The Path to Becoming a Deity Even Google Rides [Reading Science]

2020 Nobel Chemistry Award CRISPR-Cas9 Gene Scissors
Revolutionizing Medical and Life Biotechnology... Transforming Treatment of Incurable and Genetic Diseases
Life and Death Once Governed by God, Now Within Human Reach?
Global Biotech Startup Boom Fueled by Google Ventures' Massive Investment
Challenges Remain in Overcoming Off-Target Effects and Improving Accuracy and Efficiency
Immunological Responses and Ethical Issues Also Pose Significant Obstacles

Gene scissors. Photo by Korea Research Institute of Bioscience and Biotechnology

[Asia Economy Reporter Kim Bong-su] "A tool to rewrite life." This is the evaluation given by the Nobel Committee in 2020 when it awarded the Nobel Prize in Chemistry to the scientists who developed the CRISPR-Cas9 gene-editing technology. Although CRISPR gene scissors still have many limitations, they are a representative cutting-edge genetic engineering technology that carries tremendous expectations. It is even regarded as a tool that allows humans to take control of the realm of life, aging, sickness, and death, which was once governed by God. This is why a global investment boom is occurring, with Google Ventures, the venture capital arm of Google, investing huge sums. However, there are many challenges and ethical issues to overcome. Will CRISPR gene scissors truly become the ‘hand of God’ that helps humanity overcome the fear of disease and death?

◇ What Are Gene Scissors?

DNA, which makes up the genome that determines the traits of living organisms, consists of four bases arranged linearly. These four bases are adenine, guanine, cytosine, and thymine. All living organisms differ in their characteristics depending on the order and arrangement of these four bases. Gene scissors can insert, remove, or replace specific bases.

The third-generation technology developed in 2012, CRISPR gene scissors, is a representative example. CRISPR gene scissors are based on a type of defense enzyme created by bacteria in their fight against viruses. Bacteria and viruses are antagonistic; bacteria store information about viruses that recently attacked them (guide RNA), and when attacked again, they recognize the virus immediately and secrete a decomposition enzyme (Cas9) that cuts the DNA into pieces to neutralize it. Scientists thought that by utilizing this bacterial antiviral defense enzyme, they could selectively target specific genes and modify genes as desired to induce mutations.

In 2012, Dr. Emmanuelle Charpentier from Ume? University in Spain and Professor Jennifer Doudna from UC Berkeley in the United States discovered this mechanism in Streptococcus pyogenes and first elucidated the operating principle and components at the test tube level. Their paper, published in the international journal Science in June 2012, caused a huge shock in the scientific community. It was evaluated as an innovative technology that advances the future of science and medical technology by allowing humans to arbitrarily correct and improve the genetic information of living organisms. Compared to the first generation (Zinc Finger) and second generation (TALEN), it is much cheaper, more efficient, and easier to produce. It is changing the paradigm of medical and life sciences, including treatment of cancer and intractable diseases, genetic disease therapy, improvement of agricultural and livestock breeds, and modification of plant and animal traits. These two scientists were awarded the Nobel Prize in Chemistry in 2020 for this achievement.

There were earlier research results as well. In 1987, Japanese scientist Yoshizumi Ishino accidentally discovered it in Escherichia coli but did not understand its significance. In the early 2000s, Spanish scientist Francisco Mojica discovered this unusual base sequence and named it CRISPR. However, it was only speculated to be a kind of acquired immune system in bacteria. In 2011, the discovery of tracer RNA, the last component of CRISPR to be identified, accelerated progress. Almost simultaneously with Charpentier and Doudna, a team led by Virginijus ?ik?nys at Vilnius University in Lithuania also developed this technology but was three months late and missed out on the Nobel Prize in Chemistry. Later, in 2013, Professor Jin-Soo Kim of Seoul National University successfully edited human genes using CRISPR gene scissors, proving its usefulness. Kim’s team added amino acids and changed the codon sequences (triplet bases of mRNA transcribed from DNA) to enable gene scissors that worked only at the test tube level to function in human cells, achieving human gene editing.

A virtual gene scissors cutting DNA. Image courtesy of Korea Research Institute of Bioscience and Biotechnology.

◇ Ongoing Upgrade Research

Recently, research to improve efficiency and precision for practical use has been active. In 2016, research teams from Harvard University in the U.S. and Kobe University in Japan developed a base-editing gene scissors that can accurately substitute target bases with high efficiency without cutting the double-stranded target DNA. In other words, it is a correction technology that changes a single base precisely like tweezers. In September last year, the Korea Research Institute of Bioscience and Biotechnology developed an ultra-small gene scissors. CRISPR gene scissors are divided according to the cutting enzyme into Cas9, Cas12a, Cas14 (also called Cas12f), etc. Cas9 is large, making delivery into the body difficult. Cas14 is small but has low efficiency. The Korea Research Institute of Bioscience and Biotechnology developed the CRISPR-Cas12f1 system, which raises editing efficiency to the level of Cas9 while reducing the off-target cleavage rate to less than half that of Cas9.

The ‘prime editing’ technology developed by Professor George Church’s team at Harvard University in 2019 is also attracting attention. This technology can insert new gene base sequences into target genes or remove problematic base sequences within existing DNA without damaging the target gene. The team suggested that this technology could overcome the current reality where existing CRISPR gene scissors fail in treatment within dense cells due to accidental errors and lack of precision. In particular, it was able to correct mutations causing intractable hereditary diseases such as sickle cell anemia and Tay-Sachs disease. Recently, with the development of protein structure prediction artificial intelligence (AI) such as Google DeepMind’s AlphaFold2 and RosettaFold, as well as big data technologies, there has been growing interest in the biotechnology community about the potential integration with gene scissors technology.

Types of Gene Scissors.

◇ The ‘Future’ Painted by Gene Editing

Gene scissors technology is expected to bring revolutionary changes in the treatment of cancer, intractable diseases, genetic disease therapy, improvement of agricultural and livestock products, and modification of plant and animal traits. Currently, research is active on removing faulty genes or normal genes that interfere with treatment. In the near future, therapies that correct faulty genes into normal genes are expected to enter clinical research. In February 2020, the University of Pennsylvania in the U.S. succeeded in treating incurable cancer patients by transplanting T immune cells with immune checkpoint genes removed by gene scissors. It is also being used to treat hereditary vision diseases. A private research team in the U.S. developed a precise gene correction system for treating retinal genetic diseases caused by gene mutations and has entered clinical trials. It is also used in plant breeding. The Chinese Academy of Sciences announced in 2017 that it developed crops resistant to both pests and herbicides using gene editing. In South Korea, in October 2015, the Institute for Basic Science (IBS) attracted attention by being the first in the world to successfully edit plant genes using gene scissors made only of proteins and RNA without DNA.

Especially in agriculture, gene editing for breed improvement is already at the commercialization stage. A U.S. agricultural company has commercialized soybeans with different fatty acid compositions, and in Japan, tomatoes with increased gamma-aminobutyric acid (GABA) content are being produced and sold. However, South Korea still strictly regulates crops created with gene scissors technology as living modified organisms (LMOs). Professor Sang-Kyu Kim of KAIST’s Department of Biological Sciences explained, "The starting point of debates on genetically modified (GM) plants produced by conventional methods was concerns about the introduction of foreign genes and the resulting changes in plants or ecosystem destruction. Crops produced by gene scissors have solved these problems, but previous GMO discussions have often become overly emotional, leaving little hope."

◇ Limitations and Challenges Remain

However, gene scissors technology is not yet complete. First, gene scissors can act on non-target base sequences, causing unintended mutations. This is called the off-target effect. Although recent developments have identified causes and improved precision, much work remains. Immune response issues upon in vivo injection also need to be overcome. Professor Kim said, "The core challenges are improving the accuracy of gene scissors and how to deliver them inside the human body. Various attempts to increase target accuracy and technologies for precise delivery are being researched. However, these are important in all new drug development and are not unique problems to gene scissors."

There are also ethical and social issues. ‘Designer babies’ are a representative example. In 2018, a Chinese scientist announced the birth of twins whose genes were edited to remove elements causing acquired immunodeficiency syndrome (AIDS), causing a huge controversy. What if parents could edit their baby’s genes as they wish? Wealthy parents could have children with intelligence, physique, appearance, and health all perfected, while others would be left to rely on ‘luck.’ The same applies to disease treatment. What would happen if, like the recently publicized rare disease treatments costing billions of won, a single injection could cure one’s genetic defects and grant a disease-free long life?