conducted by Meyer et al. used polyIC to mimic viral infections in mice and showed that later in life, these infected mice develop Schizophrenia-like symptoms such as being unusually startled by noises, which is similar to auditory hallucinations in humans, and having disruptions in brain structure, which the authors attributed to inflammatory responses that may cause sequelae later in adult life. Meyer and his colleagues followed up with a study where they injected the pregnant mice with PolyIC and then treated some of the pups with antipsychotic drugs after their birth. They found that the aforementioned symptoms were not found in the treated mice.
If a retrovirus were linked to this Schizophrenia, it would explain why the symptoms are only apparent 10-30 years later. In addition, a constant state of inflammation could account for the grey matter decay and disruption in brain structure. However, it is important to point out once again how crucial it is to have controls or other experiments that can reach the same conclusions. PCR alone can lead to false positives as we have seen with the recent case of XMRV and other rumour viruses. Other techniques like testing for the presence of RNA and protein is of extreme importance if we are to truly discover the underlying cause of Schizophrenia. For instance, though no active parasites or viruses have yet to be detected, many of the patients who suffer from Schizophrenia have antibodies to toxoplasma and two members of the Herpes family, Epstein-Barr virus and cytomegalovirus, common culprits for many chronic illnesses such as Chronic Fatigue Syndrome.
Dr. Perron started his own biotechnology company, GeNeuro, to be able to test whether MS and Schizophrenia were the result of a chronic endogenous retroviral infection. He started a Phase 1 clinical trial for MS in 2011 which was recently completed, and plans to start another one for Schizophrenia with the hope of devising treatments for the endogenous HERV-W. No news of the results of the trial have been published as of yet, but it would be very interesting to see what the conclusions are. The idea that people could be tested and treated at an early age to avoid possible mental illness symptoms from arising in the future would not only help improve the health of these susceptible individuals but also reduce the stigma that surrounds mental illnesses.
References:
Sorry for not including the references on the text! Kinda got lazy this time. And I know there are lots of references but I also included some that I just read but might be of interest to you.
1.The Insanity Virus. Fox, Douglas. 2010. DISCOVER Magazine: Top Stories. Retrieved May 15, 2012.
2. Brain and Peripheral Blood Mononuclear Cells of Multiple Sclerosis (MS) Patients Hyperexpress MS-associated Retrovirus/HERV-W Endogenous Retrovirus, but not Human herpesvirus 6. 2007. Mameli et al. Journal of General Virology: 88(1): 264-274.
3. Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia. 2011. Huang et al. Oxford Journals. Schizophrenia Bulletin: 37(5): 988-1000.
4. Schizophrenia. van Os et Kapur. 2009. Lancet: 374: 635-645
5. Evaluating Early Preventive Antipsychotic and Antidepressant Drug Treatment in an Infection-Based Neurodevelopmental Mouse Model of Schizophrenia. 2010. Meyer et al. Schizophrenia Bulletin: 36(3): 607-623.
6. Immunological stress at the maternal-foetal interface: A link between neurodevelopmental and adult psychopathology. 2006. Meyer et al. Brain, Behavior, and Immunity: 20: 378-388
7. Endogenous retrovirus type W GAG and ENV antigenaemia in serum of schizophrenic patients. 2009. Bernard et al. Retrovirology6(Suppl 2): P71
8. HERV-W envelope is significantly expressed in Multiple Sclerosis and causes neuroinflammation in animal models with specific antibody inhibition. 2009. Bernard et al. Retrovirology6(Suppl 2): p70
9. Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia. 2006. Huang et al. Schizophrenia Research83: 193-199.
10. Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia. 2000. Lillehoj et al. 6: 492-497.
11. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. 2001. Karlsson et al. PNAS 98(8): 4634-4639.
12. Endogenous retroviruses and schizophrenia. 2000. Yolken et al. Brain Research Reviews31: 193-199.
13. Retroviruses and the pathogenesis of schizophrenia. 2001. Lewis, David A. PNAS Commentary 98(8): 4293-4294.
14. Schizophrenia: A pathogenic autoimmune diseases caused by viruses and pathogens and dependent on genes. 2011. Carter, C.J. Journal of Pathogens 2011(Article ID 128318): 37.
Comments