How to tame your virus?

All of us rightly dread virus to the extent that fear is used synonymously with virus! All of us dread cancers too, again to the extent that celebrities of likes of Angelina Jolie have endorsed amputation of organs before they turn into life threat. All of us dread many more things too. Bingo, why not let virus fight cancer so that we can rest little more peacefully in this dreaded world. So next few minutes (in case you chose to read this through) would take you to the journey of tamed virus trained to kill cancer cells.

Virus themselves are minimum genetic material packaged in a way to allow entry in to specific host cell of body, hijack the host’s genetic machinery and produce progenies till they end up depleting the host’s resources. To do this, they insert their own genetic material amidst the host’s genetic material very efficiently. Due to the similarity in chemical nature of genetic material, the host‘s machinery doesn’t recognize it as foreign and starts synthesizing whatever protein it codes for. So the scientists have started utilizing this similarity of genetic material between humans and viruses. Many scientists now have tried to engineer viral genetic material so that they can carry genes of interest inside host cells and put it amidst the host’s genome (i.e., organisation of genes inside host cell). Viruses utilized for such experiments fall into category of ship of Theseus paradox, where they are not actually themselves but yet they are viruses.

Innovative outlook in this field has lead researchers to pinpoint a particular class of viruses called lentiviruses. Human Immuno-deficiency Virus, which causes Acquired Immuno Deficiency (AIDS), is one example of this class of virus. Yeah! Virus as dreadful as HIV can be tamed too with the tools of genetic engineering. They are endowed with qualities which can turn them into very efficient vehicles to carry our gene of interest to desired cells of the body. Their foremost quality includes their ability to deliver genetic cargo inside a core compartment of cell, i.e., the nucleus, where most of our genetic material (DNA) lies.[1] Here the cargo will be dissembled and viral DNA or engineered DNA can be integrated with host DNA, leading to long-term gene expression from this DNA too. Another problem posed by HIV-based gene vehicles is that HIV can infect a subset of cells inside human body. Scientists have tried to resolve this problem by manipulating the mechanism of its attachment to the host cell. They imparted HIV with a modified envelope from another virus called Vesicular Stomatitis Virus, which can help it attach with a gamut of hosts.[2] If you are raising an eyebrow over how safe they are, scientists have already addressed this. These viruses are rendered harmless by substituting the genes they need to replicate themselves by those genes which we need to insert. So defective, yet so useful.

Now what could these genes be and what should those hosts be? Well, genes could be anyone within cells packaging limit (which is continuously being expanded by expanding researches), which are dysregulated causing abnormal growth of human cells resulting in CANCER e.g., BRCA or P53… the list and possibilities are endless. This abnormal growth or CANCER survives inside body largely because, even though being a burden, they are not recognized by the “soldier” T cells of body. These soldier T cells can otherwise recognize harmful intruders which should be cleared off the body. So coming back to the question “who these hosts could be?” Answer is “T cells,” particularly those subset which are bestowed with the ability to chop the cells which they identify as potential hazard to body like outgrown cancer cells. This subset is called Cytotoxic T lymphocytes (CTLs). So those genes coding for receptors which can identify cancer flags called tumor associated antigens (TAA) specifically can be put into virus. Such viruses are docile because their own genes are made defective to have any deleterious effect on the host or spread their progenies. Nonetheless, they effectively take genes to T cells and modify them to identify cancer cells.[3] Being soldiers, they know what to do with what is increasingly becoming the perpetual enemy of life. Modified CTLs can thus exterminate CANCER cells effectively.

Although genocide caused by mutant virus in Will Smith’s star Hollywood flick “I am the Legend” was completely fictitious, the journey of tamed virus projected in this prose is not completely fictitious. Several clinical trials have shown therapeutic efficacy and is being called cancer immune therapy because ultimately its enhancement of immunity to treat cancer which is getting cured using virus. The first successful gene therapy clinical trial was carried out in 2000. 11 kids were successfully treated for Severe Combined Immuno Deficiency or lack of optimum immune power.[4] Alas, a significant number of these kids developed a kind of blood cancer due to its unprecedented effect on other genes.

Over the years, technology has come a long way to direct the effect of inserted genes in the desired way. So the past few years have seen efficient combat of skin cancer,[5] blood cancer,[6] intestinal cancer,[7] brain tumors, [8] etc. achieved using virus as vehicles for gene delivery. The success of each of these gene therapies was attributed to stable, targeted and efficient introduction of therapeutic genes or silencing of disease causing genes. Numerous other methodologies, like targeting virus directly to cancer cells, are also progressing with the similar aim. Priorities of biotech sector and medical sciences still remain to find novel and more specific therapies as cancer is a significant health burden even in developed countries. One of the major advancements which near future should see is cut down on cost in application of this biotechnology boon and wide scale application feasibility. Throughout the world, researchers have ignored the warnings of impossibilities and jeopardized their own biosafety to indulge into world of virus to tame them. It will not be an exaggeration to envisage a world where we will have a choice of virus packed with choice of therapeutic genes packed around them.b1

 

References

  1. Bukrinsky MI, Haggerty SA, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis PF, Goldfarb D, Emerman M, Stevenson M., A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells., Nature 365, p. 666–669, 1993.
  2. Yee JK, Friedmann T, Burns JC, Generation of high-titer pseudotyped retroviral vectors with very broad host range.., Methods Cell Biol. 43, p. 99–112., 1994.
  3. Liechtenstein T, Perez-Janices N, Escors D, Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications, Cancers (Basel) 5(3), p. 815–837, 2013.
  4. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, et al, Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease, Science 288, p. 669–672, 2000.
  5. Reference not found.
  6. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH., T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia., Sci. Transl. Med. 3, p. 95ra73, 2011.
  7. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM, et al., T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis., Mol. Ther. 19, p. 620–626, 2011.
  8. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, et al., Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma., Nat. Med. 14, p. 1264–1270, 2008.

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