Proteins regulate the expression of genes in order to maintain physiological balance within the body. Improper protein concentrations can lead to over or under expression of certain genes, resulting in pathological or psychological disorders. One such protein, MeCP2, has been shown to affect genes which regulate anxiety and social interaction.
Scientists at the Neurological Research Institute of Texas Children’s Hospital have recently isolated two genes (Crh and Oprm-1), regulated by MeCP2, which have a direct effect on symptoms of anxiety and autism spectrum disorders. The researchers found overexpression of these genes in an animal model of anxiety, leading them to investigate human patients suffering from anxiety for similarities. When they found elevated MeCP2 levels in many patients suffering from anxiety, they returned to the animal model to demonstrate that elevated MeCP2 protein levels caused overexpression of the Crh and Oprm-1 genes. Thus, the researchers successfully demonstrated a link between elevated levels of MeCP2 and overexpression of Crh and Oprm-1, and overexpression of Crh and Oprm-1 to anxiety disorders.
The protein MeCP2 regulates many genes in addition to Crh and Oprm-1, making it difficult to control levels of MeCP2 without compromising other systems in the body. The researchers, therefore, chose to block activation of the Crh and Oprm-1 genes in mice (through drug induced chemical blockades) rather than directly affecting MeCP2 levels. They found that reduced expression of Crh decreased symptoms of anxiety in mice, while reduced expression of Oprm-1 decreased the severity of social disorder symptoms. With this knowledge, developing genetic therapies for the treatment of anxiety and social disorders such as autism may one day become possible.
In Badwater Basin, at the edge of Death Valley National Park, researchers from the University of Nevada, Las Vegas have discovered a new type of magnetic bacteria that could prove useful for a number of biomedical applications. This new bacterium, dubbed BW-1, belongs to a class of magnetic or magnetotactic bacteria characterized by internal structures called magnetosomes which produce magnetic nanocrystals. Magnetic nanocrystals, such as magnetite (Fe3O4) and greigite (Fe3S4) (as found in BW-1), allow bacterium to interact with and navigate magnetic fields.
“The finding is significant in showing that this bacterium has specific genes to synthesize magnetite and greigite, and that the proportion of these magnetosomes varies with the chemistry of the environment,” explains Enriquieta Barrera, program director in the National Science Foundation’s Division of Earth Sciences.
Current studies mostly focus on magnetite-producing bacteria, making BW-1 the first greigite-producing bacteria to have been successfully isolated and cultured. Inspection of BW-1 DNA further revealed two sets of magnetosome genes, likely accounting for its production of both magnetite and greigite.
Greigite, an iron sulfide, indicates that BW-1 represents a new group of sulfate-reducing bacteria in a class dominated by oxygen-reducing bacteria (i.e. that BW-1 produces a sulfate based nanocrystal as opposed to only oxygen based nanocrystals as many other magnetotactic bacteria do). With all these new properties, BW-1 and its magnetic nanocrystals hold potential in cation-based drug delivery and magnetic-particle based imaging, two research areas yet to be explored with the newly isolated compound.
The brain requires activation of many different genes to alter connections between neurons for encoding memories. Neuroscientists at the Massachusetts Institute of Technology have published findings that the Npas4 gene and transcription factor may be a singular instigator and master gene for memory formation in the brain. Npas4 was previously known for activating during new experiences.
As described in their Science article, the researchers investigated the genetic mechanisms of memory formation by monitoring gene activation pathways in mice subjected to contextual fear conditioning. When entering a specific chamber, the mice were given a mild electric shock which caused them to learn within minutes to fear the chamber and freeze upon entering it.
The findings, which indicated that Npas4 turned on very early in the conditioning regimen, set the gene “apart from many other activity-regulated genes”. Further, it was found that activation occurred primarily in the CA3 hippocampal region, an area in the brain required for fast learning.
“We think of the Npas4 as the initial trigger that comes on, and then in turn, in the right spot of the brain, it activates these other downstream targets. Eventually they’re going to modify synapses in a way that’s likely changing synaptic inhibition or some other process that we’re trying to figure out,” says graduate student Kartik Ramamoorthi, lead author of the paper.
To hit the point home, mice did not remember the fear conditioning when the scientists chose to knock out the Npas4 gene, both overall and specifically in the CA3 hippocampal region. Although the study has only identified a few of the genes regulated by Npas4 and only inspected contextual fear conditioning, scientists suspect hundreds more genes are involved in the pathway and that other learning techniques will also involve Npas4.
In the future, the MIT team intends to monitor the neural activity of Npas4 during memory retrieval as well as memory formation, which may someday lead to pinpointing the exact locations of memories in the brain.
Obesity and related disorders are a growing problem in America. This epidemic is a result of both changing lifestyles and genetic/chemical influences. Recent research, in particular, has shown just how important chemical balance is to maintaining a healthy weight.
A study published in Cell Metabolism (2011), for example, has brought to light a chemical signaling pathway which directly influences obesity. The TGF-β/Smad3 pathway, the subject of the work done in the paper, is involved in the metabolism of glucose and in turn energy homeostasis. It was shown that Smad3 deficient mice were better protected against experimentally induced obesity and diabetes, and that chemical blockage of the TGF-β signaling cascade had a similar positive effect. Further, decreased Smad3 levels were also shown to cause a phenotypic change in fat cells wherein cellular respiration and mitochondrial biogenesis (the rate at which active mitochondria are formed within the cell) increased. Mitochondria, the “power plants” of cells, break down fat-forming glucose into ATP, the cell’s version of gasoline (as shown in the image below). This increase in respiration and glucose metabolism (due to lower levels of Smad3) increases the breakdown of adipose or fat tissue.
With continued research, this knowledge could potentially be applied medically through hormone therapy to reduce the risk of obesity in patients hormonally predisposed to the condition (via chemical alteration of the TGF-β/Smad3 pathway).
Hemophilia refers to a class of genetic disorders characterized by the impairment of blood clotting or coagulation due to the lack of clotting factors normally produced by the liver. Hemophilia type A, for example, results from the deficiency of Clotting Factor VIII while Hemophilia type B results from the lack of Clotting Factor IX. In a recent study published in the New England Journal of Medicine, British researchers at University College London Cancer Institute in collaboration with St. Jude Children’s Research Hospital successfully treated six severe Hemophilia B patients by introducing into them a gene coding for Clotting Factor IX. While past clinical trials using gene therapy were not able to produce lasting expression of clotting factors, this current study shows expression lasting for at least a year. Further, animal models using the same methods have shown genetic expression for up to ten years.
In their study, the scientists used a viral vector (a virus incapacitated of reproduction and infectivity) to carry DNA containing code for Clotting Factor IX. This vector specifically targets the liver where it initiates the production of Clotting Factor IX. All six patients taking part in this study originally produced less than 1% of the normal expected levels of Clotting Factor IX. After a year into the gene therapy trial, the patients were all producing 2 – 12% of the normal levels of Clotting Factor IX (with higher dosages of the viral cocktail corresponding to higher production of Clotting Factor IX). While this appears minute, the research is making steady progress. Perhaps once the gene therapy methods reach optimal potency, the scientists can transition to studying the more prevalent Hemophilia A which requires delivery of a larger gene (for Clotting Factor VIII).
The current treatment for hemophilia B involves injecting clotting factor IX concentrate into patients with the disease. The cost for this can range anywhere from $150,000 to $300,000 a year depending on the frequency of injections needed by the patient. The proposed gene therapy, in addition to its efficacy, would bring down costs for treatment to around $30,000 per patient, since a single treatment would last at least a year as the study has shown. The researchers involved in this study explain their findings below:
Depression has become increasingly prevalent in today’s society, affecting a staggering 35 million Americans at some point in their lifetime (about 16% of the population). Research has shown that 60% of patients do not receive proper treatment, while 60% of treated patients do not respond to their first trial of antidepressants. Researchers at Layola University Medical Center have recently developed a blood test to assess the effectiveness of selective serotonin reuptake inhibitor (SSRI) antidepressants like Prozac and Zoloft.
This test could allow psychiatrists to be more selective and accurate when prescribing an antidepressant, and help increase the number of patients receiving proper treatment for their depression.
The new test detects the level of vascular endothelial growth factor (VEGF) in blood. VEGF is primarily responsible for new blood vessel formation and homeostasis, but research has shown that when combined with SSRI antidepressants, VEGF becomes a powerful player in psychological function. SSRIs are believed to increase neurogenesis; the production of new neurons within the brain. In patients with high levels of VEGF, this neurogenesis is supported by new blood vessel formation and general chemical homeostasis. In patients with low levels of VEGF, the neurogenesis caused by SSRIs is not as effective, reducing the psychological impact of the drug.
In a clinical trial, 85% of patients with high levels of VEGF showed positive results from taking Lexapro, a SSRI antidepressant. While only 10% of patients with low VEGF levels experienced similar results. These numbers suggest a legitimate correlation between VEGF levels and effectiveness of SSRIs, which should spark the attention of psychiatrists. Although a relatively expensive blood test, mass use of such a test would inevitably bring prices down.
This breakthrough suggests the eventual possibility of using a patient’s individual body chemistry to accurately prescribe any drug, greatly improving the effectiveness of treatment.
