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The current drugs available to treat this disease – nifurtimox and benznidazole - are outdated and of little value.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.  

Antibiotic Resistance – A Cause for Global Concern

Penicillin was discovered and developed as the first widely-used anti-microbial (antibiotic) agent in 1928.   Ever since that time, bacteria have developed resistance to a wide range of antibiotics as they have been introduced.  This capability can be explained based on two important properties of bacteria.  These organisms divide approximately every twenty minutes; therefore, through the course of a single twenty-four hour day, seventy-two generations have been produced.  If bacteria are in an environment permeated with antibiotic some of the progeny may develop a resistance due to a spontaneous mutation in their genetic material (DNA).  If this should happen, all the susceptible bacteria will die off leaving behind those that are resistant.  This process can be regarded as natural selection.  Since resistance is conferred by a change in the genetic makeup of the organism, resistance can then be passed on to all the progeny.  There has always been a potential public health risk in regard to this ability of microorganisms to become resistant to these agents.

 

Bacteria are classified into two distinct groups – gram-negative and gram-positive.  This classification was created based on their ability or inability to take up a particular stain.  A well known example of gram-positive bacteria that is disease producing (pathogenic) is Staphylococcus aureus that is of a particular concern in a hospital setting.  An antibiotic that has been traditionally used to combat this kind of infection is methicillin.  As a result of its universal application, a highly resistance form of this bacteria referred to as methicillin resistant Staphylococcus aureus (MRSA) has arisen.  This has created a serious public health dilemma.

 

From a public health perspective, a far more problematic issue is antibiotic resistance among gram-negative bacteria.  These bacteria possess a double cell wall that makes them more challenging to eliminate.  An example of a pernicious variety of this kind of bacteria is Klebsiella pneumoniae; this strain is particularly prevalent in hospitalized patients and is a major cause of pneumonia and bloodstream infections (sepsis).  The antibiotics that have been found to be effective against gram-negative bacteria are referred to as the carbapenems.  As one would suspect, Klebsiella has now been shown to possess resistant to the action of carbapenems.

 

Doctor Timothy Walsh and his colleagues from the Cardiff University, United Kingdom have examined the nature of this resistance and have found that the resistant strain produces an enzyme (NDM-1) that effectively inactivates carbapenems.  This is particularly disturbing since gram negative bacteria, Klebsiella as an example, also possess the capacity to transfer antibiotic resistance to other kinds of bacteria including the ubiquitous Escherichia coli that normally inhabits the large intestines of most mammals.

 

Given the seriousness of this issue, it is considerably disturbing that there are no new kinds of antibiotics against gram-negative bacteria currently being developed.  This reality holds an ominous prospect for the future in regards to global public health.  

Rheumatoid Arthritis – A Possible New Therapy

Rheumatoid arthritis (RA) is a chronic and debilitating illness.  It can strike at any age and seems to be more prevalent in women than men.  Although the specific etiology (cause) of RA is unknown it is categorized as an auto-immune disease – the body's immune system seems to mistakenly recognize normal tissue as foreign and attack it.  Other examples of autoimmune diseases are multiple sclerosis (MS) and Systemic lupus erythematosus (lupus).

The target for the autoimmune reaction in RA is primarily the joints on both sides of the body -wrists, fingers, knees, feet, etc.  The extent of the resulting disability can vary widely depending on other factors related to health.

In order to effectively treat RA, the underlying mechanism that leads to the disease needs to be better understood.  Recent evidence has implicated the so-called tumor necrosis factor α (TNFα) as a major component in the development of this illness.  TNFα is found on the cell surface of immune cells.  TNFα is a member of a group of substances referred to as cytokines.  Cytokines are small protein molecules that are secreted by both the nervous and immune systems.   They have been found to play critical roles in the modulation of the immune system.

 

Dr. Hao Wu and his colleagues from the Department of Biochemistry at the Weill Cornell Medical College in New York City have shown the disease-producing role of this substance using mouse models of inflammatory arthritis.  Furthermore, this investigative group has demonstrated that Progranulin (PGRN) slows the progression of arthritis in the mouse.  Progranulin is a naturally occurring growth factor for human fibroblasts – cells responsible for the production of collagen, an integral component of the body's connective tissue.  Progranulin seems to exert this inhibitory effect by binding to the receptor that normally binds TNFα, thereby inhibiting its role in the autoimmune process that results in RA.

 

These findings shed significant light on the immune process.  These data may ultimately contribute towards the treatment of this intractable disease.