Thursday, June 28, 2012

New Discoveries Regarding Muscular Dystrophy

Muscular Dystrophy is a devastating disease that is represented by severe muscular paralysis that is a direct result of the profound loss of muscle cells.  Faciosapulohumeral Muscular Dystrophy (FSHD) is the third most common form of the inheritable form of Muscular Dystrophy.  In order to implement effective treatment for this extremely debilitating disorder, it is essential to uncover the underlying mechanism of the disease process.

It has been previously established that a mutation in human chromosome number 4 is the underlying cause of FSHD.  It has also been shown that in FSHD patients there is the expression of the DUX4 protein that is not normally found in human muscle cells.  However, the underlying relationship between this protein and the disease has been poorly understood.   

The DUX4 gene product – a gene can be defined as the genetic information that contains the blueprint for a unique protein – is responsible for the regulation of many genes whose protein products are normally found in the male germ line but that are abnormally expressed in the muscle cells of FSHD patients.  In fact, the DUX4 protein functions as a transcription factor – a protein that regulates the expression of other genes.  Dr. Stephen Tapscott and his colleagues at the Fred Hutchinson Cancer Research Center in Seattle, WA have established that the mutation in chromosome number 4 is directly responsible for the expression of DUX4 in the muscle cells of FSHD patients and that its presence in these cells can initiate the loss of muscle cells  by a number of possible mechanisms.  It may accelerate cell death through a process known as apoptosis or it may trigger an autoimmune response  in which the patient's own immune system begins to target muscle tissue.

These findings have considerable therapeutic implications.  Some possibilities for treatment have been proposed including blocking the expression of DUX4 or interfering with its downstream effects.


Wednesday, June 20, 2012

Role of the Amino Acid Glycine in Cancer Cell Growth

One of the main and more ominous characteristic of cancer cells is their capacity to grow beyond the ordinary controls that limit cell proliferation in normal tissues.  This accelerated growth ultimately leads to metastasis – the spread of cancerous cells to surrounding tissues from the tissue of origin.  It is uncontrolled metastasis that ultimately leads to the death of the patient in the terminal stage of the disease.

It has been clearly established that cancer is the result of genetic mutation that gives transformed cells a definitive proliferative advantage over normal cells. Given this property common to all cancers, it would be efficacious to understand the mechanism through which this accelerated growth operates.  It has long been suspected that in cancer cells, key metabolic pathways have been altered in such a way as to accelerate cell division beyond normal limits.  This process is, however, poorly understood.

Through the laborious efforts of Dr. Mohit Jain and colleagues at the Broad Institute in Cambridge MA and at the Department of Systems Biology at Harvard Medical School, Boston, MA, a clearer understanding of the metabolic characteristics of rapidly growing cancer cells has emerged.

This group has painstakingly characterized the cell chemistry of 219 known metabolites from a panel of 60 well established primary human cancers in cell culture that reflect nine well known cancers and tumor types.  This was accomplished using highly sophisticated analytical tools involving liquid chromatography and tandem mass spectrometry.

Interestingly, from this data, it was discovered that the consumption of the amino acid glycine demonstrated a statistically relevant and significant correlation with cancer cell proliferation.  Glycine is an amino acid – amino acids are the chemical building blocks of proteins.  In addition, it is a non-essential amino acid i.e. the cells of the body are capable of synthesizing this amino and it is, therefore, not required in the human diet.

Furthermore, the glycine biosynthetic pathway found normally in the mitochondrion – a cell organelle that is responsible for energy production in cells – was shown to be the pathway of choice for the synthesis of glycine.  When the experimenters purposefully, blocked the synthesis of glycine by interfering with the mitochondrial synthetic pathway, the enhanced proliferation of the cancer cells studied was significantly impaired.

These findings uncover a previously unknown vulnerability of a wide range of known cancer types.  This discovery may prove to be highly significant as a strategy for the treatment of cancer. 

Friday, June 1, 2012

Drug Addiction and the Human Brain

The addiction to stimulant drugs is a serious issue that confronts modern society.  In those so afflicted, it is characterized by a satellite of issues including a behavioral pattern that grows out of control in the pursuit of obtaining and consuming ever-increasing amounts of drugs in spite of the fact that the use of these drugs negatively impacts both the individual's health and his or her social and personal life. 

In light of recent evidence, drug addiction has come to be regarded as a, "relapsing brain disorder."   In support of this view, marked structural changes in the striatal and pre-frontal brain regions have been reported in individuals with stimulant drug addiction.  The pre-frontal area of the brain is ordinarily recruited in the regulation and moderation of behavior.  Therefore, any deficit within this region may explain the dependency upon stimulant drugs on account of the fact that these chemicals impact those areas of the brain involved in motivated behavior.

The question naturally arises as to whether addiction itself causes changes in the structure of the brain or the structural anomalies described above precede the addictive behavior and predispose the affected individual to drug taking and its concomitant risky behavior.  In support of the latter argument, the structure of the individual brain is an inherited characteristic and drug addiction is known to run in families.  If, in fact, drug addictive behavior is an inheritable trait, the changes in brain structure would be regarded as an endophenotype – a trait that is a direct result of a genetic anomaly (genotype) and that is responsible for the overt clinical symptoms (phenotype).

In order to test this hypothesis, Dr. Karen D Ersche and her colleagues from the Behavioral and Clinical Neuroscience Institute and Department of Experimental Psychology and Department of Psychiatry at the University of Cambridge, Cambridge, UK, conducted a study in which,   "we compared brain structure and the ability to regulate behavior in 50 biological sibling pairs."  As a result of this exhaustive investigation, it was shown that the fronto-striatal regions of the brains showed marked abnormalities in not only addictive individuals but their biological siblings who possessed no apparent symptoms of drug dependency.  The demonstration of changes in brain structure in close family members establishes the genetic connection and strongly suggests that such endophenotypic changes predispose the individual to drug addictive behavior.

These findings are of immense importance in not only understanding the nature of drug addiction, but also informing the general public and the legal system on how to best deal with addictive individuals.  In addition, further studies designed to discover the underlying genetic abnormalities associated with this condition could provide immeasurable help in finding appropriate therapies for this brain disorder.