ANTI-AGING SCIENCE, PART II

(This is the concluding installment of a two-part article, and focuses on three important discoveries/trends in the Genomic Sciences)

RNA INTERFERENCE ~ Silencing Genetic Instructions

A cell--whether plant or animal--possesses DNA (dioxy-ribo-nucleic acid), which is in turn composed of two RNA (ribonucleic acid) molecules, or polypeptide chains ('peptide' is another term for protein). These chains, comprising our 46 chromosomes, constitute tens of thousands of genes, which in turn, encode and control the development of many thousands of proteins.

But not all of these proteins are needed for every cell function. A cell must be selective in which genes it expresses or inhibits, and at what time. Also, our cells must protect themselves from viruses (small, 'rogue' strands of RNA) and other mobile genetic elements, which, if left unchecked, could take over its replication machinery and start producing viral proteins. Thus, over billions of years of evolution, cells developed molecular mechanisms for 'silencing' gene expression.

While evidence began mounting over a decade ago, it has only been in the past 3-4 years that one of these genetic "censor" mechanisms has been revealed and given serious study. Its called RNA interference (RNAi) and it works by intercepting and destroying only the messenger RNA (mRNA) -- the 'copy me' instruction molecules -- triggered by an invading virus, or mutated protein. RNAi is able to selectively destroy these pathogenic messages without interfering with other, necessary protein transcription.

RNAi has for several years been a potent research tool for geneticists working with plants and smaller animals like worms and fruit flies. These researchers have been able to utilize this natural cellular mechanism to suppress any gene they chose, thus allowing them to deduce a gene's specific function. Later research has revealed that double-stranded RNA --RNA segments that can fold back on themselves -- seems to be the primary trigger for the RNAi effect. However, subsequent experiments with injecting these double-stranded RNAs into live animal cells resulted in triggering the cell's interferon response, which shut done all of the cell's genes. Researchers realized that a deeper understanding of RNAi was needed.

Further research revealed that selective gene silencing occurs when double-stranded RNAs are modified by two enzymes, dubbed 'Dicer' and 'Slicer'. The Dicer enzyme cuts the longer RNA molecule into smaller fragments known as 'short interfering RNAs' (siRNAs). These asymmetric, double-stranded pieces are then unwound and one strand is incorporated into a larger molecular aggregate called the RNA-induced silencing complex (RISC). The RISC uses each strand of siRNA to 'run interference', that is, the siRNA is positioned to bump into thousands of mRNAs that normally populate the cell nucleus. But the particular siRNA will only adhere to a mRNA whose nucleotide sequence (the string of amino acid bases labeled 'a', 't', 'c', and 'g') closely resembles its own. Thus this 'silencing' mechanism is far more selective than the interferon mechanism. When a matching messenger RNA docks with the siRNA strand, the 'Slicer' enzyme comes into play, chopping it in two, thus rendering the mRNA incapable of protein transcription. The RISC remains intact and moves on to other silencing tasks.

This revolutionary knowledge of our cells' natural gene silencing mechanisms has sent a tidal wave of excitement through the bio-engineering and genetic sciences. RNA interference has of course attracted the attention of pharmaceutical companies which seek to develop a new class of medicines that interfere with the protein products of specific, cancer-causing genes (oncogenes). A half dozen labs have already had success in using RNAi to stop viral replication (HIV, polio, hepatitus C) in human cell cultures.

This past September, Acuity Pharmaceuticals, a company in Philadelphia founded in 2002, announced that the FDA had granted permission for it to conduct the first human test of RNA interference. These trials will use an RNAi inducing drug to target the gene that triggers the process of macular degeneration, an age-related deterioration of the retina that is the leading cause of blindness in the elderly.

Scientists believe they can 'co-opt' this mechanism to shut down any gene in the body. Some are experimenting with 'shuttle viruses' to deliver microRNA (another form of RNA that inhibits gene expression) into a cells' nucleus. But even with such a revolutionary discovery as RNAi, many years of additional trials and experiments will be needed before a safe and reliable gene therapy based upon RNAi is in widespread use.

SINGLE NUCLEOTIDE POLYMORPHISMS / The Genome Assembly Archive

Since 2001, researchers have been taking a much deeper look at nucleotides--the basic building blocks of our DNA. There are a total of five such nucleotides comprising the human genome (designated by the letters a, t, c, g, and u). Each of these nucleotides possesses several different forms--what are known as single nucleotide polymorphisms (SNPs)-- and are directly implicated in a large number of diseases and inherited traits. As a consequence, human polymorphism studies are becoming a tremendously active and important area of research today.

Nucleotide sequences (strings of letters like aatctcggat...) are known as assemblies, and can run into the tens of thousands (or sometimes only traces of a few hundred). However, despite numerous analyses of these assemblies in genome studies, they are largely unavailable to the community of genetics researchers. There are no universal rules or protocols for collecting and cataloguing these assemblies.

Researchers are promoting the Assembly Archive and hope that the availability of this resource will encourage human genome sequencers to begin depositing their assemblies into a publicly-shared resource. The archive has been developed to store both an archival record of how a particular assembly was constructed and the alignments of any set of traces to a reference genome.

The existence of an archive will accelerate the validation of many of the polymorphisms already reported. Further, many more SNPs might be discovered. An assembly archive would also allow research centers to better coordinate their efforts to close 'gaps' in nucleotide sequences. An assembly archive would permit researchers to examine and verify the raw data that underlies the DNA sequence in any sequenced genome, thus also preventing duplication of work and diminishing the likelihood of errors.

Other scientific research groups like the Micro-array Gene Expression Data Society believe that the time is right for journals to require that micro-array data be deposited in public repositories, as a condition for publication.

THE GENE OF LONGEVITY

In late 2000, two geneticists announced their discovery of a life-extending gene mutation in the common fruit fly (drosophila). The announcement made headlines around the world. The scientists were able to isolate and mutate a gene that controls the cell life of the fruit fly. Flies possessing this artificially mutated gene had dramatically increased life spans. Many of the mutated flies lived twice the normal life span as the unaltered flies. The gene was rather comically dubbed the "I'm Not Dead Yet" (INDY) gene.

These experiments raised many questions: What were the side effects of a doubled life span? Was there a similar gene in humans? If such a gene were found, and selectively mutated, would we age more slowly--or just keep getting older?

Extrapolating from fruit flies to humans, a 2003 follow up report in the journal Betterhumans suggested that mutating a single gene could increase your life span without any "significant" side effects/trade-offs. This assertion was confirmed by researchers reporting in the Proceedings of the National Academy of Sciences who found that INDY mutations caused a 'decreased slope in the mortality curve' of fruit flies, but without any marked reduction in normal biological functions and processes, such as metabolic rate, flight-velocity, and age-specific fecundity. But so far, this has only been shown to be true in fruit flies.

Of course, many scientists warn about extrapolating these experimental findings in flies to humans. So far, the INDY gene, or a similar gene, has not been isolated in humans. Further, the human genome is twice the size of a fruit fly genome, and genes tend to function in concert with other biological feedback processes. Mutating one gene could act to suppress or express another gene. But experimenting with non-humans is the first step.

So, what happens when more and more people start living dramatically longer lives? And what of our natural resources? How do we implement population control? If a drug is developed to mutate an INDY type gene in humans, it will surely be expensive and/or limited in supply. Who gets to take this drug? To our way of thinking, these are the kinds of problems we'd like the advancement of science to force upon us.






Posted 11-22-2004 12:55 AM by Doug Casey