Gene Therapy: Nature Versus Man

Aditi Bhargava
11 min readFeb 15, 2024

With the advent of cutting-edge genome editing technologies such as CRISPR and the use of RNA moieties for modulation of cell function, it appears that we are at the brink of medical and scientific breakthrough in managing and potentially “fixing” disease-causing genetic mutations and defects. Just a few decades back, viral vector-mediated gene therapy and RNA interference (RNAi)-based methodologies were thought to be the panacea. Andrew Fire and Craig Mellow were awarded the Noble prize in Medicine in 2006 for describing a fundamental mechanism of gene regulation in their landmark paper published in Nature using RNAi in 1998. However, RNAi had been first described in 1928 for tobacco mosaic virus by S.A. Wingard. Before the term RNAi was coined, the mechanism was described as post-transcriptional gene silencing or PTGS and the role of PTGS in antiviral immunity was also described. However, discoveries made by plant biologists are seldom in the limelight or get the credit they deserve.

Generation of recombinant and non-recombinant gametes during meiosis. During gametogenesis, diploid cells (with 2 sets of chromosomes, one from the father (paternal) and one from the mother (maternal) undergo meiosis (reduction in number of chromosomes to half) to form haploid (with 1 set of chromosomes) gametes. If chromosomes fail to separate properly, the resulting daughter cell (gamete) can get both chromosomes and the second daughter cell might not get any, resulting in aneuploidy. Crossover occurs in units known as centimorgan (cM) and in linked genes.

Natural Genetic Recombination Forms The Basis of Genetic Diversity

Exchange of genetic material in nature is a unique phenomenon that is confined to the process of sexual reproduction. Even unicellular organisms (Prokaryotes) such as bacteria and yeast undergo sexual reproduction. While prokaryotes don’t have male and female gametes, they are characterized by distinct “mating types” and only different mating types within a species can exchange genetic material. In the Eukaryotes, gametogenesis results in the formation of female (eggs/ova) and male (sperm) gametes by a cellular process termed as meiosis. During a specific phase (prophase 1) of meiosis, the process of chromosomal crossover and/or genetic recombination leads to genetic variability and diversity in an individual. This basic and fundamental phenomenon forms the basis of modern-day genetic modifications performed to make transgenic model organisms for research and xenografts. Chromosomal crossovers and recombination should not be confused with random genetic mutations that can also occur in haploid cells (gametes) or in diploid somatic cells (containing two sets of chromosomes-one from the egg and the other from the sperm) at any stage of development/life. Natural recombination that occurs in the gametes is not perfect and can result in imperfect or unequal…

--

--

Aditi Bhargava

Dr. Aditi Bhargava is a molecular neuroendocrinologist with research focus on sex differences in stress biology and immunology.