When we talk about how bacteria survive from virus infection, people might think: who cares? But when it comes to “designer babies” and gene-edited food in supermarkets, it is undeniable even non-scientific laymen would care as it pertains health care and daily life. Apparently, doctors, engineers and decision makers worldwide are sharing responsibility in this era when harness technique derived from prokaryotes becomes so popular and the pace of advancement is unimaginably fast.
In the past years, studies in bacteria and yeast genetic and immune systems have provided us with fundamental tools to do gene targeting, ranging from pioneer studies of microinjection of exogenous DNA in 1980s, to more advanced gene edition with enhanced frequency of success by nucleases such as Zinc-Finger Nucleases (ZFN), Transcription Activator-Like Effector Nucleases (TALENs), and CRISPR/Cas9. The idea behind gene targeting by nucleases is taking advantage of cells’ repair machinery after endogenous or induced DNA break events to acquired desired results, and the modification can be achieved in every cell within an organism that derived from the targeted embryonic stem cells. These enable us to generated transgenic organisms, be it prokaryote or vertebrate such as mice. With these tools, we can solve research questions not only on interrogating gene function and modeling certain human diseases such as sickle cell anemia, but also on re-establishment of normal gene resulted from genetic mutations to boost agricultural production and progression of gene therapy for human.
Among newly developed nucleases in genome editing, CRISPR/Cas9 was a breakthrough in this area. CRISPR/Cas 9 presents a great example of human beings’ ability to adapt immune system in bacteria to solve problem of human diseases by precise gene editing. CRISPR stands for clustered regularly interspaced short palindromic repeats in E. coli, which was suggested to come from foreign genetic materials. CRISPR works with Cas9 that makes double strand breaks. Compared with ZFN and TALENs that need designing of new modular DNA-binding proteins for each gene target, CRISPR/Cas9 has the advantages of simplicity as a programmed gRNA that replace function of small CRISPR RNAs and trans-activating small CRISPR RNAs in the bacteria system. Injection of gRNA and Cas9 together would guide Cas9 to any predetermined site. In addition, it also allows application in adult organisms. Furthermore, it works almost in any organisms which is unprecedented.
This promising technique attracted worldwide attention at its discovery and numerous applications are ongoing, with debates and ethical concerns. By October 2018, the U.S. Department of Agriculture has given the green light to a CRISPR developed drought-tolerance soybean variety and an important oilseed crop that yields omega-3 oil. Although the U.S. Department of Agriculture decided the plant products by CRISPR will not be considered as genetically modified products and millions of dollars economic benefits, different opinions and decision makers have existed in Europe that stringently regulate these products. Despite extended applications in USA, one of the co-inventers Dr. Jennifer Doudna from University of California asked the scientific community to pause and discuss the ethics of using this new tool in clinical trials especially on human embryos. It was not unexpected that universal condemnation and criticism arose when He Jiankui announced twin girls born in China had been genetically edited by CRISPR-Cas9. The pause of advancing CRISPR/Cas9 into clinical application mostly due to the consideration of its off-target frequency and possible allergy reaction in humans due to foreign protein Cas9. Now cancer patients being treated by CRISPR for the first time in the USA in 2019, and we have to admit that the result of this clinical trial is still uncertain even with advancement in recognition of off target sites by CRISPR-Cas9 system.
Look at the history of genome engineering ever since it has been developed, there is a time when scientists called for a pause of molecular cloning in 1970s. We now have benefits from reproductive animals cloning and industrialized cloning insulin production, but human reproductive cloning remains controversial and unacceptable and we have laws to regulate this. Regulation in reproductive human cloning, swift action by Chinese Academy of Medical Sciences in proposing prohibition of productive-oriented genetic manipulation, and statement by researchers calling for more specific standards and principles that can be applied worldwide after the CRISPR edited babies all gave us good examples of brining ethic concerns into reality. As science progress, the connection between society is growing intensely as well, a researcher would have to think apart from research that might have extended influence outside lab, a policy maker would have certain knowledge and understanding to make a reasonable policy, a business owner would have to think more than profits when investing new technique etc.. It would not be easy for anyone, but we can achieve better outcomes with awareness and shared responsibility.
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