Sonic the Hedgehog

Sonic the Hedgehog, Sleeping Beauty and Cancer of the Brain

Sleeping Beauty and Sonic the Hedgehog are among my most favorite childhood heroes. Originally conceived by Charles Perrault, Sleeping Beauty is a story about a beautiful princess called Aurora who got bewitched by a fairy, condemning her into 100 years of sleep. She only wakes up when a handsome prince kisses her. They get married and live happily ever after. A creation of Sega Games, Sonic the Hedgehog is a blue-coloured, anthropormophic character who, together with his sidekick Tails, are in perpetual conflict with Dr. Robotnick. He executes his deadly attacks by curling and forming into a ball. To use clichés, Sonic the Hedgehog takes no prisoners, gives no quarter, and shoots from the hip. It now appears that these 2 characters hold the key in the fight against cancer.Quiet.

Meduloblastoma, a childhood cancer of the brain, is one of the many cancers that are caused by transposons or jumping genes. These transposons are pieces of mobile DNA that can move from one location to another. Enzymes known as transposases are the scissors that cut these genes, allowing them to move and get sewn to other locations in a cut-and –paste manner, creating an amazing patchwork cum collage of nucleotides. This movement can cause cancer in several ways. For example, if an oncogene (a cancer-causing gene) moves close to a promoter, its expression becomes elevated and this leads to cancer. Or if a segment of a tumor suppressor gene(TSG) is cut and moved to another location. TSG is like a fuse that prevents a surge in the expressive power of genes from causing cancer. With transposition, the TSG becomes dysfunctional and is unable to effectively inhibit the formation of cancer. Transposition can also lead to frameshift and nonsense mutations which change the way genetic information is transcribed thereby leading to cancer.

Now back to Sonic the Hedgehog. During the development of the embryo, an important signaling pathway required for proper development of many organs and tissues is the Sonic Hedgehog pathway (shh). This pathway binds to a receptor called Ptc1 causing the activation of a protein called smoothened (smo) which in turn activates several Gli transcription factors involved in the regulation of downstream targets essential for proper development. Therefore, a defective Ptc1 receptor or inappropriate Shh signaling can cause pathogenicities and this has been witnessed in cancers such as the basal cell carcinoma (BCC),meduloblastoma, rhabdomyosarcoma, neurofibromatosis, and several leukemias. In summary, Sonic the Hedgehog pathway is crucial for proper development.

Researchers have developed the Sleeping Beauty (SB) system, a transposon that is used in discovery of cancer genes and as a non-viral vehicle in gene therapy. The SB system consists of a transposon and a transposase and acts like a pick-up truck with a large space for carrying genes. In gene therapy, the correct gene is loaded into the SB system. The SB system is then targeted against the DNA containing the defective gene. The transposases cut out the defective gene, allowing the correct gene to be unloaded from the pick-up and inserted in place of the defective one thereby providing therapeutic relief. This method is highly preferred over the use of retroviruses as drug carriers because it is non-homogenic, promotes integration of the DNA cargo into the target DNA, can be easily formulated into pharmacological products, and has a low contamination risk. It is also unencumbered by genome size as the SB system can carry relatively large DNA cargo.

In meduloblastoma and other cancers associated with the Sonic Hedgehog pathway, Sleeping Beauty can be used to ferry a correctly functioning Ptc1 gene to replace a defective Ptc1 gene thereby ensuring that the Shh pathway has a receptor to latch onto. Several researchers have reported success in the use of SB as a tool for producing biopharmaceuticals against hemophilia, diabetes type 1, epidermolysis bullosa, fumarylacetoacetate hydrolase deficiency, among others. In discovery of cancer genes, a phenomenon termed as "local hopping" ensures that the SB system integrates close to cancerous genes. Use of SB in cancer genes discovery enables candidate genes to be identified easily and this is associated with more accurate staging and diagnosis. It has also been shown to provide highly accurate whole genome scans.

These developments provide immense opportunities in cancer biology research and bioinformatics. Using this knowledge, in silico design will provide intelligently crafted anti-cancer molecules that are highly-targeted, concise and deadly. The current fight against cancer resembles a fight led by the Kenya Police: a lot of stray bullets, a lot of collateral damage, lots of bystander casualties, and no clear suspect. These molecules will be like NYPDA - drugs that shoot from the hip, give no quarter, and take no prisoners. All in a targeted, effective manner.Or like Sonic the Hedgehog. And this is the story that we hope to write. That Dr. Robotnick is the face of cancer and Sleeping Beauty the new Tails. That cancer is no longer a Spinning Wheel. In the end, will it be a story of beauty slays the beast, of happily ever after?

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