Thursday, January 24, 2013

Modeling the Human Brain

The human brain is a highly complex organ that is responsible for remarkably sophisticated behavior.  In order to more fully elucidate the relationship between brain structure and function, investigators involved with attempting to understand the neuroscience of brain systems especially concerning  cognition are testing large-scale simulations of brain structure and function.  This is a particularly daunting challenge.


For example, there is the so-called, "Blue Brain Project" that involves the simulation of about one million neurons arranged in cortical columns.  The design of this model incorporates significant biological detail that reflects known spatial relationships and neuronal connectivity data.  Another example of a human brain-modeling project involving some 100 billion neurons has also been reported. 


A limitation to these approaches has been that although they seek to model the complexity of brain organization they do not address the relationship between brain structure and brain function, i.e. human behavior.  Dr. Chris Eliasmith and colleagues from the Centre for Theoretical Neuroscience from the University of Waterloo, Waterloo, Ontario in Canada has attempted examine this relationship.  To do so, they have created a neuron model of 2.5 million neurons that focuses on the relationship between neuronal structure in the brain and the resulting human behavior.


Within this model, the inputs are represented by images of handwritten or typed characters.  All the outputs are the movement of an "arm" that possesses appropriate physical properties such as mass, length and inertia.  The designers of this model refer to it as "Spaun" – an acronym for Semantic Pointer Architecture Unified Network.  Incorporated within Spaun are typical brain-related functions such as image recognition, serial working memory and learning.  Furthermore, the eight tasks that Spaun performs are:

·         Copy drawing

·         Image recognition

·         So-called three-armed bandit task in which it is required to determine which of the three possible choices results in the statistically greatest reward

·         Successful reproduction of a list of any length

·         Counting

·         Responding to questions

·         Ability to create variables

·         Simple reasoning.


The model is so structured that it represents the anatomical structure of the human brain as established by current brain research.  Although a more detailed examination of the theoretical basis for this model is beyond the scope of this report, this kind of intensive work indicates the degree to which the apparent enigmas associated with high-order brain function are being methodically unraveled.

Thursday, January 17, 2013

The Immunological Mechanism Behind the Battle to Contain Chronic Viral Infection

The lifelong immunity to viral infection involves a multistep process:

·         The maintenance of so-called long-lived memory lymphocytes – lymphocytes are circulating white blood cells that play a critical role in the immune response

·         Upon reinfection, these memory lymphocytes then generate large numbers of short-lived cells that actively combat infection

·         Lastly, the pool of long-lived memory cells is replenished for use in future assaults.


There are a number of viral infections in which the virus following active infection can become quiescent and actually be incorporated in the host DNA and subsequently be reactivated under the appropriate conditions.  An example of a low-level virus of this type is cytomegalovirus (CMV) – a herpes virus that can reside within a host for a lifetime.  To combat such an infection, a balance is achieved between the maintenance of a pool of long-lived immunological memory cells and short-lived lymphocytes designed to fight the infection as described above.  A balance of these modalities confers lifelong immunity to the individual.


The issue becomes more problematic in the case of persistent infections with high viral loads such as the human immunodeficiency virus (HIV) that causes AIDS.  In such infections, the ability to maintain a consistent pool of long-term memory cells can be compromised on account of the necessity to maintain a persistently high level of short-term lymphocytes.  In the case of AIDS it is believed that a constantly elevated population of CD8+ lymphocytes (CD8 is a particular protein that resides on the cell surface of these cells) that are involved in combatting the HIV infections leads to a decreased pool of memory cells and eventually results in the collapse of immunity towards HIV.


What is not clear is the actual mechanism that is responsible for this immunological imbalance in regard to chronic viral infections.  In attempt to elucidate this issue, Dr. Michael A. Paley and his colleagues at the Department of Microbiology and Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania worked with chronically infected mice as the animal model for their studies.  From their work, they discovered two unique subsets of CD8+ lymphocytes in response to chronic viral infection – one subset involved in the renewal of the CD8+ population and the other in differentiation.  Furthermore, they found that elimination of either of these subsets resulted in the organism's inability to control chronic infection.  These findings seem to suggest that an imbalance in differentiation and renewal may be ultimately responsible for the collapse of immunity in human patients suffering from chronic infection.


The clarification of this mechanism may help in the ultimate development of targeted therapies for chronic viral infections in humans.  

Sunday, January 6, 2013

The Role of inflammation in Colorectal Cancer

Chronic inflammation has been implicated as playing an essential role in a number of human cancers including colorectal cancer (CRC).  Chronic inflammation is a condition in which the body's immune system's inflammatory response is turned on.  When the inflammatory response is prevalent in the intestines, powerful factors are secreted including: Interleukin-6 (IL-6), tumor necrosis factor (TNF-α), IL-23 and reactive oxygen species.  All these may act in consort to create a microenvironment that can lead to accelerated DNA damage in the intestinal epithelia and thereby increase the likelihood of leading to CRC as is demonstrated by the discovery of a colitis-associated CRC.


Furthermore, within the lumen of the colon, literally trillions of bacteria coexist in an environment referred to as the "microbiota."  These bacteria live in close proximity to the epithelial cells that line the colon.  From this information, the question naturally arises, "Do these bacteria, under the right conditions participate in some way with the cancer-causing process – carcinogenesis?"


In attempt to determine the answer to his question, Janelle C. Arthur and her colleagues at the Department of Medicine at the University of North Carolina at Chapel Hill studied the association of the microbiota, chronic inflammation and the onset of colon cancer in mice with a genetic susceptibility to colitis.  Their findings can be summarized in the following way:


·       Monocolonization  of the experimental animal's gut with Escherichia coli (E. coli) NC101 promoted the development of CRC in azomethane treated animals – azomethane is a potent carcinogen

·         Deletion of the particular strain of E-coli – polyketide synthase (pks+) strain known to have a deleterious impact on host genes, genotoxic, decrease the amount of invasive tumors

·         Pks+ E. coli are found in a significant percentage of human patients with inflammatory bowel disease and CRC.


These data demonstrate that within the scope of the mouse model, colitis, as an example of chronic inflammation in the gut, can promote CRC by altering the microbial composition of the intestinal microbiota.  In addition, these findings may have direct application to the understanding of the development of human CRC.