By KUMAR SINGHA ROY(B.sc in Microbiology from Calcutta University and Post Graduation in Microbiology from West Bengal State University), he is our senior biology faculty, he is currently associated with many famous research institutes and has vast knowledge in the Biology & Chemistry. He has 12 years of experience.
Understanding the role of DNA in biology is arguably the single most important scientific advance of the 20th century. It provides the molecular basis of inheritance and understanding how the genetic code is translated into proteins providing a whole new insight into the workings of the human body.
In hemophilia A, which causes bleeding, mutations in the DNA of the gene that encodes a protein called Factor VIII important for normal clotting. Once the genetic basis for this deficiency was understood in the 1980s, scientists at Genentech were able to clone the normal copy of the gene and insert it into cultured cells so they could make Factor VIII, which could be purified and injected into patients with hemophilia A, effectively curing them.
The fundamental unit of inheritance is the gene, a stretch of DNA that contains the information needed to make one protein. It soon became clear that errors in the DNA sequence of a single gene caused a vast array of inherited diseases, such as cystic fibrosis and Duchene Muscular Dystrophy.
Through the latter decades of the 20th Century, advances in the methodology for sequencing DNA accelerated the pace of discovery, culminating in the publication of the first complete human genome sequence (that is, the sequence of all the DNA in a cell) at the turn of the millennium. This new molecular genetics identified literally thousands of genetic mutations that caused human diseases.
The role of DNA in biology has come to be seen as central. Reading its sequence identifies the causes of disease, and correcting any sequence errors cures the patient. Even the language of molecular biology cements this DNA-centric vision, captured in the simple phrase “DNA makes RNA makes Protein”, the Central Dogma of molecular biology. Genetic medicines, then, offer a route to a disease-free utopia, if only we can overcome remaining technical hurdles to allow us to edit the DNA at will.
But is this DNA-centric narrative accurate?
To an extent – but with some important, and often over-looked, limitations. First and foremost, this DNA-centric framework that has been so successful in uncovering the mechanisms behind so-called “rare diseases” (that is, early-onset inherited disorders caused a defect in one or two genes) does not seem to generalize very well to the later-onset degenerative diseases that affect almost all of us as we get older. The breathtaking progress towards cures for “rare diseases” is in stark contrast to the almost complete lack of progress towards treatments, let alone cures, for diseases like type 2 diabetes, autoimmune disorders, and neurodegenerative conditions such as Alzheimer’s Disease.
Proteins are made of amino acid molecules that are susceptible to change, both deliberate and accidental damage. Biologists are very familiar with deliberate changes to proteins (such as phosphorylation), but the accidental damage, though maybe just as frequent, is more or less ignored. Amino acids can become modified in a dizzying array of chemical reactions, from oxidation in the air to react with glucose to form so-called Advanced Glycation End-products (or, appropriately, AGEs – which accumulate with age).
Such protein instability remains, relative to the study of DNA, a back-water of research only because of the pervasive belief that DNA sequence lies at the top of the hierarchy. After all, if a protein becomes damaged, so what? It will be replaced in a while with a shiny new copy, freshly translated from the DNA plans. As long as the underlying DNA sequence remains healthy, damaged old proteins will just get replaced with perfect new ones.
Once the Central Dogma has been expanded into a circle, the inevitable importance of both genomic and proteomic damage in aging becomes obvious. But there is work to do, convincing a skeptical world that the promise of gene therapies, whether conventional somatic gene transfer or next-generation gene editing strategies have limits to what they can hope to achieve.
But on a more positive note, it opens up a whole new universe to discover – the domain of proteome damage. By looking for which long-lived damaged protein variants (which Professor Radman calls Hyper-Stable Danger Variants) accumulate in age-related diseases, we can uncover the true causes of diseases, like Alzheimer’s Disease and type 2 diabetes, unlocking new drug discovery efforts.
The proteome instability revolution promises even greater medical advances than those that followed the genomic revolution.
Let’s wait and watch…
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