A Possible New Approach to the Treatment of Osteoarthritis

Osteoarthritis (OA) is a degenerative condition that involves the breakdown of joint cartilage that affects over 70 percent of individuals between the ages of 55 and 70 in the United States.  If untreated, it can eventually lead to severe disability.  Currently, the available options for individuals suffering from OA are medication to relieve pain and eventual surgical invention often involving joint replacement.

The disease process is complex and multi-faceted.  It involves:

• degradation of the integrity of the extracellular matrix
•   lack of sufficient replacement and repair of this matrix
•   abnormal cell death
•   accelerated differentiation of cartilage cells.

Dr. Kristen Johnson and colleagues from the Genomics Institute of the Novartis Research Foundation in San Diego California are developing an approach to the treatment of OA using mesenchymal stem cells (MSCs).  Stem cells are cells found in the body that are so-called pluripotent cells in that they have the capacity, under the appropriate conditions, to differentiate into a variety of tissue cells.  MSCs are normally found in the bone marrow and are capable of differentiating into a variety of cell types including chondrocytes – the cells responsible for making new cartilage.

In their research, Johnson's group discovered a small molecule called kartogenin that they have shown can stimulate the differentiation of MSCs into chondrocytes and therefore lead to the enhanced production and repair of cartilage – a process known as chondrogenesis.

These results are significant in that they suggest a non-invasive stem cell- based procedure as a therapy for OA in place of the current surgical option.

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.

 

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. 

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.

A Possible Cause of Colony Collapse Disorder in Honey Bees

The phenomenon of colony collapse disorder (CCD) in honey bees is a recent one that has plagued honey bee populations in North America.  CCD is a recent condition  that is characterized by the disappearance of honey bees from the hive.  This has long puzzled investigators.  A number of different causes have been proposed including pesticides, microbial or parasitic infection and environmental degradation.

Since honey bees significantly contribute to plant propagation through pollination, It is important to uncover the actual cause of CCD so that this situation can be addressed and remedied.  Of the possible candidates as cited above, pesticides have long been suspected of playing a leading role.   Farming practices often involve the wide use of systemic pesticides.  Systemic  agents permeate all the tissues of a plant ultimately contaminating the nectar and pollen on which the bees rely.  In addition, honey bees heavily utilize common blooming crops including oilseed rape, maize and sunflower that are commonly exposed to pesticides.

Although pesticide manufacturers are required to monitor the mortality of unintended life forms in the field, there is growing evidence that sub lethal doses may adversely impact behavioral problems in aging honey bees especially in regard to navigational skills.  There is a class of insecticides, the so-called, "Neonicotinoids" routinely used to protect crops against aphids that are strong candidates for having an adverse impact upon honey bees.  The reason for this possible connection is that pesticides of this class selectively bind to nicotinic acetylcholine receptors that are essential for a properly functioning nervous system in insects.

Dr. Mickael Henry and his colleagues from the Institut de la Recherche Agronomique in Avignon, France have shown that, "nonlethal exposure of honey bees to thiamethoxam (neonicotinoid systemic pesticide) causes high mortality due to homing failure at levels that put a colony at risk of collapse."

This finding is of crucial importance, for it provides direct evidence of the actual causative agent in CCD.  These finding should provide impetus for a reexamination of the widespread use of nonicotinoid pesticides that are currently in worldwide use.

An Existing Drug May Offer Promise for Patients with Alzheimer’s Disease

Dr Cramer and her colleagues at Case Western Reserve University School of Medicine in Cleveland have discovered that the drug called bexarotene reverses the degenerative effects in the brains of mice that suffer the equivalent of Alzheimer's disease found in humans.

In the brain of Alzheimer's patients the most predominant anomaly is the presence of what is referred to as neuritic plaques and neurofibrillary tangles which are believed to lead to the disruption of normal brain activity and cell death that ultimately robs patients of the ability to remember and use reasoned judgment.  The disease process proceeds at a slow and ultimately deadly pace.

The underlying mechanism for the disease remains elusive though there are numerous hypotheses that have been proposed to explain disease onset.  What is well established, however, is the fact that the plaques result from the aggregation of the peptide – β-Amyloid (Aβ) - a peptide is a relatively small molecule made of a sequence of amino acids analogous to the structure of proteins.  Aβ is a direct product of the fragmentation of a trans-membrane protein called amyloid precursor protein (APP).  Trans-membrane proteins span the plasma membrane that encircles every cell.  There is a protein complex associated with the cleavage of APP; one of the proteins in this complex is an enzyme, protease – γ – secretase; this enzyme is a necessary component for the effective cleavage of APP. 

Furthermore, the modification   – mutation –  of three genes have been implicated in the autosomal-dominant form of Alzheimer's disease.  These genes are responsible for the production of APP and two additional factors required for the function of protease – γ – secretase .

Aggregates of the Aβ peptide are suspected of causing dementia, as mentioned earlier, possibly by interfering with the appropriate communication between neighboring neurons in the areas of the brain affected.  In spite of the ambiguity surrounding the exact etiology of Alzheimer's disease, the genetic association is unambiguous.  For example, individuals with a single copy of the APOE-4 gene have a five-fold increased risk of contracting the illness.

Of great interest is the fact that Cramer and her associates have shown that administration of the drug bexarotene to mice with the murine version of Alzheimer's disease results in the increased expression of APO-E – a protein that is known to bind to Aβ, the subsequent rapid clearance of Aβ  and , most importantly, the reversal of abnormal behavior in the diseased animals.

These findings are of immense interest.  Whether or not these results can translate into effective treatment of human Alzheimer's patients is dependent upon extensive and carefully executed clinical trials given the many differences between the architecture of the human and mouse brain.  There is, however, a cause for hope.

The Role of Protein Structure in Health and Disease

Proteins are a necessary part of the human diet.  When proteins are digested they are broken down into their building blocks – amino acids.  The body then reassembles these amino acids to produce the proteins required by the organism to live.  Proteins play essential roles in all living things, including humans.  These roles can be included into two major types – structural and metabolic.  Structural proteins maintain the shape and form of the both the individual cells of the body and the whole organism and are essentially responsible for locomotion.  As an example,  collagen is an essential ingredient of the connective tissue and is the most abundant protein found in the body.  In addition, the movement of muscle is due to a fundamental property intrinsic to the structure of muscle proteins – actin and myosin. 

A specialized class of proteins called enzymes is responsible for all the metabolic reactions that make life possible.  There are thousands of different types of enzymes; each responsible for a particular chemical reaction.  The scientific discipline that studies these reactions is referred to as Biochemistry.  An example of a protein that plays a critical role in respiration is hemoglobin.  The structure of this protein is exquisitely designed to react with molecular oxygen that is delivered to the lungs from the air.  This protein, like all proteins, is synthesized from the blueprints that are embedded in the gene responsible for its structure.  There is an axiom in biology that states that one gene has the information for the structure of one protein – this axiom basically still holds true.  Because the structural information for a protein lies in the gene that is responsible for it, a change in a gene – a mutation – can adversely impact protein structure.  Such a change would, therefore, be hereditary.  Sickle Cell Anemia is a disease in which a mutation in the gene that contains the information for the structure of hemoglobin results in a change in the protein's structure that adversely impacts it function.

The techniques devised by molecular biologists and biochemists over the years have helped elucidate the detailed relationships between the structure of proteins and their specific functions.  For example, as a result of these efforts, a relationship has been clearly demonstrated between the amino acid glutamine and protein structure.  Studies have shown that when there are sufficient repeats of this amino acid – a number of glutamines linked side by side in the protein chain - they may cause a significant change in the overall shape of the protein resulting in protein aggregation.   Protein aggregation can adversely affect protein or enzymatic function.   The evidence indicates that when these glutamine repeats become extensive in the protein huntingtin and other proteins found in neurological tissues, the result can be neurodegenerative disease.  The gene that contains the information for the structure of huntingtin is called the Huntington gene (HTT) and is strongly implicated in Huntington disease – a devastating neurological illness.

In conclusion, the examples cited above clearly demonstrate the essential role that proteins play in the human body and the implications for human health when protein structure has been changed due to a genetic aberration.   Linus Pauling, the famous Nobel Prize – winning chemist, described diseases like Sickle Cell Anemia and Huntington disease as "molecular diseases" for the reason that the underlying cause can be traced to an adverse change on the molecular level.