Our Internal Clock

Life on the planet has developed in the setting of the rhythmic cycles of day and night – light and dark.  As a result mammals have evolved an internal biological clock referred to as the so-called, "circadian clock."  This clock represents a physiological mechanism that establishes the internal rhythms of many diverse processes such as sleeping and waking patterns, body temperature, hormonal activity and the overall general metabolism.  As one might expect, aberrations in this system can have profound impacts on general health and well-being.

This clock is in effect an inherent mechanism that is driven by regulatory networks of clock genes that control gene expression through transcription factors.  It has been well established that the primary transcription factors are CLOCK and BMAL1 - responsible for the expression of the Period (PER) and Cryptochrome (CRY) genes.  The periodicity of the clock mechanism is established by a feedback loop in which PER and CRY proteins inhibit CLOCK-BMALI.  This feedback mechanism results in rhythmic gene expression.  In fact, it has been clearly shown that essential liver function and processes, for example, are under the control of the circadian clock.

These internal rhythms are so essential to good health that when they are disturbed by genetic mutation or environmental influences, ill-health is often the consequence.  To cite a number of examples of environmental disturbances, jet lag and shift work have been implicated in sleep disorders, and both cardiovascular and metabolic disease.

Through the work of Dr. Tsuyoshi Hirota and colleagues from the Division of Biological Sciences and Center for Chronobiology at the University of California at San Diego and La Jolla, a small molecule that functions as a modulator of the circadian clock has been identified.  This compound referred to as KL001 acts specifically on the protein products of the CRY gene that regulates a particularly critical metabolic pathway in the liver that is responsible for the synthesis of glucose – gluconeogenesis.  This was no meager accomplishment since over 60,000 compounds were analyzed using human cell lines in the laboratory.  Since KL001 is involved in regulating a pathway associated with glucose synthesis, it may prove to have some therapeutic potential in regards to the treatment of type 2 diabetes.

Our Ancestors – A New Addition to the Family

 It has been estimated that approximately six million years ago, the ancestral lineage that would ultimately lead to human beings diverged from that which lead to our nearest relations – chimpanzees and apes.  The fossil evidence demonstrates that between two and three million years ago, our ancestors showed indications of human attributes.  These ancestors, Lucy being an excellent example, walked upright but possessed small brains and hands that were obviously designed for the climbing of trees.  Members of this group are collectively referred to as our australopithecine predecessors.

The discovery of the complete lineage to modern humans remains unfulfilled.  However, Doctor Lee Berger, a paleoanthropologist at the University of Witwatersrand in Johannesburg, South Africa, has recently made a discovery that may provide a significant piece in this puzzle.

Fossil fragments that have been dated to be some two million years old have been found in an old miner's pit at the so-called "Malapa site" northwest of Johannesburg.  These fragments include pelvis and leg bones, ribs and vertebrae, arm bones, clavicle and skull.  From these various pieces, the partial skeletons of an adult female and young male have been assembled. 

From these cumulative findings, it became apparent to Berger and his colleagues that an entirely new hominid species had been discovered.  It was called Homo sediba.  Although the fossil evidence demonstrates a relatively small brain – a skull enclosing a volume of 420 cubic centimeters that is about one-third of the size of the brain of modern humans, its pelvis is bowl shaped.  This was an unexpected discovery, since it was previously believed that this shaped pelvis evolved to accommodate a large brain.  In addition, the shape of the skull shows an expanded frontal region indicating the further development of the frontal lobes – an area of the brain associated with higher order intelligence.  Although sediba's arms were long, the fingers were short and straight probably adapted to the fashioning of tools.

This finding sheds new light upon the evolutionary progression to modern humans – Homo sapiens.  It may also suggest that Homo habilis and Australopithecus afarensis might be, in fact, side branches and not in the direct lineage.  As a result, yet another piece of the intriguing evolutionary process has been elucidated.

Ocean Acidification and Climate Change – A Case In Point

It has long been understood that the uptake by the oceans of the increasing levels of carbon dioxide (CO₂) in the atmosphere,  produced as a result of human activity, leads to the reduction in the pH – increased acidity – of the water.  This increased acidity has the effect of disturbing the carbonate (CO₃) balance in the oceans.  What has not been clearly defined is the extent of these changes.

The index for assessing the degree of this imbalance is the so-called "carbonate saturation state."   The aquatic organisms that are especially susceptible to changes in the carbonate saturation state are those that create part of their structure from available calcium carbonate (CaCO₃).

Doctor Nicolas Gruber and his colleagues at the Department of Environmental Physics at the Institute of Biochemistry and Pollutant Dynamics , ETH Zurich, Switzerland and at the Atmospheric and Oceanic Sciences Program at Princeton University, Princeton, NJ have studied the California Current System (California CS) in attempt to quantify these changes.  The California CS is of particular importance in that it represents an essential marine ecosystem.

As a result of their findings, they have projected that by the year 2050 the carbonate saturation state will drop to levels that represent under-saturation of carbonates critical to the marine environment.  They have come to this conclusion using two different scenarios – one projecting high emissions of CO₂ and the other low emissions.  According to the authors, "Habitats along the sea floor will become exposed to year-round under-saturation within the next 20 to 30 years.  These projected events have potentially major implications for the rich and diverse ecosystem that characterizes the California CS."

These findings represent yet another example of the perils the global human community faces as a direct consequence of the anthropogenic buildup of greenhouse gases in the atmosphere.  It remains to be seen whether or not the plethora of known global environmental disruptions will provide sufficient motivation for the human community to implement meaningful solutions to this enormous problem.  

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.