Genetic Engineering: Ethical Concerns

Returning to our consideration of the genetically modified twins, one must have a framework in which to consider the ethical questions.  In the United States, research involving human subjects falls under the governance of Health and Human Services regulation 45 CFR part 46. However, though a member of the research team is a faculty member at Rice University, the work was carried outside the United States and not subject to the restrictions that come with US federal funding.

            There are international guidelines we can consider,however, that began with the 1947 Nuremberg Code and is now represented by the Declaration of Helsinki and its revisions. Much of these guidelines deal with informed consent.  As Dr. He’s work remains unpublished and unreviewed, however, there is little for us to comment upon.  Two key guidelines which we can focus on, however,are that the research participants should be put at no greater risk than were they to receive conventional treatment and that the anticipated results are not already obtainable by conventional methods.

            In China, the incidence of HIV infection is on the rise.  In 2017, it was reported that incidence of HIV in the Chinese population was 4.2 in every 100,000 individuals (Zheng,2018).  As such methods of curbing the growth of HIV is a significant public health concern in China.  Dr. He’s work, similar to vaccination, was designed to protect individuals from the risk of HIV infection. 

            Subjects were recruited through a Beijing-based AIDS advocacy group and were all couples seeking in-vitro fertilization where the mother was HIV and the father HIV+ (Marchione,2018).  The couples were offered in-vitro services and medical insurance for any resulting offspring.  The male subjects were all under well-controlled anti-viral treatment and were not considered a risk of transmission of the virus.  The male sperm was washed, the standard procedure for preventing HIV transmission to the embryo, and introduced into the ovum producing embryos that were then given CRISPR-Cas9treatment.  Of the sixteen embryos created,eleven were implanted in numerous subjects finally resulting in the birth of the twins in November. 

            One immediate consideration is that this CRISPR project offers no value from the perspective of delivering babies free of HIV.  The sperm washing technique is the standard procedure and is considered effective in removing any HIV in the sample prior to fertilization.  As such, even without the genetic engineering, the twin girls would have been born HIV-free.

            What of the risk of contracting HIV from the male parent after birth?  As stated, all male subjects in the study were well-controlled and not considered a risk for transmission (Stein, 2018).  They present little or no risk to any offspring.  However,with the incidence of HIV growing in China, perhaps a general immunity to HIV infection is a goal worth the risk?  Are there any risks to the two girls?  Initial genetic testing shows that in one girl, both copies of the CCR5 gene have been modified.  However, in the other girl,only one copy has been modified leaving her open to possible HIV infection.  Even had the procedure been completely successful for both twins, knockout of the CCR5 gene carries a higher risk of contracting other viruses, including the rapidly spreading West Nile virus and increases the chance of morbidity from contracting the flu(Stein, 2018) (Marchione, 2018).  How does potential HIV protection in one or both twins balance against increased susceptibility to other diseases?

            While CRISP-Cas9 technology is utilized for its specificity, off-target effects are not unknown (Kim et al, 2015) (Cho et al.,2014).  Such effects can be reduced by choosing unique sequences for nucleic acid cleavage. At birth, both twins appeared healthy and have gone home with their parents.  With the details of the work unpublished,there is no way to determine whether the cleavage target chosen displayed a sufficient level of specificity.  As He states he acted outside the umbrella of a review committee for the work, we are left to trust his judgement and await full genetic testing to determine what additional risks to which the children may be subjected.

            Stepping back from the particulars of this case, this work was not created in a vacuum. Genetic manipulation using CRISPR systems is a common technique in research, and the question of whether it should be applied to human research has been asked before.  In 2015,Baltimore et al. offered the following guidelines (pg. 37)

  1. Strongly Discourage any clinical attempts at germline modifications until scientific and governmental agencies have developed concrete guidelines.
  2. Create forums for dissemination of scientific and bioethical information.
  3. Encourage transparent research into CRISPR-Cas9 genetic engineering in human and non-human model systems.
  4. Convene global representatives to draft appropriate guidelines.

These sentiments are echoed by Lanphier et al. (2015) who suggested a voluntary moratorium on human germline modification while the ethical and regulatory bodies came to terms with the potentials of easy genetic manipulation presented by CRISPR.  Chan et al. (2015) offer fourteen recommendations regarding research involving modification of the human germline.  One recommendation that seems particularly appropriate to our consideration of He’s work is as follows:

Decisions about research and clinical uses of genome editing technologies should be made through inclusive, deliberative processes that will make engagement with the public and policymakers substantive,and should aim to strike the best possible balance between free scientific inquiry and social values. Further, best methods for integrating the outputs of public engagement into the policy making process should be identified and utilized (p. 45).

            What then can we take from Dr. He’s work?  Does it fall within accepted ethical guidelines?  Is it a case of an individual’s arrogance causing him to rush ahead in spite of global norms in research?  Where do you stand?

Coming Soon
Can Dr. He’s work be considered Ethical?
Can Dr. He’s work be considered Ethical?
Can Dr. He’s work be considered Ethical?

Coming Soon
Should a temporary moratorium on clinical germline modification be enacted?
Should a temporary moratorium on clinical germline modification be enacted?
Should a temporary moratorium on clinical germline modification be enacted?

            In my own case, I work at the University of Michigan and deal with stem cell and CRISPR products daily. The fallout from Dr. He’s actions are far from clear.  At this point to little is known about what went into the project, and what the final results will be for these children.  However, it has already begun to reinvigorate the global conversation around human genetic engineering, and that, at least,is a positive result.  This story serves as a reminder that all research decisions come with consequences, and hopefully this is a decision that the two girls will not come to regret.

            In research, we are required to push the boundaries of current knowledge, but always with the protection of human research participants as a primary guiding principle.  While all the information is not yet available, I do not believe that Dr. He adhered to these principles regardless of the outcome. As I work, and as I teach new investigators, this will be a used as a teachable moment in the ongoing consideration of our ethical responsibilities in science.