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.
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.
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 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.
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.
The recent appropriations bill passed by Congress this week has some good news for NIH and the biomedical research community. The Trump administration had proposed cutting the NIH budget by about 18% for the upcoming year, and stripping $1.8 billion from the current year, compounding more than a decade of funding declines. Support for NIH in general has been bipartisan over the years, but that has not shielded the agency from funding volatility over the last decade or so. As reported previously here, the Trump proposal to slash NIH funding was a pillar of the emerging March for Science movement, and a motivator for participation in the April 22 march.
The Congress has now rejected the Trump proposal:
Lawmakers increased the budget for the National Institutes of Health (NIH) in its bipartisan deal to fund the government, effectively ignoring the Trump administration’s proposal.
The explanation for the Congressional resistance is multi-layered, and certainly the visibility of the NIH proposal was very high and the resistance was very public. In addition, Democratic strategizing in the budget process negotiations played a key role. The recent 21st Century Cures Act (see here) which focuses on breakthrough projects (but was not explicitly funded; see here) is now specifically funded in this new bill. More funding fights loom, however, as the 2017-2018 fiscal year is not far away, and the future proposed cuts to NIH are not resolved. But it's fair to say that the collective resistance to this year's NIH cuts (followed by its success) demonstrated significant political muscle, likely to be exercised in the next round of annual negotiations.
Congress bolstered funding by $2 billion over the next five months, securing $34.1 billion for the NIH. It's the biggest boost the NIH has received in more than a decade, higher than at any point during the Obama administration.