Iron and Good Health

There are many so-called "micronutrients" that are required in the human diet.  Many of these are metals including Sodium, Potassium, Zinc, Cobalt and Iron.  Iron plays a special role since it is a member of the transition state elements and can assume a number of different charged states; this attribute has made it quite useful as an essential cofactor in the function of many enzymes and oxygen transport systems not only in humans but also in many diverse life forms across the entire spectrum of living things.

 

On account of these properties, iron has been shown to play an important role in host-pathogen interactions during infections.  As a matter of fact, it has been clearly shown that a host's iron status can directly impact the degree and intensity of infection.  In one particular study involving Somalis who were iron-deficient, these individuals had a five-fold increase in various infections including  reactivation of preexisting malaria in relation to those individuals that were given iron supplements.  A degree of caution needs to be stressed in regards to the ingestion of iron supplements in that excessive intake can prove toxic.

 

A hormone, Hepcidin, present in humans has been shown to play a key role in the absorption of iron consumed in the diet and its subsequent distribution to many tissues throughout the body.  In addition, Hepcidin, a peptide hormone (peptides are small protein molecules), has antimicrobial properties.

 

Dr. Hal Drakesmith and his colleagues from the Molecular Immunology Group and Medical Research Council Human Immunology Unit at the Weatherall Institute of Molecular Medicine at the University of Oxford in Oxford, UK, have shown that the synthesis of Hepcidin is regulated by not only the levels of iron present in the body but also immunological status i.e. the presence of infectious agents.

 

Another aspect of iron regulatory mechanisms relates to the presence of unbound iron or heme – that is often released during infections – in the circulation.  Unbound iron can have a number of deleterious side effects:

·         It can provide an essential nutrient to an ongoing infection

·         It can generate harmful free radicals and result in tissue damage.

For these reasons, there are proteins present that can safely bind the unbound iron.  These proteins include transferrin, lactoferrin and ferritin for iron; haptoglobin for hemoglobin – the essential component for delivering oxygen to the tissues- and hemopexin for heme.  The antimicrobial properties of these iron carriers is supported by the observation that they inhibit the growth of certain bacteria in the laboratory and by the fact that lactoferrin is found in abundance in breast milk and is released from neutrophils – immunological cells that are involved in the body's first line of defense against infection.

 

These data strongly implicate iron status in the body with good health and the natural defense against infection.

Climate Change - New Concerns

There is a growing concern among climatologists that the earth may be entering an era of accelerated climate change.  This reevaluation has at its core evidence of so-called feedback loops.  Some examples of the feedback process are the following:

·         As sea ice melts it reduces the albedo effect (reflection of the sun's heat from the surface) and, therefore, leads to an increase in ocean temperature that results in a further melting of the sea ice

·         As areas of permafrost – found in Siberia - melt due to increased average temperature in the atmosphere, this releases carbon dioxide (CO₂) and the more potent greenhouse gas, methane from vast stores of biomass that exist below the permafrost.  It is estimated that the total store of this organic material represent twice the amount of carbon (CO₂) already in the atmosphere.  The release of these greenhouse gases further increases the average global temperature resulting in further melting of the permafrost.  This kind of feedback involving the permafrost has also been implicated in the warming crisis that has been reported to occur at the end of the Permian Period (~ 250 million years ago) by A. Hallam and P.B. Wignall in their book entitled, Extinctions and Their Aftermath

·         The disruption of the thermohaline circulation (THC) as discussed in detail in a previous article (Climate Change Revisited).  It is important to understand that the THC influences global climate by transporting heat and freshwater between the oceans globally.

 

The prospect of these feedback mechanisms accelerating climate change has so concerned James E Hansen, Director of the NASA Goddard Institute for Space Studies that he has warned that, "Unless the world slashes CO₂ levels back to 350 ppm (the current level is 391), we will have started a process that is out of humanity's control."  He cited the possibility of a sea level rise of five meters during this century - if this should become reality it would be catastrophic.  Other scientists in his field believe the rise will not be that extreme but do envision a sea level rise as high as two meters.  This projection is also very troubling.

 

These data indicate that not only are we currently feeling the impact of climate change but also that these changes may very well be accelerating.  This is a global crisis that necessitates a global solution. 

Climate Change Revisited

The recent weather catastrophe that struck an area of the United States where some fifty million individuals reside brings to the forefront once again the issue of climate change.  The storm surge precipitated by the hurricane referred to as, "Sandy," was unprecedented in its severity for this region of the country.  The damage that it wrought in both its physical manifestations and its emotional impact on the lives of those directly affected together with the mounting cumulative evidence including extreme hot weather, droughts, the frequency and severity of forest fires, etc. are representative of the expected consequences of the ever-increasing concentration of greenhouse gases in the atmosphere as predicted by sophisticated computer-modeling developed by climate scientists.   

 

I have eluded to some of these factors in previous reports, that show a connection between increased surface temperature of the oceans and the expected increased severity and possible frequency of hurricanes and typhoons that derive their energy from ocean temperature. I would like to take this opportunity, however, to address a very particular aspect of climate change that may directly relate to extreme weather conditions more likely to impact global weather patterns in the more distant future..

 

Since the upper layers of the ocean have direct interaction with the atmosphere, changes in this upper level have a direct bearing on climate over shorter periods of time (decades).  However, deep ocean circulation has a direct influence over future climate conditions.  For water to sink from the ocean's surface to the deeper ocean, it must be more dense – the two criteria that meet this requirement are temperature and salt content i.e. the water must be cold and salty.  The water in the Atlantic Ocean and the Greenland Sea – between Greenland and the Scandinavian countries –  and the ocean around Antarctica are large bodies of water that meet these requirements.  This deep dense water contributes to the deep water circulation that is global in extent.  This process is knows at the thermohaline circulation (THC).  It is important to understand that the THC influences global climate by transporting heat and freshwater between the oceans globally.

 

As ice melts as a direct consequence of the level of greenhouse gases in the atmosphere, the water in its immediate vicinity becomes less dense as a result of simple dilution.  As a consequence, such water will be less likely to sink to the deep ocean.  Consequently, this weakening of the THC, lessens the heat flow from the tropics to the North Atlantic.  It is anticipated that if the level of greenhouse gases is allowed to increase unabated over the long term, the THC would be expected to breakdown entirely.  If this should happen, the winters in the North Atlantic and Western Europe could be become extremely severe.

 

This kind of scientific analysis demonstrates that if humanity fails to address the problem of greenhouse gas emission in a meaningful way, both the near term and long term effects could prove disastrous to life as we know it. 

So-called Junk DNA – Not Really Junk

In the year 2000 as a result of a momentous effort to define the human genome, the first complete sequence of human DNA was delineated.  From this work, it was determined that only about 3% of the entire DNA structure was relegated to the genes – containing the information for the structure of those proteins that help defines us as human.  It was assumed that the remaining 97% of the DNA played no important biological role and was determined to be "junk."

 

To some it seemed inconceivable that so much DNA real estate would serve no biological purpose.  As a consequence, a number of laboratories from around the world became involved in an ambitious joint project designed to determine the role, if any, of the non-gene parts of the entire human genome.  This work required a meticulous examination of extended sequences of DNA.  This endeavor was referred to as the Encyclopedia of DNA Elements (ENCODE).  The goal of this project was to find those portions of the non-gene DNA that had an identifiable purpose.

 

In 2007, ENCODE came out with its first preliminary report clearly showing that this part of the DNA contained many varieties of functional elements.  As a consequence of this work, a series of papers has been published in the September (2012) issue of the prestigious scientific journal, Nature detailing ENCODE's findings.

 

These extensive and exhaustive studies clearly demonstrate that large non-gene areas of the human genome contain information of functional significance.  ENCODE has catalogued an impressive inventory of hidden switches for the expression or suppression of encoded genes, signals –transcription factors - and signposts integrated throughout the length of the human genome.  In essence, it now appears that much of the DNA landscape is relegated to regulatory processes.  To place this in perspective, roughly 1.2% of the genome is involved in protein coding, while some 8 – 9% is involved in regulatory processes.  Furthermore, it seems that these regulatory elements are more susceptible to change – mutation - than the genes that they regulate; this fact has profound evolutionary implications.  Finally, it now appears that around 80% of the entire genome is actively transcribed into RNA; this is a remarkable finding that requires further elucidation.

 

In conclusion, it appears that the concept of "junk" DNA can now be effectively put to rest.  These results open up whole new vistas for further investigation.  

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.

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.

The Hygiene Hypothesis

There are currently many products on the market that claim to be effective household antibacterial agents that are purported to have health benefits by preventing exposure to infectious agents.  Although this may have value to some extent, these claims may, in fact, be misleading in relation to overall public health.

There is a growing body of scientific evidence that strongly suggests that normal human exposure to the microorganisms that pervade the natural environment may be of value to human health by helping to fine tune the human immune system and thereby prevent the unset of the types of immunological overreactions that are typified by asthma and some autoimmune diseases (an autoimmune disease is a condition that is a result of the human immune system attacking its own tissues).  This concept is referred to as the Hygiene Hypothesis.  According to this hypothesis, it is vital that the human immune system be normally exposed at a young age to the microbes that are so ubiquitous in the environment.  Without these kinds of interactions, it is posited that later in life the immune system would be prone to behave in such a way as to result in inflammatory and autoimmune reactions such as allergies, asthma, inflammatory bowel disease (IBS) and multiple sclerosis (MS).  Epidemiological studies have clearly shown that children growing up on farms are considerably less likely to suffer from allergies and asthma as compared to their urban counterparts.  This correlation, however, does not constitute proof given that there are many other variables involved.

The Hygiene Hypothesis has been given further credence as a result of the findings of Dr. Richard Blumberg, an immunologist, from the Brigham and Women's Hospital in Boston.  Blumberg and his colleagues studied mice raised in germ free cages and fed germ free food.  These mice are more susceptible to asthma and colitis - an inflammatory condition of the gut.  On exhaustive examination, they discovered that these animals had elevated levels of a rare immunological cell type - so-called invariant natural killer T cells (iNKT) in the lungs and the intestines.  These cells have been shown to trigger inflammatory responses following exposure to microbes or antigens – molecules that can trigger the immune response – produced by the body.  It should be noted here that the mouse animal model has been proven to be a good one; since, there is a very close correspondence between mouse and human immunology.  In addition, mice that had been genetically altered to lack iNKT cells do not exhibit colitis even when raised in a germ free environment.  Furthermore, when germ-free mice are transferred to a normal environment at an early age, they show a normal distribution of iNKT cells.

These are very interesting findings that show a mechanistic rationale for the Hygiene Hypothesis.  Hopefully, this kind of information will help individuals make more informed decisions regarding the use of anti-bacterial agents in the home. 

Climate Change

The term Global Warming that is often associated with the cumulative impact of the buildup of greenhouse gases in the atmosphere does not accurately describe the nature of the consequences of this change in climatic conditions arising from human activity.  The more appropriate term is Climate Change.  The reason for this distinction is that the near term effect of this phenomenon is not necessarily warming on all parts of the globe.  However, dramatic changes in climate including temperature are predictable within this model. 

Our first order of business is to examine the science that is the underpinnings of Global Warming.  This necessitates an examination of the earth’s atmosphere.  The major components of the Earth’s Atmosphere are shown in the following table.

Constituent	Percentage (%)	Parts per Million (ppm)
Nitrogen (N2)	78.1	780,840
Oxygen (O2)	21.0	209,460
*Carbon Dioxide (CO2)	.039	390
*Methane (CH4)	.000179	1.79
*Water Vapor (H2O)	.40	Variable
*Nitrous Oxide (N2O)	.00003	0.3
*Chlorofluorohydrocarbons (CFC)	Minuscule	Miniscule

Table 1 – Major constituents of the earth’s atmosphere are reported in percentage and parts per million (ppm) where * indicates the greenhouse gases.

Chart 1 – Pie chart showing distribution of major components in the atmosphere and the greenhouse gases (*)

The current level of CO₂ in the atmosphere is 390ppm (as shown below in Chart 2).  CO₂ is a by-product of respiration of all living things on the planet.  However, this is normally balanced by the uptake of CO₂ by the world’s oceans and by green plants that are capable of photosynthesis – these interactions are collectively referred to as the carbon cycle.  In this regard, CO₂ is the carbon source for all of life. 

Human activity since the dawn of the machine and the use of oil (hydrocarbon) as a cheap and plentiful source of energy has resulted in a continuous upward climb of this gas in the atmosphere.  The reason for this is that when fossil fuels are burned for energy, the by-products are CO₂ and water.

The following chart shows the increase in the concentration of CO₂ in the atmosphere over time.

Chart 2 – Concentration of CO₂ in the Atmosphere over Time where 1790 represents the beginning of the industrial age – the steam engine was invented in 1775. 

The following chart shows these values as a change in percentage of CO₂ per year.

Chart 3 – Change in Percentage of CO₂ per Year.

As can clearly be seen from this representation, the increase of CO₂ in recent times correlates well with the introduction of industrialization to human societies.   This change might not seem dramatic, but a doubling of the concentration of CO₂ from pre-industrial levels is expected to increase the average global temperature by 2.5 degrees C.  From the data shown in Chart 3 it can be estimated that if the current rate of increase remains constant (0.63%/year) this doubling would be reached in approximately 100 years.  This is an extremely significant increase with horrendous implications for the earth’s climate.  Given the current political and economic situation throughout the world, it is unlikely that this increase in the rate of CO₂ accumulation will remain static; unless more sustainable sources of energy are actively pursued.  In addition, even if the human production of this gas were to halt today, it would take a few hundred years for the current levels to decrease significantly.

CO₂ is referred to as a greenhouse gas based on its molecular structure.  This gas has the ability to absorb heat and retain it much like the glass of a greenhouse allows heat from sunlight to pass freely through it from the outside but prevents some of it from leaving.  Therefore, some of the heat that would normally be reflected back from the earth’s surface and dissipate into space is retained.  The net effect is a general increase in temperature at the lower part of the atmosphere.  The science regarding this property of CO₂ is irrefutable.   CO₂ is not the only greenhouse gas in the atmosphere; the others as Table 1 demonstrates are water vapor, methane, nitrous oxide and chlorofluorohydrocarbons (CFC).  Increases in CO₂, methane and CFC - synthetic compounds that used to be used widely in refrigerants - are a direct consequence of human activity; whereas, the amount of water vapor in the air is not.

There are predominantly two different processes through which heat is transferred throughout the atmosphere.  One is through radiant energy as mentioned earlier and the other is through what is referred to as convection.  In this process as air is heated near the surface of the earth it rises as it becomes less dense and is replaced by the colder and denser air from above.   This process is continuous with the net effect of transferring heat from the surface to higher reaches of the atmosphere.   It is the greenhouse gases that trap some of the heat, effectively warming the air in the lower atmosphere.

The planet Venus is a striking example of the ultimate impact of CO₂ on temperature.   Scientific probes of the planet have shown that it has an atmosphere very high in CO₂, a dense cloud cover and a surface temperature of over 500 degrees C.  Although Venus is considerably closer to the sun than the earth, the thick and nearly impermeable cloud cover would be expected to cool the planet considerably.  However, the exceedingly high concentration of CO₂ in the Venetian atmosphere would explain most the heat trapped at the planet’s surface.

There are additional processes contributing to climate change that are important to consider in addition to the direct greenhouse effect.  These are:

·         The impact that increased CO₂ concentrations has on the oceans including increasing ocean temperature.  This gas dissolves to some extent in water and increased concentrations of dissolved CO₂ increases the acidity of the oceans.  This has a significant impact on marine life and ocean-based ecological systems.

·         Increased surface temperature in the northern climes can lead to the enhanced release of methane into the atmosphere from melting permafrost.  Methane is not only a potent greenhouse gas, it also possesses toxic properties.

·         An increase in the frequency and intensity of extreme weather conditions.

·         Increased melting of land-based ice in the form of glaciers and especially in regards to Iceland and Antarctica.  This can have powerful implications in regards to sea-level rise.  As a matter of fact, it has been estimated that should all of Greenland’s ice melt, it would cause a rise of sea level by about twenty-five feet.

Climate change is a very real phenomenon and, in my opinion, is the greatest challenge faced by all of humanity.  The manner in which this issue is addressed will have serious repercussions for the future of the human race.

How the Botulinum Neurotoxin Survives the Digestive System

The botulinum neurotoxin is such a potent and deadly toxin that the U.S. Centers for Disease Control (CDC) lists it as a category A bioterrorism agent.   Some of its additional characteristic properties are that is highly selective and has a long duration of activity.  This has made it possible for this agent to be used therapeutically, at controlled doses, for focal dystonias, wound healing and used cosmetically to decrease the evidence of wrinkling of the skin associated with aging.

Botulinum neurotoxin is produced by the Clostridium botulinum bacteria – a Gram-positive, spore-forming microorganism that requires an environment lacking in oxygen to grow.  Individuals can be exposed to this deadly toxin either through ingestion or inhalation.  Certain vegetables when improperly canned are notorious for providing the right environment for the growth of the botulinum bacteria and, therefore, the production of botulinum neurotoxin. 

Once an individual has been exposed to this deadly toxin, it finds its way into the bloodstream and attacks the nervous system, resulting in muscle paralysis and autonomic dysfunction.  It is the latter capability that can prove fatal; since, the autonomic nervous system controls such basic functions as breathing and maintaining the rhythm of the heart.  It has long been known that botulinum neurotoxin's mode of action is through the proteolysis – breakdown of proteins – of a key protein involved in the release of acetylcholine from nerve terminals.  Acetylcholine is an essential neurotransmitter in a significant category of cells in the human nervous system.

Structurally, botulinum neurotoxin is a protein.  This poses an interesting question: given its protein structure how is it able to survive the onslaught of the digestive system when it is ingested?  There must be some mechanism that explains how it can survive the acidity of the stomach and the digestive proteolytic enzymes of the stomach and small intestine.

The answer to this question has recently been resolved through the efforts of Dr. Shenyan Gu and his colleagues at the Center for Neuroscience, Aging and Stem Cell Research at the Sanford-Burnham Medical Research Institute in La Jolla California.  They discovered through exhaustive studies of the structure of the intact bioactive toxin that it exists as a complex with four additional proteins associated with botulinum neurotoxin.  One of these associated proteins, referred to as nontoxic non-hemagglutinin (NTNHA), is responsible for protecting the primary toxin from the acidity found in the stomach and for its protection from the proteolytic activity of trypsin produced by the stomach.

This finding not only helps elucidate the complete mechanism of action of botulinum neurotoxin but also suggests that inhibitors could be designed to weaken the necessary interaction between the toxin and its associated proteins early in the intoxication phase of the infection.

The Antibiotic Effect of Manganese upon Shiga Toxicosis

Approximately 150 million individuals are infected with Shiga toxin (STx)-producing Shigella bacteria or enterohemmorrhagic Escherichia coli every year and of those infected, about one million deaths result.  Once inside the host, STx is released by these types of bacteria and it exerts its deadly impact by inactivating cellular ribosomes – ribosomes are the organelles within all cells that are responsible for the production of proteins.  Since the synthesis of proteins within the cells is so critical to maintain the life of the cell, the symptoms of such a disorder would be wide ranging and systemic.  The symptoms of shiga toxicosis include diarrhea, abdominal pain, vomiting and blood in the urine.  This disease is particularly damaging to the kidneys.

For bacteria that exert their impact on human health as a result of a unique toxin such as in the case of shiga toxicosis and cholera, there must be an underlying mechanism that insures that the toxin find its way inside the target cells intact.  If this pathway can be disrupted the disease process could be effectively sabotaged. 

The particular pathway for STx has been elucidated.   It seems that STx consists of two protein subunits A and B, where A exerts toxic effects and is bound to subunit B.  Once inside the cell, this complex moves through the cellular endosomes, Golgi apparatus and the endoplasmic reticulum (ER) and finally to the cell cytoplasm where the target ribosomes are found.  It also has been demonstrated that a Golgi protein, GPP130, is critical for the transport of this toxin.

Doctor Somshuvra Mukhopadhyay and his colleagues from the Department of Biological Sciences at Carnegie Melton University in Pittsburgh, PA have shown that exposure of cells in culture to 50 to 500 micromoles of Manganese (Mn)  induces the degradation of GPP130.  In addition, this particular effect is unique to STx – Manganese has no impact on the cholera toxin, for example.  As would be expected, the cultured cells grown with Mn present, were protected from the harmful effects of STx.

If this approach works for mammalian cells in culture, one would suspect that Mn would protect whole animals from the toxin as well.  In fact, mice treated with nontoxic amounts of Mn were shown to be free of disease when exposed to the lethal toxin.  This an exciting finding that may prove to be of great benefit in the treatment of shiga toxicosis.

The Human Genome Holds Many Secrets

Ever since the extraordinary breakthrough that involved the complete sequencing of the human genome, many intriguing and heretofore unknown aspects of human genetic history have been uncovered.   One of the most exciting and interesting discoveries is that members of the human species may well have interbred with so-called archaic peoples of the past.

The picture of human evolution has proven to be not quite that simple.  Previous to recent findings, it was believed that about 100,000 years ago, early human migrated from their home in Africa to Europe and Asia displacing and ultimately replacing archaic peoples such as Neanderthals.  Evidence derived from an examination of the fossil evidence and supported by mitochondrial DNA studies seemed to support the view that there was no interbreeding between these divergent peoples.

Due to recent discoveries, however, this conclusion has proven to be fallacious.  As a result of genetic sequencing of Neanderthal nuclear DNA derived from fossil evidence and the subsequent comparison of this data with modern human nuclear DNA, Europeans and Asians have apparently inherited from 2% to 6% of their nuclear DNA from Neanderthals. 

In addition, by the end of 2010, a Russian led team found a 30,000 year old fossil finger bone of a young girl, and a tooth fragment from Denisova Cave in Siberia and reported the entire genomic sequence of a new archaic human species.  Studies of the DNA of scattered peoples throughout Southeast Asia demonstrate that they inherited approximately 5% of their DNA from the so-called "Denisovans" and 4% to 6% from Neanderthals. 

It is now evident that early humans interbred with archaic humans on at least three different occasions during their migration to other parts of the world.  These findings are of importance, for they help elucidate the complex nature and subtleties of human evolution. 

Obesity and Cancer

In the laboratories of Doctor Vuk Stambolic at the University of Toronto in Canada, breast cancer cells are grown routinely utilizing a protocol that has been long established.  The nutrients that are required to sustain growth include a high concentration of glucose, Epidermal Growth Factor (EGF) and insulin.  If insulin is removed from the mix, the growth of the cells is slowed and eventually they die.  Interestingly, normal breast tissue cells from which the cancer cells were originally derived are insensitive to insulin; they lack insulin receptors on their cell surface that are required for cellular response to this factor.

Stambolic was so intrigued by this finding, that he has focused his research on the tumor-promoting effects of insulin.  There is present in healthy muscle, fat and liver cells a metabolic pathway (PI3) that is activated by insulin.    It is this pathway that is often mutated in human cancer cells.

It appears that insulin and an insulin-like growth factor (IGF) seem to play a critical role in accelerating the growth of a wide range of cancers.  Furthermore from an epidemiological perspective, the correlation between obesity and the occurrence of type 2 diabetes and cancer has been well established.  Obese and diabetic individuals have a far higher likelihood of getting cancer than their lean counterparts.  Excess body weight seems to be associated with between one-quarter to one-half of breast, colorectal and many other types of cancer. 

According to Michael Pollack – an oncologist at McGill University in Montreal, Canada – cancer "loves the metabolic environment of the obese person."  The paradigm that seems to be gaining support in regards to the mechanism behind this effect is that in the metabolic environment in the obese individual, especially in regards to increased levels of insulin and IGF, promotes and fosters the growth of incipient tumor cells as Stambolic noted in his breast cancer cell cultures.

This finding is of crucial importance, since there is an increasing proportion of the general population that is obese.  

HIV Treatment – A Promising Approach to Prevention

The use of antiretroviral drugs (ARVs) by patients infected by HIV, the causative agent of AIDS, has prolonged the lives of many individuals.  When several of these drugs are used in combination, typically three or four, this protocol is referred to as Highly Active Antiretroviral Therapy (HAART).  The application of HAART has been found to consistently lower the viral load – the number of viral particles in circulation in the bloodstream – resulting in preserving the integrity of the immune system with the resulting increase in the quality of life and longevity of AIDS patients.

Since this therapeutic approach lowers the viral burden, it might be assumed that it would also dramatically lower transmission of the disease.  Although this is a very appealing idea, the efficacy of ARVs in diminishing the spread of AIDS through sexual contact with infected individuals required further study.

Such a study was, in fact, conducted; it was referred to as the 052 clinical trial conducted by the HIV Prevention Trials Network.  Results of this study were finally reported in May on 2011 – ARVs effectively reduced heterosexual transmission of HIV by 96%.

Inspired by these encouraging data, Doctor Anthony Fauci, Director of the U.S. National Institute of Allergy and Infectious Diseases, stated that, "The idea of the tension between treatment and prevention, we should just forget about it and just put it behind us, because treatment is prevention."  On account of the profound implications of this result, the prestigious scientific publication, Science, has proclaimed this the scientific breakthrough of 2011.