Tuesday, February 27, 2018

The Molecular Biology of Celiac Disease

Celiac disease is a so-called, “autoimmune disease” that impacts an estimated one percent of the population.  An auto-immune disease is caused by an individual’s immune system attacking its own tissue.  Other examples of diseases that fit this classification are multiple sclerosis (MS), pemphigus, rheumatoid arthritis and systemic lupus.

In Celiac disease, the tissue that is impacted involves the microscopic villi that line the lumen of the small intestine.  These structures provide the surface area through which digested nutrients are absorbed (see image below).  The patient with celiac disease presents with unexplained loss of weight and fatigue, anemia and constipation for example.  The destruction of these highly complex structures is irreversible; if, this condition is left untreated, it can be deadly.

The trigger for this auto-immune response is the presence of gluten - a protein found in wheat and related plants.  Gluten is a protein that is prevalent in Western diets.  In addition, research studies have demonstrated that the agent (antigen) that induces the autoimmune response is not the intact gluten protein but the protein after it is modified by the enzyme transglutaminase 2 (TG2) within the small intestine.  It seems that in normal tissues, although TR2 is an abundant enzyme, it exists primarily in the inactive state.
Chaitan Khosla and his colleagues at the University of California at Stafford have recently demonstrated that there is a cellular enzyme protein 57 (ERp57) that inactivates TG2.  Normally, ERp57 is involved in the process of protein folding within the cell.  Furthermore, it has been established that ERp57 inactivates TG2 outside the cell within the extra-cellular environment.  These data suggest that the etiology of celiac disease may relate to the functionality of ERp57.

These findings are significant; for, a more detailed understanding of the biological chemistry of celiac disease may open avenues of therapy that have heretofore remained elusive. 

Saturday, February 17, 2018

Stem Cells and the Risk of Atherosclerotic Cardiovascular Disease

Atherosclerosis is a condition often associated with age that involves a narrowing of the lumen of the arteries usually associated with age (see image below).  This condition often leads to coronary heart disease.  Traditionally there are a number of risk factors that are generally associated with this syndrome – high blood pressure (hypertension), high cholesterol, heredity, life style, diet etc.  However, a significant percentage of those individuals that show evidence of atherosclerosis have no known risk factors.  Research done by Dr. Siddhartha Jaiswal and his colleagues that has been published in the New England Journal of Medicine (July, 2017) sheds significant light on the possible etiology of this perplexing reality.

Within the bone marrow, reside stem cells that are so-called, pluripotent cells; they are responsible for the production of the body’s complement of immune-competent cells such as red blood cells, white blood cells including lymphocytes, neutrophils etc.  It has been well documented that over the lifetime of the individual these stem cell undergo mutations that can lead to blood – hematopoietic – cancers such as leukemia.
According to Jaiswal, “Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer.”

Jaiswal and his associates now have evidence that CHIP may be the underlying cause of atherosclerotic cardiovascular disease of no known etiology.  The results of their studies indicate that the presence of CHIP in the cell population of circulating blood was associated with a near doubling of the incidence of atherosclerotic cardiovascular disease.  Furthermore, the common mutations that were present in CHIP were found to be in the genes DNMT3A, TET2 AND ASXL1.  These genetic mutations have also been shown to be associated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).   These clones seem to be more prevalent with age – more that 10% of persons older than 70 years carry such a mutation.

This finding is significant in that it shed further light upon the etiology of atherosclerosis.

Tuesday, January 16, 2018

The Scientific Method

The scientific method is a proven way to find answers to questions regarding particular aspects of the natural world. It can be summarized in the following way –

• Question arises from known information – data
• Hypothesis proposed to explain data
• Experiment(s) conducted to prove or disprove the working hypothesis
• Experimental approach is precisely documented
• Results are reported
• Results are subject to peer-review.
• To be correct, the conclusion must explain all the data
• If correct, findings must be repeatable.

The following information is presented to highlight the theories that have been effectively discredited using the scientific method, the advances made through the application of the scientific method and the potential disasters that have been effectively averted through its application.

The Homunculus -There was a theory (proposed in the 16 century and popularized in the 19 century) that human sperm carried a miniature human (Homunculus) than subsequently developed into a fully developed infant at birth following fertilization

Image of Homunculus

 Image of an actual human spermatozoa showing DNA


The Martial Canals - Percival Lowell (1855 – 1916) proposed that there was intelligent life on Mars based upon sighting of purported Martian Canals

Image of Martian Canals as reported by Lowell

Image of Mars from space telemetry data

Spontaneous Generation – Theory that living organisms can arise spontaneously from decaying organic matter

Louis Pasteur’s (1822 1895) Classic Experiment that effectively refuted this belief.

The diagram below outlines his elegant approach

Earth’s Place in the Solar System – It was believed for many centuries that the earth was the center of the cosmos

Ptolemy’s (140 AD) Earth-Centric Model

Copernicus’ Model (1543) – Current Model

Ptolemy generated this convoluted model in attempting to fit the available astronomical data into the accepted belief that the earth was the center of the known universe.

HIV AIDS – In the early 1980’s a new, infectious and deadly disease appeared within human populations. In a just a few short years and with intense research efforts spear-headed by the Center for Disease Control (CDC), the cause was determined to be a so-called“retrovirus” (see diagrams below)– a discovery that ultimately averted a world-wide pandemic.

Image of an HIV virus

HIV AIDS Virus infecting human T-cell

George Washington’s Death (1799): An Example of Unscientific Medicine
His death was ultimately attributed to standard medical practice of that era. Washington came down with a respiratory infection. He underwent the following procedures via 3 different physicians –

• A half-pint of blood was extracted via leeches (see diagram below)

• Blisters were created on his throat to balance body fluids”
• Vinegar and sage tea mixtures were administered
• Emetics were given to induce vomiting.

The current understanding is that he died of iatrogenic causes – (caused by physician). His actual death was apparently caused by hypovolemic shock – a condition that occurs when more than 20% of the body’s fluid is lost. As a result, his heart was unable to pump sufficient blood volume to effectively deliver oxygen and nutriment to all the cells.
Rachel Carson – The Silent Spring (August 1972): The Inter-Connected Nature of the Natural World

In the 1950’s, DDT was sprayed to control beetles that are responsible for Dutch Elm Disease. Rachel Carson book documented the impact of DDT pesticide on natural environment especially on bird mortality. This book awakened the scientific community and the public to the ecological implications of human-caused environmental pollution. The Environmental Protection Agency was created in 1970 as a direct result of the growing concerns about the health of the natural environment.

Models of the DDT molecule

Ecological Implications –
• Earthworms ingest DDT from contaminated soil
• Robins (as an example) eat earthworms and concentrate DDT (biological magnification)
• DDT impacts shell production in the eggs – proves fatal to developing embryos
• DDT is an example of poly-chlorinated hydrocarbon (see diagrams above) that is fat
soluble with a long biological half-life.

DDT was ultimately banned for agricultural use – a policy that averted a catastrophic decline in bird populations due to DDT’s insidious effects.

Ozone Depletion - Ozone (O3) is a pollutant in the lower atmosphere. However, in the upper atmosphere, this molecule is vital for the filtering of dangerous UV radiation that normally bombards the earth. Holes in this protective layer was first report in 1985. As a result of intense scientific study, it was soon discovered that ozone was being destroyed by a by-product of a human-produced pollutant, chlorofluorocarbons (CFC - see diagram below). CFCs were once commonly used in refrigerants; until, they were banned in 1995. This ban ultimately helped replenish the ozone concentration in the upper atmosphere.

Diagram Illustrating this Process


The Examples cited above have been included in order to demonstrate the importance and relevance of science and the scientific method in everyday existence.

The End

Monday, January 8, 2018

The Bomb Cyclone

In the winter of 2018, the American Northeast was struck by fierce and extreme winter weather. This apparent weather anomaly was referred to as the “Bomb Cyclone.” It was characterized by a sudden and precipitous drop in barometric pressure accompanied by strong winds and cold arctic air.

Climate scientists have long predicted that accompanying the warming of the lower atomosphere and the oceans, one would expect an increase in the severity and frequency of extreme weather conditions...In a report found in the science section of Time magazine written by Bryan Walsh, the author suggests just such an explanation of this weather phenomenon.

"Sea ice is vanishing from the Arctic thanks to climate change, which leaves behind dark open ocean water, which absorbs more of the heat from the sun than reflective ice. That in turn is helping to cause the Arctic to warm faster than the rest of the planet, almost twice the global average. The jet stream—the belt of fast-flowing, westerly winds that essentially serves as the boundary between cold northern air and warmer southern air—is driven by temperature difference between the northerly latitudes and the tropical ones. Some scientists theorize that as that temperature difference narrows, it may weaken the jet stream, which in turns makes it more likely that cold Arctic air will escape the polar vortex and flow southward. Right now, an unusually large kink in the jet stream has that Arctic air flowing much further south than it usually would."

It should be kept in mind that this conclusion is preliminary: climate scientists would be first to admit that there is not enough accumulated data to unambiguously make this connection, However, numerous examples of extreme weather patterns have already been cited in the scientific literature.

Wednesday, October 11, 2017

What is Cancer Immunotherapy

Cancer is a disease that can impact any tissue in the body.  When normal tissue cells become cancerous (malignant), they lose some of the fundamental properties of the tissue cells they originated from.  They also grow out of control and ultimately spread (metastasize) to other parts of the body where they bring chaos and instability.  The transformation that normal cells undergo when they become cancerous is known to be a result of genetic changes to the cells complement of DNA.  In some types of cancer there is a definitive hereditary genetic component as in certain types of breast cancer, for example.  A widely accepted model for the transformation of normal cells to the cancerous state involves spontaneous somatic mutation(s).  There are many man-made organic chemicals in the environment that are known to initiate the onset of cancers; these are collectively referred to as carcinogenic compounds.  Carcinogens have also been shown to be mutagens – chemical agents that cause genetic mutations.

The conventional therapies that are applied to a patient that presents with cancer has generally involved the use of chemotherapeutic drugs and/or radiation treatment.  The therapies that employ these agents are referred to as a shotgun approach; since, they do not discriminate between normal and cancer cells   Chemotherapeutic drugs target any cell that is actively dividing and radiation damages cellular DNA that results in cell death.  Although these techniques have become refined over the years, they still suffer from this serious limitation.

This is where Immunotherapy offers an important advantage; because, treatments that use immunotherapy specifically target cancerous cells.  What follows is a discussion of the rationale of some of these approaches.

Succinctly stated, “Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer.” This can be accomplished in a number of ways.  The patient’s natural immune system can be enhanced to better target cancerous cells.  This is possible; because, an important component of the immune system is referred to as, “the cancer surveillance system.”  Certain subsets of cells in the immune system are designed to target any cell that possesses antigens on their cell surface that are indicative of the fact that it has been transformed,  These antigens indicate to the immune system that the cell is no longer self and thereby becomes subject to destruction.  Another approach involves the addition of human manufactured immune system – related proteins.  This capability is possible on account of the fact the cellular manufacture of unique proteins depends upon a particular gene   Technologies are in wide use that can insert a particular human gene into bacteria in culture and have the bacteria manufacture the human protein product.  This approach has made possible the mass production of human insulin and human growth hormone, for example.  In addition, some types of immunotherapy are also referred to as biologic therapy or biotherapy.

The methodologies that are currently being tested and employed can be classified in the following way –

·        Monoclonal Antibodies  - Once an antigen specific for a certain type of cancer has been isolated, antibodies can be manufactured that are specific to that antigen.  This antibody can then be introduced into the patient with that cancer.  Once the circulating monoclonal antibodies bind to cancer cells, this triggers the immune system to target those cells and destroy them.
·        Immune Checkpoint Inhibitors – The immune system is a very powerful system that has built-in safeguards to keep it under rigorous control i.e. to make it possible to destroy transformed cancerous cells leaving normal cells intact.  This is accomplished by immune checkpoint factors.  These factors are on certain cells in the immune system and need to be activated or inactivated to trigger the immune response.  Some cancer cell types can use this system to prevent it from being used against them.  For these cancers, checkpoint inhibitors are designed to interact with these factors and render them ineffectual; thereby, improving the potency of the immune system targeting cancerous cells.
·        Cancer Vaccines - Cancer vaccines are being developed to treat or even prevent the onset of certain types of cancer.

The following is a table that summarizes some of these data –

Type of Cancer
Methodology Employed
Chronic Lymphocytic Leukemia (CLL)
Monoclonal Antibodies
The monoclonal antibody that has been used targets the CD 20 cell-surface antigen that is in high concentration in some forms of this disease.
Advanced Colorectal Cancer (CRC)
Immune Checkpoint Inhibitors
Many inhibitors are currently being produced and tested.  Some benefit has been shown with certain cancers that are particularly difficult to treat.
Cervical, Advanced Prostate and Bladder Cancer
Cancer Vaccine
Cervical cancer, for example, is known to be caused by the human papilloma virus (HPV).   Therefore, a vaccine that targets this virus can prevent the onset of cervical cancer

It should be remembered that the use of immunotherapy in treating cancer remains in its infancy and requires additional research efforts to improve its efficacy and diminish known side-effects.  However, it is an exceedingly promising approach and is worthy of continued research efforts and support.

Wednesday, August 23, 2017

Melting Permafrost in Alaska

It is my fervent hope that the total solar eclipse that has received so much attention is a reminder of our real relationship with this our remarkable planet and its place in the cosmos. For we need to pay close attention to the degree to which our behavior is changing the planet. The following may help illustrate this (from the New York Times) - Alaska's Melting Permafrost

Wednesday, August 16, 2017

The Biochemistry of Nitric Oxide and its Application to Medicine

Nitric oxide (see illustration below) is a highly reactive compound.  Nitrogen (N2) (see illustration below constitutes 78 % of the ambient air; whereas, the concentration of NO in the lower atmosphere has been determined to be within the range of .4 to 71 parts per billion (ppb).

Atmospheric Nitrogen

NO was discovered to play an important role in human metabolism.  Within the human body, the enzyme responsible for its production is nitrogen oxide synthase (NOS) (see diagram below) and exists in a number of forms (isoenzymes) – one residing within epithelial cells (eNOS) and another residing within neuronal cells (nNOS).  Once NO is produced, it functions as a chemical messenger that influences a wide variety of cellular processes.  The general scheme of its metabolism is represented below.
Enzymatic Synthesis of NO

NO Metaobolism

Within the human body, NO provides protection against cardiovascular diseases on account of its roles in the regulation of blood pressure.  In addition, NO inhibits the aggregation of platelets and leukocyte (white blood cell) adhesion and thereby diminishes the likelihood of blood clots.  It appears that areduced availability of NO plays a role in the onset of cardiovascular disease.

For all the reasons cited above, NO seems to be vitally important in the maintenance of the continued health of the human cardiovascular system.  The following diagram demonstrates the various stages of NO metabolism in which particular drugs can increase the bio-availability of NO.  This approach to the manufacture and use of particular drugs that can target NO metabolism is of special interest in the practice of medicine.

Bio-availability of  NO Enhanced by the Application of Particular Drugs