Leela was celebrating her third birthday but there was an uneasy calm surrounding the atmosphere. Her well to do parents were anxious and unhappy because their first born girl child was not gaining on her motor mile stones normally such as turning on bed ,neck holding ,ventral suspension and using both hands at four months , sit with support at six months or trying to stand with support at 9 to 12 months , as most of her cousins had done before her ! Leela was a floppy child . Her muscles lacked normal tone and the child doctor had suspected her to be suffering from SMA (Spinal Muscular Atrophy ) which was later proven by muscle biopsy and EMG(Electromyography)  etc . SMA  is seen in all age groups with different presentations where motor neurons do not grow due to the non functioning genes which fail to produce motor neuron cells which connects muscles .

This is the diagnosis which was until  late last year 2020 , had been a warrant for life long disability and frequently premature death. Thanks to the path breaking research in the field of genetics called ‘Gene silencing ‘ we have a cure for many such incurable genetic diseases .

Also some of the basic questions such as how plants and animals fight attacking viruses and other microorganisms which keep targeting them all the time ?

How cancer cells are generated within the body and keep getting eliminated almost  constantly ?

These are some of the fundamental issues which find answer by understanding the phenomenon of gene regulation by a complex process called GENE SILENCING about which scientists have been working on for many years now . However It  got the breakthrough in this field worth a Nobel prize in 2006 in physiology or medicine for two American scientists,Dr Andrew Fire , professor of pathology and genetics at Stanford university and Dr Craig Mello , professor of molecular medicine at Massachusetts.

No other field of science has been as fascinating and revealing as the science of Genetics .

Gregor Mendal is generally considered father of modern genetics who in the later half of nineteenth century, developed a mathematical model of inheritance which gave shape to ‘population genetics ‘ and helped explain evolution . But the real molecular genetics came later when Dr Thomas Hunt Morgen showed that genes reside on specific chromosomes present within the nucleus of the cells , for which Dr Morgen was also awarded Nobel Prize way back in 1933 .

Human body consists of approximately one lac billion cells. Each cell has a nucleus in the centre containing chromosomes (forty six of them in Human) and cytoplasm at it’s periphery . Nucleus contains chromosomes which govern all the characteristics of human form through it’s elaborate mechanism of genetic expression . Each chromosome consists of around thirty thousand genes which are primarily made up of DNA - (deoxyribonucleic acid ) discovered in 1944 . The double helical structure of DNA was discovered by Sir Crick Watson and Dr Wilkins for which they got the Nobel prize in physiology or medicine in the year 1953  . India born scientist Dr Har Govind Khorana from USA , shared Nobel Prize with two other American scientists , Marshal Nirenberg and Robert Holley for the discovery of genetic code and it’s function in protein synthesis in 1968 .

There are several types of cells. All cells carry all the genes in each cell . Depending on the nature and function of the cell types, only a select genes are activated by the presence of certain proteins known as transcription factors specific for the tissue types . For example Nerve cells will have entirely a different sets of active genes than what a muscle cells have .  When genes are activated , genetic informations present in the DNA , is copied by the mRNA and appropriate proteins  are made in the endo plasmic reticulum present within the cytoplasm of the given cells.

Some times faulty or mutated genes if present on the chromosomes , get activated and produce disease states such as cancer or various metabolic diseases . They harm the organisms through proteins generated by faulty or mutated genes. Nature controls  and corrects such occurrences by the process called “Gene Silencing”

In the year 1998 , a paper was published in famous science journal ‘Nature ‘ describing the role of double stranded RNA ( ds RNA) also generated naturally in the body system which works like a regulatory molecule for the crucial mRNA production by faulty genes .

The experiment which really launched the science of RNA interference ( RNA i ) by ds RNA to the scientific community was equally interesting

A tiny nematode (roundworm) C. elegans , one by tenth of a centimetre long , has the distinction of unfolding the nature’s mystery in many experiments in the past  due to it’s simplicity .The same nematode helped unravel the process of gene silencing in the laboratory.

It was found that If the  genes  in the embryo of the above nematode are active , it takes up the stain of active genes and starts glowing . Double stranded RNAs as mentioned above have two strands , Sense and Antisense . When antisense and sense strands of RNA  were injected one by one , the staining of genes was less intense but when both the strands of  double stranded RNA ( sense plus antisense strands of RNA ) were injected simultaneously the staining disappeared entirely . This suggested inactivation or elimination of the genes leading to “gene silencing “ by ds RNA .

Dr Andrew Fire and  Dr Craig Mello opened altogether a new research field of RNA interference which is ultimately a variety of antisense mechanism that results in mRNA being broken down and eliminated. The corresponding gene is thus silenced and can not form the protein which mRNA encodes. Such RNA interference mechanism leading to gene silencing is known to occur in all organisms including plants with proper nucleus. It plays an important role in switching off genes during an organism’s  natural development .

Double stranded RNA ( ds RNA ) initially binds to a protein complex ‘Dicer’ - an endo ribonuclease , which cleaves ds RNA into smaller fragments. These fragments bind to yet another protein complex, RISC ( RNA - induced silencing complex ). One of the RNA strand is thus eliminated while the other serves as search probe and links it to mRNA molecule destined to form the designated protein . This is the molecular part of the phenomena behind gene silencing .

Now that the synthesis of double stranded RNA can be done  synthetically in a laboratory by recombinant technology , the discovery of Gene silencing by RNA interference has raised hopes to provide effective inroads into the treatment for difficult to treat diseases such as cancer, metabolic diseases ,cardiovascular diseases ,infective diseases etc  .

Recently the role of RNA interference technology has been found to be very promising in controlling the SARS COV 2 virus multiplication as well as creation of vaccine against Covid 19.

The Author is former Professor and Head, Medicine, RIMS Jharkhand.