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What will enquire into brain cancer and how the

What is the Zika virus and could it be used to treat aggressive brain cancers as an alternative to therapies that are currently available?

PART I

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What is Zika virus and how does it cause Microcephaly?

Introduction

Until now, viruses have been seen as nothing but damaging, dangerous and detrimental to our health. Since their discovery in 1892 they have been perceived as a global health threat; not a remedy or possible treatment for one of the leading causes of mortality worldwide. However, recent scientific studies have shown that a specific strain, known as the zika virus, could potentially treat aggressive brain cancers such as glioblastomas. Due to the virus’s teratogenic traits, it has been linked to an increase in foetuses developing neural abnormalities as it infects and eventually kills cells vital in neurological development. Correctly reengineering it could lead to the pathogen selectively targeting cancerous stem cells in the brain that are responsible for tumours; if successful, this breakthrough could completely reform brain cancer treatment and consequently transform oncology.

The following essay will discuss a number of factors that will contribute to explaining whether the virus could be used as a medicinal drug. The initial paragraphs will explain what Zika is; it’s history, structure, pathogenesis and symptoms. Following this, the essay will explore Zika as a teratogen explaining how exactly it affects the developing brain and generates various abnormalities. Thirdly, the essay will enquire into brain cancer and how the zika virus can challenge aggressive tumours. Finally, it will conclude evaluating whether using the virus as a cure would be more successful than the already available treatments and if its production as a medicinal drug would be viable i.e. financially as well as ethically.

History

In order to come to a conclusion on whether or not the zika virus could potentially be re-engineered and used as a treatment for brain cancer, it is crucial to first understand what it actually is. The characteristics must be understood in order to decipher its pathogenesis and to come to an educated decision on whether harnessing the ability to infect the developing brain could revolutionise modern medicine. Zika’s name is inherited from where it was first isolated; the Ziika forest of Uganda in 1947. Initial identification was in the sentinel rhesus macaque monkey and the virus was first diagnosed in a human in 1952.  Despite being discovered 70 years ago; the first outbreak of the disease was only a decade ago in the Island of Yap.  Since then, there have been several countries experiencing outbreaks, which has ignited the scientific community’s interest into the pathogen.1

Taxonomy and structure

Zika is classed as a flavivirus and is, therefore, a part of the ssRNA (+) taxonomic group. The structure of the virus is important in understanding how it behaves. The genome is arranged linearly, which means that unlike circular RNA, it has a beginning and an end. This is paired with a monopartite genomic segmentation; Zika’s genetic material only consists of a single strand of positive RNA, that is very similar to our own human mRNA. This feature is essential in the replication of the virus in our body.2 The capsid has a T=pseudo3 Icosahedral-like structure, like all other flaviviruses, that consists of 12 pentameric and 20 hexametric capsomeres that surround the virus’    genetic material.3 It is then further surrounded by an E-dimer and M protein which make up the envelope and attachment protein. The structure of the virus is crucial for scientists to understand how exactly it utilises its components to cause damage to the human body. 

Infection

Figure 14: A cross-section diagram of the structure of the Zika virus.

 Infection is caused via certain arthropods, specifically mosquitoes, making Zika an arbovirus. Additionally, other methods of transmission include sexual contact and blood transfusions. The types that are involved in the infection and transmission of Zika come from the Aedes group; usually either Aedes Aegypti or Aedes Albopictus. When the Aedes mosquito lands on the skin, it pierces the outer most layer, the epidermis, using its proboscis. This then continues to pierce through skin and into the second layer, the dermis, that has its own blood supply, and consequently the nutrients that the female mosquitos need to feed on to make and mature their eggs. As the proboscis goes through the epidermal and dermal layer, the cells in both of those layers become susceptible to Zika. Due to this, permissive cells become infected; for a cell to be permissive to Zika it must have receptors that bind to the attachment protein from the virus.5 This then leads to the merging of the virus and the host cell, initiating replication.

Replication

Figure 26: A diagram illustrating how the virus infects human cells.

Once the virus has entered the host cell, it begins the replication process which is how the virus causes harm in our bodies and leads to detrimental effects on unborn babies. This is arguably the most important part of the process that scientists must understand in order to be able to observe what the virus would do if targeted at cancerous tumours. When the pathogen gets close enough to a human cell that is permissive to the virus, its attachment proteins bind to the host cell’s receptors. The binding that happens between the host cell and the virus triggers a process called ‘clathrin-mediated endocytosis’7; the virus is absorbed by the inward budding of the plasma membrane vesicles. These vesicles contain proteins with receptor sites specific to the molecules being absorbed. Once endocytosis has occurred, the virus successfully infiltrates the cell and begins to replicate. It does this by hijacking the cell’s ‘protein-making system’ and therefore leads to the synthesis of its own viral proteins. This is done successfully as the virus’ genome greatly mimics the human one, meaning that it can exploit the host’s cellular apparatus. The cell continues to produce viral proteins until it eventually dies, releasing the virus’ which then proceed to infect other cells. This process will continue as the infection spreads.2 However, regardless of the virus’ ability to destroy our cells, the effect and symptoms within adults are usually minimal, most commonly inducing mild fever and skin rash and more rarely headaches and conjunctivitis5.

Zika virus as a teratogen

The real danger of Zika is exposed when contracted by pregnant women as this can consequently lead to babies being born with congenital Zika syndrome; a unique pattern of birth defects found amongst foetuses and babies infected with Zika virus during pregnancy8.  Congenital Zika virus comes with five main features, one of which is related specifically to the brain and has inspired scientists to consider the possibility of re-engineering the virus as a medicinal drug; microcephaly. Other than this specific condition, the virus has also been linked to brain-related complications in babies; these abnormalities include brain atrophy and asymmetry, abnormally formed or absent brain structures, hydrocephalus, and neuronal migration disorders8.  There is a general consensus amongst the scientific community that Zika is responsible for these illnesses; but how? How does the virus that is practically harmless to adults lead to dangerous deformities in foetuses?

Figure 39: An animation illustrating a baby with typical head size, a baby with microcephaly and a baby with severe microcephaly.

As the foetus is inside the mother’s womb, it cannot be bitten by an infected mosquito and hence contracts the virus through transplacental infection: the virus is passed from the mother to the unborn child via the placenta. 10 This organ plays a pivotal role in the healthy growth and development of the foetus as it provides it with essential nutrients11. Once it is infected, the virus replicates in its cells, disrupting the placental barrier meaning the pathogen can easily gain access to the foetal brain. Breaching the barrier is the inceptive step to foetal demise; from here the virus has been shown to efficiently target human cortical neural progenitor cells (NPCs); these resemble stem cells as they have the ability to differentiate into other types of cells but are already more specific. The death of these infected cells leads to the reduced thickness of both NPC and neuronal layers and therefore an overall reduction in organoid size; the inevitable increase in destroyed cells accelerates the flattening of neuronal layers, eventually causing microcephaly12. It is this ability to efficiently target and destroy neuronal cells that have inspired scientists to consider the possible benefits that the virus’ pathological process could have regarding brain cancer.  

 

PART II

What is brain cancer and how is it affected by the Zika virus?

Applying a singular, universal definition to brain cancer is difficult due to its varieties and complexities, however, in short, cancer can be defined as ‘a class of diseases that are characterised by out-of-control cell growth.’13 As it is caused by rapid and unmanageable cell division, cancer is essentially a disease of mitosis; but how does a process that is vital in the growth and development of all multi-cellular organisms malfunction to become one of the leading causes of fatality worldwide?

The lethal process of cancer development begins when a cell is transformed from normal to cancerous; this occurs when the cell overrides or ignores the ‘checkpoints’ that control the rate of mitosis. Often this is due to a DNA mutation that occurs in one of the genes that code for control proteins that regulate growth, for example, the p53 gene.14 This gene is also referred to as the ‘guardian of the genome’ and it usually functions to control the cell cycle. It is therefore not particularly surprising that this gene was found to be mutated in over 50% of all human cancers. Once crucial cell cycle genes begin to behave abnormally, cancer cells start to proliferate fiercely via unchecked mitosis, eventually forming a mass of cancerous cells more commonly known as a tumour.

Not all tumours, however, are cancer; benign tumours remain at their original site and do not spread to infect other parts of the body. These are usually only fatal if they are pressing on vital organs; in regard to the brain, those located in critical areas can be life threatening. The more concerning effects of tumours are from those that are malignant; these metastatic cells spread to and infect other areas of the body through angiogenesis. Development of new blood vessels is triggered by chemical signals from tumours15, giving them access to their own oxygen and ‘food’ supply, as well as an avenue for escape to travel to various areas within the body. Metastasis is especially abundant throughout the brain; this is mainly due to the dense blood supply that is required for the organ to function effectively which is especially attractive to cancerous cells. Consequently, studies have concluded that about a quarter of all malignant cancers will spread to the brain, and metastatic tumours are more commonly present in the brain than cancers that originated there16, therefore, most cases of brain cancer are a result of this spread.

‘Brain cancer’ is a blanket term used to cover four main types of the disease: neuroblastoma, medulloblastoma, pineoblastoma and glioblastoma. All brain cancers and tumours are relatively dangerous and life-threatening, specifically when left untreated, however, the most common

form and also the one that is particularly dire and aggressive is glioblastoma (GBM). Less than 10% of patients affected with GBM survive beyond five years of diagnosis, even with continuous and regular treatment.16 These tumours arise from astrocytes17, the most numerous cell type within the central nervous system. Their function ‘varies from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow.’18 Origins of glioblastomas are usually in the cerebral cortex, although it is possible to find them located in any region within the brain or spinal cord.17

Figure 419: MRI scan comparing the initial tumour to the tumour after a month with no treatment.

GBM tumours are highly heterogeneous; their cells vary in structure and behaviour. A unique attribute that they possess is the way in which they can imitate stem cells: they are able to regenerate tumours as well as develop copies of themselves20. This quality does not exist in all cancerous cells, making glioblastoma’s especially difficult to treat. The most effective way to remove all glioblastomas from the brain, rather than constantly reducing the amount of GBM tumours, would be by targeting and destroying these cancer-causing glioma stem cells (GSCs); this is where the Zika virus’ harmful effects could potentially be utilised. Recent animal and laboratory research has suggested that there is a possibility that a modified version of the virus could be used to target and destroy glioma cells; Zika could also potentially be used in combination with conventional treatment to maximise effectiveness and efficiency21.

This breakthrough originates from the work carried out by researchers from the University of California, Cleveland clinic, Washington University school of Medicine and the University of Texas Medical Branch. The report titled ‘Zika virus has oncolytic activity against glioblastoma stem cells’ was published in the peer-reviewed Journal of Experimental Medicine22.

ZIKV strains Dakar (1984) and Brazil (2015) effect on glioblastomas

Figure 522: GSCs before (A) and after ZIKV infection (B). (E) shows Sox2 and DAPI markers whereas (F) shows a combination of ZIKV, Sox2 and DAPI.

To properly investigate the effects of the Zika virus (ZIKV) on glioblastomas, four patient-derived GSC models, representing the main transcriptional glioblastoma subtypes, were infected with an African strain (Dakar 1984) and an American strain (Brazil 2015) of the virus. Figure 5 (A) displays the GSCs at the beginning of infection whereas Figure 5 (B) shows the same cells 7 days later, after the obliteration of the spheres. This shows that ZIKV was effective in destroying GSCs that are responsible for the regeneration of glioma cells that lead to tumours.

Furthermore, preferential targeting of GSC cells by both ZIKV strains can be analysed by immunofluorescence microscopy; this is a method used to assess both the localisation and expression levels of proteins of interest23. This technique demonstrated that more than 60% of GSCs were infected by one of the ZIKV strains 48 hours after initial infection.  The amount of GSCs infected by the ZIKV strains was measured by analysing those which expressed the ‘Sox2’ GSC marker; greater than 90% of cells infected by the ZIKV strains were positive for this. This therefore shows that ZIKV potently infects GSCs, replicating within their cells at a much higher and faster rate than in any of the other cells, for example differentiated glioma cells (DGCs).  ZIKV could infect these cells but it was not anywhere near as effective at reducing proliferation rates as viewed with GSCs.

In addition to patient-derived GSC models, mice were also studied by recapitulating the relevant conditions for human brain tumour therapy to further explore the relationship between the virus and cancer.

*all the mouse stuff*

In summary, the results of this study suggest that ZIKV preferentially targets GSCs; thus, it could be hypothesised that genetically modified strains of ZIKV that optimise levels of safety could have therapeutic efficacy for adults that are infected with glioblastomas. Despite the theoretical effectiveness of the pathogen against these cells, would using ZIKV as a therapy for cancer actually be any more successful in reducing mortality in comparison to the conventional treatment available to patients now?

 

PART III

Would ZIKV be any more effective at treating brain cancer in comparison to current therapies?

1 World Health Organization. (2018). The history of Zika virus. online Available at: http://www.who.int/emergencies/zika-virus/timeline/en/

2 En.wikipedia.org. (2018). Flavivirus. online Available at: https://en.wikipedia.org/wiki/Flavivirus

3 Viralzone.expasy.org. (2018). T=pseudo3 Icosahedral Capsid Protein. online Available at: https://viralzone.expasy.org/809?outline=all_by_protein

4 Team, E. (2018). Zika Virus : Structure, Epidemiology, Pathogenesis, Symptoms, Laboratory Diagnosis and Prevention | LaboratoryInfo.com. online LaboratoryInfo.com. Available at: https://laboratoryinfo.com/zika-virus-structure-epidemiology-pathogenesis-symptoms-laboratory-diagnosis-and-prevention

5 YouTube. (2018). Zika virus – causes, outbreak, symptoms & pathology. online Available at: https://www.youtube.com/watch?v=oGNxGlltnOs

6 Science Sushi. (2018). No, GM Mosquitoes Didn’t Start The Zika Outbreak. – Science Sushi. online Available at: http://blogs.discovermagazine.com/science-sushi/2016/01/31/genetically-modified-mosquitoes-didnt-start-zika-ourbreak/

7 En.wikipedia.org. (2018). Receptor-mediated endocytosis. online Available at: https://en.wikipedia.org/wiki/Receptor-mediated_endocytosis

8 CDC. (2018). Zika Virus. online Available at: https://www.cdc.gov/zika/healtheffects/birth_defects.html

9 Cdc.gov. (2018). Congenital Zika Syndrome & Other Birth Defects  | Zika and Pregnancy | CDC. online Available at: https://www.cdc.gov/pregnancy/zika/testing-follow-up/zika-syndrome-birth-defects.html

10 Checkorphan.org. (2018). Transplacental infections — CheckOrphan. online Available at: http://www.checkorphan.org/diseases/transplacental-infections

11 Mayo Clinic. (2018). Placenta: How it works, what’s normal. online Available at: https://www.mayoclinic.org/healthy-lifestyle/pregnancy-week-by-week/in-depth/placenta/art-20044425

12 Wen, Z., Song, H. and Ming, G. (2017). How does Zika virus cause microcephaly? Genes & Development, 31(9), pp.849-861.

13 Medical News Today. (2018). Cancer: What you need to know. online Available at: https://www.medicalnewstoday.com/info/cancer-oncology

14 Biology.iupui.edu. (2018). Mitosis and Cancer. online Available at: https://www.biology.iupui.edu/biocourses/N100/2k4ch8mitosisnotes.html

15 Nishida, N., Yano, H., Nishida, T., Kamura, T. and Kojiro, M. (2006). Angiogenesis in cancer. Vascular Health and Risk Management, 2(3), pp.213-219.

16 YouTube. (2018). Why Cancers Spread to the Brain. online Available at: https://www.youtube.com/watch?v=PcSfze2v0z8

17 YouTube. (2018). What is glioblastoma? online Available at: https://www.youtube.com/watch?v=3WbZvuYKTqw

18 Blackburn, D., Sargsyan, S., Monk, P. and Shaw, P. (2009). Astrocyte function and role in motor neuron disease: A future therapeutic target? Glia, 57(12), pp.1251-1264.

19 Aboutcancer.com. (2018). MRI Picture of a Glioblastoma. online Available at: http://www.aboutcancer.com/mri_gbm.htm

20 YouTube. (2018). The Biology of Glioblastoma. online Available at: https://www.youtube.com/watch?v=b9FQvjL_7Ak

21 PubMed Health. (2018). Zika virus may be useful in treating brain tumours – National Library of Medicine – PubMed Health. online Available at: https://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2017-09-07-zika-virus-may-be-useful-in-treating-brain-tumours/

22 Zhu, Z., Gorman, M., McKenzie, L., Chai, J., Hubert, C., Prager, B., Fernandez, E., Richner, J., Zhang, R., Shan, C., Tycksen, E., Wang, X., Shi, P., Diamond, M., Rich, J. and Chheda, M. (2017). Correction: Zika virus has oncolytic activity against glioblastoma stem cells. The Journal of Experimental Medicine, 214(10), pp.3145-3145.

 

23 Rockland-inc.com. (2018). immunofluorescence microscopy. online Available at: https://rockland-inc.com/fluorescence_microscopy.aspx

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