Oncolytic Viruses

            Though the relationship between viruses and certain lines of cancer had been well established and characterised at the beginning of the 21^st century, it was only later in this period that genetic engineering created a virus with the opposite property, that is a tool which could selectively target tumours.

            The new viruses, called oncolytic, not only because they actively encouraged lysis in cancerous cells, but because these infections melted tumourous masses away, there mechanisms of function is not so greatly divorced from oncogenic RNA viruses in that they can only really target replicating cells.

            A cancer causing RNA virus causes the damage when it’s reverse transcribed genome is integrated into the host cell’s genome, the site of integration can sometimes associate with a previously silent oncogene, and the integrated viral promoter triggers activation of this silent gene. Because of the RNA viruses’ ability to insert new genetic material, and to promote gene transcription they are apt to disrupt the functioning of the cell, and activation of certain genes initiate cells on the path to fully-fledged cancer.

            Though these types of virus were dangerous they were later exploited for these very functions, sometimes modified viral strains could be used to hunt out and destroy previously integrated viral material, but in oncolytic viruses, the original viral systems were subverted to destroy tumourous tissue, without the necessary step of integration.

            Because RNA viruses can only take effect in replicating cells, they had already an affinity for the rapidly dividing cells of a tumour. However in the healthy body there are many other cell lines that are naturally dividing, and the virus would also attack these cells, however these cells have pretty much normal signalling systems and so can behave in a variety of different ways not available to the genetically unstable cancer cells.

            Oncolytic viruses are essentially tamed and toothless, though they can infect the same cells normal RNA viruses can, their integrase function has been neutered, so that unlike the wild type virus they can not integrate into the genome, and so have no cancer causing effect (the viral particles are grown from specially transformed helper cell lines). In addition to these natural deficiencies new artificial sequences have been inserted. One is a sequence complimentary to another gene’s mRNA, generally p53, a protein that is repressed in most cancer cells, though different complementary sequences can be used to target a particular tumours weaknesses. In a normal cell p53 mRNA would bind to the neutered virus’ sequence, creating a RNA duplex which be later degraded, by an ancient viral protection system. By contrast in a tumour cell with repressed p53 function, the viral genome would not be bound by p53 mRNA and would survive in the tumour cells for the other artificial sequences to be activated.

            The viral RNA is later reverse transcribed to form a functional DNA genome which then circularises, and activation of genes within the genome can begin, initially the genes coding for stability of the genome and it’s replication, but then later other secondary sequences. These secondary sequences also contain the artificial sequences, and one of these is a kill signal, a gene whose product accumulates and causes cell death, destroying the tumourous cell and the viral genetic material.

            A slightly modified version of this program would allow the virus to replicate, and form new infectious particles that would then escape the dying cell, as the kill agent would be inserted into the late expressed viral coat genes. This later kind of virus would require only one infection, and the viral cascade would eat through tumourous tissue destroying cancer cells in its wake.

            One of the benefits of the oncolytic viral strains was that collateral damage was largely avoided, normal cells could respond to interferon b, a signalling molecule that stimulated normal viral suppression mechanisms within the cell. Most tumour cell lines lose these kinds of fine cell signalling responses and can not block the infecting viruses so readily. In addition without the regulation of p53 only the cancer cells were prone to the viruses attack, these combined differences meant that most other normally dividing tissues avoided destruction by these tailored virii, a problem which confronted chemotherapies at that time.