Tuesday, June 29, 2010

New Frontiers in the Treatment of Alzheimer’s

Alzheimer’s is a devastating disease of the human brain that ordinarily displays symptoms in old age. It is an ailment that is characterized by progressive dementia that totally incapacitates the patient and ultimately ends in death.

Alzheimer’s is characterized by a gradual build up of protein fragments referred to as amyloid-beta peptides. These fragments accumulate in the intercellular spaces within the brain. The disease process ultimately leads to profound cell death. Anti-amyloid drugs and a vaccine have been developed to combat this disease. These novel therapies have so far been disappointing.
As a result of extensive research into the disease process, there is now a new understanding of disease progression. The buildup of the amyloid-beta peptides begins from 5-20 years before diagnosis. In addition a protein called, TAU that normally functions to maintain the infrastructure within nerve cells (neurons) is modified leading to disruption of normal cell function. This seems to occur 1-5 years prior to the appearance of symptoms, and finally, brain shrinkage becomes noticeable as a result of significant cell death 1-3 years before diagnosis.

On account of these findings, the current understanding is that the failure of new therapies to effect a beneficial change may be due to the fact that when treatments are initiated the brain damage is already too advanced to yield beneficial results.

In the town of Medellin, Columbia there are approximately 5000 members of 25 extended families who develop early-onset Alzheimer’s. This is a result of dominant gene that is found in less than one percent of 27 million Alzheimer’s cases worldwide (2006). Individuals of these families, therefore, allow an ideal setting to test this hypothesis. The planned trial is referred to as the Alzheimer’s Prevention Initiative (API). The overall approach is to have appropriate candidates – apparently healthy with the deleterious gene – who are around the age of forty treated with the anti-myeloid therapies as previously discussed.

If this approach yields promising results, - the treatments delay or stop the inexorable progression of the disease - this would be exciting news, especially since the U.S. population is aging.

Wednesday, June 16, 2010

Regarding Platelets

Platelets are cell-like bodies that represent an essential component of circulating blood. The role of platelets in blood clotting has long been understood. Since platelets, like red blood cells do not have nuclei and the DNA that is essential for life, it was assumed that blood-clotting was the only role for platelets.

In recent years, platelets have been shown to possess diverse functions. They have been found to release growth factors and other factors that help in the repair of damaged tissues. In addition, they help initiate the inflammatory response, alert immune cells and they have even been implicated in the attack of invading microbes in the midst of a bacterial infection. They also function as carriers, delivering serotonin to the liver which aids in the regeneration of the liver following a traumatic injury. Platelets also participate in the development of the circulatory system in newborns.

It is interesting to note that Doctor Weyrich and his colleagues from the Human Biology and Genetics Program at the University of Utah have demonstrated that platelets reproduce in spite of the fact that they lack a cell nucleus. They send out a strand with one or more bead-like bulges that eventually separate producing new platelets.

This new understanding of how platelets function will ultimately open the door to new kinds of therapies and treatment for diseases in which they are apparently implicated.

Pathways Toward Increasing Human Lifespan

The target of the drug rapamycin is TOR, an enzyme. An enzyme is a protein that serves as a biological catalyst in living systems. TOR has been shown to play a key role in cell growth and the metabolic pathways that maintain homeostasis on both the cellular and organismal levels. Insulin and insulin-like growth factors are activators of TOR. Additionally, caloric restriction (CR) triggers a biochemical signal that inhibits TOR activation acting as negative feedback.

Persistent activation of TOR has been clearly shown to be involved in various diseases including cancer, cardiac performance and obesity-related ailments. Conversely, the inhibition of TOR has been shown to prolong life span. The positive effect of CR on longevity has been demonstrated in many animal species. CR may exert its effect through the inhibition of TOR.

Sestrins (Sesns) are proteins that are highly conserved in nature – found in many mammalian species across the evolutionary spectrum. They increase within cells that are exposed to stress such as CR. There is evidence that they also may function as antioxidants. Sesns are, in fact, feedback inhibitors of TOR.

There is mounting evidence that Sesns are involved in preventing age-related disease and, therefore, prolonging life. This kind of understanding of the aging process may find some future application.

Monday, June 7, 2010

Advances in the Delivery of Anti-Cancer Drugs

One of the major obstacles to the effective treatment of cancer patients with potent anti-cancer medications is the successful delivery of the drug(s) to the entire tumor mass. Investigators led by Dr. Kazuki N. Sugahara at the Vascular Mapping Laboratory at the Center for Nanomedicine, Stanford-Burnham Medical Research Institute at the University of California at Santa Barbara have devised an approach to overcome this limitation.

Using the mouse as the animal model, they have utilized a tumor-penetrating peptide (a small protein) called iRGD to effectively increase the access of anti-cancer drugs to cancerous tumors and, thereby, increase the therapeutic potency of these medications.
The peptide iRGD penetrates into an actively proliferating tumor mass by specifically binding to the av integrins – proteins that are uniquely found on the endothelium (the cells that line the interior wall of blood vessels) of tumor blood vessels. In fact, when iRGD was co-injected with an albumin – albumin is a common protein found in circulating blood - binding dye used as a marker, the dye was found to successfully accumulate in five different tumor models including breast, prostate and pancreatic cancers.

In addition, the scientists involved in this research found that iRGD when co-injected with the anti-cancer drug Doxorubicin (DOX) resulted in a sevenfold increase in accumulation of DOX in prostate cancer tumors in the animals studies.

These results are especially encouraging given the fact that many anti-cancer drugs like DOX have significant side effects at high doses. This serious limitation can be sidestepped if the drug gains access to tumor cells at more manageable doses.

The Successful Synthesis of a Bacterial Chromosome

A major breakthrough in molecular biology has recently been reported from the laboratories of Dr. J. Craig Venter at the J. Craig Venter Institute in Rockville Maryland and San Diego California. The investigators in this ten year project have successfully synthesized a bacterial chromosome using the DNA sequence data from a species of microorganism called M. mycoides and subsequently introduced this product into a different bacterial species, M. capricolum replacing its DNA with the synthetic variety. This wholly modified organism grew and divided with the characteristics of the donor species.

The technique that was utilized is outlined below:
• A copy of the chromosome of M. mycoides was made by using yeast cells to assemble the DNA in stages. This was an arduous and time-consuming project that required much trial and error.
• The fully synthetic copy was then placed into the recipient microbial species M. capricolum. In order to show that the synthetic chromosome was successfully introduced, the investigators purposefully incorporated into the synthetic product DNA sequences that spelled out in genetic code the e-mail addresses and the names of many of the people involved in the project. In addition, a gene was introduced into the synthetic DNA with the information to produce a blue gene product that would make bacterial colonies visible.

After months of thwarted attempts, blue bacterial colonies were found growing, indicating success. It should be made clear that this breakthrough does not constitute the creation of a synthetic life form, since the bacterial cell machinery was already pre-existing. However, it does demonstrate that the transformation of one bacterial species to another is feasible through the technique that is outlined above, and that it may be possible to introduce synthetic genes capable of producing novel gene products into synthetic bacterial chromosomes and produce organisms with new capabilities such as producing pharmaceuticals or neutralizing chemical pollutants, etc. In addition, this technology also brings with it serious ethical considerations that need to be addressed as well.

Tuesday, June 1, 2010

Neanderthal DNA

An international team of scientists from the Department of Evolutionary Genetics at the Max-Planck Institute for Evolutionary Anthropology at Leipzig, Germany, reported a draft sequence of the Neanderthal Genome – the full complement of genes. Neanderthals lived in Europe some 30,000 to 45,000 years ago and in the Middle East some 80,000 years ago. This species did, in fact coexist with modern humans.

The Neanderthal DNA that was analyzed was harvested from three female Neanderthals that lived in Croatia approximately 38,000 years ago. Although an extraordinary amount of DNA has been successfully defined, about one-third of the genome remains ambiguous. The investigators, however, devised a novel technique to fill in these “gaps.” The scientists involved in this extensive undertaking then compared the Neanderthal-derived data to the DNA obtained from five individuals from distinct parts of the world. The results of these studies yielded some surprising conclusions.

They found that the Neanderthal and modern human genomes are 99.84% identical to each other, and that those regions of the DNA that are different represent those genes that have been modified since the human species diverged from Neanderthals estimated to have occurred between 270,000 and 444,000 years ago. Furthermore, the genetic areas that differ seem to involve genes that play a role in skin, metabolism, the skeleton and the development of higher order brain function.

The most surprising result of all was the discovery that both Europeans and Asians share from 1% to 4% of their DNA with Neanderthal DNA, whereas Africans do not. This result is strongly suggestive of interbreeding between modern humans after they emerged from Africa and Neanderthals.

These data shed some new interesting light on human evolution. It has become increasingly clear that the analysis of DNA of humans and other species is an important and often essential tool in the study of the evolutionary process.