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Gene Scissors: Evolving Double-Edged Sword

As the Fourth Industrial Revolution is rising, it is genome scissors that are strongly intriguing the field of biotechnology. After the appearance of CRISPR scissors, the genome scissor industry is facing a rapid development. Genome scissors are utilized in many areas including disease treatment and research of animals and plants. In addition, as genome-based custom medical care develops, the demand for CRISPR is expected to increase sharply. The Sungkyun Times (SKT) now introduces the definition and history of genome scissors, the latest technology CRISPR and the entangled problems associated to arouse interest about genome scissors.

Appearance of Gene Scissors
What are gene scissors?
Gene scissors are a type of genetic manipulation technology that recognizes and cleaves a problematic nucleotide sequence in a genome. Simply put, when a piece of clothing is torn, it cuts off the torn section and turns it into new looking cloth. It is expected to be a great help for fields that have difficulties in pioneering new innovations such as gene therapy. It is also likely to improve plant and animal varieties and Genetically Modified Organisms (GMOs). Recognized for its potential, it was selected as Innovative Technology of the Year by British magazine Nature. The start dates back to the 1970s when restriction enzymes were discovered. The restriction enzymes, discovered by Werner Arber, have the ability to recognize and cleave specific base sequences of DNA. Using the restriction enzymes, people were able to establish first-generation gene manipulation techniques such as the Polymerase Chain Reaction (PCR). Restriction enzymes, however, had limited accuracy. The restriction enzyme recognizes a base sequence of six lengths. Considering that the human nucleotide sequence is 3.2 billion long, recognizing six nucleotide sequences was not enough to cut the desired region exactly.

Early Gene Scissors
To cut the wanted genes exactly, people need restriction enzymes that can recognize sequences of about 18 bases. In nature, however, this cannot be found. Therefore, it must be made artificially, and this is how the first-generation gene scissors, the Zinc Finger Nuclease (ZFN), appeared. In African clawed frogs, researchers found proteins that combine and attach to DNA like a hand covering an object. As a result of the manipulation to recognize the nucleotide sequence, one protein could recognize three nucleotide sequences. Six proteins were attached to recognize 18 nucleotide sequences, and the function of the restriction enzyme was added to create the first gene scissors. ZFN, however, is close to capturing DNA by force rather than binding to DNA. Therefore, there was often a result of binding to the wrong gene, not the target gene. If the scissors cut off unwanted parts, organisms may have a bigger anomaly in life. To solve the problem, researchers looked at Transcription Activator- Like Effector (TALE) protein, a protein found in the bacterium Xanthomonas Campestris. Unlike ZFN, TALE combines to DNA naturally. Consequently, the accuracy to the target was much higher than ZFN. Using TALE, researchers created the second-generation gene scissors, TALEN. Nevertheless, gene scissors were still only able to recognize only one kind of information. Thus, to cut many kinds of information, scissors have had to be made respectively that target the base sequence of each set of information. The practicality was low, and this needed too much time and money.

xenbase.org/ TALEN and ZFN. TALEN combines more naturally than ZFN.

Development of Gene Scissors
The Emergence of Third Generation Gene Scissors
CRISPR is an abbreviation of Clustered Regularly Interspaced Short Palindromic Repeat. Its function was discovered by Danish company Danisco in 2007 and its action process was clarified by professor Jenifer Anne Daudna in 2012. It was a method of eradication which the bacteria use against the virus that invades cells. The process is done in three steps.

1. Some of the DNA coming from the outside is stored in the CRISPR part.
2. The DNA stored in the CRISPR is copied, and the copy is combined with the protein Cas9 to generate gene scissors.
3. The formed gene scissors bind to the DNA and correctly truncate the base sequence that matches the copy.

cambridge.org/ The Action of CRISPR

Advantages
Even though problems remained unsolved, CRISPR scissors have dramatically solved the problems of previous generation gene scissors. Firstly, they are cost effective. In CRISPR scissors, unlike previous gene scissors, duplicated DNA serves as scouter detecting invaders. Changing only the DNA that binds to Cas9 can make genetic scissors of different properties. It is easy to make, and the price is cheap. While ZFN or TALEN can cost $5,000, CRISPR scissors cost $30 for the same work. Secondly, they are more economical in terms of time spent. The research using existing gene scissors was almost impossible without stem cells. Even if stem cells are present, they have complex processes that can take months or years. Using CRISPR scissors, however, does not require stem cells and dramatically reduces research time. A typical example of the reduction can be found in the case of manipulating the mouse’s genes. In the conventional method, breeding was carried out over three generations to obtain manipulated genes. Then a desired sample was obtained. It takes about a year, and if there are failure factors in the middle, it takes more time. With CRISPR scissors, researchers do not have to crossbreed and can get results in six months. Moreover, accuracy has become even higher. It can recognize 21 nucleotide sequences and the probability of error converges to zero. It is safe to say that there is no error.

Problems to Be Solved
Patent Disputes
Genetic scissors are considered to be worth billions, so efforts to preoccupy related patents are also fierce. The result of judgement on patents, however, has been diverging, and it has become an obstacle to the gene scissors industry. A typical example is the dispute between UC Berkeley and Massachusetts Institute of Technology(MIT). UC Berkeley applied for a patent for CRISPR scissors in the United States(US) a few months earlier than MIT. Nevertheless, the Patent Trial and Appeal Board(PTAB) granted patent rights to MIT. Berkeley disagreed and appealed to the federal appellate court. In Europe, however, UC Berkeley gets a patent. The European Patent Office granted patent rights to UC Berkeley and its affiliated company, CRISPR Therapeutics. As UC Berkeley plans to extend its patent to China and Japan, the disputes are expected to continue. If both patents go in the direction of being recognized as they are now, patent fees must be paid to both sides when using genetic scissors. If high patent fees are paid, the price of gene scissors will increase, and commercialization will be delayed accordingly.

Ethical Issues
Genetic scissors can be used to treat hereditary diseases. They can, however, also be a form of eugenics, such as injecting superior genes and creating custom babies. Since 2015, China has attempted to genetically correct human embryos using genetic scissors. The US also corrected human embryonic genes in July. Bioethics groups oppose the commercialization of gene scissors, citing reasons like custom babies. Scientists, however, argue that people have no choice but to solve incurable diseases such as hereditary diseases. In addition, the patients suffering from genetic diseases also support the claims of scientists. In order to solve the problem, it is necessary to make flexible regulations by collecting opinions from both sides.

pazienti.it/ Editing Human Embryonic Gene

Genetic scissors can save lives like the hands of God. The gene scissor market is growing at a rapid rate of 36.2%, and it will expand to more than _ve times its current size by 2022. The future will pay attention to whether human beings can overcome the problems they are facing now and wisely utilize genetic scissors.

안광제  rhkdwp8066@skku.edu

<저작권자 © THE SUNGKYUN TIMES, 무단 전재 및 재배포 금지>

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