I don’t know how people will evaluate the significance of 2023 in the history of human science and technology a few years from now. First, the ChatGPT came at the beginning of the year, and then there was an oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo]?
Just last month, the door to commercialization of gene editing was finally opened - Vertex and CRISPR jointly announced that CRISPR/Cas9 gene editing therapy (trade name: Casgevy) has been approved for marketing in the UK for patients with transfusion-dependent β-thalassemia.
Last Friday (December 8), the FDA (U.S. Food and Drug Administration) officially followed the UK's lead and approved the listing of Casgevy. On the same day, Lyfgenia, a gene-editing therapy developed by bluebirdbio that has overlapping indications with Casgevy, was also approved.
When gene editing therapies begin to receive approval in the world's largest innovative drug market, it means that at the end of 2023, mankind has essentially launched the "gene editing" era...
Blessing or misfortune?
01
angel scalpel
A gene is a DNA fragment with genetic information, which stores all information about life’s race, blood type, pregnancy, growth, apoptosis and other processes, and supports the basic structure and performance of life.
As the name suggests, gene editing technology is a technology for directed modification of DNA gene sequences. Through this technology, humans can theoretically take complete control of their own destiny.
The starting point of this technology was in 1953, when Watson and Crick proposed the double helix structure of DNA, which kicked off modern molecular biology and introduced human cognition to the genetic level for the first time.
Although humans discovered the structure of DNA very early, there was not much new progress in the concept of genes for a long time. It was not until the 1970s that humans discovered the possibility of gene editing. In the process of studying how bacteria defend themselves against phages, scientists discovered that there is a special enzyme in bacteria that can degrade the DNA of phages and thus protect bacteria from phages. This enzyme is a restriction endonuclease.
Based on this discovery, humans began to experiment with the possibility of gene editing.
In 1996, the American genetic company Sangamo Therapeutics launched the first-generation gene editing technology ZFNs. This technology can modify the genome of somatic cells and pluripotent stem cells, but it requires the design and synthesis of complex protein modules. The construction cycle is long, the steps are cumbersome, and it cannot combine with any target gene. Obviously, such tedious steps are difficult to realize commercially.
Thirteen years after the emergence of ZFNs, the second generation of gene editing technology TALENs came out. Compared with ZFNs, although protein design is simplified, it still requires a lot of time to design and assemble. At the same time, because of its excessive size, it is more difficult to deliver to target cells and cannot perform high-throughput gene editing.
The complex mechanism greatly limits the further application of gene editing, which also points the way for subsequent iterations, which is simplicity and efficiency.
Figure: Comparison of three generations of gene editing technology, source: West China Securities
In 2012, two young female scientists, Emmanuelle Charpentier and Jennifer Doudna, developed the third-generation gene editing technology CRISPR/Cas. Compared with the previous two generations of technology, the biggest change of CRISPR/Cas is the improvement in efficiency. The system is simple, precise, highly efficient in editing, and low in operating costs, which greatly reduces the technical threshold and makes gene editing possible for clinical application.
Based on the platform value of CRISPR/Cas technology, Charpentier and Doudna were awarded the Nobel Prize in Chemistry in 2020, and Charpentier later founded CRISPR Therapeutics and moved further towards clinical application scenarios. The recently launched gene therapy Casgevy is the core product of the CRISPR company, and it has become the first CRISPR gene editing therapy approved for marketing in the world.
Casgevy therapy is similar to CAR-T therapy, which requires cells to be collected from the patient, then sent to the laboratory for transformation, and then reinfused back into the patient to achieve complete reversal of the disease. Casgevy modifies the patient's hematopoietic stem cells so that the cells can produce high levels of fetal hemoglobin.
Figure: CAR-T therapy and gene therapy, source: CICC
There is no doubt that Casgevy is only the beginning of mankind's conquest of genes. In theory, all types of diseases can be cured through gene editing, especially many genetic diseases with congenital defects, giving people hope for cure. What's more, it has been proposed to rejuvenate humans by editing aging genes.
Humans who have mastered gene editing technology are like holding the "angel's scalpel" and have the ability to change their fate against the will of heaven.
02
devil's temptation
When you stare into the abyss, the abyss stares into you.
From the day genes were discovered, humans have always wanted to conquer them, because mastering the ability to edit genes also masters infinite possibilities in life. For example, many genetic diseases that cannot be treated with drugs can be cured. Since the birth of gene editing technology, controversies surrounding its safety, ethics and other aspects have never ceased.
Breaking through the constraints of nature may not be a good thing for humans. There are still too many unknowns that need to be explored.
Gene editing is irreversible. After the edited cells divide normally, the edited genes will be inherited. In other words, human changes to genes will continue to be passed down to future generations. If errors are edited or genes that are not currently visible, it will cause genetic contamination.
Therefore, gene editing is not only an academic issue, but also a social issue.
In 2018, a "gene-edited baby" incident occurred in my country. He Jiankui, an associate professor at Southern University of Science and Technology, announced that through gene editing, a pair of newborns were successfully transformed so that they were born with natural resistance to HIV. However, this did not cause a stir in the industry. Instead, more than a hundred scientists at home and abroad jointly voiced their opposition. In the end, He Jiankui was sentenced to 3 years in prison and fined 3 million yuan for "illegal medical practice."
Industrial technology serves mankind. If the two major issues of safety and ethics cannot be resolved, the application of gene editing will inevitably be limited.
Putting aside these two issues, there are many practical issues that need to be faced if we want to comprehensively promote the commercialization of gene therapy drugs at this stage. For example, at the application level, issues such as off-target effects, transcription efficiency, transportation issues, applicability, and long-term safety need to be solved urgently. In addition, the cost of gene-editing treatments also limits its promotion. Casgevy's treatment may cost up to $2 million.
Overall, the launch of Casgevy is just the first step towards the commercialization of gene editing therapies. After all, CRISPR/Cas technology has only been around for 11 years, and there is still a long way to go. Facing new problems requires the courage to face them head-on and to overcome one problem after another. This is the driving force for human progress.
03
Another arms race begins
Gene editing technology has broad application prospects and huge market potential, attracting many high-quality domestic and foreign biotechnology companies to invest in research. Even in the cold winter of innovative drugs in 2022, at least 7 companies in the gene therapy field have bucked the trend and obtained large-scale financing of more than 100 million yuan, and Tessera Therapeutics has completed a super round C of more than 300 million US dollars.
Faced with such hot investment in the primary market, countries around the world are constantly improving their scientific and technological ethics review systems to prevent the abuse of gene editing technology. For example, the "Opinions on Strengthening the Ethical Governance of Science and Technology" released by my country in 2022 is the first national-level document in China to propose moral and ethical norms for gene editing.
What is certain is that the development and application of gene editing technology will bring the development of biological science to a new dimension. This technology has broad application prospects in gene function research, drug development, gene therapy, including cancer, Alzheimer's disease, cardiovascular diseases and other fields.
But for such a vision to be realized, the key to everything is how humans use this tool, limit it, and not be driven by it.
Up to now, more than 50 companies in my country have been involved in gene editing technology, but most of them are still start-up companies, and pipeline research and development are mostly in the early clinical stage. Such as Boya Jiyin, Bangyao Biotech, Ruifeng Biotech, Huida Gene, Bendao Gene, etc., but these companies have not entered the capital market for the time being.
Because my country's gene editing companies started late, the underlying intellectual property rights of CRISPR technology have been monopolized by Western countries, and they still face "stuck" problems in technology research and development. At least it means paying high licensing fees and royalties, or at worst it will be blocked by technology.
Given the power of gene editing technology, it is very likely to become the next strategic technology. Therefore, whether we like it or not, objectively, another heavyweight arms race in the field of innovative drugs has begun. (Author: Qingyue Yiyao)