Ever Imagined Becoming the Hulk?


At some point, every young boy and at least a few girls might have dreamt of becoming the marvel comic superhuman—the Hulk. For those unfamiliar, the Hulk is a green-skinned, muscular, and ferocious fictional creature (at least for now) who is an alter ego of Dr. Bruce Banner (a physicist). During an experiment, Dr. Banner exposes himself to gamma rays, causing a periodic transformation to Hulk, triggered whenever he incurred a heart rate over 200 bpm.

Could we achieve this sci-fi depiction in reality? Well, it’s certainly less likely in the near future. Could humans resist the ill aftermath of gamma-ray overexposure? Nope! Beyond 5 G-rays of radiation, our DNA disintegrates into Double-Stranded Breaks, leading to tissue damage, cancer, and/or death. Is there any known organism that can withstand intense gamma rays? Bingo! Deinococcus radiodurans is a gamma-resistant “supernatural” bacteria that can resist 6,000 Grays of ionizing radiation and is listed in the Guinness Records as the world’s toughest bacterium. This bacterial Hulk was discovered in 1956 during experiments to determine whether high doses of gamma radiation could sterilize canned meat. The meat subsequently spoiled, and D. radiodurans was isolated.

D. radiodurans possesses an exceptional DNA repair mechanism, regulated by its recombinase A (recA, eukaryotic analogue-RAD51) gene. Upon damage, the single-stranded DNA fragments trigger a recA upregulation, and the RecA protein synthesized initiates a cascade of responses to restore the genomic integrity employing homologous recombination.

Figure 1. Tetrad Structure of D. radiodurans

What confers this highly efficient repertoire of restoration to D. radiodurans, and how could we incorporate it into the human genome? It would seem appropriate to replace the human recombinase (RAD51) gene with deinococcus recA through molecular cloning and gene replacement therapies. Could we directly clone recA (~4.5 kbp) into the human genome? Only if it were that easy! Among the many limitations, present cloning strategies are effective only when used for smaller inserts and vectors. 

Instead, studies have shown that an upstream regulatory sequence (a ~450 bp region) located near the promoter of deinococcus recA plays a crucial role in recA expression as it homes Guanine-quadruplexes (G rich secondary DNA conformation). These single-stranded coiled G4 motifs reside in the recA coding strand (rendering a more accessible template strand to polymerase recognition and binding), thereby indicating a role in the enhanced and efficient upregulation of recA protein traffic at the sites of gamma mediated DNA damage. This observation was corroborated by blocking G4 dynamics with stabilizing drugs (N-Methyl Mesoporphyrin) which caused a loss of radioresistance in D. radiodurans.

Fig 2: Structure and Folding patterns of Guanine Quadruplex: G-quadruplexes contribute to DNA replication, transcription, and translation, which significantly contributes to gene expression and genome stability. Contrary to the trivial Watson-Crick base-pairing, the G-quartets are bonded by Hoogsteen hydrogen bonds to give the structural motif characterized by four-strand helical structures with the tetrads stacked one upon the other.

Breakthroughs in molecular biology would allow scientists to develop a preliminary recombinant system wherein the recA upstream sequence is directly introduced into skeletal muscle cells via viral/plasmid-based vectors and regulate the human rad51 promoter activity, and they soon could be able to determine the change in DNA repair efficiency upon gamma radiation. If we observe a significant recovery in DNA integrity, we could then employ focussed-radiation exposure to study its implications on muscle growth factors and associated regulatory genes. 

Limitations, however, can be put forth as challenges that need to be overcome in implementing this. Gamma rays being highly ionizing may create a ROS overload within cells and tissues, leading to discrepancies in other cellular mechanisms. Also, current gene therapy approaches fail in eliciting efficient incorporation of the desired DNA into the host chromosomes and ensuring effective host regulation.

At last, IF all is accomplished… who knows, the Gen Alpha may witness the sight of a real hulk someday.

Reference (Apr-21-A1)

About the Author
Straight out of an undergraduate program in Biotechnology, I’m currently working as a BD Manager at an EdTech startup and looking forward to joining a university as a Masters of Biotechnology student with a dash of Business/Management studies.

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