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A Brighter, CRISPR Vision of the Future

Its the cure to cancer. And Lou Gehrigs. And AIDS. What is it, and why hasnt it
spread like wildfire already? It is CRISPR-Cas9 technology, and it actually has spread like
wildfire, just not in spheres typically accessed by the general public (Ledford 20). The reason it
has been confined to the world of biomedical research, and not clinical trials, is because of one
buzz-word label that comes along with the technology: gene editing. Classic and contemporary
debates about gene editing ethics have impeded the technologys launch. The alarms are not
invalid: this issue of gene editing has long been pierced by thorny and undeniable ethical
questions concerning the ability to play God over the human race, control the traits of someone
yet unborn, and choose trial subjects who might die or might live for a fancy fee. Weighty issues
make many fearful of allowing the development of the technology. But heres the thing: they
make scientists fearful, too, and measures are being taken to ensure that humans dont have to
face the dangers of misusing the technology. The steps that have been taken by global
policymakers and scientists thus far to promote safe development of CRISPR-Cas9 gene editing
technology have been responsible, and with certain policy changes and research enhancements
for those same actors, humans will be able to bring about safely a medical revolution on a
celeritous timescale. A review of what has been done thus far, followed by next step
recommendations, will show that there is little reason for the general public to fear and much
reason for policymakers and scientists to act.
From the beginning, CRISPR-Cas9 has been recognized as different from other gene
editing technologies. Scientists and policymakers have taken steps that control the new potentials
it opens up. For a bit of background, CRISPR-Cas9 consists of a special protein, Cas9, which
holds on to a piece of genetic material, CRISPR RNA. Cas9 uses the RNA as a map to find a

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specific location in a cells DNA. Then, the protein cuts the DNA at that site. This can allow new
DNA (the stuff of genes) to be inserted, or it can simply cut down the middle of a bad gene and
render it harmless. This system is different than technologies seen in the past because Cas9 can
be given any map, while past proteins used, taken from viruses, could only cut at the single site
at which the virus usually cut. CRISPR-Cas9 complexes can cut out any bad gene or insert any
new gene anywhere you want it. It is cheap, very easy to use, and can be used on almost any
organism (Ledford 21). This has raised questions about how fast humans should dive into slicing
and dicing the genome, who should be used as test subjects, how to deal with the rush of new
clinical trial/experiment funding applications, and if research should be extended to germline
(embryo) editing. Each of these have been addressed responsibly.
Among the first to speak up on the question of how fast humans should launch into direct
trials with CRISPR-Cas9 was Dr. Jennifer Doudna, the original discoverer of the protein. She
was the lead author of a Science article that, according to a New York Times summary, called for
an international moratorium on the use of the technology until it is better understood (Wade).
The product of a group of highly involved scientists (henceforward the Doudna group), the
original article also recommended open forums for information sharing, continuous
conversations with the public, a research focus on the unintended effects of editing, and
especially a halt on the use of the technology for germline editing (Baltimore et. al. 37). This
paper, embodying the reaction of such a closely involved sector of the scientific community,
demonstrated a responsible start to development of CRISPR. As one Techonomy writer pointed
out, this came even before the reactions of policymakers, which, in a situation such as this, could
have confounded progress with misunderstanding/unnecessary restrictions (Salisbury).

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Therefore, the voluntary-limits stance adopted by scientists has been the best form of addressing
the question of how quickly to launch into gene editing trials.
The next major ethical question that was raised is important for when human CRISPR
trials do someday start: who will receive experimental treatment? The first human gene therapy
trials in 1990 (using old methods) were used on subjects for whom the only likely alternative was
death. They did show mild success in two very young girls who both had a genetic disorder that
killed off their own disease-fighting cells (Walters and Palmer 17-19). However, CRISPR-Cas9
makes it possible to treat almost any genetic disease in any person. This includes many that
arent immediately deadly or deadly at all when controlled with other methods (such as sicklecell and diabetes). For these diseases, should children be exposed to clinical trials? Will cures
only be available to the wealthy? Should a person be treated if viable alternatives exist? (Is gene
editing strictly a last-ditch effort?) Science and CRISPR already have responded with
satisfying answers to these questions. The perspective taken since the 1990s is that clinical trials
are carefully controlled versions of the newest life-saving capabilities, so no class of individuals
should be excluded; indeed, children should likely be some of the first to benefit (Walters and
Palmer 42). As mentioned above, CRISPR is also very cheap compared to alternatives: about
$30 per trial vs. $5000 for zinc fingers, another recent technology (Ledford 21). Though
delivery-to-cell technique has not been developed, CRISPR itself will be much more universally
accessible. As for treating when not absolutely necessary, the worldwide moratorium called by
Doudna and others automatically limits questionably invoked testing. The question of who to
treat has been innately, responsibly addressed by the genetics field and CRISPR developers.
The next challenge was how to deal with the rush of applications to the government for
clinical trial permits and funding. This, too, has been addressed responsibly this time by the

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policymakers. In a November 2015 meeting of the National Center for Toxicological Research
Science Advisory Board, Dr. Rosario of the Center for Drug Evaluation and Research (part of
the FDA) spoke to the members present about what his department is doing to help researchers
get faster feedback on their applications and ensure reviewers only receive thorough
applications. In the manuscript of the dialogue, he describes how the program JumpStart makes
one-stop shopping for researchers trying to submit proposals while filtering out
incomplete/unqualified ones from reviewers desk piles (National Center). By increasing
efficiency for both researchers and reviewers, those who regulate the rush of experiment
applications have acted conscientiously concerning this field.
The final set of upright actions concerned the question of germline editing. Germline
editing refers to changing the genes of a few-celled embryo, so that when the organism grows,
every one of its cells will have the new genes. This type of change is wrought with ethical barbs:
changing a life before ability to consent; the possibility of creating designer babies with
specified traits; the ability to define any genetic trait (ethnic characteristics, skin color, mental
handicaps, etc.) as a target for editing out. No one need fear runaway scientists and unethical
governments: responsible actions have again been taken. The very first recommendation of the
Doudna groups meeting was that germline editing in labs should be vehemently discouraged
until ethical decisions could be defined (Baltimore et. al. 37). A plethora of national governments
have already taken action: 40 have explicitly outlawed, suggested a ban for, or severely restricted
germline research of any kind (Ishii and Motoko). And in the United States, the National
Institute of Health, a very major funding source, has issued a formal refusal to fund any germline
editing projects due to unquantifiable safety issues, ethical issues presented by altering the
germline in a way that affects the next generation without their consent, and a current lack of

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compelling medical applications justifying the use of CRISPR-Cas9 in embryos (Collins).

Policy and science agree: the ethical challenges surrounding germline editing are currently
insurmountable, and no one should be permitted to invoke them before the challenges are
answered.
Thus, action so far concerning CRISPR-Cas9 has been responsible. But there is more to
be done. In order to safely develop this technology and access its benefits on a celeritous
timescale, scientists must refocus research efforts strictly on the non-treatment-oriented changes
of CRISPR editing, and policymakers must streamline funding and regulatory processes even
more.
Scientists have two essential frames in which they can address CRISPR-Cas9 research:
first, how to apply the technology to a certain disease and cure it; second, what else CRISPR is
doing. The first option is perhaps more glamorous, but the second is what is now acutely needed.
Though CRISPR can be specified to only cut at a specific sequence, DNA code is so repetitive
that there is a large chance that there are many, many sites within a genome where the sequence
and hence cutting occur. Keith Juong of Massachusetts General Hospital researches off-target
gene cutting, and his lab found that the percentage of mutations at extraneous cutting sites ranges
from 0.1 to 60% (Ledford 22). Those mutations could lead to cancer. Further, even successful
edits could have unforeseen consequences something that the Doudna group members
acknowledge. To the New York Times, Doudna group member and former president of the
California Institute of Technology David Baltimore gave this statement: I personally think we
are just not smart enough and wont be for a long time to feel comfortable about the
consequences of changing heredity, even in a single individual (Wade). When the primary
researchers state that humans now are not smart enough to understand what they could be

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unleashing, it is evident that more research about understanding the mechanisms behind CRISPR
and its side effects is vital. Therefore, scientists should turn from seeking cure applications to
focus wholly on off-target cutting and the long term effects of on-target editing.
Policymakers also have their share of work to ensure safe and timely development of this
life-saving technology. Though the FDA has taken steps to make applying for clinical trials a
more efficient process (as mentioned earlier), there remains a lot to be done. The committees in
charge of CRISPR-related approval also supervise other unrelated biotechnologies. Guidelines
and reference packets are available for researchers applying for grants/trial approval through the
FDA, but the rules remain long and confusing, the process arduous and slow (US
Department). If CRISPR-Cas9 technology has applications against AIDS, Lou Gehrigs
disease, diabetes, cancer, and many of the other most threatening human diseases, it is imperative
that its development is supported as strongly as possible. This means that the policymakers and
government should take two major actions.
First, a specially dedicated commission should be created to oversee applications solely
for CRISPR trials and grants. Instead of competing alongside other drug technologies, CRISPR
applications should have a direct pathway to approvals so that its safe development can be
expedited. This priority on CRISPR is not unreasonable; CRISPR-Cas9 has already been used
successfully to eliminate the HIV virus from infected human cells (Kaminski et. al). Second,
additional funding should be channeled toward the background research on extraneous cutting
and long-term effects mentioned above. This preferential proposal review and monetary attention
is not only merited for promotion. It is also needed to prevent the opposite of promotion:
CRISPR runs the risk of falling victim to the same policy mistakes made concerning stem cells
something that must be proactively avoided. In an analogous situation, stem cell technology was

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also feared for its potential when first discovered. Federal funding of embryonic stem cell
research was banned in 2001, with the unintended consequence that researchers widely
abandoned labs, decimating this field of valuable research (Salisbury). A similar blow to
CRISPR, either through passive mistakes like keeping funding and approvals at current rates or
active fear of its development, cannot be permitted to occur. Responsible research limits are in
place. More funding for the right research means a deeper understanding and even safer
procedures. Rather than allow a valuable field to slow in the current of viscous application
procedures and funding, a streamlined approval commission and increased funding flow will
propel safe research and results. Combined with a research focus on unknown effects rather than
cures, this will make accessible the benefits of ethical gene editing on a propitious time scale.
CRISPR-Cas9 is a medical technology so valuable that it will likely stand alongside
penicillin in the history books. As the cure for countless chronic diseases and genetic disorders,
its no wonder it has aroused such an ebullient clamor in the biomedical field. Gene technology
can be scary because of its power. But steps have been taken by both scientists and policymakers
to make sure that this ultimate gene technology is developed responsibly. With further research
focus on the unknowns, expedited trial approvals, and increased funding, the positives of this
power can soon be in human hands. These continued efforts and the new changes will require
collaborative effort not just between scientists and policymakers in one country, but around the
world. As with many international issues, this could face roadblocks trying to collaborate across
nationalist and cultural barriers. But if anything can bring the worlds people together, might it
be the incentive of eliminating many dozens of the worst human diseases? The image of the
future is fuzzy. But with continued and additional steps that responsibly develop this gene
technology, we can develop that image into a brighter, CRISPR, truly wonderful one.

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Works Cited
Baltimore, David, Paul Berg, Michael Botchan, Dana Carroll, R. Alta Charo, George Church,
Jacob E. Corn, George Q. Daley, Jennifer A. Doudna, Marsha Fenner, Henry T. Greely,
Martin Jinek, G. Steven Martin, Edward Penhoet, Jennifer Puck, Samuel H. Sternberg,
Jonathan S. Weissman, and Keith R. Yamamoto. A Prudent Path Forward for Genomic
Engineering and Germline Gene Modification. Science 348.6230 (2015): 36-38. Web.
31 March 2016.
Collins, Francis S. Statement on NIH Funding of Research Using Gene-editing Technologies in
Human Embryos. National Institute of Health. US Department of Health and Human
Services, 29 April 2015. Web. 31 March 2016.
Ishii, Tetsuya, and Motoko Araki. Table S1. Policies on Human Germline Gene Modification
for Reproduction Excluding Reproductive Cloning. 14 Aug. 2014. Web. 31 March 2016.
Microsoft Excel file.
Kaminski, Rafal, Yilan Chen, Tracy Fischer, Ellen Tedaldi, Alessandro Napoli, Yonggang
Zhang, Jonathan Karn, Wenhui Hu, and Kamel Khalil. Elimination of HIV-1 Genomes
from Human T-Lymphoid Cells by CRISPR/Cas9 Gene Editing. Scientific Reports.
Nature, 4 March 2016. Web. 4 April 2016.
Ledford, Heidi. CRISPR, the Disruptor. Nature 522 (2015): 20-24. Web. 30 March 2016.
National Center for Toxicological Research Science Advisory Board, November 4, 2015, Bldg.
12, SAB Conference Room. US Food and Drug Administration. Web. 31 March 2016.
Salisbury, Meredith. For Genome Editing, Self-Regulation Beats a Government Ban.
Techonomy. Techonomy Media Inc., 4 June 2015. Web. 29 March 2016.

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U.S. Department of Health and Human Services Food and Drug Administration Center for
Biologics Evaluation and Research. Guidance for Industry: Preclinical Assessment of
Investigational Cellular and Gene Therapy Products. US Food and Drug Administration,
2013. Web. 31 March 2016.
Wade, Nicholas. Scientists Seek Ban on Method of Editing the Human Genome. The New
York Times. The New York Times Company, 19 March 2015. Web. 31 March 2016.
Walters, Leroy and Julie Gage Palmer. The Ethics of Human Gene Therapy. New York: Oxford
University Press, 1997. Print.