The Role of the Human Immune System in Obesity

Human immunity has developed, over evolutionary time, into a complex system that impacts a great deal of human biology.  It is for this reason that it often a key player in the cause of many ailments.  It has recently been implicated in human obesity, insulin resistance and type 2 diabetes – these three conditions constitute the so-called metabolic syndrome.  Immune responses are potent reactions to bodily insults and, therefore, must be tightly regulated.  These responses are activated and suppressed by a large family of small regulatory proteins referred to as interleukins.

The white blood cells (WBC) that are found circulating in human blood are, in fact, comprised of a complex mixture of cell types that all perform unique immunological roles.  Eosinophils are a particular WBC type that is classically involved in combating helminth (parasitic worm) infections and allergies.  In addition, macrophages are a subtype of WBC that is characterized by its large size and ability to respond to a wide range of human infections. 

Extensive studies of obesity using animal models led by Dr. Davina Wu at the Howard Hughes Medical Institute at the University of California in San Francisco have implicated Eosinophils and a particular subtype of macrophage referred to as alternatively activated macrophages (AAMs) in the maintenance of glucose balance in fat (Adipose) tissue.  It appears that the role of eosinophils in this process involves the secretion of a type of Interleukin called Interleukin-4 (IL-4).  When eosinophils are not present in adipose tissue, the level of glucose is no longer subject to regulation.

Doctor Wu and colleagues, working with the mouse model, have shown that the macrophages resident in the adipose tissue of obese subjects are actively involved in an inflammatory response while the macrophages in the adipose tissue of lean mice are not.

This study reinforces the established relationship between metabolism and immunity.  Furthermore, these findings support the connection between obesity and the enrichment of those genes involved in inflammatory and immune responses in humans – a strong indication of the health dangers posed by obesity. 

A New Approach to Immunization Against the Flu Virus

Influenza – the flu – continues to infect millions of individuals each year and cause thousands of deaths.  In addition, the economic losses associated with this illness are considerable.  Although immunizations against this virus exist, their effectiveness is diminished by the fact that this virus mutates readily and produces a variety of strains that evade the immunization strategy.  These vaccines provide only limited protection against these strains.  In order to more fully understand the nature of the global health problems posed by the influenza virus, we will examine the nature of its action.

 

The influenza virus is essentially spherical in shape.  Its outer layer is, in fact, a lipid membrane that it has acquired from the host cell that it has previously infected.  Embedded in this outer layer are proteins that are characteristic of the strain of the virus.  It is these proteins that are potential targets for antibodies used in various vaccine regimens.   The virus – like all viruses – is essentially inert outside of living cells.  Once it effectively infects a target tissue – usually in the respiratory system –the virus delivers the infective material directly into the target cell.  The influenza virus belongs to a class of viruses called Ribonucleic acid (RNA) viruses; because, RNA is the infective agent.  Once the viral RNA enters the cell, it commandeers the cell machinery to produce more viruses and eventually kill the cell.  The dead cell releases its contents including many copies of the virus and each of these goes on to infect neighboring cells.

The strategy behind the development of vaccines against this virus is to discover an identifying protein on the virus' surface that persists (highly conserved) over a wide variety of subtypes.  This has proved to be a very elusive quest.   However, there has been a recent discovery of what is referred to as V_H1-69 antibodies that knock out almost all type A Group 1 viruses.  This is an exciting development in its own right, since it is the type A virus that represents the most virulent strain.

One of the major surface proteins on the Influenza virus is Hemagglutinin (HA).   Antibodies that target HA, for example, bind with a unique part of the protein referred to as an antigenic determinant or epitope.  Doctor Damian C. Ekiert and his colleagues from the Department of Molecular Biology at the Scripps Research Institute in LaJolla California have isolated and characterized a human monoclonal antibody called CR8020 that has been shown to have broad reactivity to most group Type A 2 viruses.  It seems quite possible that a cocktail containing these two antibodies -  VH1-69  and CR8020 - may produce an effective universal flu vaccine.  This would be an exciting development from the global public health perspective.

A Potentially New Therapy for Chagas Disease, a Parasitic Infection

Chagas disease is the result of an infection caused by the parasite, Trypanosoma cruzi.  The vector for this parasite is the so-called assassin bug or kissing bug that targets its hosts for blood, usually at night.  The parasite is usually transmitted through the insect's feces.  Millions of people in Latin America carry this parasite.  In addition, the United States and Spain have reported the highest incidences of this disease outside of Latin America.  Furthermore, the World Health Organization (WTO) has estimated that ten million people worldwide are infected with this parasite. 

 

The symptoms are somewhat benign at the early stages of infection.  Unfortunately, the parasite persists within the body for years or decades and can ultimately lead to serious damage to the heart, often resulting in death.

 

The current drugs available to treat this disease – nifurtimox and benznidazole - are outdated and of little value.  In addition to their serious side effects, their efficacy depends upon a 60 to 90 day course of treatment – this requirement makes their use highly impractical. 

 

In regards to the etiology of the disease, there is a crucial enzyme, cruzain, that is a necessary component in the life cycle of Trypanosoma cruzi.  Cruzain belongs to a class of enzymes referred to as proteases – enzymes that catalyze the degradation of proteins.  Doctor James McKerrow, a biochemist at the University of California, was in search of a suitable inhibitor of this enzyme.  He enlisted the help of his colleague Doctor Jim Palmer, a chemist who had synthesized a number of protease inhibitors when he was at Khepri Pharmaceuticals in San Francisco.  In response to this request, Palmer synthesized a potent version of an inhibitor that effectively led to the death of the parasites grown in the laboratory.

 

This is an exciting development that has captured the attention of the Food and Drug Administration (FDA) that has approved a phase I safety trial of the compound referred to as K777.

The Waste of Human Potential

Every day, within the human world, there is the regrettable and apparently inexorable waste of human potential.  Every day, countless numbers of individuals die from the starvation not because there is a scarcity of food, but because they do not have access to the abundance that does exist.  Everyday large numbers of humans die from diseases and conditions that are preventable, treatable and, in some cases, curable, only because they lack the resources to gain access to the wondrous medical advances that exist in the larger world.  Every day, tens of millions of children are denied access to meaningful educational resources; the net effect of this reality is that these children will never realize the wondrous gifts that they possess.  Instead, they will be relegated to a future in which their primary behavior will be directed towards survival in a world that apparently rejects their possible contributions to the larger society.  Every day, millions upon millions of human beings are without a place of shelter to which they can retreat from the relentless onslaught of their daily lives.  Every day, the natural environment worsens as human societies continue to pursue reckless and short-sided policies that suggest a grim future for the species.

Contemporary humans are living a tragedy that is wholly preventable.  There is no legitimate reason why any individual cannot have access to all the necessities required for a meaningful life.  There is no reasonable explanation for the barbaric conditions in which so many live.  There is no rational discourse that can abide the miserable fate of so many of the human kind other than the belief that only a few of us are deserving and the rest are the castoffs in the pursuit of wealth and power.

The pathetic aspect of the human condition is that we can be the architects of a very different world – a world that can not only sustain human life, but also enrich the lives of all of us, everywhere. 

An Entirely New Breed of Bacteria

It has been well established that the fundamental building blocks for life are proteins, fats, carbohydrates and nucleic acids (DNA and RNA).  The elements that are required to assemble these constituents are carbon, hydrogen, nitrogen, oxygen, sulfur and phosphorus.  In addition there are trace metallic elements that are required for metabolic activity through the agency of enzymes, oxygen transport and other biological functions; examples of these are iron, zinc and molybdenum.  These are usually present in trace amounts and function as necessary co-factors in a host of enzyme activities.  There have been many reported instances of substitutions in regard to these co-factors; examples include the substitution of tungsten for molybdenum and cadmium for zinc.  There has also been reported the substitution of copper for iron as an oxygen carrier in some arthropods and mollusks.

Doctor Felisa Wolfe-Simon and her colleagues at the NASA Astrobiology Institute have recently made quite an astounding discovery.  They discovered a bacterium, strain GFAJ-1, isolated from Mono Lake in California  that is capable of growing in the presence of Arsenic (As).  Furthermore, they were able to show in the laboratory that As was incorporated into the structure of nucleic acids and proteins. As is a chemical analog of phosphorus (P); it resides directly below P on the periodic table.  Its similarity to P in terms of its chemical properties explains why it is a deadly poison for complex multi-cellular organisms such as humans.

This is quite a significant discovery; it dramatizes just how adaptable living organisms can be.  Furthermore, it may broaden our perspective regarding the possibility of extra-terrestrial life.

New Hope for Those Suffering from Type 1 Diabetes

Unlike adult-onset diabetes, type 1 diabetes occurs early in life and is considered to be an autoimmune disease where the body's own immune system becomes mobilized against the insulin-producing cells that reside in the Islets of Langerhans in the pancreas.  This is an extremely devastating illness, since the resulting dramatic loss of insulin results in high levels of glucose in the blood – a condition known as hyperglycemia.  Although insulin treatments can control this condition, excess glucose circulating in the blood system reacts with tissues throughout the body and leads to devastating side effects over time including blindness, kidney dysfunction, heart disease and the enhanced likelihood of amputations on account of poor circulation.

 

There is, however, encouraging news on the horizon.  Results from a clinical trial conducted by Doctor Denise Faustman and her colleagues from the Immunology Laboratory at Massachusetts General Hospital indicate that a medication, bacillus Calmette-Guerin (BCG) used routinely as part of the treatment regimen for bladder cancer and as vaccination against tuberculosis could significantly improve the treatment for type 1 diabetes.  BCG is produced from a strain of the weakened live bovine tuberculosis bacillus.

 

In regards to the mode of action of this medication, it appears that it targets the immunoreactive cells responsible for the death of insulin-producing cells of the pancreas.  It seems that BCG stimulates the production of tumor necrosis factor produced used by certain cells in the immune system's repertoire to kill abnormal immune cells that invade healthy tissue.   In addition, those patients treated with high doses of BCG showed evidence of insulin production - a significant finding.  Faustman indicated that ,"Not only did we observe and measure the death of these self-targeting immune cells, but we also saw evidence of restoration of insulin production even in patients who've had type 1 diabetes for more than a decade."

Climate Change Mirrors an Earlier Era in Planetary History

Doctor Lee R. Kump, a professor of geosciences at Pennsylvania State University, has illustrated some disturbing parallels between the changes in global climate of today with a well-studied era in the planet's past.  At that time, about fifty-six million years ago, temperatures worldwide rose some five degrees Celsius in the course of a few thousand years.  This period is referred to as the Paleocene-Eocene Thermal Maximum (PETM).  At that time in the planet's history the huge land mass known as Pangaea was in the final phase of breaking up into the current day continents.  This process led to the formation of the north-eastern Atlantic Ocean.  As a result, enormous volumes of molten rock were released producing intense heat.  Carbon-enriched sediments that were close to the surface were subsequently burned releasing greenhouse gases into the atmosphere, especially carbon dioxide and methane.   In addition, it is postulated that the concomitant warming of the ocean seabed led to the release of vast quantities of frozen methane.

The cumulative effects of these changes were the following:

•          Marked increase in global temperatures (as noted above)
•          Climate zones shifted towards the poles both on land and in the ocean propelling the migration of living things to accommodate this change
•          Within the ocean depths, acidity increased and the supply of oxygen diminished killing of many organisms there.

These changes are striking similar to what is being reported currently.  In regard to the status of the oceans, an international workshop, sponsored by the International Programme on the State of the Ocean (IPSO), has recently met in Oxford, UK.  Their goal was to study the impact of human-made stressors including warming, acidification and overfishing on the overall health of the ocean.  The conclusions this international group of experts reached are quite alarming.  In essence, they have concluded that the stresses imposed on the world's oceans as a direct result of human activity may lead to "globally significant marine extinction."

In addition, Doctor Kump has determined from his studies that, in fact, "global temperature today is rising much more quickly than it did during PETM."  If the current rate of increase in atmospheric greenhouse gases continues unabated, it is estimated that global temperature will increase by eight degrees Celsius by the year 2400.  This kind of increase would profoundly and dramatically change the nature of life on the planet and drastically impact the possibility of continued human survival.  This kind of change can only be averted by a global commitment to dramatic changes in human behavior and expectations.  It should also be noted that it took some 200,000 years for the planet to cool down during PETM.