By: Elizabeth Richardson, writing for The Science in Society Review
Viruses present persistent dangers to human health and they have caused many of the most terrifying and lethal diseases throughout history, from smallpox to influenza and HIV. There is no antibiotic equivalent for the virus: the only weapons we have against the spread of viral disease are vaccinations and drugs that work by slowing, but not preventing, their replication. However, with advances in genetics and development of sophisticated techniques that allow material on the scale of viruses to be manipulated and modified, viruses are increasingly appearing in a different light. It is becoming probable that one of the world’s largest killers may become the unlikely saviour of twenty-first century medicine.
Viruses consist of only a few elements. The genetic material at their core can be either double or single stranded RNA or DNA. The genome is usually extremely small, which enables rapid replication; influenza has 9 genes, whereas smallpox has about 150 genes. Protecting this genetic material is a protein coat, which can allow the virus to survive for several hours outside the host cell. Once a virus has infected a cell, it will hijack the replication machinery of the host and use it to produce more copies of its own genome. Lacking a metabolism of their own, they are entirely dependent on the host cell to replicate in the purest form of parasitism.
Viruses are best known as destructive and persistent killers. But what is it about a virus that makes them such a difficult pathogen to destroy? Viruses have evolved over time to do two things very well: infect cells and replicate their own genetic material inside them. Once a virus has infected a cell, it is almost impossible to kill the virus without also destroying the cell and viruses replicate extremely quickly .
Fast replication and efficient cell infection make viruses deadly pathogens in every organism, from bacteria to plants and animals. However, the exact qualities that have made viruses so deadly are those that we can exploit for our own benefit. Since the first advances were made into the study of genetics, viruses have become a common vector for introducing recombinant DNA into a target cell. As viruses require very few genes themselves to survive and replicate – relying mostly on the replication machinery of the host cell – the viral genome can be replaced with another gene sequence that can then be carried into a cell. This has enabled significant advances in the techniques used to study genetics and today many common lab techniques require the use of viral vectors.
Though the use of viruses in studying genetics is extensive and the origin of many major breakthroughs in our understanding of the genome, use of viral vectors in genetic engineering has potential applications which extend far beyond academic study. In medicine, viruses that infect bacteria, called bacteriophage, are being considered as a potential antibiotic treatment. Bacteriophage infection of a bacterial cell will usually result in lysis: once the phage’s replication cycle is complete, the bacterium will rupture and die, releasing many more phage to infect further bacteria. Combined with the high specificity of phage – most species will only infect one bacterial strain – this property could result in an efficient antibiotic treatment with few side effects on our ‘good’ bacteria. There are still some issues with the therapeutic use of phage: occasionally the cell will mutate to be resistant to the bacteriophage. Nonetheless, this is an extremely important area of study, particularly considering the increase in bacterial infections which are resistant to conventional antibiotics .
Another use for which viruses are particularly well-adapted is in the treatment of cancer, an area of medicine with potential for massive growth. There are striking similarities between the effects of viruses and carcinogenic mutations on cells, and this means than some viruses will preferentially infect cancerous cells over healthy ones . These viruses, known as oncolytic viruses, can be engineered to further increase the specificity for tumour cells . The virus may still infect healthy cells but is unable to replicate without the transcription factors associated with expression of a tumour-specific gene. Though the focus is often on finding viruses which can destroy the target cells, this is not necessarily the only use of viruses in treating cancer. It is possible to engineer a virus to express green fluorescent protein (GFP) in cancer cells . GFP causes the infected cells to glow bright green under UV light – locating and removing all the cancer cells in a patient then becomes a relatively simple task.
A clinical trial by Breitbach et al, published in Nature, shows one of the first successful applications of this technique using a modified pox, JX-594 . This virus, a relative of smallpox, had been engineered to be oncolytic and was intravenously given to patients with solid tumours. The virus was able to reduce the size of these tumours by lysing the cancerous cells, and showed remarkably little expression in adjacent tissues. This showed that the virus was able to selectively target the cancerous cells and that it was safe to inject a genetically-engineered virus into patients, a vital criteria in the selection of viruses for treatments.
Another striking example of the use of viral vectors in the treatment of cancer occurred in 2011, in a patient suffering from leukaemia. A research group at the University of Pennsylvania modified some of the patient’s own T cells – cells in the immune system usually responsible for destroying damaged cells within the body – to kill the cancer cells, causing the patient to go into remission. Ten months later, the patient is still in remission. This is a dramatic improvement on current treatments for leukaemia, which can include a full bone marrow transplant, a dangerous procedure which carries a 20% mortality risk and only a 50% chance of a cure .
Though the leukaemia trial was small, involving only three patients, the results now being observed from virotherapy were extremely promising for further development of the treatments. Ideally these results will be only the first, as more viral-based treatments are developed. The potential for medical benefit is incredible, now that we can engineer viruses from pathogens into unusual allies in the fight against disease.
- Tumpey T.M., Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus, Science , 2005:310 (5745).
- Harper, D. R., Kutter, E., 2008, Bacteriophage: Therapeutic Uses, eLS.
- Kirn, D, Martuza, R.L., & Zwiebel, J, 2001, Replication-selective virotherapy for cancer: Biological principles, risk management and future directions Nature Medicine 7, 781 – 787
- Kishimoto H, Zhao M, Hayashi K et al, 2009, In vivo internal tumour illumination by telomerase-dependent adenoviral GFP for precise surgical navigation, PNAS, 106, 14514-7
- Breitbach, C, et al, 2011, Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans
- Porter, D, Levine, B et al, 2011, Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia, N Engl J Med 2011;365:725-33
- Image credit (Creative Commons): Carl Zeiss Microscopy, 2012, Bacteriophages, Flickr.
This is an excerpt of an article that was originally published in The Science in Society Review, a sister publication of The Triple Helix Online. Elizabeth Richardson is a student at Cambridge University. Contact us to read the original article, and follow us on Facebook.