National Institutes of Bioscience Journal

Genome Editing and the Future of Farming meeting report

Monica Hoyos-Flight, Emily Brady, Helen Sang, Bruce Whitelaw

A report on the Genome Editing and the Future of Farming meeting held at The Roslin Institute on 6th September 2016.

Opportunities to improve health, production efficiency and sustainability through applied gene editing

Jonathan E Lightner

Recent advances in gene editing technologies and in the application of these technologies to livestock animals have created a wealth of opportunity for improving animal health and well being and thereby the production and sustainability of animal protein productions. I review two technology examples in porcine and bovine systems that Genus is engaged in advancing through development. In porcine, recent published work has demonstrated that a simple edit producing a loss of function variant for the gene product CD163 can produce full resistance to the devastating pig disease porcine reproductive and respiratory syndrome virus (PRRSv) . In cattle, a more subtle edit, involving an edit of the -5 amino acid before the signal cleavage site of the CD 18 gene product from glutamine to glycine has been shown in cell model systems to confer resistance to the Mannheimia haemolytica leukotoxin , hypothesized to improve resilience to bovine respiratory disease (BRD). Among other challenges, the development and successful commercialization of these types of gene editing technologies will require the creation of multiple, consistent, reproducible edits in commercial founder lines of elite genetics. The practical challenges of deploying these technologies in beef, dairy and pork production systems are considered.

Genome editing in poultry - opportunities and impacts

Tim Doran, Arjun Challagulla, Caitlin Cooper, Mark Tizard, Kristie Jenkins

Poultry products (meat and eggs) are a major source of animal protein on which the world is increasingly reliant to feed a rapidly growing population. Improved breeds and advances in farm management practices have had a large impact on the poultry industry. For example, using current genetic stock and production practices, broiler chickens can weigh 2 kg in about 34 days. Forty-five years ago it would have typically taken over 60 days. These impressive advances have been made using traditional selective breeding methods and more recently by using genomics. Now, with the availability of precision genome engineering tools there are new opportunities to improve poultry production above and beyond those achievable by traditional means. One major opportunity is disease resilience, particularly for viral diseases such as avian influenza that has devastating impacts on the poultry industry. Resilience to specific diseases can be a notoriously difficult trait to select for using traditional breeding and the latest technologies that precisely edit the genome have created new ways to address this challenge.

Genome editing to the rescue: sustainably feeding 10 billion global human population

Modern animal breeding strategies based on population genetics, molecular tools, artificial insemination, embryo transfer and related technologies have contributed to significant increases in the performance of domestic animals, and are the basis for a regular supply of high quality animal derived food at acceptable prices. However, the current strategy of marker- assisted selection and breeding of animals to introduce novel traits over multiple generations is too pedestrian in responding to unprecedented challenges such as climate change, global pandemics, and feeding an anticipated 33% increase in global population in the next three decades. Here, we propose site-specific genome editing technologies as a basis for “directed” or “rational selection” of agricultural traits. The animal science community envisions genome editing as an essential tool in addressing critical priorities for global food security and environmental sustainability, and seeks additional funding support for development and implementation of these technologies for maximum societal benefit.

Improving milk for human consumption through genetic engineering technologies

Improved living conditions, food security and particularly access to comprehensive health care systems resulted in a continuous increase of the human life expectancy. However, living longer does not immediately mean quality of life can be maintained into old age which is commonly compromised by disease and the full benefit of a longer life can only be realized when the later stages of live can be enjoyed in good health. This has generated strong demand for new innovative foods that are not only save and nutritious but also have health enhancing properties. Genetic modification technology provides a direct approach of enhancing existing attributes that are beneficial for human health, minimizing any undesirable characteristics or enabling the introduction of novel, health promoting traits. Focused on milk as an important human food source, we will review the humble beginnings of testing transgenic approaches with mouse models, transfer of these simple overexpression strategies into livestock species, application of programmable nucleases for the targeted modifications of milk characteristics and discuss future opportunities that are becoming feasible with today’s sophisticated technical capabilities.

Genome reference quality an essential resource in an age of genome editing

Wesley C. Warren, David W. Burt

With the recent exploration of how we may improve livestock production and meet growing demand for animal protein products using genome editing technology, we argue that exemplary genome references will be required to ensure that the proposed edits are specific and carefully evaluated for any potentially harmful side effects. We explore in this short review the status of existing genome references for the major food producing animals (cattle, chicken, pigs, goat and sheep) and summarise best practice for creating future higher quality genome references. Each will serve as a central conduit in the study of genetic manipulation outcomes, and provide a computational workflow for how the edited genome could be evaluated for no other unexpected base changes in the rest of the genome.

The Genetic Architecture of Economically Important Traits Provides Major Challenges for the Implementation of Gene Editing in Livestock

Dirk Jan de Koning

Gene editing has been hyped as a game-changer in many biological fields including medicine and agriculture. This includes the promise to manipulate the DNA of livestock animals at sufficient throughput, both in terms of number of loci and animals, to consider gene editing as a routine component of livestock breeding programmes. In this essay I will argue that the application of gene editing for complex traits in livestock will prove extremely challenging for a number of reasons: 1) our understanding of the genetic control of complex traits remains sketchy; 2) even with cutting edge ‘omics technologies, the identification of functional mutations remains very challenging; 3) before selecting certain mutations for gene editing, we need to capture the pleiotropic effects of the mutation and test whether its effects are truly additive. With the current understanding of complex traits there is a risk that gene editing will revert to a candidate gene approach without knowledge or understanding of where the important mutations reside. This means that it will be some time before we can really benefit from gene editing for truly complex traits in livestock. In the meantime gene editing could deliver quick wins by ‘repairing’ lethal recessive defects that are present in many elite breeding animals. Furthermore I will outline how gene editing can have an important role in the identification of QTN via in-vitro genetics.

Gene editing: Breeding or GMO?

Alison Van Eenennaam

Global regulatory frameworks will soon be challenged by recent scientific developments in methods for generating genetically modified animals, particularly gene editing techniques. It is unclear whether animals produced using such technologies will fall under or outside of the regulations developed for genetically engineered (GE) animals produced using recombinant DNA (rDNA) techniques. Many gene editing applications will result in animals that carry induced mutations in target genes or desirable alleles or sequences that originated in other breeds or individuals from within that species. As such, there will be no rDNA or transgenic construct in the animal, and no novel combination of genetic material that has been altered in a way that could not be achieved by natural mating or techniques used in traditional breeding and selection. The current regulatory approach to GE animals has had a stifling effect on the use of this technology in animal breeding programs, and to date no GE animal has yet been sold for food purposes anywhere in the world. Given the importance of improved genetics to the overall environmental footprint of food production, precluding breeder access to safe innovations for use in genetic improvement programs has a large opportunity cost. If genome editing is going to have an opportunity to impact global animal breeding programs its oversight should ideally be proportional to risk based on the novelty of the trait, consider and evaluate both benefits and risks, and fit for purpose, meaning that the reduction in risk obtained by regulatory oversight is greater than the costs of compliance.

Regulatory frameworks for genetically modified animals are concurrently being formulated in many countries in concert with rapidly advancing technologies for creating such animals including gene editing and approaches to generate targeted gene knockouts in livestock species. These new animal breeding techniques result in genetically modified organisms (GMOs) that do not fit the classic definition of “transgenic” or genetically engineered (GE), although they are produced through human intervention using recombinant DNA (rDNA) techniques. Some groups have argued that because these genetic modifications are, for at least part of the procedure, produced outside the organism by people using in vitro techniques this alone should be the trigger for regulation (1). However, this seems to disregard the plethora of in vitro techniques that are commonly utilized in conventional animal breeding programs (2). If risk is the main rationale for regulating genetic modification methods, there does not appear to be a clear rationale for regulating only traits and DNA sequences produced using rDNA techniques. If human intervention using in vitro techniques in breeding programs is the trigger for regulation, this would seem to apply equally to many of the breeding methods used in the production of modern broiler chickens and high-producing milk cows which are clearly genetically modified animals relative to their wild ancestors the jungle fowl and auroch, respectively.

Genome editing in context

Laura Bellingan, Tom Livermore

Genome editing has created a new continuum between what might occur in nature and what can only occur in the laboratory. Remarkable though it is that we have developed the capacity to predictably and finely alter genetic codes it is perhaps as remarkable that a new technology enabling this has appeared, spread widely and become easily affordable and accessible within such a short timescale. The speed at which the CRISPR/Cas9 technology use has grown almost defies comparison. A factor contributing to this, and also to the complexity of the surrounding debates, is the sheer breadth of possible applications of the technology, in terms of target organisms and genetic constructs, and in terms of the processes it could be used to influence. These combined characteristics, while opening a world of possibilities for science and society, also present a pressing and complex set of questions about governance and regulation; it is difficult to have appropriately informed discussion let alone for regulation to keep pace.

Genome editing: the promise and the politics

Huw D. Jones

Efficient and sustainable agriculture depends on a high degree of predictability. Both in the short-term, for growers and agronomists to make informed management decisions for the immediate upcoming seasons, but also in the long term to establish future agricultural policy and trade agreements, to define crop and livestock breeding goals, and to stimulate innovation in new products with transparent regulatory frameworks for pesticides and biotechnology; all of which require decade-long timeframes or longer. However, there are many factors with implications for world agriculture that are becoming increasingly unpredictable and which pose significant challenges for sustainable future food production. I will highlight two major areas of uncertainty, one which is environmental and beyond the control of humankind in the medium-term and the other, involving regulatory policy that is absolutely with in our short-term grasp. I will argue that providing certainty and transparency in the latter will make a significant contribution to global food security by ameliorating the effects of the former.