Friday, October 14, 2016

Natural Killer Cells in the Treatment of Cancer

It has been well established that the human immune system has the inherent capability to recognize and eliminate aberrant tissue cells in the body that have become transformed into cancerous cells capable of metastasis.  The natural process of finding and eliminating these cells is referred to as cancer surveillance.  It is this understanding that has led to the development of clinical approaches taking advantage of this phenomenon.  The techniques employed in this regard are classified under the heading, cancer immunotherapy.

There is a particular subset of circulating immuno-competent white blood cells referred to as natural killer cells that play a significant role in the body’s response to infectious pathogens as well as in cancer surveillance (see image below).  Dr. Rizwan Rowee and is colleagues from the Department of Medicine, Oncology Division Washington University School of Medicine in St. Louis investigated the properties of natural killer cells in regard to their ability to identify and destroy cancerous cells.  They were particularly interested in their “memory” capacity.  It has long been known that subsets of immuno-competent cells retain the capacity to recognize and attack particular targets from previous encounters.  This is an indispensable feature of a normal immune system.

Natural Killer Cells Attacking a Target Cell

Following exhaustive study and analysis of these natural killer cells with human leukemic cells in culture, the investigators discovered that natural killer cells with memory-like capability actually demonstrated an anti-leukemic effect against patients with acute myeloid leukemia (AML).  In some cases, this treatment led to clinical remissions.  The investigators reported that, “Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.”

These are very important findings especially in regard to the treatment of patients with AML; since, this disease is a particularly aggressive form of leukemia.

Monday, October 10, 2016

Dr. Arnoldo Gabaldón

Malaria is one of the world’s deadliest diseases.  It is especially prevalent in the tropics.  The life cycle of the causative microbial parasite – members of the plasmodium genus i.e. Plasmodium vivax is complex involving the Anopheles mosquito as a vector (see images below).  The nature of the infection is such that it has eluded the development of an effective vaccine for many years. 

Human red cells infected by Plasmodium vivax

In light of this, it is quite surprising that Dr. Arnoldo Gabaldón, born in 1909, in Venezuela made a significant contribution to the understanding of this disease and its implications in regard to public health.
Gabaldón earned a doctorate in medical sciences at the Universidad Central de Venezuela. He continued his education internationally working in Hamburg and the United States at  the Rockefeller Foundation and ultimately received a doctorate from Johns Hopkins University in hygiene sciences with a specialty in protozoology. With this kind of medical background and expertise in infectious disease, he was asked to head the newly created Special Directorate of Malariology in his home country of Venezuela in 1936.  He held this post until 1950.
He successfully applied his understanding of the methodologies required to combat infectious disease to the rate and severity of malarial infection that gripped his country in the 1930s.  This included the emphasis on public hygiene and sanitation and the judicious application of anti-malarial drugs. His approach was so successful that mortality resulting from malarial infection was decreased significantly by 1944 and, more importantly, its control was seen as within reach.
This initial success was followed by an attempt to significantly reduce the Anopheles mosquito population.  For this purpose, the insecticide dichlorodiphenyltrichloroethane  (DDT) was used.  The historic data has revealed that “by 1950 the death rate from malaria in the country had been reduced to 9 per 100,000 inhabitants and was eradicated in an area of 132 000 km2. In 1955, 10 years after the program started the rate was lowered to 1 per 100 000 population and the eradicated area had increased to 305,414 km2.” On balance, it should be kept in mind that the discovery of the ecological burden posed by the use of DDT on the natural environment has effectively banned its application for many years.
Gabaldón is also credited with discovering a new species of malarial parasites and had focused a great deal of his efforts on further study of the Anopheles mosquito.  He was later appointed Minister of Health and Welfare between 1959 and 1964 in recognition of his premier understanding regarding issued of public health.  He died in September of 1990.

Arnoldo Gabaldón made a significant contribution to the principles and practices of public health around the area of infectious disease.  The example of his leadership has been emulated throughout the world and possibly has saved countless lives. 

Tuesday, September 20, 2016

The C9ORF72 Protein as a Suppressor of Autoimmunity

There are many chronic illnesses that are referred to as autoimmune diseases such as multiple sclerosis, amyotrophic lateral sclerosis (ALS) and pemphigus vulgaris for example; the etiology of these diseases originates from the patient’s immune system attacking normal tissue.   

ALS is a disease that presents as a progressive degeneration of the normal function of motor neurons resulting in paralysis and death.  It has been shown that mutations in the C9ORF72 gene are commonly found in ALS and frontotemporal dementia.  This gene is located on the short arm of chromosome 9 in humans.  This gene contains the information for the production of the C9orf72 protein.  Furthermore, in animal model studies using the mouse, it has been found that mutations in this gene result in Autoimmune-like symptoms.  Transplantation of normal murine bone marrow positively impacted diseased mice with this mutation and bone marrow transplantation of diseased mice into normal animals alternatively resulted in symptoms of autoimmunity.  These latter results led investigators to suspect that the C9orf72 gene is normally active in hematopoietic cells – cells residing in the bone marrow that produce circulating blood cells - in suppressing autoimmunity.

Recent findings have clearly established that mice that harbor mutations in the C9orf72 gene that result in the loss of function of the C9orf72 protein gene product develop the following symptoms –
  • splenomegaly – enlarged spleen
  • neutrophilia – increased population of neutrophils in the circulation
  • thrombocytopenia – decreased numbers of platelets
  • increased expression of inflammatory cytokines
  • severe autoimmunity.

These diseased animal suffer a high mortality rate.

These data represent strong evidence that the C9ORF72 gene plays a very important role in the suppression of autoimmunity and may prove to be of future therapeutic value.

Tuesday, September 6, 2016

What Will be Our Legacy?

The essential questions I would like to pose are the following-
  • Are we prepared to leave as our legacy not only to future generations of humans, but also the future of our fellow creatures a world whose living populations will be severely decimated by the onslaught of climate change brought on by human activity?
  • Are we prepared to jeopardize the quality of life and security of future generations of humanity on planet Earth so that we can maintain our privileged and comfortable lifestyles based upon a patent disregard for the environmental degradation that we necessarily impose upon our planet?

These questions are no longer simply philosophical in nature.  The current data is clear that we are in the midst of a major change in the global environment caused primarily by human activity.  The following statement was made within the Smithsonian Museums website – – “According to the International Union of Geological Sciences (IUGS), the professional organization in charge of defining Earth’s time scale, we are officially in the Holocene (“entirely recent”) epoch, which began 11,700 years ago after the last major ice age.

“But that label is outdated, some experts say. They argue for “Anthropocene”—from anthropo, for “man,” and cene, for “new”—because human-kind has caused mass extinctions of plant and animal species, polluted the oceans and altered the atmosphere, among other lasting impacts.”

Humanity’s response, within the 21st century, to this real crisis will determine the future that awaits the living world.  Of course, the earth has been through at least five major mass extinctions in its long geological history and will certainly survive another.  The kind of adjustments involved, however, require long stretches of time involving many thousands if not millions of years.  We do not have the luxury of waiting.  The future of the natural environment depends upon what we do, or what we fail to do now.

Wednesday, August 31, 2016

The Role of the Enzyme Acid Ceramidase in the Etiology of Cancer

Ceramide belongs to a class of bio-active organic compounds referred to as sphingolipids.

This class of compounds has been shown to play important roles in many cellular processes including cell growth and proliferation, growth arrest and most importantly, apoptosis – programmed cell death.  Furthermore, research studies have strongly implicated sphingolipid signaling dysfunction in tumor progression – metastasis.  In addition, sphingolipids seem to play a role in the effect of chemotherapy and radiation upon cancer progression in patients with metastatic disease.

The current data strongly suggests that the enzyme acid ceramidase (AC) is implicated in both tumor growth and resistance to various therapeutic modalities as suggested above.  AC is an enzyme that catalyzes the breakdown of ceramide to sphingosine and fatty acid (see diagram below).  

AC over expression has been found in association with certain metastatic cancers including prostate cancer.  A decrease in the intracellular levels of ceramide has been shown to result in a decrease in apoptosis that would ordinarily lead to cell death for proliferating tumor cells.

As a consequence of these data, Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences at UCI, and colleagues at the Italian Institute of Technology, have also established an association with over expression of AC and metastatic disease in melanoma patients.  This group has proceeded to successfully develop drugs that effectively inhibit AC in an attempt to restore an appropriate level of apoptosis and slow down tumor progression.

This approach is experimentally sound and has been shown to be efficacious in in-vitro experiments with cancerous cells in culture.  This 

Monday, August 15, 2016

Last Universal Common Ancestor

It has long been suspected that the progenitor of life on planet earth most likely came from the sea.  It has been proposed that the possible origins of life could have been in shallow pools or under more extreme conditions such as within deep-sea vents or proximal to active volcanoes.
The current domains of life consist of bacteria –prokaryotes, the archaea -found in deep sea vents and the eukaryotes that comprise all the animal and plant life on the planet.  It has also been proposed that the archaea and the bacteria preceded the more complex eukaryotic cell type.
William F. Martin, an evolutionary biologist, from Heinrich Heine University in Düsseldorf, Germany, focused his research efforts on finding the progenitor of archaea and bacteria.  To do this, the known genetic structure of members of the archaea and bacteria domains were extensively examined.  This involved the examination of some six million genes representing thousands of microbes.
From these data, Martin and his colleagues were able to construct evolutionary family trees and were able to deduce that 355 gene families originated from single cell bacteria-like organism.  That organism is referred to as the Last Universal Common Ancestor (LUCA).  Furthermore, it is believed that LUCA lived some four billion years ago when the young earth was barely 500 million years old.
If this conclusion is correct, it clearly proposes that life began very early in the evolution of the planet earth and that the evolution of life was a much longer process than previously envisioned.

Wednesday, July 13, 2016

Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) represent a disease state that has its origin in the bone marrow.  Within the bone marrow are resident stem cells that are the progenitors of the circulating white and red cells and platelets that play vital roles in immune function (white cells), oxygenation of the tissues (red cells) and the ability of blood to clot as the result of trauma (platelets) - see diagram below.  The wide range of types of human leukemia are cancers of these progenitor stem cells.

In the case of MDS, these stems fail to mature and produce cells that are referred to as blasts and so-called dysplastic cells.  As a result, the number of mature stem cells are diminished in number; a state that results in diminished numbers of circulating white (neutropenia) and red cells (anemia) and platelets (thrombocytopenia).  It is this diminished cell count that produces the symptoms associated with MDS.  These symptoms may include –
·         Fatigue
·         Weakness
·         Easy bruising or bleeding
·         Fever
·         Bone pain
·         Shortness of breath
·         Frequent infections.

There are also cases in which the overall cell counts appear normal, but the circulating cells are abnormal.  Chromosomal abnormalities have also been found associated with MDS.  What makes MDS particularly significant from a human health perspective, is that certain subtypes of MDS have been shown to be a precursor to acute myeloid leukemia (AML) – a particularly aggressive form of leukemia

From the perspective of scientific research, the question that remains to be answered is what are the cause(s) of MDS.  This question has been and continues to be the focus of a concerted and intense collaborative effort.