The powerful technology CRISPR/Cas9 has brought unprecedented ease to gene editing. Since then, numerous debates about human gene editing have aroused among scientists and the public. In November 2018, the world’s first genetically modified babies were claimed to be born in China. Despite the outcry and critique about this bold experiment, the scientific community has been aware that this day would come sooner or later. With an inevitable start, we have to look into the unknowable ending of the research ethics behind human germline gene editing.
Gene editing in human embryos or gametes has always been a captivating topic for both scientists and the public, since the discovery of DNA. This idea has inspired numerous scientific fictions and movies to discuss the potential harm and ethical challenges brought by gene editing. Nevertheless, the goal was unreachable until the emergence of the new generation of genetic editing tool CRISPR/Cas91, allowing scientists to modify genes with unprecedented ease and accuracy.
Human germline gene editing means intentionally modifying the genes passed on to children, and the modified genes will be inherited by future generations. Despite the prevalence of CRISPR/Cas9 technique in labs and scientific research, applying this technique to human germline gene modification is widely prohibited in many countries, due to ethical and safety concerns. That’s why the birth of the first CRISPR babies in China last month received so many critiques from all over the world2. One the one hand, Scientists all over the world expressed their shock and disappointment; on the other hand, the discussion about CRISPR babies within scientific community has been going on for many years. For example, back to 2005, Nature magazine published a feature article “where in the world could the first CRISPR baby be born?”3. The truth is that scientific community always knew that the birth of CRISPR babies is inevitable. They just could foresee neither when and how, nor the ending.
Before dissecting the ethical challenges brought up by the human germline gene editing, I think it’s important to recognize that we will encounter distinguishing ethical issues based on the maturation of this technology: at the early stage of CRISPR development, clinical safety is one of the major concerns; when this technique is mature and acceptable in the clinic, genetic classism then might become inevitable. I will discuss the ethical dilemma scientists and medical researchers will face during this process.
First, let’s look at the four broadly accepted principles of medical research ethics: respect for autonomy, nonmaleficence, beneficence and justice4. In theory, violation of any of the four principles in medical research shall be identified “unethical”. Yet, it’s not difficult to find examples that two or more principles are often in conflict with each other. For example, a new drug in clinical trial can ease the pain of patients (obeying Principle of Beneficence), but also has the risk of certain side effect (violating the Principle of Nonmaleficence). Under such scenarios, balancing of potential risks and benefits is essential for applying the principles.
Next, I’d like to apply each principle to the case of human germline gene editing, dissect the ethical concern behind it, and propose potential mitigation methods.
Principle of Respect for Autonomy
In medical research, respect for autonomy implies that the patient will make informed and voluntary decisions, without any deliberate influences from researcher side. In the case of the first CRISPR babies in China, “informed consent” was signed by the parents to assure the respect for autonomy. However, it is hard for us to find out whether the scientist had emphasized the potential harm of such practice enough. I doubt the parents would agree to participate in this research, if they had been sufficiently informed the severity of “off-target effect” and unknown side effect of CCR5 gene knockdown. To mitigate the influences from researchers, especially for such novel and even radical trials, I would suggest that a third party should be involved in the process of signing informed consent, so that both neutral and professional counseling will be provided to potential participants.
Besides the autonomy of parents, we also need to consider the autonomy of those gene-modified children. Parents shall be given the right to stave off a life-threatening disease or disability of their kids by gene therapy, but how about non-medical related traits, such as height, skin, pupil color etc.? Majority scientists advocate that human germline gene editing should be limited to disease treatment. For non-medical related traits, the autonomy of children should be respected, in other words, children can make decisions about their height or pupil color independently when they reach the age of adult.
My questions, how about the traits lying between life-threatening and absolutely non-medical related? If parents find out their kids might have higher tendency to be nicotine-addictive or to get bald at early age, wouldn’t their children prefer parents making such changes earlier, rather than waiting for another 20 or 30 years? No one knowns whether the boundary of human germline gene editing will be, but we all know that it will start from disease treatment, to disease prevention, and perhaps will reach traits enhancement someday.
Principle of Nonmaleficence and Principle of Beneficence
I’d like to discuss the principle of nonmaleficence and the principle of beneficence together, since researchers are often required to weigh and balance the potential benefits and risks.
At the early stage of human germline gene editing, potential risks often outweigh benefits. The off-target effect of CRIPSR might lead to the unexpected alteration of crucial genome elements, and eventually causes diseases or other unintended consequences. Although substantial advances in understanding human genome have been made in the past decades, many questions are still unknown for scientists. Radical human experiments might cause public panic, and eventually backlash and halter scientific advancement. Experts and government agencies should establish comprehensive and unified guidelines to assure the steady progress of such studies.
Once the off-target risk is minimized or even eliminated, human germline gene editing is likely to be widely-accepted in the clinical trials. We need to emphasize the importance of the principle of beneficence under such scenario. Just as I mentioned before, it’s inevitable that gene editing will be used to alter or enhance all kinds of traits. The key question here is: how beneficence should be defined? Imagine parents ask a doctor to edit certain gene in their germline cells, because this gene can bring 10% risk of cardiovascular disease to their future babies. The doctor refuses the parents because the beneficence is marginal. How if the risk is 20%? Or 50%? What is a reasonable reference number for beneficence? And who should define it? It’s possible that such numbers will show up in our healthcare reimbursement policy guideline one day.
Principle of Justice
Justice in health care implies the fair distribution of treatments or services in a study or in society. However, justice has to be carefully interpreted when goods and services are scarce and expensive.
Gene therapy can cost $500,000 to $1 million5, while human germline gene editing might cost even more, combining gene editing and prenatal screening. Ethicists are worried that high cost leads to unequal access, and ultimately genetic classism. Although it still sounds like a scientific fiction at current stage, it’s necessary to think through the possible outcomes of “gene injustice”. Some people believe that such injustice will diminish once the gene therapy is covered by health insurances. However, let’s be practical. If such gene editing treatment is covered by health insurance, most people probably won’t be able to afford such insurance policy at all. No one can deny the fact that classism has existed long before the emergence of gene editing technique. Gene is never the ultimate cause of classism.
Another possibility is that the cost and difficulty of gene editing will decrease to a level that most people can afford it in the future. In that case, genetic classism won’t be a big concern, since everyone will have the chance to edit genes of their own or their descendants. However, I hesitate to say that I look forward to that day. I just can’t image what the world is like when such a powerful yet dangerous technique become prevalent.
Human germline gene editing has had an inevitable start. “The technology itself is neither good nor bad. People are good or bad”. Thus, instead of panicking and criticizing, scientists and government agencies should focus on establishing international and enforceable guidelines to help navigate the development of such techniques. With many ethical questions remaining to be answered, human germline gene editing should always be under deliberate management.
YQ Chen in December 2018