The technology for genetic editing of humans, still in the embryo or after birth, has already been applied in practice. However, there are open ethical questions. Understand how these therapies work and what their limits are. In 2018, a Chinese scientist named He Jiankui shocked the world by announcing the birth of two genome-edited babies. To do this, he used a method for genome editing known as CRISPR-Cas9 or “genetic scissors”. The researcher altered the CCR-5 genes of the twin embryos to create resistance to the HIV virus. These two children, plus a third who was born a year later, are the first babies in the world to have their genes modified. Five years after the experiment, all three are healthy and lead normal lives. The experiment, however, generated great condemnation from scientists and lay people, and ended up resulting in Jiankui’s imprisonment for three years for the use of “illegal medical practices”. While the three children may represent the first cases of genetically modified embryos, they are not the only human beings with an edited genome. The “genetic scissors” technique has been applied to more than 200 adults in clinical trials for the treatment of sickle cell anemia. Gene-editing therapies changed the participants’ lives by curing the blood disease that crippled them. New tests for other diseases are in preparation. The CRISPR-Cas9 method The sudden explosion of gene therapies in the last decade is due to the development of the CRISPR-Cas9 method. While gene editing has been around since the 1990s, CRISPR was revolutionary because of its precise and programmable way of altering DNA. CRISPR-Cas9 is a two-part molecular system. CRISPR is a cluster of sequences that can be programmed to find a specific stretch of DNA in a gene, and Cas9 is an editing element that cuts the DNA strand and adds a new piece to it. It sounds simple, but the hard part is implementing it – the process needs to take place in trillions of cells in the body if it is to be used to treat disease. “Genetic scissors” are only suitable for treating diseases such as “simple” genetic mutations in one type of cell. If a disease is certain to be caused by an error in a gene, such as sickle cell anemia or certain types of cancer, CRISPR has the potential to treat it. The limits of gene therapy The method is not applicable to the treatment of complex genetic diseases, with multiple mutations in several genes and in different types of cells. “Few patients have an identifiable genetic cause (of disease) that can be targeted,” says David Curtis, an expert in clinical genetics at University College London. Curtis is doubtful that “genetic scissors” can be used to treat any disease that has more than one genetic mutation involved, at least for now. “The therapy is not going to help with complex genetic diseases such as schizophrenia. The brain is an insanely difficult target to treat – it would take multiple DNA changes in billions of brain cells to renew those that developed wrongly. That doesn’t seem likely.” it works,” he points out. There are two main approaches to gene editing: germline editing and somatic cell therapies. Germline editing is performed during embryonic development. When modifying an embryo while it is just one cell or a small number of cells, all the cells that were created from them are also edited, that is, the genetic editing takes place in all the cells of the body. This method is great for curing diseases, but it also affects sperm and eggs, causing the edited gene to be passed on to children and grandchildren. Thus, editing embryos alters the course of evolution for future generations. It is precisely the use of this method that is at the heart of the “designer baby” debate that landed Jiankui in jail. Defenders of this technique argue that it can eradicate diseases such as AIDS or various types of cancer. Critics raise questions about “playing God”. Potential of Somatic Cell Therapy In the somatic cell method, genes are edited in cells taken from the patient or a donor and then reimplanted. This process was used to treat sickle cell anemia and has potential for treating diseases caused by other genes with mutations in just one stretch. Most scientists argue that somatic cell editing has more potential uses than germline editing. It works, and it avoids complex questions about designer babies. But this therapy also has its problems, the most serious of which are the potential off-gene effects on the target. “There is a risk of introducing mutations in unwanted places in the genome when using CRISPR, altering or deactivating the function of other genes. Its effects in the body are not yet known”, says Van Trung Chu, researcher of this method at the Max Delbrück Center of Molecular Medicine in Berlin. Some random mutations in the genome may be harmless, but others can cause cancer and other genetic diseases. There are ways to scour the genome for mutations, but it’s not yet clear what would happen if they were found. More gene editing to correct the mistakes of the first edition? “The mutations are not completely random. Depending on the Cas gene editing tool used, you can get an idea of where the mutations are likely to be,” adds Chu. All scientists can do now is perform deep genome sequencing analyzes to find potential changes outside the target gene. It’s kind of like a needle in a haystack, if you know which haystack to look for. “In the long term, new forms of CRISPR-Cas9 are being developed with fewer potential side effects”, says Chu. The ethical issue Gene editing is not being developed in an ethical vacuum. Scientists and laypeople alike have been questioning this technology even before it became possible. The ethical issue is, in part, monitored by the researchers themselves, most of whom agree that editing embryos is off-limits. The legal setback over Jiankui’s HIV-resistant babies set the precedent for how seriously countries treat gene editing. “It’s pretty clear now, you can’t edit germline DNA,” Chu points out. Gene editing is here to stay, but not without resistance. For many, scientists would be “playing God”. For others, the method causes discomfort and even disgust, as it interferes with nature. But then again, wouldn’t parents be happy if their children could be cured or diseases prevented with gene editing? The tool to treat and eradicate some diseases already exists. What is more ethical: using available technology for healing or not using it at all? Author: Fred Schwaller
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