Several technological waves of genetic modification of crops have ensued over the last several decades. Genetic engineering has generally referred to the insertion of genetic material into an existing organism (often described as transgenic). Genetic editing is a later wave of genetic intervention, involving the direct alteration of a gene’s sequence on site (this CRISPR-fueled technology taking off since about 2012). A conceptual question of recent origin is whether both transgenic and genetically edited crops are classified as genetically modified organisms (GMOs). In the U.S., regulators have decided that genetically edited crops will not require any specific regulation, unlike transgenic organisms. In
March, the U.S. government announced that it would not impose any
particular regulation on genetically edited crops, regarding such crops as closer to those derived from traditional mutagenenesis. The U.S. Department of Agriculture (USDA) stated:
Under its biotechnology regulations, USDA
does not regulate or have any plans to regulate plants that could
otherwise have been developed through traditional breeding techniques as
long as they are not plant pests or developed using plant pests. This
includes a set of new techniques that are increasingly being used by
plant breeders to produce new plant varieties that are indistinguishable
from those developed through traditional breeding methods. The newest
of these methods, such as genome editing, expand traditional plant
breeding tools because they can introduce new plant traits more quickly
and precisely, potentially saving years or even decades in bringing
needed new varieties to farmers.
A new ruling from the European Court of Justice addresses whether genetically edited crops fall within the 2001 E.U. Directive on the Deliberate Release of Genetically Modified Organisms:
In today’s judgment, The European Court of Justice takes the view, first of all, that organisms obtained by mutagenesis are GMOs within the meaning of the GMO Directive, in so far as the techniques and methods of mutagenesis alter the genetic material of an organism in a way that does not occur naturally. It follows that those organisms come,in principle, within the scope of the GMO Directive and are subject to the obligations laid down by that directive.
In keeping with its more stringent regulation of genetically engineered (transgenic) crops, the E.U. has decided to maintain a cohesive scheme for modern genetic technologies, classifying genetically edited crops as GMOs. In contrast, the U.S. has bifurcated its oversight of genetically altered crops, with recent decision-making that allows genetically edited crops to advance quickly in field testing.
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 long running patent dispute between two leading players in the development of the genome editing CRISPR-Cas9 (CRISPR) technology has finally reached the Federal Circuit. On April 30, 2018, the University of California, Berkeley (UC) and the Broad Institute of MIT (Broad) met at the court to argue inventorship rights in foundational patents on methods for the use of CRISPR technology.
Briefly, the first-filed UC patent application to Jennifer Doudna, Emmanuelle Charpentier and their colleagues is directed to methods for the use of CRISPR in all cells. A later-filed application by Feng Zhang and his colleagues at the Broad resulted in an issued patent for the use of CRISPR in eukaryotic cells (includes human and animal cells). Between these two rivals, the UC scientists were first to publish on the CRISPR technology in the scientific literature.
Historically, U.S. patent law, requiring the issuance of a patent to the first inventor, has had a mechanism for identifying the first inventor where two separate applicants file for a patent on overlapping subject matter, known as an interference proceeding. The 2011 America Invents Act (AIA) instituted a first inventor to file regime, which largely eliminated the need for interferences. These CRISPR patent applications were filed before the effective date of the AIA in 2013, and are thus subject to the older regime. Thus, the patent rights to one of the most important advances in biotechnology are being sorted out according to the now-discarded first inventor paradigm of U.S. patent law. UC requested an interference proceeding from the U.S. Patent and Trademark Office (USPTO) Patent Trial and Appeal Board (PTAB), believing that the Broad application covered the same subject matter as their own patent application and was therefore not valid (asserting that eukaryotic cells are a subset of all cells, and fall within the scope of the UC patent). The
UC argument is that their patent application is prior art to the Broad
patent, and provided enough information to allow other scientists to use
CRISPR in eukaryotic cells with a “reasonable expectation of success.”
UC asserted that the Broad subject is therefore obvious and not patentable. The PTAB declared an interference in 2016 (more background here).
In early 2017, the PTAB ruled that there were no conflicting patent rights (no interference) between the pending UC patent application and the already issued Broad patents. According to the PTAB, the Broad patent was not obvious in view of the UC patent application. Therefore, the existing grant of patents to the Broad for the use of CRISPR in eukaryotic cells was upheld, and the UC application for the use of CRISPR in all cells could continue prosecution. Effectively, this was a win for Broad. UC then appealed the PTAB decision to the Federal Circuit.
In the oral argument at the Federal Circuit on April 30th, the dispute centered on whether the PTAB applied the correct evidentiary standard to the determination of nonobviousness, and whether it properly considered all available evidence in its review. The PTAB had found that there was enough uncertainly about the technology in the 2012 time frame that the Broad scientists had no “reasonable expectation of success” and its work in eukaryotic cells was nonobvious; UC argued that the PTAB misapplied the obviousness standard.
It appears that the Federal Circuit may be likely to affirm the ruling of the PTAB. Looking forward, it is possible that the coexistence of a UC patent (upon issuance) and the Broad patents could require licenses from both patent holders for the use of CRISPR in eukaryotic cells by third parties, and cross-licenses between the patent holders for such use. The fate of patent rights to one of the most important biotechnologies in decades could soon be clarified. Depending on the ruling, a Supreme Court appeal could follow; however, it is unlikely that the Court would take the case.
Yesterday, the Recombinant DNA Advisory Committee (RAC), a federal advisory committee to the NIH, held a public meeting to consider the first submission for approval to use a CRISPR/Cas9-based (CRISPR) study protocol with human patients. CRISPR is a technique that allows genes to be edited; it has swept through biomedical science in the last few years as a breakthrough technology. The
RAC committee has provided oversight for the field of gene transfer
therapies for decades (and supplements FDA and local institutional oversight by IRBs and IBCs). As an advisory committee to NIH, first
constituted in 1974, RAC's regulatory portfolio for human experiments began with reviewing gene transfer studies pursuant to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. The field of "gene therapy" has largely been comprised of studies involving gene transfer into patients to correct, replace, or diminish gene activity relevant to various clinical conditions; to date, several thousand gene therapy clinical trials worldwide have been conducted. RAC's jurisdiction extends to the use of gene-editing
protocols, as well as other gene-altering technologies such as RNA
interference. Now,
a collaborative effort from the University of Pennsylvania (Penn), M.D.
Anderson Cancer Center, and the University of California, San Francisco produced a proposed study protocol involving CRISPR gene-editing that was discussed and evaluated by the
RAC this week at its meeting. The protocol involves an ex vivo technology where T cells of cancer patients will be removed and subject to gene-editing to alter several
cell receptors before the cells are infused back into the patient. The goal is to engineer the T cells of the immune system so that they target and destroy cancer cells; this initial study is to identify any safety issues that might emerge. The recruited patients have either myeloma, melanoma, or sarcomas and would be those for which conventional therapies are not available or effective. During the meeting, questions were raised about potential conflicts of interest due to financial interests of some investigators, as well as the involvement of Penn, as it was the site of the now well-known 1999 gene therapy trial that resulted in the death of Jesse Gelsinger; that trial had notable flaws involving the transparency of preclinical testing and of competing financial interests. After public review and discussion of the protocol, the committee voted to approve the protocol. Yesterday's approval marks the first RAC-sanctioned use of CRISPR technology in human patients.
This is the first study protocol submitted to RAC that uses CRISPR in humans, but it is not the first gene-editing human protocol that RAC has considered. Sangamo BioSciences received approval to use its zinc-finger gene-editing technology (ZFN) in two different human trials: an ex vivo protocol approved in 2007, and an in vivo protocol approved in 2015. In what appeared to be a coincidence, yesterday's meeting also considered the first proposed gene therapy trial to treat Ornithine Transcarbamylase (OTC) Deficiency since the 1999 Gelsinger trial. Several discussants referenced the Gelsinger incident in their comments. The committee held a discussion of whether preclinical trials for the gene transfer method in non-human primates were necessary before approval (only mice studies were provided); RAC then voted an approval with stipulated conditions.
As gene transfer studies have become more routine over the last several decades, the scope and need for continued RAC oversight has been questioned. A recent study of RAC that was conducted by the Institute of Medicine examined whether gene transfer oversight by RAC continued to be necessary; the report concluded that only new protocols presenting novel vectors or technical approaches needed to be evaluated by RAC. However, the IOM committee explored whether the RAC model of a public advisory committee could be utilized more generically for other emerging biotechnologies. including, for example, protocols from the field of nanobiotechnology or synthetic biology, for example. The IOM report endorsed consideration of an expanded scope for RAC or an advisory committee with similar attributes to provide the kind of oversight for new technologies as RAC has provided for decades in the field of gene therapy.
Genetic alteration since the beginning of the biotechnology age has largely relied on the introduction of new genetic material into an organism to create a genetically engineered (GE) bacterium, plant or animal (also known as a genetically modified organism, GMO). Regulatory schemes reflected that dominant paradigm. Now, however, the use of gene-editing technology for genetic manipulation in plants can result in genetically altered plants that bypass the regulatory requirements for the introduction of standard GE plants into the marketplace. The traditional genetic engineering of crops employed the introduction of foreign genetic material into the crop; such gene transfer generally triggered formal review of the altered product because of the phenotype conveyed by the introduced gene(s), or because of the use of a vector that had plant pest characteristics. A GE plant product would trigger review if the newly introduced trait posed environmental or other safety-related risks. The review was conducted by the Animal and Plant Health Inspection Service (APHIS) of the USDA, pursuant to its statutory authority under the Plant Protection Act of 2000. (Depending on the product, additional oversight by the FDA or EPA could be required). Today, genetic alteration has moved beyond simple gene transfer into more precise techniques for changing the genome of an organism. Now, in a regulatory first, APHIS has made a determination that a white button mushroom altered by CRISPR/Cas9 gene editing technology to exhibit reduced browning is an “unregulated article” that will not require the kind of formal review usually applied to traditionally genetically engineered products containing foreign DNA:
APHIS does not consider CRISPR/Cas9-edited white button mushrooms as described in your October 30, 2015 letter to be regulated.
Here, CRISPR/Cas9 gene editing technology was used to introduce a small deletion in a polyphenol oxidase gene in the mushroom, with the result that the altered enzyme cannot produce the browning that shortens shelf life. The final product has no foreign DNA and no plant pest characteristics. This decision by APHIS follows earlier determinations that have resulted in at least 10 genetically altered products being approved without requiring a formal review. These products have been produced with, e.g., techniques that did not rely on the introduction of new genetic material using any plant pest vector, or non-CRISPR gene editing technologies. This shift in regulation highlights how modern genetic alteration writ large encompasses multiple technologies, some of which fall into an existing regulatory mandate, and some of which do not. The central theme of biotechnology regulation to date has been to focus on the product, not the process. As far back as the introduction of the federal Coordinated Framework for Regulation of Biotechnology in 1986, the prevailing scheme ensured that genetically engineered products would not be singled out for heightened review simply because of the way they were produced. The product was the focus; more precisely, the actual phenotypes of the GE plants or insects were evaluated to identify traits that required additional oversight. The traditional dichotomy between product-based or process-based paradigms for regulation biotechnology products has been criticized as a poor fit for the realities of the biotech marketplace. Evidence for an evolution of the regulatory scheme has been provided by the Obama administration’s announcement of a deliberative process to overhaul and modernize the regulation of biotech products, with the recruitment of the FDA, EPA, and USDA in the process (see earlier post). This regulatory renewal will no doubt eliminate a strict focus on gene transfer as the only genetic technology producing altered organisms, and strive to broaden the definition of the field of genetic alteration to reflect new realities, such as CRISPR and other gene-editing technologies. Then the calculus of risk/benefit analysis will need to be applied, in the context of emerging genetic technologies where risk profiles are not yet established.
The powerful gene editing technology, CRISPR/Cas9, is now the subject of debate over its uses and applications (see here), and whether any limits should be set on possible applications in reproductive medicine (see here). However, a wholly separate controversy has been circulating in the field, involving a messy patent dispute between two of the main players in the development of the technology. A patent application on the technology was filed by Jennifer Doudna and her colleagues (Doudna) (assigned to UC Berkeley). In the same time frame, CRISPR-related patent applications were also filed by Feng Zhang and his colleagues (Zhang) (assigned to MIT and its Broad Institute). Doudna filed in May, 2012, while Zhang filed in December, 2012. Doudna's application is still pending, while Zhang has a number of issued patents to date (e.g., U.S. Patent No. 8,607,359); Zhang requested an accelerated patent examination and thus received the earliest issued patents. U.S. patent law underwent a significant change in 2013 when the America Invents Act (AIA) came into force, establishing a first-inventor-to-file standard in the law. Until then, the U.S. required that a patent be awarded to the first inventor (in time); that individual might or might not be the first to file a patent application on the invention. U.S. patent law has had a mechanism for identifying the first inventor where two separate applicants file for a patent on overlapping subject matter, known as an interference proceeding. The U.S. Patent and Trademark Office (PTO) has issued a Declaration of interference between Doudna and Zhang, based on the sequence of the Doudna/Zhang patent filings, which both claim overlapping subject matter (since both were filed before the AIA took effect, the conflict will be settled under the old first-to-invent standard). The Administrative Patent Judge has issued a "count," which is a fictional claim that encompasses the conflicting subject matter:
A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:
contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising:
a) a DNA-targeting RNA comprising
i) a targeter-RNA or guide sequence that hybridizes with the target sequence, and
ii) an activator-RNA or tracr sequence that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, and
b) a Cas9 protein,
wherein the DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.
Although this is an oversimplification, a key dispute centers on whether Doudna is only entitled to patent rights on an in vitro CRISPR/Cas9 component system, while Zhang is entitled to patent rights on the use of CRISPR in eukaryotic cells (the most valuable application of the technology). In an interference, the first filer (Doudna) is deemed the senior party, while the second filer (Zhang) is the junior party, and thus has the burden of proof to establish an earlier date of invention. Invention requires conception of the inventive idea, as well as either actual or constructive reduction to practice (meaning actual work on the invention or the actual filing of a patent application). A judge from the PTO’s Patent Trial and Appeal Board (PTAB) will conduct the proceeding. The interference could be expected to take several years, at least. The parties could settle along the way, with priority conceded and possible licensing options established. Since U.S. patent interferences are phasing out of American law due to the changes instituted by the AIA, it is no small irony that one of the most high-profile interferences will occur 3 years after the statute took effect. In addition, the patent rights to one of the most important advances in biotechnology will be sorted out according to the now-discarded first inventor paradigm of U.S. patent law. The patent rights at stake are immensely valuable, and even with an uncertain IP landscape, gene editing startups are proliferating as well as investments from established pharmaeutical companies in gene editing ventures.
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.
On two separate fronts, Congress has now engaged with the controversy over the use of genome-editing technology, particularly the CRISPR/Cas9 (CRISPR) protocol. Last week, the House Research & Technology Subcommittee of the Committee on Science, Space and Technology held a hearing, The Science and Ethics of Genetically Engineered Human DNA. The use of CRISPR for editing of the human germline was suddenly a public concern when Chinese scientists published a set of gene-editing human embryo experiments (see here). At the hearing, several scientists testified on the current level of CRISPR development and possible applications. One presenter, Dr. Jennifer Doudna, is one of the developers of the CRISPR technology, and was part of a scientific ad hoc group that published a call for caution in the use of the technology, particularly as applied to reproductive purposes, such as genetic engineering of the human germline (see here). Several themes emerged during the testimony and subsequent questioning by Congressional panel members (the webcast of the House hearing is available here). The application of CRISPR to actual clinical/medical uses is still a work in progress, although panelists agreed that the pace of development is swift, as the relative ease of use and efficiency of the CRISPR technology has excited the scientific community. In the questioning from the House members, some dominant concerns emerged: would potential regulation apply to privately funded research as well as government-sponsored; how would a U.S. based regulatory regimen have any effect on international scientific efforts; is the U.S. at the forefront of technology development in these life science sectors. The hearing was clearly exploratory and a way for concerned representatives to weigh in on an emerging scientific debate. All participants noted that the National Academy of Sciences and National Academy of Medicine will be holding an international summit on gene-editing this fall in order to develop guidelines for use of the technology:
The committee will consider and recommend standards, guidelines, and practices governing the use of gene-editing technologies in biomedical research and medicine.
The second intersection of Congress and gene-editing technology comes in the form of an amendment introduced into the current appropriations bill under consideration by the House that would prohibit the FDA from reviewing any application for clinical trials on the use of genome editing in embryos or gametes. It's not clear if this provision could make its way into the final bill, but more importantly, it is likely a shot across the bow to the private sector, creating a roadblock for any commercial endeavors of germline gene-editing in reproduction, as any such government-funded research is already blocked by existing laws that prohibit most embryo-based research.
Following on the recent post, the rush to develop some initial policy statements on the use of genome editing techniques for germline engineering is now understood following the first publication of an attempt to perform germline engineering on embryos using the CRISPR/Cas 9 (CRISPR) system, as reported by Chinese scientists. Several weeks ago, two separate policy statements were issued by experts in genome editing who called for either a moratorium or an ethics-initiated slowdown on any use of the technique on embryos. At the time, there were rumors of an imminent publication, and this was true. The new publication reports that the use of CRISPR to alter the germline of about 86 non-viable embryos had mixed results; some of the embryos accepted the genetic changes, but some did not and “off-target” events were reported, indicating that unintended genomic alterations occurred. These experiments have been widely reported, and have alerted the general public to an issue that they were generally unaware of. Public reaction has followed as well as some official commentary. The journal that published the paper has now issued a statement on its decision to publish:
Protein & Cell has fully realized that this study can provide direct evidences to address some of safety concerns of the CRISPR/Cas9 technique. It may also raise a series of questions and bring further controversies to the field of gene-editing research. In this unusual situation, the editorial decision to publish this study should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw immediate attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos.
Official responses have also followed the publication of the CRISPR embryo studies. The NIH has issued a policy declaration making it clear that no federal funding is available for research that uses genome modification to the germline of a fertilized egg or embryo. The statement anchors the policy in the already existing legal/regulatory climate:
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. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey-Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee “will not at present entertain proposals for germ line alteration.” It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312).
The NIH reiterates the lack of federal funding for any CRISPR (or other technology) attempts at germline engineering. It notes that the combination of existing prohibitions on funding embryo research combined with the ongoing supervision of gene therapy by RAC, supplemented with FDA pronouncements on its jurisdiction over some biotechnology products, create a patchwork of constraints on research in the U.S. RAC considered fetal gene therapy in 1999; as the NIH statement summarizes, the committee was not receptive to this form of prenatal genetic intervention. This new debate, however, focuses on a much more radical genetic intervention. The Chinese experiments were generally not "successful" in the goal of altering the specific gene in the target embryos; this lack of success, while derived from controversial experiments, will only bolster the case for halting any such scientific work, as the recent work validates the safety concerns alone. But what is emerging - despite any enforceable international restrictions - is an urgency to codify resistance into regulation sooner rather than later.
In recent weeks, there has been growing attention to the possibility that recently developed technologies which allow precise editing of genomic DNA could be used for human reproductive purposes, possibly modifying the genomic DNA of a fertilized egg or embryo to create heritable genetic changes. The growing use of the genome editing technology known as CRISPR/Cas9 (CRISPR), first reported in 2012, is permeating much of current genetic research and is driving the policy discussions. A meeting on germline applications held in January of this year at Napa, California, and convened by some of the founders of the original Asilomar conference on recombinant DNA, took up the question of using CRISPR for germline genome engineering. This working group, which included Dr. Jennifer Doudna, an originator of this technology, has now published a call for caution as this technology could be employed to perform germ line editing that would manifest in human offspring. The CRISPR technology allows for more precise and efficient editing in genomic DNA than earlier editing techniques, and has a number of useful applications, both for research and clinical use. According
to several reports, there might be attempts at CRISPR-mediated human germline
modification that are already underway but unknown and that possibility
has stirred the scientific community to action. The participants at the Napa meeting called for further research and more transparent discussions for all stakeholeders. Finally, they called for scientists to refrain from employing CRISPR in any attempts at human germline engineering. The scientists agreed to:
Strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated.) This will enable pathways to responsible uses of this technology, if any, to be identified.
In parallel with that statement, a second group of researchers in the field of gene editing called for a complete moratorium on the use of CRISPR for germline genetic engineering. They stated:
In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, namely making genetic changes that cannot be inherited. At this early stage, scientists should agree not to modify the DNA of human reproductive cells. Should a truly compelling case ever arise for the therapeutic benefit of germline modification, we encourage an open discussion around the appropriate course of action.
Already, there are published reports of germline modification in monkeys. As for human gene modifications writ large, in 2015, there is the established field of gene therapy, overseen by the Recombinant DNA Advisory Committee (RAC), and slowly embraced by the FDA. These therapies provide genetic alteration to living persons through their somatic cells, so there is no heritability of the changes. RAC was asked to consider fetal gene therapy protocols in the late 1990's, but concluded that the risk/benefit ratio did not justify approval. Current reproductive medicine offers preimplantation genetic diagnosis to prospective parents seeking to avoid transmitting known genetic diseases, but that technique does not involve genome editing. The speed at which CRISPR-based technologies are entering genetic science guarantees that the debate over controversial applications will continue. Not surprisingly, any proposed CRISPR-based reproductive technologies are likely to encounter much more resistance that many other assisted reproductive technologies (ARTs) have encountered to date. Will CRISPR-based reproduction elicit the kind of furious legislative responses to the possibility of human cloning that followed the creation of the cloned sheep Dolly in 1997? Since there are no credible reports of use, the public is not confronted with the issue, but the scientific and bioethical communities can see ahead, and are trying a proactive rather than reactive approach to getting a public debate started.
