Friday, July 26, 2013

Neurogenesis in the Human Brain

It was once believed that the growth of new neurons – those specialized cells in the human central and peripheral nervous systems that allow for the transmission of nerve impulses – did not occur in the adult brain.  This has been shown to be substantially incorrect.  How the growth of new neurons – through a process referred to as neurogenesis – in the adult human brain was discovered is quite interesting.

Indirect evidence for neurogenesis was derived some fifteen years ago though an ingenious approach.  This study focused on the hippocampal region of the brain that is known to be involved in the storage and processing of memories.  This area of the brain would obviously be an excellent candidate for studying neurogenesis.  The result of this investigation was that neurogenesis was detected in five individuals up to 75 years of age.  To accomplish this, the investigators injected the human subjects with a label that binds permanently with the host’s DNA.  The compound used was bromoedeoxyuridine (BrdU).  Once BrdU is incorporated in the DNA, it can be detected using antibodies that specifically react with the modified DNA.  This specific binding can then be visualized by the experimenter with the proviso that the patients so injected were willing to donate their brains following death.  This type of study was eventually curtailed due to problems associated with its safety.

Recent studies conducted by Dr. Kirtsy L. Spalding and colleagues from the Department of Cell and Molecular Biology Karolinska Institutet in Stockholm, Sweden were based on more direct evidence derived from an unusual source.  It seems that during the era of extensive above-ground testing of nuclear warheads between 1945 and 1963, a considerable amount of the radioactive isotope of Carbon (C14 ) was released into the atmosphere.  The amount of C14 in the air has steadily declined since the Limited Test Ban Treaty of 1963 effectively banned above-ground testing.
Since dividing cells require carbon and since the source of that carbon is from the atmosphere, C14 becomes incorporated into the cellular DNA.  Furthermore, the amount of incorporated C14 directly corresponds to the amount of C14 in the atmosphere at the time of cell division.  Therefore ,to calculate the age of the cell, the investigator simply has to measure the amount of this isotope that was incorporated into its DNA.
From the analysis of the data, Spalding and his investigative group were able to show that human adult-brain neurogenesis is, in fact, confined to the hippocampus and some subpopulations actively divide while others do not.  From this data, it has been estimated that one-third of adult hippocampal neurons are actively dividing.  This activity within the hippocampus makes sense given the role of this region of the brain in creating and managing memories throughout the lifetime of the individual.

This is an important and elegant study for it answers the question whether or not the adult human brain undergoes neurogenesis unambiguously and is also able to provide a quantitative as well as a qualitative answer.

Friday, July 19, 2013

How the Malaria Parasite Hides Itself from the Mosquito’s Defenses

Malaria remains a potent killer to the human inhabitants of the tropical regions in the so-called “undeveloped world.”  This disease results in approximately one million deaths a year in Africa, alone.  An insect vector, the female Anopheles mosquito that requires blood to mature its eggs, is responsible for its transmission to humans.  There are a host of human maladies caused by such diverse organisms as viruses, protozoans and even worms that infect humans and that are carried by mosquitoes and other insects.

The causative agent for human malaria is a parasite referred to as Plasmodium falciparum.  The life cycle of P. falciparum is quite complex and intriguing.  When it is first inadvertently ingested by the mosquito from an infected host, the parasite undergoes a progression of transformations.  The specialized sexual precursor cells – male and female - are rapidly activated to form complete and functional sex cells – gametes.  Male and female gamete pairs subsequently fuse to from the incipient new organism called the zygote.  Within 18 – 24 hours, this zygote develops into a motile organism called the ookinete that is infectious to the mosquito.  This ookinete rapidly enters the insect’s midgut and forms an oocyst.  Within the oocyst more than 10,000 sporozoites are created within ten days.  Once this oocyst ruptures, these sporozoites navigate to the mosquito’s salivary glands where they are transferred to the next human host upon the mosquito’s bite.

Given this information, the questions that comes to mind are the following –
  • What are the mosquito’s natural defenses against this parasite?
  • How does the P. falciparum successfully elude these defenses?

The investigations of Dr. Alvaro Molina-Cruz and colleagues at the Laboratory of Malaria and Vector Research at the National Institute of Allergy and Infectious Diseases at the National Institute of Health in Rockville Maryland helped elucidate the mechanism by which the parasite escapes the immune defenses of its host.

It has been well established that insects have a first line of immune defense, as do vertebrates, referred to as the innate immune system (IIR).  IIR utilizes both humoral (chemical) and cellular defense mechanisms; it is quite sophisticated.  In spite of this ability to fend off foreign invaders, P. falciparum manages to survive and propagate in this hostile environment.

Molina-Cruz and the team of collaborators were able to identify a gene product from the parasite that enables the invading organism to infect its host mosquito without activating the innate immune system described earlier.  The gene responsible for producing this product was identified as Pfs47.  In fact when this gene was disrupted from its normal functionality, the parasite’s survival within the host was greatly reduced.

This finding is significant, for it establishes the fact that the Pfs47 gene contained within P. falciparum is essential for the efficient transmission of the parasite responsible for malaria from the vector to its human host.

Thursday, July 4, 2013

The CCR5 Receptor and HIV/AIDS

The recently reported news that an AIDS patient has been successfully cured of his disease is a very exciting development in regards to global public health.  The methodology used to affect this outcome is directly related to the manner in which the human immunodeficiency virus (HIV) gains entry into its host cell.  HIV enters and ultimately kills the so-called,” T-Helper” cell that plays a critical role in adaptive human immunity.  Once a significant portion of these cells are destroyed, the patient displays the classic symptoms of AIDS – the inability to successfully fight off infections by invading micro-organisms.

In order to successfully invade its target cell, HIV must bind to specific proteins found on the surface of T-Helper cells.  One of these cell surface proteins is referred to CCR5 (CD195) – a member of the chemokine receptor family – and the protein product of the CCR-5 gene.  Chemokines are factors that are used to attract T cells to particular tissue or organ targets when battling infection.  If this protein is absent or the product of a mutated gene, HIV will fail to bind and therefore be unable to infect the target cell.  It is important to remember that viruses have an absolute requirement for access into a living cell in order to produce an infection; for, they need to exploit the intracellular processes of a living cell in order to make copies of themselves.  The molecular biology of HIV has been studied extensively and, as a consequence, this mechanism of action is well understood.

In addition, there is a percentage of the human population that is innately resistant to HIV infection even upon exposure to the virus.  This apparent insensitivity to HIV infection is readily explained by the fact that these individuals possess defective variants of the CCR-5 gene.
Thanks to the ingenuity and inventiveness of Drs. Gero Hutter, Eckard Thiel and colleagues from the Charite Hospital in Berlin Germany, an approach to a potential cure of AIDS was recognized that involves the widely used procedure of bone marrow transplantation – the first successful human bone marrow transplantation was accomplished in 1975 in Seattle pioneered by Dr. Donnall Thomas who won a Nobel Prize in Medicine for his efforts.
In this particular case, the patient presented with acute myelogenous leukemia (AML) as well as AIDS.  The protocol that was developed involved the destruction of the AIDS patient’s immune system followed by recovery using bone marrow from a suitable donor who was also immune to HIV infection on account of a defect in the CCR-5 gene as described above.  As a result of this approach, the patient became asymptomatic and free of HIV.  This is possible because all the immuno-competent cells in the human immune system repertoire are derived from progenitors found in the bone marrow and once the patient’s own immune cells were successfully replaced by the donor’s, then he became HIV resistant.

Since bone marrow transplantation has inherent risks, it is not the recommended approach for AIDS patients; unless, they also suffer from leukemia.  However, there is considerable hope in developing methodologies to use gene modification techniques to modify an AIDS patient’s own immune cells so that they would exhibit the CCR-5 gene variant and render them HIV resistant.