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The Bridge between Science and Medicine

Gene therapy is sciences answer to previously

incurable medical conditions. Whether it is used to create

fluorescent zebrafish1or in medical trials it has various ethical

dilemmas.

Almost all cells in the human body contain geneswhich produce proteins; therefore gene therapy can affect

almost the whole body. Gene therapy is the alteration of a

gene, most commonly to replace a defective or absent gene,thus enabling the production of a lacking protein2. Initially, the

gene of interest is isolated and copied and a construct is

produced containing the correct expression of protein3which

is inserted into an organism. This insertion requires a

specialized transportation mechanism called vectors. These

vectors mainly consist of viruses, most commonly

adenoviruses4; (Image 113) they use their replication cycle to

introduce the altered gene.

The use of viral vectors has sparked concern

regarding the level of safety involved, and although the viral

ability to cause infections has been removed, there is a chance

that this could be re-established. Following a successfulinsertion, the corrected version will integrate into the host

genome. Gene therapy consists of two types: germ line gene

therapy3 (sperm or egg) which hasnt yet been legalized for

humans8and somatic gene therapy3(other cells). Whilst gene

therapy in somatic cells only remains in the patient treated and

are not hereditary, alterations in germ line cell are. TheParliamentary Assembly of the Council of Europe9refer to a

humans genome as having the right not to bemeddled with,

and that mans decision shouldnt be allowed to replace

natures9. A list of harmful disorders was released that would

allow gene therapy9. So what can be classified as harmful, is amole harmful because it could evolve into skin cancer?After

initial testing on mice2the first approved human gene therapy

was performed on Ashanti DeSilva in 19905. This four-year-

old girl suffered from a deficiency of the enzyme adenosine

deaminase (ADA)8, without which there is a high likelihood of

developing cancers and opportunistic infections8. With genetherapy, ADA was re-incorporated; although this was

successful it was only a temporary cure5and required repeat

therapy. Ten years later, the world of gene therapy was shaken

by the tragic death of 18 year-old Jesse Gelsinger6, who was

taking part in a clinical trial at the University of Pennsylvania.

Although other patients had died in trials, he was the first

whose death could be linked directly to the adenovirus vector

that he received6. Jesse suffered from a deficiency in ornithine

transcarbamylase (OTC)6which is an enzyme vital in breaking

down ammonia (toxic in high doses). This condition is

hereditary and usually presents after birth, leading to rapiddeath, but in Jesses case mutations caused this deficiency6 and

was therefore less severe. His death followed only days after

he began the gene therapy and not only scarred his family butalso the world of science. After an investigation from the Food

and Drug Administration (FDA), who are responsible for

granting permission to these sorts of trials, it was discovered

that the university had failed to report two other patients7with

severe side effects and previous fatalities in test trials on

monkeys7. The withholding of information cost Jesse his life

which led to the halting of all gene therapy trials for four

years7(1999-2003).The first successful genetic editing to create a

disease-resistant gene in AIDS/HIV patients has recently been

created. HIV causes AIDS which leads to a continuous

deterioration of the immune system, with 33.3 million

sufferers it is now classed as a pandemic11. The white blood

cells prone to HIV infection, called CD4+ cells12 wereextracted from an HIV patient and the CCR5 gene was

blocked12, and then returned to the patient. CCR5 is the

molecular doorway for HIV to enter cells 12. This alteration

makes it impossible for HIV to infect the CD4+ cells which,

in some patients, are replicating in typically colonised HIV

locations12.Apart from political regulations there are also

biological ones. Most gene therapy is short-lived due to the

rapid division of many of our cells, the new gene cant stick

to the cells and long-term benefits are reduced. This suggests

that multiple rounds of therapy are necessary, which is very

expensive and stressful for the patient. As Jesse Gelsinger

showed, problems with viral vectors can be fatal and lead to

severe immune responses. The innate ability of our body to

fight invaders would be detrimental and reduce the therapys

effectiveness. The new gene could also be inaccurately

integrated into a tumour suppressor gene. One clinical trialshowed that 3 out of 20 patients developed leukemia10.

Other aspects of gene therapy to consider are religious

implications and human rights yet ultimately only the future

will tell whether incurable illnesses can be cured or whether

playing God will backfire on us.

1 Alestrm, P., Liang, M. & Collas, P.Mol. Repro. & Dev.55, 8-

13 (2000).2Mulligan, R.C. Science260, 926-932 (1993).3 Anderson, W.F.J. Med.Philos.10, 275-292 (1985).4 Kay, A.M., Glorioso, J.C. & Naldini, L. Nature Med.7, 33-40

(2001).5 Salvi, M. Med., Health Care & Philos. 5, 73-77 (2002).6 Somia, N. & Verm, I.M.Nat. Gen. Rev.1, 91-99 (2000).7Greenberg, D.S."Science for Sale. The Perils, Rewards, and

Delusions of Campus Capitalism" p. 104-106 (2007).8 Munson, R. and Davis, L.H.Kennedy Instit. Eth. Jo.2, 137-158

(1992).9 Elmquist, J.P. Report of the Legal Affairs Committee [online]

(1989).10 Woods, N.B. et al,Nature 440, 1123 (2006).11 Kallings, L.O.J Intern Med263, 21843 (2008).12 Anon.,New Scientist2802, 6 (2011).13 Anon., Gene. Home Ref. [online] (2011).

Image 113: Adenoviruses are used as a vector in gene therapy andare processed into the cell as is shown above.

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References:

Alestrm, P., Liang, M. & Collas, P. (2000) Glowing zebrafish: Integration, transmission, and

expression of a single luciferase transgene promoted by noncovalent DNAnuclear transport

peptide complexes,Molecular Reproduction and Development55: 8-13

Anderson, W.F. (1985) Human Gene Therapy: Scientific and Ethical Considerations

Journal of MedicalPhilosophy10: 275-292

Anonymous, (2011) Door closes on HIV,New Scientist2802: 6

Anonymous, (2011) Genetics Home Reference[online] Available at:

http://ghr.nlm.nih.gov/handbook/illustrations/therapyvector, [Accessed 09.03.11]

Elmquist, J.P. (1989) Assembly Debate (24thsitting) - Report of the Legal Affairs Committee, [online]

Available at:

http://assembly.coe.int/Main.asp?link=/Documents/AdoptedText/ta89/EREC1100.htm,

[Accessed 12.03.11]

Greenberg, D.S. (2007) Science for Sale. The Perils, Rewards, and Delusions of Campus Capitalism,

Chicago Press, Chicago, p. 104-106.

Kallings, L.O. (2008)The first postmodern pandemic: 25 years of HIV/AIDS,Journal of International

Medicine263: 21843

Kay, A.M., Glorioso, J.C. & Naldini, L. (2001) Viral vectors for gene therapy: the art of turning infectious

agents into vehicles of therapeutics,Nature Medicine7: 33-40

Mulligan, R.C. (1993)The basic science of gene therapy, Science260:926-932

Munson, R. and Davis, L.H. (1992) Germ-Line Gene Therapy and the Medical Imperative, Kennedy

Institute of Ethics Journal2: 137-158

Salvi, M.(2002) Genetics' dreams in the post genomics era,Medicine, Health Care & Philosophy5: 73-

77

Somia, N. & Verm, I.M. (2000) Gene therapy: trials and tribulations,Nature Genetics Review1: 91-99

Woods, N.B., Bottero, V., Schmidt, M., von Kalle, C. & Verma, I.M. (2006) Gene therapy: therapeutic

gene causing lymphoma,Nature440:1123

http://assembly.coe.int/Main.asp?link=/Documents/AdoptedText/ta89/EREC1100.htmhttp://www.blackwell-synergy.com/doi/full/10.1111/j.1365-2796.2007.01910.xhttp://www.blackwell-synergy.com/doi/full/10.1111/j.1365-2796.2007.01910.xhttp://assembly.coe.int/Main.asp?link=/Documents/AdoptedText/ta89/EREC1100.htm