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To what extent do the benefits of CRISPR/Cas 9-based
gene editing therapy outweigh the risks?
Dingquan Yu
Tutor: A, Cooper
Date of submission: 11/04/2016
Word count: 2030
UPCSE Research Project
UCL Centre for Language and International Education

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Genetic diseases are congenital disorders at genes level, which are unusually caused
by mutations on the DNA sequence in a genome. So far, scientists have established
the purpose for about 25000 genes of the human, among which 3000 have already
been proved to be linked with disease syndromes (Cox, Platt and Zhang, 2015, p.
121). Unlike epigenetic illnesses that are affected by external modifications to DNA,
genetic diseases are inheritable and the effects of this type of disease could be
influential on the entire body for the long term. Moreover, using medicines, such as
chemotherapy and antibiotics, could treat normal diseases completely whereas a
genetic illness seems to be untreatable unless the mutations in the genome are
modified directly.
Being aware of increasing threat from genetic illnesses, biochemists have been
working hard on developing a genetic editing tool, trying to find a treatment to cure
inheritable diseases. So far, the most efficient method developed is called ‘clustered
regularly inter-spaced short palindromic repeat-associated system’ (CRIPSR/Cas-
9)(Smolenski, 2015, p.35). In 2013, CRISPR/Cas-9 technology was used for the first
time, having revolutionized the biomedical field strongly since then (Savic and
Schwank, 2015, p.1). This technique stems from a bacteria enzyme system which uses
RNA molecules to recognize certain human DNA sequences. Acting as guides, these
sequences of RNA molecules will match the nuclease, the enzyme which can cut off

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DNA sequences, with the areas to be corrected in the human genome (Lanphier et al,
2015, p.411). However, CRISPR/Cas-9 not only brings a potential way to cure
genetic diseases but also a series of concerns about the possible risks caused by
experiments conducted at embryonic level. This essay will introduce the benefits and
possible risks about applying CRISPR/Cas-9 to clinical research and argue that the
benefits outweigh the risks.
One typical genetic disease is Duchene Muscular Dystrophy (DMD). DMD, a type of
muscular dystrophy, can weaken the patients’ muscular tissue thereby shortening their
life span significantly: on average DMD patients will not live until 25 (Long et al, 2014,
p.1184). A mutation of gene coding dystrophin, an essential protein making up muscle
fibres, is the main cause for DMD because the genetic error results in the lack of
dystrophin and leads to the degeneration of muscles eventually. To be specific, this
mutation is on the X chromosome so the frequency of suffering this disease is higher
among boys rather than girls: approximately 1 in 3500(ibid, 2014, p.1184). Patients
who suffer from DMD will gradually lose the ability to move and even to breathe finally.
Biomedical researchers have been working on developing possible gene therapy since
genetic pathology was discovered about three decades ago. They tried to genetically
cut off the pathogenic DNA sequence but only a few treatments made curative progress
due to the lack of genetic editing tools. Additionally, there was no efficient treatment
invented until CRISPR was applied to fix the mutation (ibid, 2014, p.1184). What is

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worse, the therapies developed by biochemists seemed to be unaffordable to the public.
For example, biologists discovered and applied an enzyme called ‘zinc finger nuclease’
to edit the genomes but this treatment would cost almost more than US$5000. CRISPR-
based operation developed recently and rapidly, in contrast, is likely to cost as little as
US$30 in total (Ledford, 2015, p.21). In other words, once the CRISPR technology can
be applied safely, widely, and inexpensively, there would be a significant decrease in
curing genetic diseases such as DMD. Some progress has been made recently. In 2014,
Long et al (2014) from Texas successfully conducted and proved the feasibility of using
CRISPR to cure DMD in mice models. In addition, Duke University succeeded in
correcting human DMD mutation, using CRISPR to delete the mutation DNA slice in
2015(Ousterout et al, 2015). Those breakthroughs have indicated a possible and
promising future about applying CRISPR to cure human genetic diseases.
Apart from the relatively lower cost and wider sources of CRISPR-based therapy,
scientists are focusing more on how efficient and safe it is. Generally, the main steps of
CRISPR editing are three. Firstly, scientists recognize the target DNA sequence. After
the reorganization, a period of RNA called ‘single guide RNA’ will connect the enzymes
with a corresponding sequence in the genome. Finally, the CRISPR is able to cut off
the mutation part of DNA sequences (Lanphier et al, 2015, p.411). As for the efficiency
and feasibility of using CRISPR to correct pathogenic genes, specific experimental data
on correcting DMD mutation are likely to prove these strengths in an optimistic way.
After conducting a correction experiment on mice models and evaluating the data they

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had produced, Long et al (2014, p.1187) found a considerably higher percentage of
dystrophin-positive fibre. In addition, they also measured the level of serum creatine
kinase (CK) which is an indicator embodying muscular leakage. The CK level of their
tested models was much lower compared with those who were not modified. Based on
these and other data, Long et al (2014, p.1187) concluded that using CRISPR to mediate
the primary genetic error causing DMD is capable but in mice rather than in humans.
Similarly, Ousterout et al (2015, p.9-10) reported the first research on deletion of whole
pathogenic exons from the human genome in order to fix the expression of dystrophin.
Ousterout et al (2015, p.9) also observed that CRISPR had mediated almost 90% of
their specimen. Furthermore, all of these researchers predict a bright future of applying
this clinical technology. Long et al (2014, p.1187) posited that although genome editing
on humans was not practical at their time, modifying target cells outside an organism
directly was a possibly optimistic method to repair muscles in DMD in the future. This
was agreed by Ousterout et al (2015, p.2) who believed CRISPR was probably reliable
and practical enough to be applied on many other dystrophin mutations.
Although recent experimental statistics might approve a safe and sustainable future of
gene editing technology, some other scientists still suggested holding cautious opinions.
They argued that there were also some potential risks to be noticed. One drawback
encountered in trials was that genetic modification could lead to or even aggravate the
disease sometimes. In a CRISPR-based therapy, if the number of modified cells were
not large enough, the patient would likely not recover and their position could even

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deteriorate (Cox, Platt and Zhang, 2015, p.125). Furthermore, inducing the
rearrangement seems comparatively inefficient respecting that the results could easily
be affected by various factors, such as the length between corresponding sites and target
DNA’s availability of CRISPR/Cas9 (Modallo et al, 2014, p.427). For instance, after
modifying the muted tumour suppressor genes in cancer cells, the competition between
edited cells and pathogenic ones seemed to reduce the beneficial outcome (Cox, Platt
and Zhang, 2015, p.125). Because scientists inject CRISPR enzymes into somatic cells
and the combination among these enzymes and DNA sequences is random, there could
be some unforeseen disease-linked mutations generated. Maddalo et al (2014, p.423)
reported the possibility of inducing a carcinogenic mutation by CRISPR/Cas 9 in mice
models. After the experimental specimen was infected by a virus that contains CRISPR
components, these enzymes unpredictably redesigned mice genes and created human
lung cancer cells within the mice body. This discovery indicated the likelihood of
inductive unwanted mutations in human patients in consideration of that mice share
about 97.5% working DNA with humans (Coghlan, 2002). The high similarity between
human genes and mice’s might be a potential reason for the existence of human lung
cancer cells in mice. In other words, based on the report, mice pathogenic cells might
also be capable of being induced in human bodies if CRISPR were injected without
precise control over it. Apart from the potential risk of reversing somatic genes into
pathogenic ones, researchers also worried about the existence of unpredictable results
which would be inherited by a further generation at a rapid speed. Ledford (2015, p.24)
illustrated how an unwanted mutation of genome affects an organism’s offspring.

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Compared with natural mutations’ inheritance, CRISPR-based editions seem to be far
more influential through population. The graph created by Ledford (2015,p.24) showed
that almost 100% offspring contain the edited genes after three generation while
standard mutation will only affect about 1/8 of the total species. In other words,
CRISPR could significantly increase the frequence of modified genes and spread them
through future generations irretrievably. Moreover, these mutations can be not only
pathogenic but also carcinogenic so that even an alternation occurring with a low
frequency could probably result in an extraordinary acceleration of cell growth and then
induce the spread of cancer (Ledford, 2015, cited in Smolenski, 2015, p.37). Similarly,
another research conducted by Chinese biochemists came across a series of severe
health problems commonly occurring among their specimens’ generations and they
tended to conclude that these issues were on account of random results caused by
CRISPR-based editions(Smolenski, 2015, p.37).
Besides scientific arguments on the safety of CRISPR’s possible applications in the
future, bioethicists also debated on potential ethical perils generated by genetic
therapy. Given CRISPR’s inexpensiveness and adequacy in the nature and its capacity
of being exploited from bacteria easily, this technology would be popular among
biotechnology companies if it were valid and acceptable. However, the convenience
would lead to the abuse of using as well. On account of this, some researchers warned
about non-therapeutic usage in the future, such as redesignining babies’ eyes in order
to meet parent’s satisfaction (Cyranoski, 2015, p.272). Furthermore, if this technique

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was in the charge of certain groups of people and applied to selfish aims, such as gene
enhancements and genetic tests before recruitments, another type of discrimination
could be generated and social contradictions would likely be stimulated. Apart from
the possibility of misusing CRISPR, informed constants required by targets tested
could become a problematic issue if human embryos were chosen as targets in gene
editing experiments. Normally, scientists should inform and assure their subjects are
fully acknowledged of the hidden risks and benefits in the research in which they
participate (Smolenski, 2015, p.35-36). However, when it comes to human embryo
modification, who is suitable to be defined as a participant deserving informed
constants seems to be controversial. Smolenski (2015, p.36) opposed treating human
embryos as subjects used in experiments since a fetus was not capable of developing
personality and it could not express whether it was willing to participate in such a
research or not. In addition, such research at embryonic level needs a long distance to
measure the results, presuming that participants have allowed scientists to conduct
trials on them. Therefore, carrying out this type of experiments should be under strict
supervision and administration. There have been several cases where society
cooperated with science attempted to break barriers in front of gene editing but also
set up control over it. For example, on Febuary 1st , 2015, the UK’s Human
Fertilisation and Embryology Authority (HFEA) issued the green light to edit human
genome after a group of researchers and patients decided to advocate this type of
experiments(Park, 2015, p.5) .

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In conclusion, this essay has argued that the most direct treatment for genetic disease
seems to be editing the disease-relevant variations. Among genetic editing tools
invented so far, CRISPR /Cas-9 is likely to be the best choice although this new
technology can still generate potential risks not only to the scientific research but also
to the human society. However, with the development of clinical technique and the
increasing knowledge of the mechanism of how to edit genes efficiently, unwanted
mutations are highly likely to be diminished in the future thereby improving the
efficiency of this type of therapy. On the other hand, bioethicists have already alerted
to the public of how powerful this therapeutic genome editing could be, working on
regulations and management of this certain areas. Therefore, the efforts from both
scientists and managers will probably help humans undergo CRISPR/Cas-9 more
safely and ethically. Exploring a new technology in a poorly understood area might
need expenditure or sacrifaces but considering that medical research skills are more
developed than before, these potential dangers and threats would probably be
overcome more quickly. The whole society should have patience on this method and
be ready to welcome the coming of a new age.

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Reflective component
One reason why I chose CRISPR/Cas-9 as my topic is that I am enthusiastic about
modern genetics and biochemistry. This field is where I can find that even a tiny
cause is capable of resulting in an inevitable and dramatic effect. What’s more, due
to a rapid development in biochemistry, genetic editing has become a science fact
ratherthan ascience fiction. The coming new ageofgenetics is anothermotivation
and I chose this field as my whole career.
During researching all kinds of academic sources, I realised that there were not
only huge benefits which could be given by CRISPR but also possible catastrophes
if this powerful technique was out of control. Moreover, there were many pioneers
testing and debating on CRISPR. Therefore, I decided to discuss both negative and
positive aspects of applying gene editing in the future. When I was searching for
further academic resources, I found many articles which were enjoying high
scientific reputationsbut theyweretoo hardforthepublic to readandunderstand.
Consequently, it was a little difficult to paraphrase or summarize those ideas and
arguments but I then started rereading those sources more than once and finally I
could retold the contents with my own words. Therefore, I could handle these
obstacles when I began to write.
I am confident about self-control and being automatic so that I managed my time
well even though this project was hard and taken a large part of my final score. I

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wrote whenever I was free and wherever I was. Therefore, my first draft was
finished before reading week. During the reading week, I spent plenty of time
rereading my draft as well as sources and improving some parts of it. However, I
still find it hard for me to synthesise sources. In addition, explaining some
academic terms also became an obstacle because I was not good at summarizing.
This experience helped me gain skills about searching for certain academic
sources efficiently and accurately. Besides, I also learnt about knowledge of gene
editing’s benefits and drawbacks, which would help me study better in further
education.

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References
Coghlan, A., (2002) Just 2.5% DNA turns mice into men. Available at:
https://www.newscientist.com/article/dn2352-just-2-5-of-dna-turns-mice-into-men/
(Accessed: 10 April 2016).
Cox, D.B.T., Platt, R.J. and Zhang, F., (2015) ‘Therapeutic genome editing: prospects
and challenges’ Nature medicine, 21(2), pp.121-131.
Cyranoski, D., (2015) ‘Ethics of embryo editing divides scientists’ Nature, 519(7543),
pp.272-272.
Lanphier, E., Urnov, F., Haecker, S.E., Werner, M. and Smolenski, J., (2015) ‘Don't
edit the human germ line’ Nature, 519, pp.410-411.
Ledford, H., (2015). ‘CRISPR, the disruptor’ Nature, 522(7554), pp.20.
Long, C., McAnally, J.R., Shelton, J.M., Mireault, A.A., Bassel-Duby, R. and Olson,
E.N., (2014) ‘Prevention of muscular dystrophy in mice by CRISPR/Cas9–mediated
editing of germline DNA’ Science, 345(6201), pp.1184-1188.
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Ogrodowski, P., Crippa, A., Rekhtman, N., de Stanchina, E. and Lowe, S.W., (2014)
‘In vivo engineering of oncogenic chromosomal rearrangements with the
CRISPR/Cas9 system’ Nature, 516(7531), pp.423-427.
Ousterout, D.G., Kabadi, A.M., Thakore, P.I., Majoros, W.H., Reddy, T.E. and
Gersbach, C.A., (2015) ‘Multiplex CRISPR/Cas9-based genome editing for
correction of dystrophin mutations that cause Duchenne muscular dystrophy’ Nature
communications, 6.
Park,A., (2015) ‘U.K. Approves First Studies ofNew Gene Editing Technique CRISPRon
Human Embryos’ Time, February,2016.
Savić, N. and Schwank, G., (2016). ‘Advances in therapeutic CRISPR/Cas9 genome
editing’ Translational Research, 168, pp.15-21.
Smolenski, J., (2015). ‘CRISPR/Cas9 and Germline Modification: New Difficulties in
Obtaining Informed Consent’ The American Journal of Bioethics, 15(12), pp.35-37.