The National Academies of Sciences, Engineering, and Medicine (NAS) has issued a report on gene drive technology, Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct. A gene drive is a method by which specific genetic mutations (or alleles) are preferentially inherited, and over time, the effect is to eliminate other competing alleles. This has population-wide consequences for an organism, and can permanently alter (or reduce) the genetic diversity of a species. The phenomenon of a gene drive occurs in nature, and has been observed in many organisms:
In nature, certain genes ‘drive’ themselves through populations by increasing the odds that they will be inherited.
Now, however, advances in gene-editing technology have facilitated the development of deliberately engineered gene drives. From the report summary:
A wide variety of gene drives occur in nature. Researchers have been studying these natural mechanisms throughout the 20th century but, until the advent of CRISPR/Casfor gene editing, have not been able to develop a gene drive. Since early 2015, laboratory scientists have published four proofs-of-concept showing that a CRISPR/Cas9-based gene drive could spread a targeted gene through nearly 100% of a population of yeast, fruit flies, or mosquitos.
In other words, use of gene drive technology can impose a specific genetic allele (variant) on a population and eliminate all other forms of the gene. Effectively, the population is now homozygous for the preferred variant. That is both the attraction and the concern regarding the use of this technique. Genetic traits could be eliminated, and at its most extreme, whole populations could be "driven" out of existence. It is simple to imagine particular uses of the technology that would eliminate undesirable traits in a target population, such as the ability of mosquitos to spread malaria, or very currently, the ability of the Aedes aegypti mosquito to transmit the Zika virus. The report summarizes possible applications and the requirement for a deliberative approach to use of the technique:
Gene-drive modified organisms hold promise for addressing difficult-to-solve challenges, such as the eradication of insect-borne infectious diseases and the conservation of threatened and endangered species. However, proof-of-concept in a few laboratory studies to date is not sufficient to support a decision to release gene-drive modified organisms into the environment. The potential for gene drives to cause irreversible effects on organisms and ecosystems calls for a robust method to assess risks. A phased approach to testing, engagement of stakeholders and publics, and clarified regulatory over-sight can facilitate a precautionary, step-by-step approach to research on gene drives without hindering the development of new knowledge.
The report did not recommend a moratorium on research, despite noting the potential for adverse consequences. Instead, it endorsed continued research on the technology with some limited field evaluations:
Although there is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment, the likely benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and highly-controlled field trials.
The current regulatory landscape for gene drive applications is summarized:
In the United States, regulation of gene-drive modified organisms will most likely fall under the Coordinated Framework for the Regulation of Biotechnology, which includes the U.S. Food and Drug Administration, the U.S. Department of Agriculture, and the U.S. Environmental Protection Agency. However, the diversity of potential gene-drive modified organisms and contexts in which they might be used reveals a number of regulatory overlaps and gaps. The U.S. government will need to clarify the assignment of regulatory responsibilities for field releases of gene-drive modified organisms, including the roles of relevant agencies.
At the present time, the patchwork structure for biotechnology regulation is currently under formal review by the Obama administration (see earlier post for more background). In general, as the new products of genetic engineering have been developed over the years, they encounter oversight from any one (or more) of three agencies: the FDA, EPA, or USDA. As the regulatory framework is redesigned, we could expect that various applications of gene drive technology will face an approval process customized to the particular goal and purpose of the technology. The report states:
It is important to note that a one-size-fits-all approach to governance is not likely to be appropriate. Each phase of research activity—from developing a research plan to post-release surveillance—raises different levels of concern depending on the organism being modified and the type of gene drive being developed.
The NAS report has received criticism from opponents of field testing, who noted that precise control of such experiments is not possible, and wider, possiblly uncontrolled spread of altered organisms could occur. Other criticisms suggest that the scope of the report is too limited, and does not adequately address possible dual-use concerns (malevolent uses of the technology). The report has some conceptual overlap with efforts of the World Health Organization (WHO) has previously released a guidance framework for how to introduce genetically engineered mosquitoes that are reproductively disabled, thus reducing the population of a malaria vector. In summary, the NAS panel has cautiously endorsed further gene drive research in the U.S., and contemplates eventual field trials of engineered organisms.
The Ebola virus disease crisis continues in western Africa. To date, in the hardest-hit countries of Liberia, Guinea and Sierra Leone, at least 23,913 cases are reported by the World Health Organization (WHO), with 9,714 deaths. At the height of the Ebola outbreaks on several continents last fall, the experimental biotech drug, ZMapp, made by Mapp Biopharmaceutical of San Diego, and comprised of several humanized monoclonal antibodies, was given to several U.S. health care workers who had contracted the virus while working in western Africa, with positive results. Although no drug had received formal approval for treating Ebola virus disease, WHO assembled an expert panel to consider the ethical implications of using non-approved, but potentially promising drugs (including ZMapp) during the expanding Ebola crisis; a summary of their consultation stated:
In the particular circumstances of this outbreak, and provided certain conditions are met, the panel reached consensus that it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment or prevention.
Now, the first formal clinical trial for ZMapp has been announced by the National Institute of Allergy and Infectious Disease (NIAID):
In partnership with the Liberian government, the National Institute of Allergy and Infectious Diseases (NIAID) today launched a clinical trial to obtain safety and efficacy data on the investigational drug ZMapp as a treatment for Ebola virus disease. The study, which will be conducted in Liberia and the United States, is a randomized controlled trial enrolling adults and children with known Ebola virus infection.
“Although ZMapp has been used to treat several Ebola-infected patients in recent months, we cannot determine if the drug actually benefitted those patients because it was not administered within the context of a clinical trial,” said Anthony S. Fauci, M.D., director of the NIAID, at the National Institutes of Health (NIH). “This clinical trial will help us determine if ZMapp and other treatments are safe and effective for use in the current devastating outbreak in West Africa as well as in future outbreaks.
ZMapp, developed by Mapp Biopharmaceutical Inc., based in San Diego, is composed of three different proteins called monoclonal antibodies. ZMapp is designed to prevent the progression of Ebola virus disease within the body by targeting the main surface protein of the Ebola virus. The antibodies comprising ZMapp are produced in tobacco plants specially bioengineered to produce large quantities of these proteins. Studies in nonhuman primates demonstrated that ZMapp has strong antiviral activity and rescued the animals from death as late as five days after infection with Zaire ebola virus. The drug has not yet been tested in human clinical trials, but was administered under emergency use authorization to nine infected patients in Africa, the United States, and Western Europe.
The current picture for containing Ebola virus is mixed; while western Africa is still a focus of public health and relief efforts, there are warnings regarding the possibility that other countries with poor public health infrastructure could be susceptible to future outbreaks. Furthermore, there is still no vaccine available, although some promising candidates are in development. From the U.S. perspective, the American troops committed to public health assistance in western Africa are being withdrawn. The Ebola "czar" has now finished his term, and has called for improving the WHO response capacity, decreasing reliance on overburdened NGOs and establishing a formal international public health responder force ready to be deployed in similar crises. The Ebola crisis illustrates a paradox of modern public health management: specific therapeutic options may originate in cutting-edge biotechnology, but the overall containment of any infectious disease crisis is equally dependent on the availability of basic, old-fashioned public health infrastructure.
The urgency of calls for reliable and scaled public health responses to the magnitude of the international Ebola virus disease (EVD) outbreak is increasing; a media frenzy over the apparent emergence of Ebola in Dallas, TX is underway. At the present time, over 7,000 cases and over 3,300 deaths are attributed to the outbreak concentrated in West Africa, where the virus emerged earlier this year. The crisis requires a combination of public health resources (personnel, facilities, diagnostic capabilities) and effective countermeasures (vaccines, drugs). To date, the most effective drug against the virus appears to be ZMapp, an antibody-based treatment developed by Mapp Biotherapeutical. However, ZMapp supplies are limited, and efforts to scale up production, while necessary, will still not produce enough to meet demand. An expert consultation called by the World Health Organization this week to review vaccine candidates has identified two Ebola vaccines that are ready for Phase I clinical trials. Scheduled milestones for the testing and evaluation of these potential vaccines are now published. Even in a best case scenario, in which a vaccine candidate performs well enough to justify scaleup and distribution, WHO does not anticipate that a significant number of vaccines to be ready before around March, 2015. The WHO meeting participants noted the unprecedented severity and spread of this viral disease relative to other public health crises:
Participants also drew heavily on lessons learned, in the African setting, during trials for candidate malaria, HIV/AIDS, cholera, epidemic meningitis, hepatitis B, and other vaccines. As some experts noted, never again can the international community allow what boils down to “market failure” to create such catastrophic suffering for humanity in any country, in any region of the world. The sense of urgency and need for speed, without compromising the integrity of studies or the quality of their data, are fully justified by the dire situation in affected countries and the risk that other countries may soon experience their first imported cases. The Ebola outbreak currently ravaging parts of West Africa is the most severe acute public health emergency in modern times. Never before in recent history has a biosafety level 4 pathogen infected so many people so quickly, over such a wide geographical area, for so long.
The CDC has already estimated that 1.4 million cases of EVD could emerge by January next year. Case projections from WHO are smaller, but both agencies point out that a near-term ability to reverse the course of EVD will depend on successful public health efforts, including patient isolation and contact avoidance measures. Drugs and vaccines will not be produced fast enough in the short term to meet demand, but the efforts described above are good starts. More generally, as the WHO acknowledged with its reference to “market failure,” it is clear that government expenditures for research on countermeasures need to continue, but the development of a true pipeline from lab to clinic is still lacking. That is a translational failure here: the emergence of rare but deadly outbreaks of diseases like Ebola are not met with stockpiles of drugs. The U.S. Strategic National Stockpile maintains supplies of drugs for use in viral epidemics, but these are directed to the more familiar diseases such as influenza and anthrax. The current Ebola outbreak illustrates the consequences of focusing national resources too narrowly on the usual suspects in bioterrorism or pandemic crises, with the consequence that new or remote pathogens emerging in the U.S. are not met immediately with effective countermeasures that would contain disease outbreaks.
Ebola virus disease (EVD) has appeared in several West African nations over the last several months, and is now spreading with increasing speed. The international public health response has involved World Health Organization (WHO), Centers for Disease Control (CDC), Doctors Without Borders (MSF), and local public health authorities, among others. WHO has now formulated an Ebola response roadmap for the crisis.The history of Ebola virus outbreaks shows the first recognition of the pathogen in 1976, followed by several decades of periodic outbreaks with various virus subtypes. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), placed the current EVD outbreak in historical context:
In most instances, the virus emerged in geographically restricted, rural regions, and outbreaks were contained through routine public health measures such as case identification, contact tracing, patient isolation, and quarantine to break the chain of virus transmission. In early 2014, EVD emerged in a remote region of Guinea near its borders with Sierra Leone and Liberia. Since then, the epidemic has grown dramatically, fueled by several factors. First, Guinea, Sierra Leone, and Liberia are resource-poor countries already coping with major health challenges, such as malaria and other endemic diseases, some of which may be confused with EVD. Next, their borders are porous, and movement between countries is constant. Health care infrastructure is inadequate, and health workers and essential supplies including personal protective equipment are scarce. Traditional practices, such as bathing of corpses before burial, have facilitated transmission. The epidemic has spread to cities, which complicates tracing of contacts. Finally, decades of conflict have left the populations distrustful of governing officials and authority figures such as health professionals. Add to these problems a rapidly spreading virus with a high mortality rate, and the scope of the challenge becomes clear.
To date, at least 3,000 cases and over 1800 deaths have been reported in the West Africa nations of Sierra Leone, Guinea, and Liberia, with numbers rising. Isolated cases are also observed in Nigeria and Senegal. To date, the case fatality rate is estimated at around 60%. No vaccine or effective antiviral is currently available against the virus. An unapproved cocktail of monoclonal antibodies produced by Mapp Biopharmaceutical of San Diego, called ZMapp, was administered to several health workers from the U.S.; their recovery may be partially explained by the use of this drug (although their access raises ethical questions regarding how to allocate scarce countermeasures). That drug essentially transfers an immune response to the patient (passive immunity). The other modalities for EVD treatment and prevention are the more commonly known avenues of vaccines that elicit the patient’s own immune response and/or antiviral drugs which interfere with virus replication. The availability of vaccines and antivirals for “emerging or reemerging diseases” illustrates the deficiencies in matching market realities to public health demands. The research that led to ZMapp was partially funded by the U.S. government as part of its program to establish medical countermeasures against a bioterrorist attack (resources that greatly expanded after 9/11). The supply of ZMapp is limited; HHS is now funding expanded production and formal clinical trials of the drug. In addition, several Ebola vaccines will enter clinical trials soon. But the availability of countermeasures, while necessary, is not the only determinant of how soon the outbreak (not yet called a pandemic) will be contained. The international public health infrastructure, ideally coordinated by WHO, is dependent on funding from national governments, and mandated funding has declined over the years, undercutting WHO's capabilities. WHO did not declare a public health emergency until August, despite the fact that cases began to spread in March. While more vaccines and antivirals can make a difference in any viral disease outbreak, the spread of EBV could have been managed with a more robust public health emergency response earlier this year. MSF has called for countries with biological disaster response teams (e.g., U.S.) to send these personnel to the regions to augment field hospitals, diagnostic laboratories, and other facilities needed to manage the crisis.
Last week, an emergency meeting was called by the World Health Organization to consider the recent development of a genetically refined H5N1 influenza with apparent pandemic potential. Those in attendance included virologists, public health officials and scientific publishers. Two issues were paramount. Is this research worth continuing despite possible adverse consequences? Should the full details of the virus production and structure be published? In November, the leading journals Science and Nature were asked by the U.S. National Science Advisory Board for Biosecurity (NSABB) to publish only redacted versions of the submitted publications detailing the virus work; see here for their reasoning; this issue has been under advisement at these journals. Now, the WHO meeting has come to a recommendation that the scientific articles be published in full with no redactions, but that more delay to consider all ramifications is advisable. This meeting now places WHO into the mix of authorities who are weighing in on these issues; of course, the research under focus was funded by NIH and conducted in the Netherlands and the U.S. It also means that the NSABB is not the only party that is considering how to modulate scientific publication (here, it’s a delay, but that lines up with evaluating the act of publication for its public health consequences). The participants endorsed the value of the research, but agreed that a continued moratorium on further research into this H5N1 virus was advisable to allow fuller deliberation on the biosecurity risks and benefits. More meetings are planned for the future. Apparently, the U.S. continued to argue for redacted publication, which is interesting given the central role of NIH as the funder of the controversial research. So this is a small victory for those who oppose publication controls on scientific research; no doubt, however, that all the attention given to publication decisions resulted in an attention to the underlying research that might not have occurred otherwise.
The annual meeting of the United Nations (UN) General Assembly is underway in New York. We're used to seeing either the UN - or the World Health Organization (WHO) - play a leading role in the containment of infectious disease outbreaks, whether acute (e.g., H5N1 flu pandemic) or more chronic (HIV/AIDS). But there has been more pressure for international public health authorities to also focus on the effort to reduct the health burden of non-communicable diseases (NCD) - cardiovascular disease, diabetes, cancer, and chronic respiratory disease. Advocacy efforts to get the NCD agenda into center stage on the international public health agenda have culminated in the UN responsiveness seen this week. A 2011 report from the UN declared its new focus: "Non-communicable diseases represent a new frontier in the fight to improve global health. Worldwide, the increase in such diseases means that they are now responsible for more deaths than all other causes combined." This week, a special UN session was devoted to the NCD public health agenda. The session had been planned for several years, and a draft political declaration had been prepared in advance for adoption at the meeting this week. While no one quarrels with the recognition that the NCD health burden is staggering, the declaration notes, in so many words, that the prevention of NCD (reducing risk factors, including environmental and social adversities) and control of NCD (providing medical services and pharmaceuticals) inevitably draws in a large menu of social and political controversies that are no more amenable to consensus now than before. In that sense, it will be interesting to see how the NCD framing of health disparities summons political will to address the same. Also, to what extent does the elevation of NCD health issues translate to defining such health conditions as "national emergencies" which could invoke the Article 31 of the TRIPS Treaty - authorizing compulsory licensing mechanisms which have been used to alleviate limitations on drug access for infectious diseases (e.g., AIDS)? The UN has used language in its statements ("epidemic proportions") which calls attention to the magnitude of the NCD burden; Dr. Margaret Cho, the director of WHO, has called NCDs "a slow-motion disaster." Thus, this week's meeting and attention accelerates some reframing of public health needs, with the possibility that progress toward allevating both NCDs and non-NCDs ensues, using this egalitarian lens.
