It is 2018, only six years after the discovery of CRISPR-Cas9, and genome engineering has become a rapidly evolving, incredibly exciting field. In order to understand why CRISPR-Cas9 is considered a revolutionary technology, it is important to look at the history of genome editing.
The field of genetics was originally pioneered by Austrian scientist Gregor Mendel in the late 19th century. His work relied on the analysis of breeding patterns and spontaneous mutations in the genome. During the mid-twentieth century, many scientists demonstrated that random gene mutations could be caused by the application of intense radiation and specific types of chemical treatment, but they couldn’t control the mutations produced. In the 1970s, targeted genetic changes were first created in both yeast and mice models by taking advantage of a process known as homologous recombination. Scientists would insert a fragment of a specific gene into an organism, and during cell replication, this fragment was incorporated into the genome, but it had incredibly low efficiency (1).
Modern genome engineering methods, such as Zinc-Finger Nucleases (ZFNs), Transcription-Like Effectors (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are all engineered proteins which are capable of introducing double-stranded breaks in DNA (2). They essentially act as a pair of programmable molecular scissors, which are capable of cutting the DNA at a precise location. CRISPR is revolutionary compared to older ZFN and TALEN technology because it is able to be easily matched with tailor-made guide-RNA sequences which lead CRISPR to its target. When using TALEN and ZFN, the proteins themselves need to be reengineered for each specific target, which is enormously time-consuming, difficult, and expensive (3). CRISPR is far cheaper than alternatives, and functions in the vast majority of organisms.
Since the advent of CRISPR, billions of dollars have been invested in CRISPR-based startups, such as Editas Medicine and CRISPR therapeutics (4). These companies are working diligently to translate lab-based studies to therapeutics for patients around the world. The idea of being able to modify our genome, and possibly enhance or disrupt the function of any gene has led to much speculation about medicine’s future. Many journalists are reporting that in just two or three decades, parents will be able to choose their child’s eye color, hair color, and possibly even their intelligence (5–6). However, the biological reality starkly contrasts with these ideations.
Many of our traits, including intelligence and height, are not encoded by a single gene. They are polygenic, or monogenic, indicating that thousands of genes (in some cases, more than 93,000) impact the expression of these traits (7). Identifying each gene locus that has correlation with a specific trait and then using genome engineering to selectively modify each of these locations would be incredibly difficult, and is very unlikely to occur anytime soon (7–8). That being said, over 10,000 of the world’s most devastating genetic diseases, including Huntington’s, Sickle Cell Anemia, and Progeria, are linked to very specific mutations in the genome (7,9).
Chinese physicians have already employed CRISPR-based therapeutics to treat cancer and HIV, according to Quartz (10). Cambridge-based biotech companies have recently launched a trial using CRISPR therapy for the inherited blood disorder beta-thalassemia (11–12). However, these trials truly are just the tip of the iceberg. Many scientists believe that CRISPR technologies could be key to developing therapies for thousands of other diseases (5,9).
With these rapid advancements in genome engineering, it’s incredibly important to consider the vast ethical complications which arise from the use of these technologies. Many individuals have moral objections to germline editing or changing the genome of the embryo and future generations (13). Germline therapy would make it impossible to obtain informed consent, since the patient isn’t even born yet (14). Additionally, while few people would disagree with using gene editing to cure a devastating disease, many would object to using it for prophylactic purposes. If it were possible to reduce the chance of contracting Alzheimer’s from 5% to 1% using CRISPR, would it be ethical to administer patients this treatment? If only the rich can afford these optional therapies, are the less fortunate going to be left behind (9,15)? Balancing these key factors will be crucial in the successful deployment of genome editing tech, and scientists and ethicists around the world are grappling with these difficult questions.
In summary, CRISPR is a revolutionary technology and has the potential to improve the quality of life of billions. However, the scientific and medical community must agree on a set of moral standards which define the way gene editing therapeutics can be used in humans. In the age of CRISPR, how far is too far?
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