The prospects and ethics of CRISPR/Cas gene editing therapy are disputed

Recently, gene editing therapy CTX001 was reported to be promising to be a potential one-time cure for patients with transfusion dependence β thalt anemia (TDT) and severe sickle cell anemia (SCD).
month, the world's first study to prove that the CRISPR/Cas9 system is effective in treating metastasis cancer in live animals was published in the journal Science.
the use of gene editing to treat various diseases is advancing, can gene editing technology be used in clinical treatment? What are the problems with gene editing? On October 7, 2020, the Swedish Nobel Committee awarded this year's Nobel Prize in Chemistry to Emmanuele Carpenter of France and Jennifer Doudna of the United States for their contributions to major basic research in the development of genome editing methods.
first published research on CRISPR/Cas gene editing technology in the prestigious journal Science in 2012, winning the Nobel Prize in Chemistry in just eight years, officially heralding the era of gene editing.
01 A new generation of gene editing tools was born before CRISPR/Cas technology was born, zinc finger nuclease technology and class transcription activation sample effect factor nuclease (TALEN) technology, as the first generation of gene editing tools and second generation gene editing tools, has demonstrated the powerful function of precise modification of the target gene throughout the genome.
, however, CRISPR/Cas technology has quickly become the brightest "star" of the era of gene editing, with more efficient targeting, lower off-target rates, and easier-to-operate CRISPR/Cas technology.
CRISPR/Cas Technical Principles Diagram Source: Science In the 1980s and 1990s, scientists in Japan, Spain and other countries discovered strange DNA sequences in bacteria or ancient bacteria, which scientists later named "short echo repetition sequences of clustered regular intervals", a series of English words called CRISPR.
Found to contain this sequence in about 50 percent of bacteria and 90 percent of paleobacterial bacteria, and found proteins that always go hand in hand with them, with the function of nucleic acid incision enzyme (DNA scissors), which scientists named Cas protein.
it was only around 2008 that scientists discovered that the CRISPR/Cas combination was in fact an immune weapon for bacteria to defend against phage attacks.
CRISPR is a tool used by bacteria to record genetic information about phages, identifying the DNA of invasive viruses and then carrying the endoenzyme Cas protein to cut off the genetic material of the virus to remove the invading virus.
of course, this combination doesn't always work in bacteria, and it's even harder to use as a gene editing tool, but it's Dudner and Carpentier that really make CRISPR/Cas technology work.
2012, Dudner and Carpentier published their first paper in the prestigious journal Science.
in this study, they added a guide RNA to CRISPR to find the target DNA more precisely, selected Cas9, the ninth-ranked Cas9 in the Cas protein family, as a partner of CRISPR, and modified the Cas9 protein to form a new gene editing combination CRISPR/Cas9.
Cas can be used to program the cutting and editing of DNA sequences Source: Science Followed, with the joint efforts of Dudner, Carpentier and other scientists, CRISPR/Cas9 gene editing tools became increasingly perfect, becoming the absolute star of gene editing, sweeping the entire life sciences like a "storm."
Scientists, you followed me in using CRISPR/Cas technology to genetically edit bacteria, fungi, plants, animals, including human cells and embryos, the hottest of which is gene editing therapy.
history of CRISPR/Cas technology: Science02 gene editing therapy is in full swing in the field of gene therapy, gene editing technology has three main applications.
The first is to genetically edit certain damaged cells in a patient and then send the gene-editing cells back into the patient to treat or replace the damaged cells, a gene-editing therapy that has been conducted in clinical trials for diseases such as cancer, leukemia, AIDS, and hereditary eye disease.
reported that since 2016, Sichuan University Huaxi Hospital and Hangzhou Cancer Hospital and other units have launched clinical trials using CRISPR/Cas9 gene editing to treat cancer, although the peer-reviewed results have not yet been published.
February 2020, Science reported the results of an early clinical trial of gene editing therapy.
Researchers at the University of Pennsylvania's Perelman School of Medicine edited the patient's own T-cell CRISPR/Cas9 gene, removed three genes, transferred a gene that helps T-cells identify tumor cells, and then entered three patients (two with advanced resuscable myeloma and one with metastasis sarcoma) to enhance human T-cell resistance to cancer.
workflow schematic source: Nine months after the injection of these engineered T-cells, patients showed strong tolerance, indicating that the treatment was safe, but the efficacy of cancer treatment needed to be confirmed in larger clinical trials.
second gene-editing therapy is aimed at patients with genetic diseases, who can be genetically modified to obtain healthy offspring.
now, scientists in China, the United States and other countries have tried gene editing of human embryos, including AIDS-related genes, thalassemia mutation genes and genetic "fat cardiomyopathy" mutation genes.
because of the greater ethical controversy in this way, it is mainly at the level of cellular or embryo operation.
third gene-editing therapy is to use viral vectors to deliver gene-editing tools directly to the patient to correct mutant genes.
The world's first clinical trial of live gene editing therapy will be conducted at the Casey Ophthalmology Institute at Oregon Health and Science University and will be initiated by institutions such as Editas Pharmaceuticals of the United States to develop adenovirus vectors, according to the Anti-Blind Foundation website. CRISPR/Cas9 gene editing drugs were delivered to the retina of about 18 patients with Lebo congenital black eye disease 10 (LCA10) to assess the safety and effectiveness of the gene editing therapy in the treatment of hereditary eye disease.
Currently, gene editing technology also shows great potential for the treatment of genetic diseases such as haemophilia type A and B, Duxing muscular dystrophy, type β thalassemia, cystic fibrosis and alpha-1-antitant trypsin deficiency, although most clinical trials are just beginning and the efficacy is worth looking forward to.
03 gene editing is still ethically controversial Why is there an ethical dispute about gene editing? On the one hand, there are public concerns about the immatureness of gene editing techniques, such as off-target effects, which can cause additional harm to patients, and on the other hand, there are concerns that reproductive gene editing will permanently alter the human gene pool and have some irreversible effects on humans.
gene editing is off-target for two main reasons, one is that CRISPR/Cas9 identification components typically identify DNA sequences of 20 bases, but there may be many similar sequences in the genome, such as 15 bases and The target sequence is the same, the identification component may be mistaken for the target sequence, so that the cutting component of the non-target DNA sequence was mistakenly cut, another reason is that the cutting component cut is not "which cut which", it is possible to cut a gas.
Some non-target gene mutations hide deep, still "disguised", a little attention, it will let it mix, may bring potential threats to the health of patients, no doubt also to the hot gene editing technology cast a shadow.
, of course, scientists are working to invent new techniques to retrieve as many off-target points as possible, minimizing the risk.
In February 2019, a team of Yang Hui researchers at the Institute of Neuroscience of the Chinese Academy of Sciences reported in the journal Science that the team had developed an efficient way to detect the off-target effect of gene editing, which detects the slightest gene-editing off-target effect.
the method's experimental design process source: Science therefore, through continuous technical improvement, gene editing off-target problem is expected to be effectively solved.
, gene editing for reproductive purposes remains an absolute research exclusion zone.
On August 3, 2017, 11 institutions, including the American Society of Human Genetics, the British Association of Genetic Nurses and Consultants, the Canadian Genetic Counseling Association, the International Society for Genetic Epidemiology and the Asian Professional Association of Genetic Consultants, jointly issued a policy statement in the American Journal of Human Genetics calling for "cautious and proactive" reproductive cell gene editing, arguing that basic research should continue, but opposing the use of the technology for reproductive purposes.
However, at the end of 2018, He Jiankui from Southern University of Science and Technology used CRISPR/Cas9 gene editing technology to obtain two so-called anti-AIDS gene editing girls, causing a global uproar, causing a bad impact, He Jiankui was also sentenced to three years in prison for violating the relevant laws, self-defying results.
source: In any case, gene editing technology has shown great potential for the treatment of diseases such as cancer, AIDS and genetic diseases in humans and is favored by many scientists and investors, but in the face of ethical controversy, scientists should act cautiously and minimize the safety risks of gene editing through continuous technological innovation.
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