The Rewriting Revolution

Earlier this week, I discussed the ethical and safety implications of the potential for germline editing using CRISPR/Cas9 technology, referencing  the ‘rumors’ that international scientists had already begun experimenting with human embryos. On Wednesday, the rumors became fact, as Nature News reported the world’s first example of gene editing in human zygotes. The study, led by Junjiu Huang at Sun Yat-sen University, was published in the online journal Protein and Cell.

The scientists targeted the human beta globin gene (HBB) which, when mutated causes the blood disorder b-thalassemia. The investigators used non-viable embryos; eggs that are fertilized by two sperm and therefore do not develop. They are typically discarded by fertility clinics, providing a potential ethical alternative model system for normal human embryos.  While CRISPR/Cas9 was shown to be successful in cleaving the endogenous HBB gene, the paper details numerous obstacles to using this technique for clinical applications in human embryos.

First, the efficiency of the technology was found to be much lower than what would be necessary for use in normal embryos. The researchers injected 86 embryos with Cas9, guide RNA to target HBB, and single-stranded DNA (ssDNA) that, if successful, would be inserted into the HBB locus. Seventy-one of these embryos survived. Out of these, 28 were cleaved by Cas9, but only 4 or 14.3% were edited with the ssDNA. Instead, the double-stranded breaks induced by Cas9 were preferentially repaired by direct ligation of the broken ends, which would not correct the mutations and could also induce additional mutations into the target gene. For ethical reasons, the efficiency and survival would need to be close to 100% to be used in viable human embryos.

Second, numerous off-target effects were detected, meaning the guide RNA induced double-stranded breaks in other genes besides HBB. These unintended mutations were seen at much higher rate than what had been observed in stem cells or mouse embryos, which is alarming. Off-target editing can damage healthy DNA to cause numerous side-effects and diseases if propagated in human embryos.

The results of this study further underscore the need to halt the use of CRISPR/Cas9 in human embryos until the technique can be optimized in human cells or animal models to improve the efficiency of gene-editing and reduce off-target mutations. However, rumors continue to suggest that at least four other groups are editing human embryos. 

Bioethics and Ebola

In December 2014, Presidential Commission for the Study of Bioethical Issues requested public comments on the complex ethical landscape of U.S. public health emergency response to the Ebola virus disease (EVD). Specifically the Commission sought comment on the following 7 topics:

  1. Ethical and scientific standards for public health emergency response;
  2. Ethical and scientific standards that guide the use of quarantine or other movement restrictions during public health emergencies;
  3. The impact of quarantine or other movement restrictions on the availability or willingness of health workers to volunteer to contain the epidemic in disease-affected areas;
  4. The impact of quarantine or other movement restrictions on public fear and anxiety about potential threats to public health;
  5. How U.S. public policy and public health response to the current EVD epidemic might or should affect public attitudes to, and further U.S. policy and public health response to, other current and future public health issues and emergencies;
  6. Ethical and scientific standards for placebo-controlled trials during public health emergencies;
  7. Ethical and scientific standards for collection, storage, and international sharing of biospecimens and associated data during public health emergencies.

The UPMC Center for Health Security submitted comments on each of these topics, which are available here.  The following are our comments on the first 2 topics. The Commission issued its final report on February 26, 2015.


1) Ethical and scientific standards for public health emergency response

There is a set of ethical norms and procedural principles that should guide all preparedness and response actions in public health emergencies including the Ebola response. First among the norms is a commitment to fairnesspolicies and actions that:

  1. Balance the potentially competing duties to care and steward resources (see below);
  2. reflect the specific values and needs of the affected communities;
  3. address the potentially differing viewpoints of patients, clinicians, government authorities and the general public;
  4. are evidence-based (see below); and
  5. are carefully considered and vetted in advance by a broad cross-section of relevant stakeholders.

Duty to Care - Clinicians have a well-recognized duty to provide medical care to the sick and injured especially when the needed care is urgent, such as in an epidemic like Ebola. This duty to care is complicated by the risk that is posed to care providers by the virus. The risk of exposure to the clinician must be weighed against the duty to care, and balancing the two is not easy. Clinicians should not be expected to take extraordinary risks for a patient with no chance of survival. On the other hand, patients should not be abandoned because of a fear of contagion.  

Duty to Steward Resources - The duty to care is also complicated by the potentially competing need of the individual patient and the population.  Clinicians, healthcare facilities, and public health organizations have a duty to steward limited resources in order to do the greatest good for the greatest number. In a crisis such as Ebola, health professionals and policy makers must constantly make difficult allocation decisions based a commitment to doing the most good.  

Evidence-base - In crises like the Ebola epidemic, scientific certainty is hard to come by. Rigorous studies (e.g., epidemiologic, virologic, clinical and therapeutic) that might help answer critical clinical and public health questions  have not been conducted in the past and likely are very difficult to conduct during the ongoing crisis. Nonetheless, clinicians, public health officials, and policy makers have a responsibility to make difficult decisions even in the absence of hard facts and therefore should do all that is possible to secure the best information possible, even if it is only a consensus of experts.

Among the process and procedural principles that should guide actions in preparing for and responding to a crisis are:

  1. Transparency in planning and decision-making
  2. Consistency in application among individuals and across populations
  3. Proportionality - the actions taken must be commensurate with the scale of the emergency and degree of scarce resources
  4. Accountability of governments and policy makers for making reasonable and just policies and clinicians and healthcare facilities for implementing such polices in good faith with reasonable judgment 

2) Ethical and scientific standards that guide the use of quarantine or other movement restrictions during public health emergencies

The use of quarantine and travel restrictions is premised on the assumption that they will reduce the likelihood of disease spread. If this were true, they maybe ethically permissible as a means of preventing harm to many even while imposing limited hardship on a limited number. The problem with this argument is that there is no evidence to support these assumptions.   There is no data or historical evidence to shows that quarantine and travel restrictions significantly slow disease spread, and the hardship imposed maybe substantial and counterproductive.  For example, in the Ebola outbreak, large scale quarantine contributed to areas of hunger and economic crisis in West Africa and made people fearful to report disease.  For these reasons, we conclude that larger scale quarantines and travel restrictions are misguided policies that could worsen rather than improve outbreak control and are therefore both ethically and scientifically unsupportable.   Limited forms of quarantine of specific individuals who have known high risk exposures to a highly contagious disease might be justifiable in certain circumstance but the degree of sequestration of the individual must be commensurate with the risk of exposure and the risk of subsequent transmission, scientifically sound, and the least restrictive possible.

Travel restrictions- The World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have opposed imposing travel bans during the Ebola crisis because there is no scientific evidence that bans have ever been effective at limiting the spread of contagious diseases. At best, modeling studies of Ebola, influenza and other contagious diseases suggest that highly effective travel restrictions (which are probably impossible in the real world) would delay cross-border disease spread by a matter of only 1 or 2 weeks.  Unless there were a vaccine or other intervention that could suddenly be deployed in this short timeframe, this delay is insignificant. But is comes at substantial cost. It interrupts essential trade and causes significant damage to the economies of the affected countries. It also drives travel underground. If people cannot travel legally, they will travel illegally.

Geographic Quarantine- Geographic quarantine, what used to be called cordon sanitaire, involves sequestering a population who may (or may not) have been exposed to the contagious disease but who are not yet ill. Often this means confining people who are not infected along with those who are; thereby greatly increasing the risk of infection to the not-yet-infected. Furthermore, such geographic quarantine often leads to food and water shortages and cut off of basic medical care to the sequestered group. Such “collateral damage” might be ethically justifiable if these measures effectively reduced disease spread, but time and time again we see that many people escape quarantine or flee in anticipation of it and thus the imposition of quarantine promotes rather than hinders disease spread. 

Limited individual “quarantine”- Some forms of limited quarantine (work/home quarantine) and other related forms of movement restriction or monitoring of specific individuals with known or suspected high risk exposures are ethically justifiable if they meet the tests of being scientifically sound, proportional, and consistent. Authorities must also ensure adequate support (e.g., medical, food, emotional, financial) to those whose movement is restricted. Authorities involved should be transparent in their decision-making and accountable. For many people and many diseases that are not transmissible until the onset of symptoms, self-monitoring and active public health surveillance are reasonable courses of action.