Thursday, April 29, 2010

Cancer Vaccine – A New Hope for Patients with Prostate Cancer

For those patients with aggressive prostate cancer there are a number of available therapies, including prostate gland removal, radioactive seed implants, and androgen deprivation therapy. Each of these has significant drawbacks. There is a vaccine, however, that has been developed for prostate cancer that may provide yet another modality to the treatment of this disease.
The first vaccine that directly treats cancer could be available soon if Seattle’s biotech company, Dendreon Corporation secures U.S. approval of its product called Provenge. The mechanism of action of this vaccine employs what is referred to as immunotherapy – the recruitment of the patient’s own immune system to preferentially destroy cancer cells. This approach has been used in the past to fight cancer with limited success. This particular application may prove to be more fruitful.

Dendritic cells which are found in the bloodstream play a key role in the immune response. They are referred to as Antigen Presenting Cells (APC). These cells interact with antigens – substances that induce the immune response – and by presenting these antigens to immunological T cells, trigger them to divide and find and destroy those cells carrying the antigen. For prostate cancer, the antigen is prostatic acid phosphatase (PAP). PAP is found predominantly on prostate cancer cells, and, therefore, would be the antigen of choice.

With this information in mind, the strategy used to produce the vaccine is the following:
•The patient’s Dendritic cells are harvested and stimulated to divide in the laboratory
•These APCs are then exposed to PAP, and bind to it
•These APCs armed with the antigen are then injected back into the patient.

Hopefully, these cells will then trigger the appropriate T Cells in the body to multiply, find and ultimately destroy the cancer cells carrying PAP. Initial clinical trials of this vaccine have proven quite promising. If successful, this would be very exciting news, for it would represent an essentially non-invasive technique to cure prostate cancer without any real risk to the patient, since it is the patient’s own cells that are used in the treatment.

Monday, April 26, 2010

Obesity , Inflammation and the Human Gut

Obesity is a condition that has reached epidemic proportions not only in the United States but a good portion of the developed world. A number of factors contribute to this condition; predominant among these are high daily caloric intake accompanied by an increasingly sedentary lifestyle for many. A more alarming trend is the extent to which this is being seen in children.

One of the more serious side effects that are directly related to obesity are Type II Diabetes – a condition that results in the inability of cells in the body, especially those of the muscle and the liver, to properly absorb glucose – a major component of cellular metabolism. As a result, the level of glucose in the blood increases significantly. This condition has serious implications for the health of the diabetic including heart disease, blindness, an increased likelihood of amputation and other consequences.

Scientists have spent considerable effort trying to understand the underlying processes that can more thoroughly explain the condition of obesity. The term that is used to describe the complex interaction that lies at the heart of obesity is referred to as the Metabolic Syndrome. Low-grade inflammation has been implicated in this syndrome, and the gut may play an important role. It has been established that obesity is associated with increased immune system activity.

The human gut harbors a large spectrum of bacteria that are beneficial. If there is an impairment of the body’s first line of defense, the innate part of the immune system, this might impact the bacterial population in the gut and trigger an inflammatory response. As a result of the studies done by Dr. Vijay-Kumar and his colleagues from the Department of Biology at Emory University in Atlanta, Georgia, this hypothesis has been shown to have validity in the mouse, an animal model often used in immunological research. In his studies, the obesity of mice with this dysfunction was exacerbated when fed a high caloric diet.

This kind of study demonstrates that obesity is a complex problem and, therefore, needs to be addressed from a variety of different perspectives.

Wednesday, April 14, 2010

Concerning a Theory of Human Emotions

Humans are endowed with a life of the mind that encompasses the unique ability to reason and a diverse range of emotions. It is the emotions that provide the drive and motivation to act in the world as well as imbue an individual existence with both color and spirit. Emotions project the individual’s reaction to personal experience. They are felt internally and are an external manifestation of a person’s response to external conditions.

I believe it is reasonable to assume that the emotions have a neurological basis; it has been well established that the area of the brain referred to as the amygdala, located within the limbic system, is the site where neurological activity associated with the emotions is found. Over the millions of years of human evolution, the neuronal infrastructure of this section of the brain was assembled in order to improve the survivability of the species in an essentially hostile environment.

In my mind, the panorama of the emotions can be conceptually divided into two distinct categories. Within one subset, I place those emotions that are elicited in response to a perceived and imminent threat to the safety and integrity of the individual or group. These emotions include fear, anger, hatred and rage.

Humans are gregarious by nature and have a natural affinity towards others. This socially-oriented proclivity has immense ramifications in regards to the fate of human populations. There exists in all of us what is perceived as a need for a sense of “connectedness” that drives this movement towards others. It is the state of health of this connectedness that is the source of the emotions I place in the second category. The sense of belonging can either be enhanced or diminished. The emotions that reflect this enhancement are love, joy, delight, happiness and elation. Those emotions that are elicited as a result of the feeling of diminishment of belonging are grief, sadness, sorrow, depression and despair.

This innate need for feeling connected not only applies to others in the human family but to the natural world as well. This reality is reflected in the richly textured myths of early human societies. Native American populations viewed themselves in a context of connection to all that surrounded them including the inanimate world. Life in the modern technological era has deprived us of this sense of belonging to the greater world. I have concluded that it is this schism that is at the heart of anxiety that drives so many to distraction.

The internal and overwhelming sense of isolation that is the hallmark of the modern world has diverted humans from their true nature. Collectively, humans are neurologically wired to be an integral part of all that surrounds them. This desire for “oneness” lies at the heart of so many of the world’s religions. It is this state of harmonious relationship that so many seek, especially in form and texture of their god(s).

We are essentially a tribal species. It is this need for fully participating within the fabric of a social environment that is so often thwarted by the hard-edged structures that are imposed by the exigencies of modern life.

I am convinced that it is possible to retain the benefits of technological progress while seeking to soften our rigid social structures and permit a greater sense of openness and inclusion. The significant threat that human activity poses to the health of the natural environment may provide an impetus for a change in the way we have come to perceive others and the natural world. We should seek to enhance and not curtail the internal desire for wholeness, while utilizing and maintaining our higher faculties as well.

HIV Vaccine – A Promising Development

The human immunodeficiency virus (HIV) is responsible for the complex of symptoms that characterize acquired immunodeficiency disease syndrome (AIDS). The devastating impact of this disease resides with the fact that HIV targets a particular subset of cells that play a critical role in the human immune system. These cells are called Helper T cells that carry a particular protein marker (CD4) on their cell surfaces. When an individual, infected with the HIV reaches a certain threshold in viral load, the number of CD4+ cells, circulating in the bloodstream, drops dramatically. Under these circumstances, the infected person is prone to infections of all kinds, especially opportunistic infections – infections that result from bacteria, fungi or viruses that the general population is protected against with a healthy immune system.

This disease had a devastating and profound impact on the millions of lives throughout the world and has resulted in orphaning many children in the developing world. As a direct result of the intense research into the nature of HIV, there is now a “cocktail” of medicines that greatly reduces the viral load in AIDS patients; however, these drugs are prohibitively expensive. The application of safe sex practices can reduce the probability of becoming infected in sexually active individuals, but real the hope lies in the development of an effective vaccine.
HIV is a member of a class of viruses called retroviruses. These viruses are particularly troublesome for two reasons:
•They are capable of integrating into the host’s DNA and can repeatedly re-emerge and, therefore, re-infect
•They can produce many variants through minor changes in their genetic makeup.
This latter characteristic has proved problematic in developing an effective vaccine. There has been a modicum of hope and interest, however, in phase III of the trial of a vaccine that recently enrolled more than 16,000 participants in Thailand. Although analysis of the results of this trial showed an effectiveness of only 26.4%, it seems to have provided some encouragement on the part of investigators. Jerome Kim of the Walter Reed Army Institute of Research remarked that, “We’ve taken a small step. It’s not a home run, but it opens the door to future work.”

The development of a truly effective vaccine would have enormous implications for the world in general and the millions that are at risk in particular. It would also put an abrupt halt to the spread of this horrendous disease.

Tuesday, April 13, 2010

Mental Illness - a New Frontier

There is currently a considerable effort being undertaken to revise the Diagnostic and Statistical Manual of Mental Disorders (DSM). This endeavor has been inspired by the significant strides that have been achieved in understanding the nature of mental imbalances made possible by breakthroughs in the areas of neuroscience and neurobiology. As we have noted previously, many disorders including Chronic Depression and Obsessive Compulsive Disorder (OCD) have been shown to result from a dysfunction in particular neural circuits in the brain.

In spite of these findings, there remains much to be discovered in regards to the biological basis of mental disorders – what causes these disruptions in the brain’s circuitry. For this reason, the DSM will remain focused on symptoms for the various disorders.

There is a new initiative that has been launched by the U.S. National Institute of Mental Health (NIMH) to fund the pure scientific research that is required to uncover the root causes of mental disorders. According to Bruce Cuthbert, an NIMH scientist, “What we are doing is trying to develop new ways to classify disorders that are based on identifiable neural circuits.”

To date the draft DSM has outlined five domains of mental function that correlate with specific regions of the brain or particular chemical signaling pathways or both. The road to completion of the DSM will be a long and arduous one, but well worth the effort, especially in regards to improved treatments for those unfortunate enough to be plagued by mental illness.

Tuesday, April 6, 2010

The Beginning of Cellular Life - An Hypothesis

A necessary first step in examining the evolution of cellular-based life from the pre-biotic world is to discern what constitutes the makeup of cells in the broadest possible terms. In deconstructing cell structure from the viewpoint of prokaryotes, I have come up with the following:

•Cell Membrane to delineate the cell and protect it from the local environment
•Cell infrastructure composed of the most basic structural components including actin, myosin, etc.
•Source of readily available energy
•Proteins especially enzymes involved in catabolic and anabolic activities
•Signal transduction pathways that allow for both intracellular and extra-cellular communication.
•Nucleic Acids: DNA and RNA to serve as information stores for the cell.
•Mechanisms for DNA and cellular replication.

Any Attempt to propose a mechanism by which primordial cell-like structures evolved into the complex cells that exist today, strongly suggests a gradual stepwise process that took eons to accomplish. It also suggests, in my mind, that the process would involve steps in which cellular organization would grow in complexity from the level of simple molecules (substrates) through proteins and finally through protein-nucleic acid interaction to the encoding of the genetic material. In this way, selection pressures and processes would enhance each succeeding step.

Elements of Hypothesis:

•There existed in an aqueous environment (possibly shallow ponds or along coastal regions or possibly the sea floor) where there was an abundance of nucleotides, fatty acids, amino acids, peptides and polypeptides. It is possible that some of this organic material may have been seeded by meteorites.
•In these organic-enriched regions, conditions were appropriate for the spontaneous formation of cell-like structures.
•These cell-like structures developed semi-permeable membranes formed from the spontaneous assembly of proteins and lipids (probably a more primitive structure than found in present day cells) and highly permeable to dissolved organic matter in the local environment.
•The local environment was such that amino acids, nucleotides, fatty acids and carbohydrates could readily penetrate the cell membranes of these primordial cells and concentrate there.
•Ambient conditions including oxygen concentration, temperature, abundance of ammonia and methane made the spontaneous synthesis of proteins and nucleic acids not only possible but highly likely.
•Assuming that spontaneous formation of tRNAs were a likely scenario, these tRNAs could bind to their appropriate amino acids. These amino acid carriers collided with each other and result in the formation of random polypeptide chains. Subsequently, Polypeptides that were capable of binding to carbon sources such as glucose stabilized these small proteins and gave them a competitive advantage over more non-specific proteins. Since the metabolic pathway for glucose metabolism is universal to all life, one must assume that glucose was abundant in pre-biotic times. This same argument can be applied to the presence of ADP/ATP, since this molecule is the essential ingredient for all energy sustaining life activities.
•Some of these selected proteins also possessed catalytic capabilities and were able to breakdown carbon rich substrates and ultimately capture energy in ATP molecules. This energy may have been used in accelerating the synthesis of more complex molecules and intra-cellular structures, the precursors of cellular organelles.
•There is mounting evidence that strongly suggests that RNA may have played a pivotal role in information storage in the early evolution of cellular life. As I have postulated above, tRNAs may have been abundant. Additionally, evidence for the role of RNA in information storage includes:
oThe discovery of RNA that possesses catalytic activity referred to as ribozymes. There is a ribozyme that has been found in the core of Ribosomes.
oThe discovery of small pieces of RNA that can readily bind to a variety of organic molecules and that are found on the ends of mRNA in prokaryotes. These pieces function as switches that can turn translation on or off and are referred to as riboswitches.
oDouble-stranded RNA that can silence gene transcription in a complex referred to as RISC.
•What is now referred to as the anti-codon region of tRNA may have been used to make mRNA possibly happening spontaneously utilizing an environment rich in small pieces of RNA or assisted by a ribozyme. These nascent mRNAs served as templates for the further synthesis of specific and biologically valuable proteins. Whether or not such associations are possible today in conditions that simulate the pre-biotic environment would need to be tested. It is possible that “ancient” RNA had a different structure than the current form. This early mechanism was probably inefficient and prone to error.
•These early cells were infiltrated by competing entity that gradually assumed a symbiotic relationship and was to become what is now referred to as ribosomes. These structures contributed a much more efficient mechanism for the synthesis of proteins.
•Messenger RNAs were no longer able to sustain the growing complexity of cell life as embodied in metabolism and energy transfer mechanisms. A more highly conserved store of information was required. The appearance of an enzyme capable of using mRNA as a template to make highly stable double-stranded DNA encouraged the further development of cellular complexity and evolution. This transition was necessitated by the fact the extra-cellular environment was no longer as rich in nutrients and building materials as was previously the case. It has become clear that large portions of the genome of humans and other complex organisms are made up of retrotransposons. There are relatively small pieces of DNA that code for reverse transcriptases that allow for copying of these segments and ultimately inserting them in other places in the genome. These were originally discovered by McClintock and referred to as so-called “jumping genes.” Integration of these pieces in the promoter or structural regions of active genes can have profound impacts on gene expression. Certain diseases have been associated with this process. Furthermore, there are retrotransposons that have been conserved among and between organisms. This suggests that the increasing complexity of the genome as seen in evolution may be in large due to retrotransposons. In addition, retrotransposons have many characteristics similar to retroviruses suggesting that retroviruses may have played a significant role in delivering novel genetic material to the genome.
•Gradually the repertoire of catalytic and structural proteins and genes grew in complexity leading ultimately to modern DNA and cell replication and both anabolic and catabolic pathways.
•At some point in this process cells became “alive”: able to do work against the forces of entropy, grow in complexity and produce more of themselves in a chaotic environment.

Functional Heart Muscle Made from Embryonic Stem Cells in the Mouse

Currently, the demand for organs for transplant far exceeds the number of organs harvested from human cadavers. As a result many seriously ill individuals die from diseased essential organs such as the heart, liver and lungs. This is a dilemma that plagues modern medicine
The work of Ibrahim J. Domian from the Cardiovascular Research Center in Boston Massachusetts suggests an alternative to the reliance on intact organs for transplantation. Dr. Domian and his colleagues have successfully grown functional mouse heart muscle from mouse embryonic stem cells (ESC) in a laboratory (in vitro).

The process by which an embryonic stem cell becomes a cell with a specialized function such as a muscle cell is referred to as differentiation. This group has discovered a progenitor cell capable of in vitro expansion, differentiation and assembly into functional muscle tissue. This work is preliminary in nature. However, the implications are far reaching. One can envision a time in the future when ESC are engineered to produce an intact organ in the laboratory. Such a development would potentially save innumerable lives.

Sunday, April 4, 2010

Multiple Sclerosis – Prevalence in the Pacific Northwest

Multiple Sclerosis (MS) is a characterized as an autoimmune disease – the body’s immune system attacks its own tissue. It is a chronic, disabling disease of the central nervous system (brain and spinal cord). The disease causes inflammation, destruction, and scarring of the sheath that covers nerve fibers, called myelin, in the brain and spinal cord. As a result, electrical signals from the brain are impaired and disrupt muscular activity throughout the body. The onset of this disease generally occurs between the ages of 20 and 40; women are twice as likely to develop MS as men.

In MS, the target of the immune system is the myelin that covers the axons of nerves (neurons) of the central and peripheral nervous system. Myelin is a complex substance made up of 80% lipid (fat) and 20% protein. One of the primary functions of myelin is to serve as insulation for the neurons. These neurons transmit signals from the central nervous system to the muscle; these signals are essentially electrical in nature. Without the proper insulation provided by the myelin, these signals degrade and impact muscular activity. Destruction and deterioration of the myelin has a dramatic and deleterious impact on the peripheral nervous system. The MS patient experiences periodic and acute episodes in which proper function of the muscles is impaired and can be crippling. These episodes eventually subside but generally leave behind some residual impairment. MS is a chronic disease whose cause is unknown and remains incurable; its impact can range from mild to severe. There are, however, some promising therapies that have been perfected to help with the symptoms and hopefully retard the disease’s progress. These approaches will be discussed in a subsequent article.

MS has been shown to be particularly prevalent in the northern latitudes; residents of the Pacific Northwest are particularly susceptible. The reason(s) for this phenomenon is poorly understood and is the subject of intense investigation. A possible explanation may relate to the climate and the fact that many of the inhabitants of the Pacific Northwest are from Northern Europe whose people have an increased susceptibility to the disease. In regards to the impact of climate on the prevalence of MS, there has been some evidence that the lack of Vitamin D, whose production in the human body is triggered by sunlight, may play a role.

MS is a disease that is under intense investigation. The hope remains that its cause and eventual cure will be discovered.

Thursday, April 1, 2010

The Crisis in Antibiotic Resistance and One Possible Solution

There is a looming public health crisis in regard to the growing incidences of infectious diseases that have become resistance to the usual repertoire of antibiotics. Insidious examples of this are the troublesome occurrence of Methicillin-resistant Staphylococcus aureus (MRSA), especially in hospital settings, and antibiotic-resistance strains of such communicable diseases as Tuberculosis and Gonorrhea found throughout the United States and other parts of the world.

On account of this problem, there is an urgent need to discover new families of antibiotics that possess novel mechanisms for their action. Promising results have recently come from the laboratory of Dr. John A. Robinson from the Chemistry Department of the University of Zurich in Switzerland. Dr. Robinson and his colleagues have synthesized a new class of antibiotics they refer to as peptidomimetic antibiotics. This class of compounds is based on the naturally occurring antimicrobial peptide (a peptide is a small protein) called protegrin 1 (PG-1).

This group demonstrated that this type of antibiotic was particularly effective against Pseudomonas aeruginosa (PA). This particular organism is ubiquitous and is particularly threatening to those individuals who have a compromised immune system, or suffer from a wound as a result of injury. If these bacteria infect the lungs, kidneys or the urinary tract, the results can be fatal.

These investigators clearly demonstrated that peptdiomimetic antibiotics protects against lethal infections in whole animal studies. Although, the particular antibiotic tested had no appreciable effect on other types of bacteria, it may have use against so-called nosocomial infections - infections that appear as a result of a prolonged stay in hospital - and lung infections in patients suffering from cystic fibrosis, who are especially susceptible to drug-resistant strains of PA.