The National Academies of Sciences, Engineering, and Medicine (NAS) has issued a report on assessing biodefense capabilities in view of new biotechnologies that could be used to reactive, alter, or design dangerous microorganisms or toxins. Specifically, the report scrutinizes synthetic biology (an umbrella term for a wide array of techniques available for the purpose of biological design). The report, Biodefense in the Age of Synthetic Biology, is publicly available here. This is an era where public health authorities must think beyond currently existing microorganisms (viruses, bacteria) and contemplate biological attacks or events resulting from novel biological agents.The U.S. Department of Defense asked the NAS to “develop a strategic framework to guide an assessment of potential security vulnerabilities related to advances in biology and biotechnology, with a particular emphasis on synthetic biology.”
In its endeavor, the study committee developed a framework to identify the relative level of concern that should attach to particular technological scenarios. In the event of an outbreak from a novel organism, or an attack with a novel toxin, how should public health officials determine the level of risk? The report's framework for assessing concern consists of four factors, along with descriptive elements within each factor. The factors are Usability of the Technology, Usability as a Weapon, Requirements of Actors, and Potential for Mitigation. Looking at these factors more simply, they assess the ease of using a technology, how feasible it is to use it as a weapon, the identification of what actors could achieve certain technical goals (having both knowledge and access to resources), and finally, the existence of measures to counteract a new biological threat. With that framework for guidance, the report ranks certain threats as warranting higher concern than others:
Of the potential capabilities assessed, three currently warrant the most concern: recreating known pathogenic viruses, making existing bacteria more dangerous, and making harmful biochemicals via in situ synthesis. The first two capabilities are of high concern due to usability of the technology. The third capability, which involves using microbes or synthetic pathways to produce harmful biochemicals or toxins to be used against humans, is of high concern because its novelty challenges potential mitigation options.
The report is a timely summary of how current genetic technologies recast and expand biosecurity threats. The framework that the NAS has provided for a methodical evaluation of a new biological organism or biochemical capability will allow public health and national security responders to more quickly determine risk and response during unanticipated events.
Over the last several years, the genome editing field (exemplified by the CRISPR-Cas9 technology) has rapidly expanded to all manner of applications in medicine, agriculture, environment, etc. The attention to legal, regulatory, and bioethical implications of this powerful new technology has grown in parallel. The U.S. National Academies of Science and Medicine launched the Human Genome Editing Initiative in 2015. Most notably, the First International Summit on Human Gene Editing was organized by several national science academies, and took place in December, 2015 (consensus statement here) (see earlier post). Now, 3 years later, the Second International Summit on Human Genome Editing has been announced by a group of science academies (U.S., U.K., and Hong Kong). The summit will take place on Nov. 27-29, 2018, at the University of Hong Kong, and will be webcast live. The organizers issued this statement of purpose:
The science of human genome editing has advanced rapidly since the first international summit was held in 2015 in Washington, D.C. An explosion of new research is employing CRISPR/Cas9 and other powerful, precise editing tools, and clinical trials are planned for applications to treat diseases. However, many questions remain unanswered concerning the science, application, ethics, and governance of human genome editing. Of particular concern is the possibility of genome editing that might lead to heritable alterations, and applications for purposes other than to treat diseases or disabilities.
The Second International Summit on Human Genome Editing will continue to advance the global discussion on these issues by bringing together a broad range of stakeholders – including researchers, ethicists, policy makers, patient groups, and representatives from science and medical academies and organizations worldwide. Participants will examine issues including:
• scientific advances that have been made since the 2015 summit;
• progress in the study of non-heritable genome editing to treat diseases;
• the state of the science for genome editing in germline cells and the potential for clinical applications;
• efforts to address technical challenges identified at the 2015 summit;
• prospects for developing international regulatory frameworks;
• ethical and societal issues surrounding the pursuit of human genome-editing applications; and
• efforts to engage the public.
This second summit will focus global attention on the rapid technological pace of the field, and can draw on 3 more years of research since the 2015 gathering. In 2018, there is more clarity on the scientific challenges of the technology. There is also more technical heterogeneity in the field, such as the development of more precise versions of the Cas9 enzyme in the CRISPR-Cas9 system. Finally, the scope of applications for genome editing techniques is broadening all the time, and the 2018 snapshot will reveal just how widely the technology has shaped modern biological science.
The National Academies of Sciences, Engineering and Medicine (NAS) have released a report on the safety and impact of genetically engineered (GE) crops: Genetically Engineered Crops: Experiences and Prospects. This was an extensive evaluation by a committee comprised of academic experts to consider health and/or environmental effects of GE crops (note that the term "genetically modified organism/GMO" is used widely as well). As the authors described the scope of the report:
The committee examined almost 900 research and other publications on the development, use, and effects of genetically engineered characteristics in maize (corn), soybean, and cotton, which account for almost all commercial GE crops to date.
Here is a summary conclusion from the report:
[T]he study committee found no substantiated evidence of a difference in risks to human health between current commercially available genetically engineered (GE) crops and conventionally bred crops, nor did it find conclusive cause-and-effect evidence of environmental problems from the GE crops.
The committee noted that the majority of GE crops in commercial use are engineered to carry just a few additional genetic traits:
The committee used evidence accumulated over the past two decades to assess purported negative effects and purported benefits of current commercial GE crops. Since the 1980s, biologists have used genetic engineering to produce particular characteristics in plants such as longer shelf life for fruit, higher vitamin content, and resistance to diseases. However, the only genetically engineered characteristics that have been put into widespread commercial use are those that allow a crop to withstand the application of a herbicide or to be toxic to insect pests.
The fact that only two characteristics have been widely used is one of the reasons the committee avoided sweeping, generalized statements about the benefits and risks of GE crops. Claims about the effects of existing GE crops often assume that those effects would apply to the genetic engineering process generally, but different characteristics are likely to have different effects. A genetically engineered characteristic that alters the nutritional content of a crop, for example, is unlikely to have the same environmental or economic effects as a characteristic for herbicide resistance.
There is a reiteration of the basic U.S. regulatory paradigm, which focuses on the nature of a GE product, rather than a process-based approach:
All technologies for improving plant genetics – whether GE or conventional -- can change foods in ways that could raise safety issues, the committee’s report notes. It is the product and not the process that should be regulated, the new report says, a point that has also been made in previous Academies reports.
In determining whether a new plant variety should be subject to safety testing, regulators should focus on the extent to which the novel characteristics of the plant variety (both intended and unintended) are likely to pose a risk to human health or the environment, the extent of uncertainty about the severity of potential harm, and the potential for human exposure – regardless of whether the plant was developed using genetic-engineering or conventional-breeding processes. ” –omics” technologies will be critical in enabling these regulatory approaches.
The United States’ current policy on new plant varieties is in theory a “product” based policy, but USDA and EPA determine which plants to regulate at least partially based on the process by which they are developed. But a process-based approach is becoming less and less technically defensible as the old approaches to genetic engineering become less novel and as emerging processes — such as genome editing and synthetic biology — fail to fit current regulatory categories of genetic engineering.
On the contentious issue of labeling food derived from GE crops (see here), the committee did not find a compelling scientific basis to require labeling, but noted that there are other considerations:
[T]he issue involves social and economic choices that go beyond technical assessments of health or environmental safety; ultimately, it involves value choices that technical assessments alone cannot answer.
The report therefore endorses the existing product-based framework, but coupled with a nuanced determination of what products should receive enhanced oversight. Critically, the report notes a fact which is not widely appreciated, which is that GE crops largely contain only two added traits: insect or herbicide resistance. Both of these characteristics serve agronomic ends, in contrast to alteration of product attributes, such as nutritional enhancement. As a result, the NAS committee notes that other GE traits could be introduced and require specific regulatory focus. This could be especially true when the goal of a GE alteration is a deliberate change in food composition. Finally, and not insignificantly, the committee finds that GE crops, on balance, have not led to increased yields, and notes the development of resistance in both insects and weeds. These latter conclusions will feature prominently as the cost/benefit calculus for the use of GE crops continues to be debated.
The federal regulation of biotechnology products is grounded in a design that was first announced in 1986 as the Coordinated Framework (CF) for the Regulation of Biotechnology, later updated in 1992. Those documents have largely shaped the the federal regulatory regime for biotechnology. A key concept in this original framework was that products produced through genetic engineering (or recombinant DNA) techniques would not receive special oversight because of the processes used to produce them. Instead, a risk-based approach was instituted that focused on the characteristics of actual products, not underlying production techniques. In 2015, the White House, through its Office of Science and Technology (OSTP), announced that it would launch an overhaul of the 1992 policy. In the memorandum, the OSTP provided a definition of “biotechnology products” to be included in the review:
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memorandum.
Since the 1980’s, the existing coordinated framework has divided the primary regulation of biotechnology products among three agencies: the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). The OSTP is involved in a more general role as overseer of the regulatory design, rather than as a formal regulatory body. In the memorandum sent to the heads of the EPA, FDA and USDA, the OSTP alludes to the regulatory overlap, redundancy and confusion that has arisen with the multi-agency design:
Each of the Federal regulatory agencies with jurisdiction over the products of biotechnology has developed regulations and guidance documents to implement its authority under existing laws, resulting in a complex system for assessing and managing health and environmental risks of the products of biotechnology. While the current regulatory system for the products of biotechnology effectively protects health and the environment, in some cases unnecessary costs and burdens associated with uncertainty about agency jurisdiction, lack of predictability of time frames for review, and other processes have arisen.
As part of the modernization initiative, the Administration held 3 meetings organized by the relevant agencies to receive feedback on the proposed overhaul. Two documents were issued that are helpful to understanding the current climate that is precipitating calls for redesign: a table of current agency responsibilities, and a series of case studies illustrating how a singular GE product can be subject to multi-agency review. Pursuant to the OSTP charge, a committee formed by the National Academy of Sciences, Medicine and Engineering was commissioned to conduct a formal study, “Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System.” This committee has set the following objectives:
Describe the major advances and the potential new types of biotechnology products likely to emerge over the next 5-10 years.
Describe the existing risk analysis system for biotechnology products including, but perhaps not limited to, risk analyses developed and used by EPA, USDA, and FDA, and describe each agency’s authorities as they pertain to the products of biotechnology.
Determine whether potential future products could pose different types of risks relative to existing products and organisms. Where appropriate, identify areas in which the risks or lack of risks relating to the products of biotechnology are well understood.
Indicate what scientific capabilities, tools, and expertise may be useful to the regulatory agencies to support oversight of potential future products of biotechnology.
The first public meeting of the NAS committee will be held on April 18, 2016. The agenda for the meeting is posted here.
In 2016, the National Science Advisory Board for Biosecurity (NSABB) has returned to reconsider the issues regarding the approval, funding and oversight of experiments on pathogens that are engineered to contain mutations conferring elevated transmissibility in mammals and/or enhanced pathogenicity (virulence). This line of research has been called gain-of-function research (GOF). Such pathogens are studied to determine which genetic changes in a virus or bacterium confer attributes which create a more dangerous pathogen. Knowledge that a specific genetic mutation could confer a higher risk profile could theoretically allow more precise and knowledgeable public health surveillance of naturally occurring mutations. In addition, therapeutic countermeasures could be developed in advance of an actual strain appearing in the population. Nonetheless, these experiments could produce what have been called potentially pandemic pathogens (PPP) and are therefore controversial because of the possible release of a dangerous microbe, either by accident (biosafety) or design (biosecurity). The NSABB is charged with advising the federal government on bioterrorism-related scientific matters, the panel being created post-9/11. In the wake of controversial experiments published in 2011 and 2012 describing the creation of GOF H5N1 influenza viruses with enhanced transmissibility in humans, the NSABB has been working on formalizing a risk-benefit framework for determining whether certain experiments should be restricted or their funding limited. In 2014, a federal moratorium on the funding of GOF studies was imposed following a series of biosafety incidents at federal laboratories (some GOF studies have been allowed to resume, involving Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza). The NSABB is now conducting public meetings as the next stage in the deliberative process it outlined in 2015. The NSABB commissioned a formal risk and benefit assessment (RBA) from an outside contractor to provide the board with qualitative and quantitative information about the risks and benefits of conducting certain scientific studies. The NSABB also commissioned a formal study of the ethical frameworks that could be relevant to the formulation of official policy. In addition, a working group of the NSABB has published their review of the current issues. Their findings are as follows:
Key Finding 1: There are many types of GOF studies and not all of them have the same level of risks. Only a small subset of GOF studies - GOF studies of concern - entail risks that are potentially significant enough to warrant additional oversight.
Key Finding 2. The U.S. government has effective policy frameworks in place for managing risks associated with life sciences research. There are several points throughout the research life cycle where, if the policies are implemented effectively, risks can be managed and oversight of GOF studies could be applied.
Key Finding 3. Oversight policies vary in scope and applicability, therefore, current oversight is not sufficient for all GOF studies that raise concern.
Key Finding 4. There are life sciences research studies that should not be conducted on ethical or public health grounds if the potential risks associated with the study are not justified by the potential benefits. Decisions about whether GOF studies of concern should be permitted will entail an assessment of the potential risks and anticipated benefits associated with the individual experiment in question. The scientific merit of a study is a central consideration during the review of proposed studies but other considerations and values are also important.
Key Finding 5. The biosafety and biosecurity issues associated with GOF studies are similar to those issues associated with all high containment research, but a small subset of GOF studies have the potential to generate strains with high and potentially unknown risks (emphasis added). Managing risks associated with all high containment research requires Federal-level oversight, institutional awareness and compliance, and a commitment by all stakeholders to safety and security. Biosafety and biosecurity are international issues requiring global engagement.
Last month, the NSABB held an public committee meeting to review all of these recently commissioned reports, with the purpose of making progress in developing a formal roadmap for the federal government to use in deciding whether and/or how to support GOF experiments. The NSABB also invited public comments on the studies cited above. Criticism from other scientists include critiques of the GOF definition itself, objections to the comparatives used in the RBA assessment (e.g., 1918 pandemic influenza virus), a call for more clinician involvement in the process, as well as general objections to a lack of avenues for more public participation in the debate. As this deliberative process plays out over the next several months, the fate of the government-imposed moratorium will also be a consequence of the NSABB conclusions. The deliberative process continues: the second public National Academies of Sciences Symposium on GOF research will be held on March 10 & 11, 2016 and will include a discussion of the RBA study as well as NSABB’s preliminary findings and draft recommendations (the first symposium was held in 2014, see here). There will be an opportunity for the public to participate in the event as well as to submit questions online.
The rapid adoption of the CRISPR/Cas9 gene editing technology is evident in the explosion of papers describing the use of the technique for possible use in a variety of applications (e.g., retinitis pigmentosa, Duchenne's muscular dystrophy, HIV infection). As described in earlier posts here, the use of gene editing falls into two broad categories: altering genes in somatic cells (non-reproductive) to treat disease in individuals or altering the germline DNA in embryos to preemptively treat or minimize later-developing disease. It is the latter application that has led to many calls for an official moratorium, a ban on funding, and the convening of a wide public discussion on whether scientists should be able to edit germline DNA, which would create heritable genetic changes passed on to later generations. As reported here earlier, a development biologist in the U.K. applied to the Human Fertilisation and Embryology Authority (HFEA) for permission to use gene editing to study early embryonic development. That application has now been approved:
Our Licence Committee has approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. The committee has added a condition to the licence that no research using gene editing may take place until the research has received research ethics approval. As with all embryos used in research, it is illegal to transfer them to a woman for treatment.
The goal of Dr. Nakian's research is described:
To provide further fundamental insights into early human development we are proposing to test the function of genes using gene editing and transfection approaches that are currently permitted under the HFE Act 2008. We also propose to use new methods based on CRIPSR/Cas9, which allows very specific alterations to be made to the genome. By applying more precise and efficient methods in our research we hope to require fewer embryos and be more successful than the other methods currently used. Importantly, in line with HFEA regulations, any donated embryos would be used for research purposes only. These embryos would be donated by informed consent and surplus to IVF treatment.
The HFEA approval in the U.K. is without precedent and represents the first officially sanctioned use of gene editing on germline DNA. The 2015 publication of a gene editing experiments on non-viable embryos by Chinese scientists was widely condemned and it accelerated the urgency of considering ethical and regulatory aspects of this research as soon as possible. As described here earlier, a recent National Academy of Sciences (NAS) international summit on gene editing technologies had concluded with a consensus statement that it would be "irresponsible" to use gene editing for the purpose of altering germline DNA in the creation of embryos for reproduction. This research does not do that, explicitly. It will use gene editing to study how genetic changes affect embryonic development as its end goal. With regard to the U.S., there is already an NIH-imposed ban on any federal funding for gene editing on human embryos; in addition, the U.S. has no regulatory equivalent of the U.K. HFEA to consider any possible requests for the approval of non-reproductive embryonic developmental studies like the one approved here. The ongoing NAS study committee will convene another public meeting next week (February 11) to consider more impacts of gene editing technologies; details here.
The International Summit on Human Gene Editing, hosted by the National Academies of Science and Medicine (NAS, NAM) and international partners, has just concluded a 3-day meeting (archived webcast available here). This summit was called following the rapid dissemination of human gene editing research using the CRISPR/Cas 9 technology (see earlier posts here and here). The impact of this technology cannot be understated:
The rapid development and widespread adoption of easy-to-use, inexpensive and effective genome-editing methodologies has changed the landscape of biology. The simplicity of the CRISPR–Cas9 system allows researchers and students to make precise changes to genomes, thereby enabling many experiments that were previously difficult or impossible to conduct.
Widespread concern over possible attempts to engineer the human germline (perform gene editing on embryos or gametes for reproductive purposes) led to calls for caution or even a research moratorium (see here). At the conference this week, panels discussed the current technical state of human gene editing, existing and potential governance structures, international perspectives, and social consequences of the technology. The most controversial application of human gene editing – germline editing creating heritable genetic changes – was central to many of the discussions, and the conference oscillated between considering the legitimacy of germline editing and considering the arguably more mundane regulatory control of somatic gene editing. The conference coordinating committee has released a consensus statement that endorses further research on both somatic and germ-line gene editing, subject to existing regulations and oversight mechanisms. The full statement is here. I reproduce the portion of that statement that focuses on the hotly contested issue of germline gene editing:
3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.
Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.
It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
As reported by David Baltimore, chair of the conference committee, the members did not recommend either a ban or a moratorium on research into germline gene editing, but they state that any use of gene editing in reproduction at this time would be "irresponsible." In the U.S., the NIH has already ruled out federal funding for such research:
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.
The NAS contemplates ongoing public engagement with the controversies raised by human gene editing, in the form of an upcoming formal NAS study and the establishment of a publicly accessible forum to continue the discussion. More analysis of the conference and the effects on the current research climate will be posted here.
Over the last year, several ad hoc and professional organizations have continued to weigh in on whether the CRISPR/Cas9 gene-editing technology should be subject to any pauses in its adoption as a method of genome alteration or correction (see here). The advent of CRISPR/Cas9 technologies, beginning with the first publication in 2012, has accelerated scientific interest in gene editing because the technique has offered a more efficient approach than previous genome-altering methodologies. Here is an overview of the directions such research can take:
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and nonhuman animal biology; 3) research to generate preliminary development of human somatic applications; and 4) research to inform the plausibility of developing safe human reproductive applications.
However, the CRISPR age is encountering fits and starts. Most controversially, the specter of CRISPR becoming a novel reproductive technology to perform gene editing on a human embryo has raised the most attention and concern. Earlier, this year, two groups of American scientists issued cautionary statements (see earlier post here); the NIH then reiterated its ban on any federal funding of research on gene-editing in embryos. More recently, other international bodies are weighing in. The U.K. Wellcome Trust has now issued a statement:
Research using genome editing tools holds the potential to significantly progress our understanding of many key processes in biology, health and disease and for this reason we believe that responsibly conducted research of this type, which is scientifically and ethically rigorous and in line with current legal and regulatory frameworks, should be allowed to proceed. We will continue to support the use of genome editing in preclinical biomedical research as well as studies that progress and refine these technologies. Within the UK, this research may involve the use of somatic (non-reproductive) or germ cells, including human embryos up to 14 days old - within the confines of the HFE Act 2008 - where appropriately justified and supported by rigorous scientific and ethical review.
Against that backdrop, a U.K. developmental biologist has applied to the Human Fertilisation and Embryology Authority (HFEA), for permission to edit the genome of a human embryo (there is no such agency in the U.S). The goal of the proposed research is to identify what genes in the developing embryo are active in the early post-fertilization stages; the research would use surplus embryos from IVF clinics where permission has been granted for such use. The license may be granted:
The Human Fertilisation and Embryology Authority (HFEA) has yet to review her application, but is expected to grant a licence under existing laws that permit experiments on embryos provided they are destroyed within 14 days. In Britain, research on embryos can only go ahead under a licence from an HFEA panel that deems the experiments to be justified.
In a separate development, The Hinxton Group, an international consortium centered on stem cell issues, published a statement calling for caution in possible reproductive applications, but not a moratorium:
Oversight structures must be in place prior to any attempts to use genome editing in human reproduction. Effective oversight requires the development of appropriate standards for preclinical data (e.g., What are acceptable thresholds for off-target events and mosaicism? What are appropriate methods for determining the impact of off-target events?). Initial attempts should be conducted only in the context of formal clinical research or trials. In addition, the health and well-being of participants, developing fetuses, and pregnancy outcomes should be monitored carefully. The health and well-being of those born should also be monitored in long-term follow-up and research, albeit with a mind toward the burdens this would impose.
Finally, in an event that will likely feature a spectrum of viewpoints, the Chinese Academy of Sciences (CAS) and the Royal Society (the science academy of the U.K.) are joining the U.S. National Academy of Sciences (NAS) to hold a highly anticipated international summit on human gene-editing on December 3, 2015 in Washington, D.C. A preliminary meeting (and webcast) to organize the summit will be held next week on October 5, 2015; details here.
