Translated from “Implementasi CRISPR-Cas9 pada Manusia: Risiko dan Perdebatannya”
February 22, 2020
Genome editing technology in humans raises various controversies. The emergence of CRISPR-Cas9 genome editing is claimed to have succeeded in making humans resistant to HIV and other diseases. On the other hand, its premature development risks causing the genome editing process to be missed or even gene mutation that causing susceptibility to various diseases.
At the beginning of the 20th century, a movement called Eugenics Movement in the United States emerged. This movement was initiated by Francis Galton, a British scientist who believed that the human quality from the physical and mental aspects could be improved. By limit the reproduction of individuals who are considered inferior, such as physical disabilities and mental retardations. However, this practice was not based on qualified genetic science because it only referred to Mendelian pea-plant experiment. This practice in humans doesn’t have a solid basis for application in humans (Norrgard, 2008).
Development in genetics cannot be separated from the DNA discovery by Oswald Avery, an immunochemist at the Rockefeller Institute for Medical Research Hospital in 1944. Avery said that DNA is the transforming principle (Cobb, 2014). Scientists found that DNA plays a role in carrying biological information including hereditary disease and non-congenital disease. This information is contained in the fragments of DNA or genes that arrange the human genome. If the DNA produces abnormality, an attempt can be made to editing the gene by genome editing. It was from here, scientists began to develop human enhanced mechanisms. The most recent genome editing is clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9).
CRISPR-Cas9 technology may allow the scientist to edit targeted DNA in human somatic cells. CRISPR itself is a repetitive bacterial DNA sequence. This technology works when the CRISPR sequence in bacteria acts as a mechanism the certain bacteria to defend themselves from virus infection. Bacteria are able to detect the presence of viruses that have infected them because the memory cells have the ability to record virus infections. With the direction of RNA, bacteria send Cas9 protein to cut DNA that has infected by the virus. RNA is part of the nucleus of the cell that has a role in cell communication by transfer information between components in the cell (Campbell and Reece, 2005). This DNA-cutting leads to two probabilities, namely incomplete DNA-recombination until it becomes inactive or imitating the sequence of DNA arrangement to fill in the structure that has been cut (Dance, 2015).
CRISPR-Cas9 is considered superior because of its capacity to target specific genes with high accuracy. CRISPR-Cas9 acts like ”molecular scissors” that cut the DNA chain at the desired sequence. Unlike other genome editing –TALENs and zinc finger – which tend to be complicated and more expensive because they have to synthesize new proteins. CRISPR-Cas9 makes sufficient use of existing RNA as an introduction to editing. The results can also be seen in months, unlike other methods which take several years (Pennisi, 2013).
This technology also looks promising because of its ability to enhance or change certain characteristics in individuals. Professor Jennifer Doudna from Universit of California Berkeley, on of the pioneer in the use of CRISPR, she stated that this technology is very likely to be used to ‘produce’ humans with specific desirable features, for example, humans without baldness, high IQ, and strong bones (TED 2015).
CRISPR-Cas9 has been widely used, but its application is still limited to animals and plants. One of the animal studies was conducted by the Group of Epigenetic Reprogramming from the Shanghai Institutes for Biological Sciences on mice that inherit cataract-induced genes. CRISPR-Cas9 is used to edit certain genes in mouse zygotes before being injected into the mother’s body. A number of mice born were identified as free from cataracts. After the cataract-free mice were mated, new heredity was obtained carrying the edited genes (Wu, et al, 2013). Research on plants has been carried out in Africa. Valentine Otang Ntui and his team from the International Institute of Tropical Agricultural, Nairobi, Kenya made edits to the banana gene (Musa sp.) by targeting The Phytoene Desaturase (PDS) gene that causes albino and dwarf banana. The result is that the PDS gene is successfully disrupted so that plans grow normally without triggering by other mutations (Ntui, et al, 2019).
The use of CRISPR-Cas9 in humans itself was only initiated in 2016. The first application was made by a team lead by an oncologist from Sichuan University, Lu You. He and his team conducted a clinical trial of this technology by injecting edited cells to a lung cancer patient at West China Hospital. The researcher took immune cells from the patient’s blood, then modified them with CRISPR-Cas9. Certain genes in these cells are deactivated because the PD-1 proteins they contain are often used by cancer cells to develop. These cells are reproduced, they returned to the patient’s bloodstream. This study has received ethical approval from the hospital review body.
Even so, it is too early for the CRISPR-Cas9 technology to be applied to humans. Joyce Harper, a researcher on women’s reproductive health at University College London, reported regarding current gene editing for HIV immunity is premature, dangerous, and irresponsible. According to her, science will need years of research to ensure that changing the genome arrangement in the embryonic phase will not cause harm. Her research, which is seven years old, has not been able to identify the various possibilities that could arise. The inheritance of the modified genome cannot be guaranteed for the benefit and the risk of off-target. Until now, it has not been confirmed. What’s more, scientists have yet to investigate the ethical suitability of genome editing technology and its social implication.
There are still many things that should be explored from using the CRISPR-Cas9. Things that need to be explored are the characteristics of CRISPR itself (Zhang, et al, 2014) as well as ways to increase knowledge on how to transfer CRISPR to cells, how to maintain DNA reparation after cutting, and limit its misdirected application. CRISPR delivery is specific to the kind and type of cells or tissues targeted.
Doudna predicts that this technology will only be able to be used in humans by 2025, with an emphasis only on adults (TED 2015). In an experiment to correct tyrosinemia in mice, Daniel Anderson from the Massachusetts Institute of Technology (MIT) found that he and his team had to pump enormous amounts of blood to transfer the Cas9 protein and RNA via blood vessels to the targeted organ, the liver. This is difficult and likely to be impossible in humans.
The effectiveness of this technology is still a question. Paula Cannon, a scientist from the University of California who focuses on HIV studies, stated that HIV does not always target the protein in the CCR5 genes, but can also target CXCR4 genes that are accommodating to HIV. The He’s research is thought to even make normal children vulnerable to the risk of editing genome without a clear benefit instead of strengthening immunity. This statement is made clear by the research of Eric Lander from the Broad Institute of Harvard and MIT which states that although the absence of CCR5 can prevent an individual from HIV infected, the individual becomes more susceptible to contracting other diseases. This possibility exists because a gene has certain functions and some diseases are composed of the presence and or absence of certain genes (The National Academy of Sciences, 2015)
Despite its questionable effectiveness, the editing process is also likely to be missed, RNA may fail to transfer the Cas9 protein to the targeted DNA and instead target other DNA that is structured similarly to the mRNA. DNA that is wrongly targeted can even be cut, activated, or deactivated (Pennisi, 2013). Instead of disease resistance, inaccurate editing processes can increase the chance of cancer cells developing due to chromosomal rearrangement (Dance, 2015).
This technology also does not meet current medical ethics. Changes in human genes in the embryonic phase will be inherited to the next generation. Previously, scientists had never conducted a study to modify the parts of humans that could be inherited from generation to generation. Later, if there is a gene mutation error in the baby, this error will be inherited. What’s more, there is no medical ethic that addresses the use of genome editing, particularly with CRISPR technology.
The discussion of genome editing in humans was only taken seriously by the scientific community at the First International Summit on Human Genome Editing in 2015. According to the results of the conference, somatic cells – cells that will not be inherited – may be edited as long as they are within the framework that conforms to the regulations there is. However, modification of germline cells — cells that will be inherited — is labeled “irresponsible” until the question of the risk of genome editing technology has been resolved by the scientific community and consensus is reached on its feasibility (National Center for Biotechnology Information, 2019). With germ cell editing, the individual who inherits the edited DNA cannot give consent against the modification process.
Besides its scientific effects, gene editing also has other social implications that have a negative impact when applied to humans. Paul Knoepfler, a stem cell and genetics researcher, predicts ‘designer humans’ will have excessive aggressiveness and narcissism associated with feelings of superiority due to enhancement. According to him, humans who are labeled as natural will experience social exclusion (TED 2017). In addition, the Nuffield Council of Bioethics in a report on Genome editing and human reproduction predicts that there will be marginalization in society towards certain traits.
The CRISPR-Cas9 genome editing technology needs more research until it is ready for use in humans. Seven years of development have not been able to map the various possibilities and impacts that will result. Its potential inaccuracy, breaches of medical ethics, questionable effectiveness, and other implications are taken into account for its current lack of readiness. It will take at least half a full decade of research to reach a feasible level before it is applied to humans. As promising as it is, man does not need to rush to adopt this knowledge for himself. The calculated benefits, both in the form of immunity to disease and the perfection of physical and mental qualities, will be reaped when the time comes when this technology is guaranteed its feasibility.
Author: Medisita Febrina, Megantara Agustina Pertiwi Massie
Editor: Tita Meydhalifah
Translator: Aufa Fathya
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