Stem Cell Research Provides New Approach to Study Bipolar Disorder

 

Researchers have detected mitochondrial abnormalities, and differences in neuronal firing, in young neurons from patients with bipolar disorder by using induced pluripotent stem-cell (iPSC) technology. These stem cells are created from patient’s skin cells (fibroblasts) or from patient’s white blood cells (lymphocytes). It is possible to take skin cells or white blood cells and reverse engineer them back to the state where they have the ability to grow into different types of cells (basically back to the very early embryo state when the original template cells are just beginning to turn into different types of cells.)  Then these stem cells can be grown in the lab and encouraged to become neurons. By imaging these created neurons from people with and without bipolar disorder, researchers have seen a difference in neuron firing between people who respond to lithium treatment vs those who don’t respond to treatment. This hyperexcitability activity of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment.

Mitochondria are structures found within all cell types, and they are the organelles that help provide energy for the cells, along with other important functions. Mitochondria contain their own DNA separate from the cell’s nuclear DNA. Mitochondria DNA is mainly inherited from the egg, therefore the maternal side of the family. In one study, in about 80% of the bipolar patients, hippocampal mitochondria were smaller than even the smallest of the control subjects’ mitochondria. The hippocampus is the elongated ridges on the floor of each lateral ventricle of the brain, thought to be the center of emotion, memory, and the autonomic nervous system. Differences in expression of the genes in the mitochondria were also found between subjects and controls. Is it possible then that a greater predisposition to bipolar disorder could be influenced by the maternal family side?

Brain research is complicated because tissue is difficult and dangerous to extract, and studying brain tissue after death doesn’t give us a good picture of cause and effect across the lifetime. In post-morteum brain tissue, abnormalities could be due to a number of different environmental exposures (such as drug treatment) or trauma such as concussions that are difficult to control in living subjects. A model that does not use living subjects is difficult to create.

However,  researchers have been able to use stem cell from patients to create tissue in the lab for study.  They can take stem cells and “engineer” them to create many different types of tissues; in this study they use patients’s stem cells to create neurons. The hyperexcitability of the neurons is one early indicator of bipolar disorder, and this model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Here is a link to the study in Nature:

https://www.ncbi.nlm.nih.gov/pubmed/28242870

And a link to one of the earlier studies:

https://www.nature.com/nature/journal/v527/n7576/full/nature15526.html

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23andMe Ordered by FDA to Stop Marketing Genetic Tests

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I’ve been on the fence about 23andMe’s personalized genetic tests.I like that it’s a cheap way to access your own DNA- which many of us may never have the opportunity to do. On the other hand, many of the gene allele interpretations are based on very small research studies that may not apply to the general population. The test has risk predictors for mental health conditions like schizophrenia, bipolar disorder, depression and alcholism. I have looked at the studies that 23andMe bases their intrepretations on, and I find them lacking. I would not recommend that anyone make decisions on treatment, medication, or personal life decisions such as having children, on such results.

23andMe is backed by Google, so obviously there is a lot of money behind the company. I think it is very important that the FDA takes this stand, and demonstrates to the American public that profit has to take a backseat to safety.

Alberto Gutierrez, director of the FDA’s Center for Devices and Radiological Health, said in a letter to the company made public on Monday that 23andMe had failed to address concerns raised on multiple occasions since the agency began working with it on compliance in July 2009. He commented that the the FDA does not have any assurance that the firm has analytically or clinically validated the tests for its intended uses.

23andMe responded  “We recognize that we have not met the FDA’s expectations regarding timeline and communication regarding our submission,” the company said in a statement. “Our relationship with the FDA is extremely important to us and we are committed to fully engaging with them to address their concerns.”

23andMe has plans to start markeing to the public via televison. As far as I can see from the report, they will not be able to do this immediately.

Here is a link to more information:

http://www.theguardian.com/science/2013/nov/25/genetics-23andme-fda-marketing-pgs-screening

 

Do People With Mental Illness Age Faster Than People Who Are Unaffected?

Last week I attended a talk by Dr. Owen Wolkowitz, psychiatrist and professor at UCSF Langley Porter Institute.  His answer to this question is “yes.”  He refers to mental illness as “disorders of the whole body.”

There is data that people with mental illness die, on an average, 25 years earlier than people in the general population.  30-40% of people with mental illness die of suicide or accidents, but the remaining 60% die of natural causes earlier than the general population.

There are some obvious reasons as to why:

1)      Poor lifestyle – smoking , drinking, illicit drug use, bad nutrition

2)      Poor access to healthcare, poor medication compliance, homelessness

3)      Medication side effects such as obesity, increased lipids

Less obvious are some of the behind the scenes factors, such as inflammation due to stress.

It is also possible that mental illness actually changes our DNA, in particular our telomeres. Telomeres are the pieces of DNA at the ends of the chromosomes. Each time a cell divides, it duplicates its chromosomes, and a little bit of the end of the chromosome is lost. At some point, too much information is lost, and instead of dividing, the cell dies. This is the aging process in a nutshell. We can’t have cells that live forever (that’s what happens in cancer, the mechanism gets screwed up and the cell keeps dividing forever.)  Telomerase, the enzyme that adds the telomeres to the end of the chromosome, can be measured in the blood, and can be used as a marker for aging.

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Studies have been done on telomeres of people with mental illness. Studies of people with depression show telomere shortening. Adults with early life trauma have shorter telomeres, demonstrating perhaps a “scar in the brain.”  There’s evidence that people with schizophrenia who take anti-psychotic meds have longer telomeres than people with schizophrenia who aren’t taking any medication- demonstrating a potential benefit of medication. It’s possible that anti-psychotics can have an effect by reducing inflammation and oxidative stress.

The good news is that telomeres can lengthen. Factors known to extend telomere length to a healthy level include exercise, dietary restraint, multivitamins, folate, Omega 3’s, stress management, statins, estrogen and social support. So while good nutrition, good sleep, exercise and avoidance of illicit drugs are good plans for everyone, they are especially important for people with mental illness, or people at risk for mental illness.

Link to article on telemore shortening:

http://www.sciencedirect.com/science/article/pii/S0006322306001363

Genetic Clues to Anorexia Nervosa

Teen Anorexia Treatment

Anorexia nervosa is a complex disorder, a combination of genetic predisposition and environmental and behavioral factors. A recent study looked at 152 genes that are known to be involved in eating behavior, dopamine function, and brain communication to look for genetic variations that might be associated with Anorexia. Three groups of research subjects  were looked at for a total of 1205 case subjects and 1948 controls. Results from the study linked anorexia with two genes: ESR2 and EPHX2

ESR2 is an estrogen receptor. Estrogen receptors are found in both men and women, but play a higher role for women, particularly starting in adolescence. Anorexia is more common in women, and typically develops around the start of puberty, so the connection here at least follows logically. It may come to some as a surprise that men also can have anorexia, and men also need a small amount of estrogen for strong bones and brain function.

EPHX2 ‘s connection is not as obvious. The gene codes for the epoxide hydrolase protein which is involved in the breakdown of fats and toxins. EPHX2 is involved in cholesterol metabolism, and defects in the gene are associated with a disease called familial hypercholesterolemia. Anorexia nervosa patients often display hypercholesterolemia, which is counterintuitive, given the under-nutrition and low body weight of affected individuals. The study says, “It has been hypothesized that low levels of cholesterol may decrease the activity of serotonin receptors and transporters and that significantly lower cholesterol levels are associated with depressive symptoms, impulsive/self-harmful behavior (cutting and/or burning) and suicide thoughts/attempts in anorexia patients. Moreover, lower cholesterol levels have been associated with increased suicidality more broadly, including ideation and attempts, in depressed patients.”

Dr. Schork, one of the paper’s authors said, “The hypothesis would be that in some anorexics the normal metabolism of cholesterol is disrupted, which could influence their mood as well as their ability to survive despite severe caloric restriction.”

The study hopes that their results will provoke interest and more research into the connection between these genes and anorexia.  It’s exciting news for researchers studying eating disorders.

Here’s the link to the article:

http://www.nature.com/mp/journal/vaop/ncurrent/pdf/mp201391a.pdfmale anoerxia

New Clues to the Cause of Schizophrenia

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A research study published Aug 25th on Nature Genetics online has found 22 genetic risk loci for schizophrenia, 13 of which are new discoveries. Genes at these loci suggest involvement of two pathways- the calcium signaling pathway and the “micro-RNA 137” pathway. Calcium plays a major role in normal cell functioning. It is a signaling molecular involved in synaptic activity (the junction between nerve cells where neurotransmitters like serotonin are released), cell to cell communication and cell adhesion. In the brain, calcium is fundamental in the control of synaptic activity and memory formation. Calcium signaling disturbances are already known to be involved in different brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The Micro-RNA 137 pathway is involved in neuronal development. This association of development and regulation of brain nerve cell genes with schizophrenia may further understanding and help with new treatments for the disease.

The lead author of the study, Patrick F. Sullivan, MD , commented:

“This study gives us the clearest picture to date of two different pathways that might be going wrong in people with schizophrenia,” Sullivan said. “Now we need to concentrate our research very urgently on these two pathways in our quest to understand what causes this disabling mental illness.”

The link to the study is here:

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2742.html

Potential Genetic Testing For Schizophrenia

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A type of genetic testing may be useful for detecting schizophrenia.  A study published July 14th in the journal Human Molecular Genetics demonstrated a significance difference between the number of rare copy variants (CNVs) in patients with schizophrenia vs. the general population.  CNVs are duplications or deletions of small parts of the genome.  The  test for them, called a microarray, has only been around for about 10 years,and is becoming standard of care for people with autism and intellectual disabilities.. This study found a CNV detection rate of about 1 in 13 patients with schizophrenia- about 8%, which is a similar detection rate to some clinical CNV studies on autism.

The study excluded deletions in chromosome area 22q11.2, which are already known to be associated with condition that can include schizophrenia, birth defects and intellectual disabilities. The patients in this study had no obvious physical or mental disabilities.

This is the first study to implicate the area 2q13  as having a significant risk for schizophrenia. Information gained from further study of CNVs may help with medical and/or psychiatric management. This information can be used right now to help families understand reproductive implications for siblings and patients themselves.

Here is the link to the abstract:

http://www.ncbi.nlm.nih.gov/pubmed/23813976

Supreme Court Decision: Genes Cannot Be Patented

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The U.S. Supreme court ruled today that “a naturally occurring DNA segment is a product of nature and not patent-eligible merely because it has been isolated.”

Myriad, a genetic testing company, holds patents to two genes sequences that indicate a large risk for breast and ovarian cancer. In order for women and men to be tested for these sequences, Myriad charges a large fee.  To be fair, Myriad has spent a lot of money developing these tests, and does offer some funding for patients who cannot afford to be tested.  However a lot of underinsured patients slip through the cracks, and genetic counselors struggle to find funding for some low income women’s tests.

The unanimous Supreme Court ruling will allow researchers more freedom in experimentation and testing. It is not known how this will affect future genetic test development.  It is now possible to sequence the entire genome (whole genome sequencing) and the parts of the genome we know that code for proteins (exome sequencing) . As genetic testing progresses, single gene testing may become outdated anyway.  This does allow whole genome and exome sequencing companies the freedom to counsel on these previously patented genes.

Synthetic versions of the gene material may be patented.

Everyone has a copy of their entire genome in every cell of their body. Personally I feel that no one owns the genome, and am pleased with the Supreme Court decision.

 

L.A.Times: http://www.latimes.com/news/politics/la-pn-supreme-court-dna-patents-20130613,0,4076014.story

CNN: http://www.cnn.com/2013/06/13/politics/scotus-genes/index.html

Washington Post: http://www.washingtonpost.com/politics/courts_law/supreme-court-says-human-genes-cannot-be-patented/2013/06/13/f7681b22-d436-11e2-b3a2-3bf5eb37b9d0_story.html