The Bridge between Science and Medicine

Gene therapy is sciences answer to previously

incurable medical conditions. Whether it is used to create
fluorescent zebrafish
1
or in medical trials it has various ethical
dilemmas.
Almost all cells in the human body contain genes
which 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 protein
2
. Initially, the
gene of interest is isolated and copied and a construct is
produced containing the correct expression of protein
3
which
is inserted into an organism. This insertion requires a
specialized transportation mechanism called vectors. These
vectors mainly consist of viruses, most commonly
adenoviruses
4
; (Image 1
13
) 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 successful
insertion, the corrected version will integrate into the host
genome. Gene therapy consists of two types: germ line gene
therapy
3
(sperm or egg) which hasnt yet been legalized for
humans
8
and somatic gene therapy
3
(other cells). Whilst gene
therapy in somatic cells only remains in the patient treated and
are not hereditary, alterations in germ line cell are. The
Parliamentary Assembly of the Council of Europe
9
refer to a
humans genome as having the right not to be meddled with,
and that mans decision shouldnt be allowed to replace
natures
9
. A list of harmful disorders was released that would
allow gene therapy
9
. So what can be classified as harmful, is a
mole harmful because it could evolve into skin cancer?After
initial testing on mice
2
the first approved human gene therapy
was performed on Ashanti DeSilva in 1990
5
. 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 infections
8
. With gene
therapy, ADA was re-incorporated; although this was
successful it was only a temporary cure
5
and required repeat
therapy. Ten years later, the world of gene therapy was shaken
by the tragic death of 18 year-old Jesse Gelsinger
6
, 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 received
6
. Jesse suffered from a deficiency in ornithine
transcarbamylase (OTC)
6
which is an enzyme vital in breaking
down ammonia (toxic in high doses). This condition is
hereditary and usually presents after birth, leading to rapid
death, but in Jesses case mutations caused this deficiency
6
and
was therefore less severe. His death followed only days after
he began the gene therapy and not only scarred his family but
also 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 patients
7
with
severe side effects and previous fatalities in test trials on
monkeys
7
. The withholding of information cost Jesse his life
which led to the halting of all gene therapy trials for four
years
7
(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 pandemic
11
. The white blood
cells prone to HIV infection, called CD4+ cells
12
were
extracted from an HIV patient and the CCR5 gene was
blocked
12
, 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
locations
12
.
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 trial
showed that 3 out of 20 patients developed leukemia
10
.
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).
2
Mulligan, R.C. Science 260, 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).
7
Greenberg, 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 Med 263, 21843 (2008).
12
Anon., New Scientist 2802, 6 (2011).
13
Anon., Gene. Home Ref. [online] (2011).
Image 1
13
: Adenoviruses are used as a vector in gene therapy and
are processed into the cell as is shown above.


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 Development 55: 8-13

Anderson, W.F. (1985) Human Gene Therapy: Scientific and Ethical Considerations
Journal of Medical Philosophy 10: 275-292

Anonymous, (2011) Door closes on HIV, New Scientist 2802: 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 (24
th
sitting) - 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
Medicine 263: 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 Medicine 7: 33-40

Mulligan, R.C. (1993) The basic science of gene therapy, Science 260: 926-932

Munson, R. and Davis, L.H. (1992) Germ-Line Gene Therapy and the Medical Imperative, Kennedy
Institute of Ethics Journal 2: 137-158

Salvi, M. (2002) Genetics' dreams in the post genomics era, Medicine, Health Care & Philosophy 5: 73-
77

Somia, N. & Verm, I.M. (2000) Gene therapy: trials and tribulations, Nature Genetics Review 1: 91-99

Woods, N.B., Bottero, V., Schmidt, M., von Kalle, C. & Verma, I.M. (2006) Gene therapy: therapeutic
gene causing lymphoma, Nature 440: 1123