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Genomics revolution has opened Pandora’s box for all life forms and continues to present challenge at every breakthrough. It pushes boundaries of what is possible and acceptable. For example, today, it is realistic to obtain the complete DNA sequence (genome) of any individual. This linear sequence made up of four bases, adenine (A), thymidine (T), cytosine (C) and guanine (G) holds the clue to our relationship across the evolutionary tree, including interrelatedness among individuals. It also provides the clues to our differences including risks to develop diseases. The consensus among researchers, clinicians and other professionals is that the ‘omics’ revolution will transform lifetime healthcare and lifestyle decisions. A global Personal Genome Project (PGP) network that currently comprises five active PGPs in the United States (Boston, since 2005), Canada (Toronto, since 2012), United Kingdom (London, since 2013), Austria (Vienna, since 2014) and China (Shanghai, since 2017) is already underway and has begun to report on valuable findings. To this end, some argue it is desirable to obtain the complete genome sequence of every newborn and use it in dealing with health concerns throughout life. This appears logical given that such individual specific sequences may become a reality for as little as $100 in the near future. It will save diagnostics costs and contain the most relevant information possible. On reflection, this information is bound to have positive as well as negative connotations that will apply to the life of the individual from birth to death. Further it may challenge the decision of the parents to generate a child’s genome sequence without consent. After all, the child will have to live with the consequences. The lesson for the future – proceed with care.
The most recent dilemma in genomic revolution has been presented by the announcement (November 25, 2018) that a researcher in China has genetically altered a gene in human embryos that has resulted in two babies, Lulu and Nana1. Apparently, the twins carry disabled CCR5 gene that may provide them with protection against HIV infection. They are now test subjects. Apparently, these babies were generated under the false pretense of an “aids-vaccine development project” and in secrecy, going against global consensus. Unlike the use of gene-editing protocols as therapies to correct genetic alterations in somatic cells, the gene-editing protocol used to generate the twins would make a permanent change to the germ line that could be passed on to future generations.
The birth of Lulu and Nana has pushed the boundary of genomic revolution to include generation of genetically engineered babies. It has been widely condemned as premature, dangerous, alarming and unethical. It has been proclaimed as a ‘monstrous’ immorality. The genie is out of the bottle and we will hear increasing number of reports on genetically engineered babies in the future. Yet another pregnancy in China is expecting the birth of another child with genetic modifications. It’s a new territory.
Like it or not, it forces us to ask – where do we go from here? First, there has been a failure of self-regulation by the scientific community. Second, it should not lead us to stick our heads in sand and not consider a more responsible path. The outcry of the announcement is natural and expected. It reminds us of the societal reaction in response to the news of the first heart transplant (1969), first recombinant DNA molecule (1972), first test tube baby named Louise Joy Brown (1978), first GMO (1980) and first GMO food (1994) among others. All of them enticed societal uproar at the time and brought us to new and uncomfortable territory. Today, they are rather routine and mainstream practices. To the best of my understanding, they have contributed societal good and opened new economies. The question remains, are we overreacting with the birth of the first genetically engineered baby? There is a need for informed reflection.
First, the genetic technology for the creation of genetically engineered babies is freely available and being used routinely in plants and animals. Further, it has been used to treat various genetic disorders affecting different tissue types, including bone marrow, muscle and skin, without affecting reproductive systems. Such practices are now commonplace. The technology to undertake these procedures is relatively easy and does not require expensive laboratories. In fact, it is becoming routine in many research labs dealing with genetic methods and almost any lab can do it. The birth of Lulu and Nana is not a scientific breakthrough. Still it represents a novelty and a line that has not been crossed before for variety of reasons.
Second, manipulation of embryos is relatively common in labs around the world that deal with reproductive issues. They have been subject to extensive genetic manipulation for many animal species and have successfully generated modified versions of each animal in question. Also, human embryos are routinely handled in in vitro fertilization programs operational in several countries. Further, genetically manipulated human embryos have been generated, although to the best of my understanding, modified human embryos have not been implanted for further development and are terminated within 14 days. Progression of such embryos beyond this point is banned by all research ethics committees and funding agencies in almost all countries. I do not know of any exception where such a practice is viewed as appropriate.
Third, since its inception the CRISPR/Cas-9 system, the method used to generate Lulu and Nana, has been recognized to have enormous potential for gene editing in most life forms. The technology however, is still in its infancy and will require significant research and trials before it could be practiced without any risk. Also, its application in altering the genome of the human embryos resulting in new born babies has remained heated in theoretical debates, some comparing it to the experience with eugenics. Many argue that all genetic modification of human embryos towards production of a baby with desired genetic alteration, although possible, must remain banned and under strict scrutiny. It just crosses the boundary of what is acceptable today in society, any society. Apparently, the Chinese researcher who produced Lulu and Nana has been fired from his position. There is a need for extensive societal conversations about the ethics and scientific risks of its applications.
Finally, the recent report from China, if true, will be the first time genetically manipulated human embryos have been implanted and resulted in live births. The genetic modification introduced in this case is expected to protect the children from HIV infection. If no other changes have resulted during genetic manipulation (still not known) the girls will develop normally and show protection against HIV infection not unlike vaccination against HIV. More important, they will transmit this trait to their children. Is it ethically acceptable to the society given that there are safe and effective ways to use other approaches to protect people from HIV that do not involve editing an embryo’s genes?
In conclusion, the potential for gene editing in humans is enormous. However, the potential for abuse is also significant. The more important immediate question deals with two areas of concern. First, there are many unknowns with the outcome that deserve reflection. For example, what do we do with off-target effects? They are bound to happen and will generate undesirable effects. We do not know if Lulu and/or Nana carry any such effects. How do we deal with mosaics of unknown impact that will emerge during fetal development? How about the effect of such a modification on future generations? How stable will it be? These questions by no means represent a complete list of serious unknowns that must be dealt in developing any guidelines. Second, and probably the most problematic concern is the question of what gene (attribute) to alter? The CCR5 gene used in this attempt does not meet necessary requirements. As discussed in recent media coverage2, when polled nearly 70% of those asked supported gene editing if it allowed infertile couples to have children, or if it allowed a couple to alter a serious disease-causing mutation in an embryo. Respondents were opposed to using it to enhance IQ or athletic ability, or to change skin colour. We also note that some of these attributes are rather complex in their determinants. They depend on genes as well as environment. It is easier to enhance them by appropriate environment, nutrition and education. We do not understand the mechanisms of action of such gene-environment interactions. Such traits should always remain out of bound of any attempt on human germ line genetic engineering.
Finally, there is need for societal discussion towards finding a comfortable place to draw a line and develop mechanisms to obey it. The decision should not be left for researchers and scientists at the bench. It has the potential to affect humanity and must find societal contentment. Otherwise we are left with the question, should eugenics fears stifle scientific progress that may include avoidance of serious genetic diseases from the family lineage?
1. Cyranoski, D. First CRISPR babies: six questions that remain. Nature (2018). doi:10.1038/d41586-018-07607-3
2. Cyranoski, D. & Ledford, H. Genome-edited baby claim provokes international outcry. Nature 563, 607–608 (2018).
Shiva M. Singh, Distinguished University Professor
The University of Western Ontario, London, Ontario N6A 5B7