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 – Smithsonian.com – “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.

Monday, June 6, 2016

A Very Promising Treatment for Patients with Glioblastoma

Glioblastoma is an exceedingly aggressive cancer of the brain that usually leads to death within months of its initial diagnosis. However, in clinical trials conducted by Drs Gordana Vlahovic and Matthias Gromeier at the Preston Robert Tisch Brain Tumor Center at Duke University in Durham, NC, amazing results have been achieved in patients with this disease using a human-engineered polio virus that has been stripped of its ability to cause disease. This modified virus with the ability to kill cancer cells (oncolytic) is referred to as PVS-RIPO (see illustration below). The results to-date have been so impressive, that the Federal Drug Administration (FDA) has accelerated the approval process for its use in clinical settings opening up its application to perhaps hundreds of patients who would otherwise face a grim future.



PVS-RIPO

PVS-RIPO was engineered by removing the genes that are responsible for causing the neuronal damage that produces the deleterious effects of polio in humans and added in its place a portion of the genetic code of the ubiquitous cold-causing rhinovirus.


The rationale for this approach is multi-faceted. The polio virus has a natural receptor that can attach to many different forms of cancer. This receptor binds to CD155. CD155 is a cell surface glycoprotein that spans the outer cell membrane (transmembrane). It is often referred to as the Poliovirus Receptor (PVR). It has been established that CD155 plays a role in the establishment of intercellular junctions between epithelial cells. It seems that CD155 is over-expressed and abundant in various kinds of cancers including glioblastoma and pancreatic cancer.  The strategy employed was to use PVS-RIPO to preferentially infect the patient's cancerous glioblastoma cells.


In the case of the patients involved in clinical trials suffering advanced stages of glioblastoma as mentioned above, PVS-RIPO was infused directly into the tumor in order to maximize exposure to the virus. It seems that the amazing success of this treatment is due not only to successful infection with PVS-RIPO but also the subsequent mobilization of the immune system against the cancer cells.

This approach to treating advanced glioblastoma may ultimately extend to the treatment of other intractable cancers such as pancreatic cancer. This is an exceedingly exciting development that may have broad application in the treatment of and ultimate cure of cancer.

Thursday, May 26, 2016

Origin of Life on Planet Earth

A question that has plagued scientists for a long time is centered around the question as to how life began on planet earth.  It is well known that life is found even under the most inhospitable conditions – a stunning example of this is that life exists within the deep sea hydrothermal vents that are found on the ocean floor.  In addition, microorganisms such as Hormoconis resinae contaminate jet fuel – using this hydrocarbon source as a vital nutrient – and are known to cause corrosion in the tanks that hold this fuel.

Therefore, it can be reasonably postulated that simple life forms could thrive in the harsh conditions of prebiotic earth when oxygen was not present within the atmosphere at that time.  But the question remains as to how did life begin – what was the process by which self-sustaining living organisms were formed from rudimentary compounds.

It has been shown that in an artificial environment created in the laboratory  in which an atmospheric environment was created to simulate the conditions believed to have existed in the prebiotic world, the addition of an energy source – such as lightening – produced rudimentary organic compounds found in living cells.  These experiments were conducted in the 1950's, by the biochemists Stanley Miller and Harold Urey.  These results are only suggestive evidence that organic compounds could have been created spontaneously in the early-earth environment.  It is, of course, far from the complete story.

Since DNA and RNA are fundamental ingredients to all of life as we know it and capable of self-replication, a key step in the evolution of life would be the conversion of simple organic compounds to purines that are some of the important building blocks for both DNA and RNA and for the synthesis of Adenosine Triphosphate (ATP) – the molecule that is responsible for trapping energy derived from metabolism for all of life.

Furthermore, the preponderance of evidence now suggests that RNA may have preceded DNA as the repository of genetic information capable of self-replication.  Certain forms of RNA also demonstrate catalytic properties (ribozymes) that are essential to sustain life.  Of course, contemporary advanced cell structure uses a host of enzymes to accomplish essential catalytic functions.
 
RNA is made of four different nucleobases  -two pyrimidines – cytosine and uracil – and two purines adenine and guanine.  Previous work done by John D. Sutherland from the School of Chemistry, University of Manchester, UK has shown a plausible synthetic route to pyrimidines in an abiotic environment.  But the route to purines has been more elusive.



Recent work by T. Carell from the Department of Chemistry, Ludwig-Maximilians University Munich, Germany and fellow investigators has recently demonstrated a mechanism that could account for spontaneous creation of purines from simpler compounds readily available within the natural environment of early earth.  The pathway involves the spontaneous synthesis of aminopyrimidines from hydrogen, cyanide and water – compounds readily available in the early earth environment.  Although aminopyrimidines can produce a wide range of synthetic products, in an environment of formic acid, the predominant product is formamidopyrimidine (FaPy) known to readily produce purines.  Furthermore, formic acid has been shown to be present in comets that collided frequently with earth during the early stages of its evolution.


Formamidopyrimidine



Although this work is very significant, it does not explain how purines and pyrimidines would lead to the creation of more complex and sophisticated RNA molecules.  Nor does it shed any real light on the requisite formation of a cellular environment for biosynthetic reactions so necessary for the containment and sustenance of life processes.