Author: alvane (Page 2 of 5)

This is part 3 of a 1, 2, 3 part series on Genetic Engineering in Livestock

In 1996, the year of Dolly  the infamous first somatic cell nuclear transfer (SCNT) cloned mammal and the promulgation of the United States Coordinated Framework for Regulation of Biotechnology , a review paper found that of the 289 published papers in PubMed when searching for the term “transgenic livestock”, the vast majority of original reports focused on growth enhancement, and that 24% of them were review articles. This proportion has not changed much, with that same search today returning approximately 30% review articles. What happened to the promise of transgenic livestock that almost one quarter of the publications in the field are reviews rather than original research articles, and only a single transgenic food animal has been commercialized in 35 years (as discussed in Part 2 of this series)?

The livestock breeding sector is distinct from the plant breeding sector where transgenic plants are grown by over 17 million farmers globally. Some of this is due to biological differences between the two kingdoms, including the mode of reproduction (e.g. plants can self-pollinate), and the number of progeny per reproduction cycle. A major difference between animal and plant breeding is that the former places greater emphasis on population improvement, with product development consisting primarily of multiplication of these improved genetics through outcrossing, whereas in the latter greater emphasis is placed on selection of an improved product in the form of a recognizable plant variety, which is often also the source of parents for the next breeding cycle .

One transgenic plant transformation event (often protected by IP) can be amplified in seed multiplication, but in animals the founder event will have to occur in elite stock in the breeding nucleus and then be transmitted down to the commercial sector through multipliers, a process that can take decades depending upon the generation interval of the species.

Additionally, desired traits will need to be introduced into several breeds or lines in animal breeding programs because they often make extensive use of heterosis (or hybrid vigor) through crossbreeding. For example, a typical modern broiler chicken breeding program is shown in Figure 1.

Figure 1. A typical modern broiler chicken breeding program, represented as a pyramid where each level represents a generation, and the approximate timeline to move genetics from top of the broiler breeding pyramid to the consumer. (Modified)

Genetic improvement and pedigree selection for desired traits occurs at the top of the pyramid across four lines. Within the pedigree segment there are specific male and female lines, with the males typically selected for heritable growth and production traits and the female lines selected for early growth and conformation. The commercial broiler (5th generation) at the bottom of the pyramid is a four-way cross derived from the cross of a male and female parent line.

Genome editing offers an efficient approach to introduce useful genetic variation into livestock breeding programs through targeted inactivation of gene function, and/or through allele introgression in the absence of undesired linkage drag. Genome editing involves the use site-directed nucleases (e.g. TALENS (Transcription Activator-Like Effector Nucleases) or the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/CRISPR-Associated Systems (CAS)) to efficiently introduce a double stranded break (DSB) at a predetermined location in the genome. The DSB can be repaired by the cell’s natural DNA repair mechanism (non-homologous end joining; (NHEJ)), often resulting in single nucleotide changes, deletions or small (1-2 nucleotide) insertions at the DNA cut site. In this case, although the location of the cut site is very precise, the exact change that occurs when the DNA is repaired is random and so a number of different outcomes representing minor sequence changes are possible.

Alternatively, repairs can be directed to introduce, delete, or replace a series of letters in the genetic code using a nucleic acid template. This essentially enables the introduction of known, desired alleles or haplotypes via homology directed repair (HDR) based on what is understood about naturally-occurring genetic variation in the target species. It is now possible to alter animal genomes without necessarily incorporating transgenic genetic material. To date SCNT cloning of edited somatic cells, especially HDR donor-template defined alterations, has been the primary method to produce livestock carrying nuclease-mediated genetic changes, especially HDR donor-template defined alterations, in their genomes.

Researchers have already produced a number of gene-edited farm animals for biomedical research applications, and also for agricultural purposes (see Table 2 in my recent review paper). The latter group includes animals carrying no novel DNA sequences (e.g. Porcine Reproductive and Respiratory Syndrome (PRRS) virus-resistant CD 163 knockout pigs ; myostatin knockout sheep and cattle with increased lean muscle yield ; and knockout sheep with increased wool length and yield ; intraspecies allele substitutions (e.g. hornless dairy cows due to an allele substitution at the POLLED locus ); intraspecies gene insertions also known as cisgenics (e.g. cows with increased resistance to tuberculosis due to knock-in of bovine NRAMP1 gene); and animals with interspecies allele substitutions, analagous to traditional transgenic applications (e.g. domestic pigs (Sus scrofa) carrying an allele from the African Swine Fever-resistant African warthog (Phacochoerus africanus).

Not surprisingly, the traits that have been targeted by researchers with gene editing (animal health and well-being, product quality and yield) are common to the breeding objectives of traditional selection programs. Health and welfare traits are also of particular interest to the general public, especially projects like the female-only layer chickens. As with earlier genetic engineering approaches, whether breeders will be able to employ gene-editing in commercial farm animal genetic improvement programs will very much depend upon global decisions around regulatory frameworks and governance.

A chance to rethink

In early 2017, the United States Food and Drug Administration (FDA) released its updated draft “Guidance for Industry #187” and changed the title to “Regulation of Intentionally Altered Genomic DNA in Animals”. This guidance proposes to regulate all food animals whose genomes have been intentionally altered using modern molecular technologies, including gene editing technologies, as new animal drugs. This includes many of the same nucleotide insertions, substitutions, or deletions that could be obtained using conventional breeding.  No longer is it the presence of a transgenic rDNA construct that triggers mandatory premarket FDA regulatory oversight prior to commercial release, but rather it is the presence of any “intentionally altered genomic DNA” in an animal’s genome that initiates oversight.

This runs against the wording of the 1986 Coordinated Framework which indicated regulatory review was only required for organisms deliberately formed to contain an intergeneric (i.e. transgenic) combination of genetic material. It also runs counter to the OSTP policy,  the 2016 U.S. National Academies of Sciences, Engineering, Medicine report, which recommended a “product not process” regulatory trigger. In addition it is contrary to the USDA approach to the regulation of gene edited food plants, and is also out of step with decisions being made by other regulatory agencies in a number of countries around the world (e.g. Argentina), with implications on global trade. Mandating premarket regulatory approval for deletions, mutations, and the conversion of one wild-type allele to another wild-type allele in the same species (cisgenic) that could have been obtained using conventional breeding is not scientifically defensible, given the known genetic variation that exists naturally in livestock genomes.

Figure 2 shows the global regulatory landscape for gene-edited animals. If those animals do not carry novel DNA (transgenic DNA), meaning that the DNA alteration could have been achieved using conventional breeding, then a number of countries are not requiring additional regulatory oversight. To date only a single entity, a large global animal genetics company, has announced plans to commercialize a gene edited food animal. The University of Missouri signed an exclusive global licensing deal for potential future commercialization of PRRS virus-resistant pigs with UK-based Genus plc. This company has also entered into a strategic collaboration with Beijing Capital Agribusiness Co. Ltd, a leading Chinese animal protein genetics business, to research, develop, register and market elite pigs that are resistant to PRRS virus in China.

Figure 2. Global picture of whether additional regulations will be triggered for gene-edited animals that do not carry transgenic DNA

In a February 2020 correspondence entitled Genome editing in animals: why FDA regulations matters published in Nature Biotechnology, FDA Center for Veterinary Medicine (CVM) Director Steven M. Solomon  made the case for “why it is necessary for there to be regulatory oversight of intentional genomic alterations in animals, even when the intended modification seeks to replicate a naturally occurring mutation.” He then specifically distances his argument from intentional genomic alterations performed in organisms from other kingdoms that we eat, i.e. plants and microbes, with the statement  “Readers should note that our statement here relates to intentional genomic alterations in animals; we are not commenting on alterations in plants or other organisms.”

This suggests there is something uniquely risky about intentional genomic alterations in animals. However, the history of plant breeding is rife with examples where antinutrients in plants have inadvertently been increased through conventional selective breeding efforts (e.g. think solanine in potatoes, or psoralens in celery). I have a hard time coming up with an analogous food safety concern from conventional animal breeding. Dr. Solomon then goes on to support his argument with the a case of a naturally-occurring genomic variant that was deleterious to animal health and that increased in frequency due to conventional selection. “There is a particularly compelling example of the risks of occult genomic alterations in cattle produced by traditional breeding techniques: a high incidence of bovine leukocyte adhesion deficiency (BLAD) syndrome, a lethal autosomal recessive disease, in Holstein calves.”

In an unusual move, Nature Biotechnology published its own editorial response the FDA’s correspondence countering that, “If the BLAD case history tells us anything, it is that the origin of a DNA arrangement (conventional breeding, recombinant DNA or gene editing) makes little difference to an animal. The genomes of domestic cattle contain millions of natural variants: the 1000 Bull Genomes Project found >86.5 million differences (insertions, deletions and single nucleotide variants) among cattle breeds. According to prominent researchers in the field, none of these variants has been shown to produce ill effects on consumers of milk or meat. Amidst this background of innocuous variation, how can the presence of one identifiable variant justify the costs and delays of mandatory FDA oversight?

“The US Food and Drug Administration is sticking to its plan to carry out mandatory premarket review of all gene-edited livestock, irrespective of trait risk. It should rethink.

The US Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) continues to argue that every animal created by gene editing should be subject to mandatory premarket review and substantial safety testing. This position, first outlined in a 2017 draft guidance, presupposes that all gene-edited animal are potentially hazardous — despite the evidence and the views of many researchers. It canonizes a precautionary stance to gene-edited animals, irrespective of the trait engineered, even if the animal is indistinguishable from one created by conventional breeding. It is out of step with the practice of the US Department of Agriculture (USDA), which recently deferred from regulating gene-edited products. And it goes against decades of US policy focusing on appropriate product risks and benefits through the Coordinated Framework.”

Course Correction editorial, Nature Biotechnology, February 2020

I have spent a career in animal genetics and genomics. For a good chunk of that time, it has not been possible to use the tools of molecular biology to introduce useful genetic variation like disease resistance  into livestock breeding programs through transgenesis. Genome editing offered a new opportunity to use molecular tools in a way that would not necessarily introduce transgenic DNA. It was hoped that this would help avoid the regulatory costs that effectively strangled transgenic applications like the USDA ARS’ mastitis-resistant cow,  and University of Guelph’s “Enviropig“. Precluding these transgenic animals from coming to market is associated with a forgone opportunity cost as we have not cured mastitis, and pigs still can’t digest phytate. Genetic solutions that could have helped to address these animal disease and phosphorus pollution problems have just been sidelined.

There was some hope that gene-edited animal alterations that could have been achieved using conventional breeding, would not be treated differently to conventional breeding from a regulatory standpoint. This was the decision of the USDA regarding genome edited plants, and that of several countries (Figure 2). However, the decision in some countries including the US, is to regulate gene-edited animals based on the fact they are gene-edited, rather than product novelty or risk. I fear this will lead to another long list of forgone genetic innovations in US animal agriculture, and advantage countries with a product-risk focused regulatory approach.

This is part 2 of a 1, 2, 3 part series on Genetic Engineering in Livestock

When AquaBounty sought to commercialize the first transgenic food animal in the mid 1990s (first produced in 1989), there was no official regulatory approach in place. Former CEO of AquaBounty technologies Dr. Ron Stotish in a 2012 abstract entitled “AquAdvantage salmon: pioneer or pyrrhic victory” (Transgenic Research 21: 913-914) wrote :

“AquaBounty consulted FDA and other government agencies in hopes of identifying a regulatory process that could be employed to review and approve the AquAdvantage salmon for food use in the United States. AquaBounty established an Investigational New Animal Drug [INAD] file with the Center for Veterinary Medicine in 1995, well in advance of any clear regulatory paradigm. Between 1995 and 2009, the sponsor [AquaBounty] conducted a variety of GLP studies aimed at meeting what was hoped to be the eventual regulatory requirement for an application of this nature. Although there was informal consultation and communication between the sponsor and CVM staff during this time, it was not until 2009 that CVM [FDA Center for Veterinary Medicine] released Guidance Document 187, codifying requirements for consideration of an application for a transgenic animal.”

This 2009 Guidance Document 187 was entitled “Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs”. The Federal Food Drug and Cosmetic Act (FFDCA), defines a drug as an “article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” A “New Animal Drug includes a drug intended for use in animals that is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in the drug’s labeling, and that has not been used to a material extent or for a material time.” Using this definition the FDA considered the “regulated” article to be “the rDNA construct in a GE animal that is intended to affect the structure or function of the body of the GE animal, regardless of the intended use of products that may be produced by the GE animal.”

In that guidance the FDA defined GE animals as animals with both heritable and non-heritable rDNA constructs. The classification of transgenes in animal genomes as drugs meant that each animal lineage derived from a separate transformation event (or series of transformation events) was considered to be a separate new animal drug, subject to a separate new animal drug approval. This determination meant that all unapproved GE animals, their offspring, and their food products were “deemed unsafe”. The FDA exercised enforcement discretion for GE animals of non-food-species that are raised and used in contained and controlled conditions such as GE laboratory animals used in research institutions. In other words, researchers working with the literally millions of GE laboratory animals did not have to go through the INAD and NADA  (New Animal Drug Application) requirements.

That left the small group of mostly public sector agricultural researchers working with food animals saddled with the requirements needed to get a new veterinary drug approved if any of their work was to ever reach the market. These requirements include a seven-step regulatory process in which the agency examines the safety of the recombinant DNA (rDNA) construct to the animal, the safety of food from the animal, and any environmental impacts posed (collectively the “safety” issues), as well as the extent to which the performance claims made for the animal are met (“efficacy”).

Molecular characterization of the rDNA construct determines whether it contains DNA sequences from viruses or other organisms that could pose health risks to the GE animal or to those eating the animal. Molecular characterization of the GE animal lineage determines whether the rDNA construct is stably inherited over multiple generations. Phenotypic characterization assesses whether the GE animals are healthy, whether they reach developmental milestones as non-GE animals do, and whether they exhibit abnormalities. A durability assessment reviews the sponsor’s plan to ensure that future GE animals of this line will be equivalent to those examined in the pre-approval review. If the GE animal is intended as a source of food, FDA assesses whether the composition of edible tissues differs and whether its products pose more allergenicity risk than non-GE counterparts.

In the meantime, all investigational GE animals, their littermates, and surrogate dams and their products were deemed “unsafe” and had to be disposed of by “incineration, burial, or composting.” My colleague, Dr. Matt Wheeler, at the University of Illinois has been working on transgenic pigs for over twenty years. His work has included expressing the bovine lactalbumin gene in the milk of transgenic pigs (1998), which enhances lactation performance and preweaning piglet growth rates (2002). This work has been carried out under an INAD, which initially authorized the rendering of a certain subset of experimental animals. A misunderstanding over the regulatory status of cogestating one INAD line of transgenic pigs with littermates of another INAD line of transgenic pigs resulted in the FDA determining that Dr. Wheeler had “failed to follow protocol”. One Friday, Dr. Wheeler relayed to me, that the FDA swept down on his laboratory and confiscated his computer and laboratory note books. They also locked him out of his own laboratory for several days,

The experience he says, “made him do some soul searching as to whether he wanted to continue doing work with transgenic livestock.”

Such actions have done little to build trust with the regulated academic  community. Dr. Wheeler estimates he has incinerated thousands of transgenic pigs and their littermates and surrogate dams as unapproved new animal drugs during the course of his research, and guesses the added costs of being under INAD requirements to be in the vicinity of USD$2 million. Fortunately academic research institutions and small companies are exempt from additionally paying the recurring annual INAD review fee, which can be thousands of dollars.

The genetically modified AquAdvantage salmon (top) gets to market weight in half the time required for its traditional counterpart. AquaBounty.

To continue on with the AquAdvantage saga, Dr. Stotish wrote in 2012 “by mid 2010 [AquaBounty] had concluded all the necessary research, submitted all required regulatory studies, and received the results of the CVM reviews indicating satisfaction with the submitted data in addressing all requirements for approval. The Center convened a Veterinary Medicine Advisory Committee [VMAC] to review the results of the CVM assessment and conclusions on September 20, 2010. ” Little did the company know that there would be a 5 year delay and to complete “radio silence” from the FDA following the 2010 VMAC meeting until approval in November 2015. The salmon has had a long road to market.

The VMAC meeting for the AquAdvantage salmon was held in September 2010. During the course of the meeting the VMAC members discussed the strengths and weaknesses of the data (4). Ultimately the consensus document of the VMAC charged with providing advice and recommendations to the FDA found (1) “no evidence in the data to conclude that the introduction of the construct was unsafe to the animal,” (2) that the studies selected to evaluate whether or not there was a reasonable certainty of no harm from consumption of foods derived from AquAdvantage salmon were  “overall appropriate and a large number of test results established similarities and equivalence between AquAdvantage Salmon and Atlantic salmon,” and (3) that the AA salmon did grow faster than their conventional counterparts.

The potential environmental impacts from AA salmon production were mitigated by the proposed conditions of use which limits production to FDA-approved, physically-contained fresh water culture facilities. The eyed-egg production site is located on Prince Edward Island (Canada), and the grow-out of market fish is proposed to occur in Panama with multiple biological (all female, triploid), physical (land-based tanks with fencing/screening), and geographical (hydroelectric dams with no fish passage, thermal-lethal downstream temperatures) redundant containment measures. The VMAC concluded that although they “recognized that the risk of escape from either facility could never be zero, the multiple barriers to escape at both the PEI and Panama facilities were extensive”.

Activist disinformation campaign

Disinformation that was created to misinform about the nutritional data of the AquAdvantage salmon

The data package that AquaBounty voluntarily made publicly available in advance of the 2010 VMAC in a good-faith attempt to increase transparency in the regulatory process, was used by special interest groups like the Center for Food Safety who misrepresented the data by suggesting that “FDA’s 2010 data release showed that GE salmon have 40% higher levels of the growth hormone IGF-1, which increases the risk of cancer. And finally, wild salmon has 189% higher levels of omega-3 fatty acids than GE salmon can produce.” This false interpretation stands in stark contrast to the FDA finding which was “AquaBounty (ABT) salmon meets the standard of identity for Atlantic salmon as established by FDA’s Reference Fish Encyclopedia. All other assessments of composition have determined that there are no material differences in food from ABT salmon and other Atlantic salmon.” This type of vilification of technology and fearmongering by special interest groups with no interest in truthfulness does nothing to benefit society.

The U.S. Food & Drug Administration ultimately approved AquAdvantage salmon for sale in November 2015. But an obscure rider was attached to a budget bill by Alaska senator Lisa Murkowski in December of that same year, effectively blocking the FDA from allowing salmon into the U.S. In the meantime Canadian regulatory authorities approved the fish in 2016, and sold 5 tons of fillets (4.5 metric tons) there in 2017, and the same in 2018. “The people who bought our fish were very happy with it,” Stotish is quoted in a press article. “They put it in their high-end sashimi lines, not their frozen prepared foods.”

It is worth noting that the US imported 339,000 metric tons of salmon in 2016, worth more than $3 billion. The vast majority of that came from farmed Atlantic salmon raised in floating cages off the coasts of Canada, Chile, Norway and Scotland, and flown to the United States. Atlantic salmon raised in land-based tanks like the AquAdvantage salmon is rated “best choice” by Seafood Watch, and  the carbon footprint of salmon produced in land-based closed systems is <50% lower than that of salmon produced in conventional marine net pen fish farms in Norway and delivered to the U.S. by air.

In 2018, FDA approved an application by AquaBounty for a growout facility in Indiana, offering an opportunity to produce US-raised Atlantic salmon. And finally on March 8, 2019, 30 years after the founder fish was produced in Canada in 1989, the FDA  deactivated this import alert pertaining to the GE salmon.  It still has not reached US consumers, despite recent court victories.

AquaBounty estimated it has spent $8.8 million on regulatory activities to date including $6.0 million in regulatory approval costs through approval in 2015, $1.6 million (and continuing) in legal fees in defense of the regulatory approval, $0.5 million in legal fees in defense of congressional actions, $0.7 million in regulatory compliance costs (~$200,000/year for on-going monitoring and reporting including the testing of every batch of eggs), not to mention the $20 million spent for maintaining the fish while the regulatory process was on-going from 1995 through 2015 (David Frank, AquaBounty; pers. comm; January 2020).

Meanwhile

While the AquAdvantage fish has been awaiting regulatory approval, salmon breeders in Norway have been busy selecting for fast-growing salmon. The genetic gain for growth-rate in salmon has been estimated at 10–15% per generation. Farmed salmon have been exposed to ≥12 generations of domestication and was the first fish species to be subject to a systematic family‐based selective breeding program which began in 1975. Studies on farmed salmon in the 9-10^th generation of selection showed their size relative to wild fish was 2.9:1 under standard hatchery conditions, and 3.5:1 under hatchery conditions where growth was restricted through chronic stress. In other words, selective breeding programs have produced genetically-distinct lines of fast-growing salmon, and since the 1970s, tens of millions of these fertile farmed salmon have escaped into the wild. Glover estimated that over three to four decades, introgression of farmed salmon into Norwegian wild salmon populations ranged from 0% to 47% per population, with a median of 9.1% .

Presumably these fast-growing salmon pose the same risks as the AquAdvantage salmon, although conventional breeding is not regulated and the latter was associated with decades of delay, millions of dollars in new animal drug regulatory approval costs, and all fish must be raised as sterile triploid females in land-based containment tanks and is subject to ongoing regulatory compliance costs.

This might sound like an argument to just let conventional breeding do its job. As a geneticist I have to agree,  and this is absolutely an option, albeit a slower one, for traits that vary in the target population. But for some traits like disease resistance, having the ability to bring in useful genetic variation enables breeders to introduce novel traits that cannot be achieved by conventional breeding. The problem is that it has not be possible to bring transgenic food animals to market, even those that address traits of interest to the consumer like disease-resistance and animal welfare traits. All of it is blocked.

Having a different regulatory standard triggered by the process (i.e. rDNA versus other breeding methods) used to make a product , rather than on the risk associated with the product itself  runs counter to the The United States “Coordinated Framework for the Regulation of Biotechnology,” which is technically agnostic towards the technology or process under review.  According to the Office of Science and Technology Policy (OSTP) in the Federal Register in 1992:

“Exercise of oversight in the scope of discretion afforded by statute should be based on the risk posed by the introduction and should not turn on the fact that an organism has been modified by a particular process or technique … (O)versight will be exercised only where the risk posed by the introduction is unreasonable, that is, when the value of the reduction in risk obtained by additional oversight is greater than the cost thereby imposed ”

This suggests that the U.S. should only exercise regulatory authority over organisms — plant or animal — based on the risks they pose.  This is irrespective of the breeding technique used to produce them, and used only when the risk posed is unreasonable, which is clarified to mean the cost of regulatory oversight is not greater than the reduction in risk obtained by that oversight. it is difficult to see how this applies to transgenic animals given the history of the fast-growing salmon.  It was hoped that new breeding methods like gene-editing would be treated more like conventional breeding. Unfortunately, that is not how it happened, as discussed in Part 3 of this series.

This is part 1 of a 1, 2, 3 part series on Genetic Engineering in Livestock

2020 signals the dawn of a new decade, 35 years after the arrival of the first transgenic livestock, and offers an opportunity to let knowledge gained inform current and future perspectives. Despite the fact that genetically engineered (GE) crops have been commercialized for 22 years and were grown on 191.7 million hectares by 17 million farmers in 26 countries in 2018, only a single GE food animal has ever been commercialized. There are a myriad of reasons for this disparity, including technical issues, differences in the commercial structure of animal breeding programs versus seed propagation, regulatory obstacles, and public perception and ethical concerns around animal experimentation and welfare.

Early reviews on transgenic food animals detailed some of the technical issues associated with the production of GE livestock including low rates of transgene integration, mosaicism, unpredictable expression patterns due to the random location of introgression, and the expense associated with the production of large transgenic food animals. Almost without exception these papers finished with optimistic projections regarding future developments and expected applications.

The first review I could find was written in 1985 prior to the production of the first transgenic livestock, and optimistically predicted that “Clearly, gene transfer and recombinant livestock offer a means to alter the fundamental genetic makeup of livestock to a greater extent, in a few decades, than may have been achieved in the entire past history of the science of livestock genetics. Those of us involved in this research look forward to the challenge and promise of this exciting new technology”. I well remember that excitement during my undergraduate studies in agricultural science.

Figure 1. An abbreviated schematic history of 35 years of GE livestock featuring some of the well-known celebrities in the field.

Figure 1 summarizes the major milestones of GE livestock. It is sobering to contemplate the considerable scientific progress that has been made in the production and utility of literally millions of transgenic mice, and even in transgenic pigs for biomedical research, as compared to transgenic livestock for agricultural purposes where commercialized applications can be counted on one hand. One reason for this is the relatively small scientific community that has been working in this field due in part to a paucity of both public sector and private funding, especially as compared to basic and applied biomedical research.

It is also true that this research is very expensive. It was estimated that the cost of producing a single founder transgenic pig in 1992 was $25,000; and a single functional transgenic calf was put at greater than $500,000. The high cost of researching transgenic livestock has been, and continues to be, a major factor limiting those interested in exploring the potential of this technology for agriculture. Despite this, researchers have been trying to get food applications funded, especially those working on health and welfare traits.

Funding Issues

The lack of progress on agricultural applications can be attributed to a scarcity of both public and private funding sources, and the absence of a clear path to market. In 2004 the USDA National Food Initiative (NRI) request for proposals (RFP), the main source of public sector agricultural research funding in the United States, read “For FY 2004 proposals are invited in the following priority areas…development and application of methods to modify the animal genome (e.g., nuclear transfer, embryonic stem cells and transgenics)”.

My own proposal to this RFP to produce transgenic cows that produce high omega-3 milk, following on from successful proof of concept experiments in mammalian cells and transgenic mice funded by the NIH, received a technical review which stated that “The techniques proposed are sound and there are no insurmountable obstacles in the proposed studies”. However, the reviewer continued “While it may be putting the cart before the horse, the proposal has not mentioned the problems with acceptance of transgenic food products. Given the “pure and wholesome” public perception of milk products, it may be particularly difficult to gain widespread public acceptance for transgenic milk products – despite their health benefits.” In the meantime, transgenic Fat-1 cattle and sheep have been successfully produced in China.

Likewise, my departmental colleague Dr. Elizabeth Maga, who in 2003 proposed expressing immune modulators in the milk of transgenic ruminants to improve animal health (following her successful experiments in transgenic mice and characterizing their milk), received a grant review which read “While the approach to express genes in animals to improve their resistance to bacterial infection has merit, the feeling was that the general public would not accept such animals, especially food producing animals. Demonstration that animals are clearly protected by ingested lysozyme would greatly strengthen this application and such demonstration could possibly sway the public outlook about transgenic animals.”

Despite that setback, Dr. Maga went on to produce GE goats expressing lysozyme in their milk, and clearly demonstrated that ingested lysozyme protects animals from bacterial infection including diarrhea (here,  here and here). Unfortunately, this has not swayed the public outlook about transgenic animals. Work on this application has now moved to the Northeast region of Brazil, where the number of infant deaths due to malnutrition and infectious diseases is high.

Then in the mid 2000s, the USDA NRI RFP language ominously shifted to “Priorities for Research Projects …development and application of methods to modify the animal genome to aid in the understanding of gene function or expression (e.g. RNAi, nuclear transfer, embryonic stem cells, and transgenics)”. With the added proviso that “Applications whose primary aim is to improve the efficiency in the production of clones or transgenic animals through manipulation of the nucleus will no longer be accepted by the Animal Genome program (emphasis added)”.

This directive continued for almost a decade, and the current USDA National Institute of Food and Agriculture (NIFA) RFPs do not even include the word “transgenic”. There has likewise been little private sector interest in taking transgenic food animals through an expensive and unpredictable regulatory process. In the absence of a clear and predictable path to market, there has been little support or market pull for transgenic animals from the livestock breeding sector.

Extant Applications

As a result of these  issues, the promise of the multiple applications of transgenic livestock developed by research scientists  has never been realized. The publication date of much of the research in Table 1 is rather confronting, given that many date back to last century(!), and their agricultural or food-use applications have never moved beyond the research laboratory.

 Table 1. Listing of published transgenic food animals for agricultural applications.

Transgenic Animal Approvals

There have been some transgenic animal applications that have been successfully commercialized. There have been three approvals for therapeutic proteins produced by transgenic animals. These include goats producing ATryn1® (human antithrombin-III) approved to treat hereditary antithrombin deficiency by the European Commission in 2006 and by the U.S. Food and Drug Administration in 2009, rabbits producing Ruconest^TM (Rhucin® outside the EU) approved to treat hereditary angioedema in 2014 , and chickens producing Kanuma^TM (sebelipase alfa) in their eggs for the treatment of patients with a diagnosis of lysosomal acid lipase deficiency in 2015 .

Perhaps the most visual commercialized transgenic animal is the fluorescent aquarium “GloFish®”. These GE designer tropical fish, first produced by a laboratory in Singapore and licensed to Yorktown Technologies in 2003, are marketed to aquarists in the United States where they are now sold in every state in the nation.

Figure 2. GloFish® https://www.glofish.com/

The GloFish® was allowed to come to market under “enforcement discretion”. According to the FDA website in 2003, “FDA chose to exercise enforcement discretion for a GE aquarium fish that fluoresces in the dark. FDA made this decision in part because the fish (Zebra danio) is not a species used for food, and in part because the agency was able to determine that it did not pose any additional environmental risks compared with conventional Zebra danios. Zebra danios are unable to survive outside the very warm waters of the tropics, which effectively limits the ability of an escaped or released fish to affect the U.S. environment)”. 

The sale of GloFish is restricted in other countries including Canada, Europe, Australia, and Singapore . There are a total of four species of transgenic fish (zebrafish (Zebra danio), tetra (Gymnocorymbus ternetzi), tiger barb (Puntius tetrazona), and Rainbow Shark (Epalzeorhynchos frenatum)) in six fluorescent colors (Figure 2). GloFish® sales represent about 15 percent of US aquarium fish sales. Yorktown Technologies sold GloFish® to a consumer goods company for approximately $50 million in cash plus incentives in 2017. The success of this product suggests that consumers are willing to purchase transgenic animals, at least as aquarium pets. With regard to the public acceptance of transgenic animals, Alan Blake Chief Executive Officer and Co-founder of Yorktown Technologies stated at the 2015 Transgenic Research Conference  that consumers will purchase a product that they desire, irrespective of the breeding method that was used to produce it. In his words, “It is not about the process [of genetic engineering], it is about the product”.

The demand for GloFish, and more recently the Impossible Burger, a plant-based meat imitation product that contains GE ingredients, (and in the face of irrational activist opposition to such ingredients) would suggest that if GE products are allowed to come to market, at least some consumers are interested in purchasing them despite the protestations of opponents. Unfortunately regulatory costs and timelines have effectively precluded the advancement of all but one transgenic food animal to market, as detailed in Part 2 US Regulation of Transgenic Food Animals of this BLOG series.

This is part 3 of a 1, 2, 3 part BLOG series on this January 2020 two-day event featuring Dr. Vandana Shiva at UC Santa Cruz

Finally, during the course of the January 2020 two-day event featuring Dr. Vandana Shiva at UC Santa Cruz,  there was the nonstop attack on glyphosate (and by association Monsanto, and therefore Bayer). The California glyphosate law suits were of course mentioned, along with the 2015 IARC hazard classification of glyphosate as a probable carcinogen. Perhaps predictably, there was no mention of the US Environmental Protection Agency (EPA) RISK determination which reaffirmed glyphosate as safe to use and non-carcinogenic, the 2018 pesticide applicator study  which found no apparent association between glyphosate and any solid tumors or lymphoid malignancies overall, or the response of potentially affected farmers to looming glyphosate bans in other countries such as France and Germany.

Dr. Shiva alluded to the 2014  Sri Lankan paper that proposed an untested hypothesis that glyphosate was responsible for chronic kidney disease of undetermined causes (CKDu). CKDu disease has emerged as a major illness among workers in hot climates. In that paper the authors posited that glyphosate “may destroy the renal tissues of farmers by forming complexes with a localized geo-environmental factor (hardness) and nephrotoxic metals”.   This paper was particularly highlighted by Dr. Shiva, in part because the authors  were awarded the 2019 AAAS Scientific Freedom and Responsibility award for proposing a hypothesis that there was “a possible connection between glyphosate and chronic kidney disease.” A more recent systematic 2018 review and meta-analysis of data collected to  actually test that hypothesis “found little evidence that pesticides were the main cause of CKDu in Central America” was  (again unsurprisingly) not mentioned. However, this Sri Lankan example provides an interesting case study of what eliminating that herbicide meant for one country.

Owing to social pressure created by the 2014 untested hypothesis paper,  the Sri Lankan government banned glyphosate in 2015. The consequences of that decision on smallholder farmers, income disparity, woman farm workers, erosion, and public health, are outlined below. They provide a cautionary tale of what happens when unsupported hunches, rather than objective evidence, drive agricultural policy as detailed in this 2018 report “Impacts of Banning Glyphosate on Agriculture Sector in Sri Lanka; A Field Evaluation” by  LM Abeywickrama et al. from the Faculty of Agriculture at the University of Ruhuna in Sri Lanka. Ironically, many of the outcomes that resulted from this ban were the opposite of the values that were repeatedly voiced by the audience attending the UC Santa Cruz  Vandana Shiva event.

“The ban has imposed significant economic costs on growers of all operation sizes – but smallholders have been most negatively affected. Over 94% of smallholder corn farmers reported a reduction in family income, while over 86% farmer in corn have reported that family income has reduced and cost of production has increased. Over 40% of tea farmers reported a reduction in family income, while increased weed prevalence has reduced yields for over 40% of corn farmers. There has been a decline of 11% in tea production during year 2016 compared with year 2015.” Around 52 percent of tea workers are women who are among the poorest paid in the country.

“Food production in agricultural areas has reduced and the income of the farmers with limited resources has also reduced. Therefore, food security of the rural farmers has been challenged. Also, the disparity of the income between resource-rich and resource-poor farmers has widened. Rich farmers have the capacity to face the consequences of the banning glyphosate since they have tractors while the poor farmers have to face the increased rate of hiring charges of tractors and increased prices of available illicit herbicides. Migration of rural youth from the rural areas to the urban centers due to increased costs of cultivation has created labour scarcity in agricultural areas which leads to negligence of productive lands.

Increased use of tractors in sloping lands of Monaragala and Anuradhapura districts in maize and field crop cultivation in Maha season, had led to severe soil erosion. About 80% of the farmers verified that the erosion has drastically increased with the use of tractors in the absence of suitable herbicide. Further, mechanization because of absence of glyphosate has also affected farming under drip irrigation as mechanical weeding damages the irrigation pipes and system.

The study also showed that Kalanduru, a difficult weed to control in the absence of glyphosate, has become a threat in Chili fields. Due to enhanced weed pressure, in crops that need intensive care such as chili, farmers cultivate only manageable portion of their land abandoning the rest creating a suitable ecosystem for of pigs and snakes to survive and reproduce, leading to challenging public health scenarios.”

The Sri Lankan government ultimately reversed the ban against glyphosate on July 11, 2018. According to an article in The Sunday Times, “In the absence of an effective alternative weedicide, however, the tea industry in particular was severely hit, with plantations becoming plagued by weeds, and resulting in a drastic drop in production.” A senior research officer at the Sri Lankan Office of the Registrar of Pesticides Lasanatha Ratnaweera said the ban was clearly a political decision. He pointed out that his department had nothing to do with the decision.

“Decisions on modern technologies in agriculture should be based on the scientific research findings published by the scientists in the relevant field. Agriculture chemicals have played a critical role in crop production and this study has shown the impact of glyphosate ban on crop production in Sri Lanka. Following glyphosate ban, the cost of production of maize and tea has increased, the yields are impacted, the farm income has reduced, and illicit chemicals are proliferating in the market.”

Dr. L. M. Abeywickrama, Faculty of Agriculture at the University of Ruhuna in Sri Lanka

Moving from Sri Lanka, back to the “Poison-Free, Fossil-Free Food & Farming” workshop presented by the Right Livelihood College at UC Santa Cruz,  where one of the Sunday afternoon breakout session afternoon was on “glyphosate, the main ingredient in Roundup, its widespread use in the world, and the dangers it creates for the health of people, plants and soil.” I will note that Dr. Shiva had left the workshop by this time, but this was still a workshop hosted by a university, and sister campus UC Santa Cruz. As a participant I  expected to be presented with evidence-based information. It felt more like I was a participant in Gwyneth Paltrow’s GOOP lab. 

I will not go into details but it was suggested that glyphosate was associated with non-Hodgkin lymphoma (NHL) and cancer, although again no mention of the 2018 pesticide applicator study which involved more than 50,000 applicators and which  found no association  between “glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes” which I might have expected to be at least mentioned or referred to at workshop at a University.

Glyphosate detoxer

At the workshop it was suggested that  I would likely have high levels of glyphosate in my urine, and that I should take a test offered  by John Fagan at a discount rate. I was also offered some advice on a product that would “cleanse” (aka detox) my body of glyphosate, and warned that California beer and wine are high in glyphosate. I am pretty sure they are packed full of a proven carcinogen too – alcohol. Else I want my beer money back!

But then the list of ailments resulting from glyphosate continued – based on a list of references and internet links provided by Don Huber that  inexplicably contained no references more recent than 2013 – which suggested that glyphosate was also associated with  honey bee mortality, birth defects, kidney disease, infertility, low testosterone, small penii and testicles, chronic botulism, fungal toxins, livestock deaths, and babies born without brains and one eye.

Wait – what?  The last one really hit me – because of the associated images that came along with it (below). Fully supported by an article in Natural News. And some sort of bizarre suggestion of a conspiracy theory that Monsanto had changed the allowable level of glyphosate  to be increased in Washington State so as to coverup that these birth defects were being caused by glyphosate. Rather than the folic acid deficiency as suggested by an investigation by Washington State Department of Health.

This information and these images were presented at a University of California-sponsored workshop! At an institute of higher learning my own son attends.  Irrespective of the fact that I am myself the mother of a stillborn baby, I find the exploitation of such tragic images to intentionally mislead and frighten parents, and would-be-parents, into believing pseudo-science garbage, and the fact that this scaremongering was presented as fact at a university event to be beyond repugnant. It was an educational disgrace. There were UC Santa Cruz personnel at this event, helping to project these images and enabling this misinformation and propaganda to be distributed, unchallenged.

I owe my graduate education, over 20 years of fulfilling professional employment, and even meeting my husband to the University of California, but on this day I was embarrassed to be a UC alumna, a faculty member, and a UC parent. We owe it to the citizens of California to do better.

If public universities become the distributors and amplifiers of misinformation, I seriously wonder what institutions the public will have left to trust.

I will finish this BLOG series with a quote from Sri Lankan researchers Buddhi Marambe, Senior Professor, Department of Crop Science, Faculty of Agriculture, University of Peradeniya, Sri Lanka, and Swarna Herath, who detail the effects of the ill-advised ban on glyphosate in their country, in a forthcoming  Weed Science paper  which offers a glimpse of what can happen when ideology over-rules scientific principles.

“The ban on glyphosate has been imposed without scientific evidence. The agriculture sector and the Sri Lankan economy has taken the brunt of this disastrous and abrupt policy decision. Climate change has further exacerbated the impact of ban imposed on glyphosate. By nature, weeds thrive and compete vigorously with crops when resources are limited and negatively impact on the final harvests. With the ban imposed on importation of glyphosate to the country, it has opened avenues for the entry of illegal products with no quality control. Hence, the agricultural practitioners have become the victims again. The societal forces based on political and spiritual ideologies have unfortunately continued to succeed in Sri Lanka, over-ruling even the most basic scientific principles. Hence, policy makers must follow science and make evidence-based decisions considering the totality rather than focusing political gains out of the situation. Scientists, too, need to support the policy makers by being open and providing conclusive and scientifically valid data to facilitate decision making.”

“Banning of Herbicides and Its’ Impact on Agriculture – The Case of Glyphosate in Sri Lanka” Weed Science November 2019 , pp. 1-29.

This is part 2 of a 1, 2, 3 part BLOG series on this January 2020 two-day event featuring Dr. Vandana Shiva at UC Santa Cruz

Do public Universities have an obligation to present evidence-based information? Does freedom of speech extend to sponsoring speakers who spread misinformation and fear? These are important questions to ask in the current climate, and the answers must be true for all polarizing speech – irrespective of which side of the political spectrum it may fall.

As someone who works in agricultural science, and is passionate about evidence-based policy, I attended a two-day event at UC  Santa Cruz featuring Dr. Vandana Shiva in late January 2020. She was doing a speaking circuit around California Universities, and had preceded the visit to Santa Cruz with a visit to Stanford. Her visits were not without controversy. I attended the session at Santa Cruz to see for myself what all the fuss was about as detailed in Part One of this BLOG (Poison-free, fossil-free California agriculture) , and had some concerns regarding the factual basis of some of the claims made by Dr. Shiva.

One of the statements that Dr. Shiva made at the Sunday session entitled “Poison-Free, Fossil-Free Food & Farming” workshop was that citrus greening disease was not affecting organically-grown citrus plants. This plant disease kills citrus trees and has devastated the Florida citrus industry. It is carried by the Asian citrus psyllid which feeds on citrus leaves and stems.

The Asian citrus psyllid can spread the bacteria as the pest feeds on citrus trees and other plants.

This insect infects citrus trees with a bacteria that causes citrus greening disease also called Huanglongbing (HLB). HLB has been confirmed in California, Florida, Georgia, Louisiana, Puerto Rico, South Carolina, Texas, and US Virgin Islands.

The best way to protect citrus trees from HLB is to stop the Asian citrus psyllid, and this often involves spraying with synthetic insecticides which are not in compliance with organic standards. Once a tree is infected with HLB, it will die. Diseased trees need to be removed in order to protect other citrus trees on the property, neighbors’ trees and the community’s citrus. One hope is perhaps a genetically engineered disease-resistant tree will one day provide a solution to this problem.

However, Dr. Shiva claimed that “Soils rich in soil organisms are giving immunity to the plant. And even with the citrus failure, trees organically grown actually don’t get the disease” and she followed on to suggest that conventional trees get citrus greening disease because they are weak. Evidence please?

So do organic production methods protect citrus plants from citrus greening disease?

No. According to the organic center who have developed a helpful “Organic grower’s guide for combatting citrus greening disease, “Organic citrus producers have suffered terrible losses from citrus greening, and they need to be aware of organic solutions to ward off this disease,” said Dr. Jessica Shade, Director of Science Programs for The Organic Center. “Conventional and organic farmers alike have had their groves decimated by citrus greening,” she said. “While our report provides tools for them, to help them in their struggle, without more research we’ll continue to see a dramatic decline in citrus production – especially organic citrus.”

Another questionable statement Dr. Shiva made was that genetically engineered (GM) Bt cotton (which is protected from caterpillars by expressing a protein known as the Bacillus thuringiensis (Bt) toxin which is toxic to caterpillars but not mammals) “results in farmers using more pesticides”. And to add some emotion to that statement she said she “had rushed to where 130 farmers growing Bt cotton had died from spraying pesticides”, with the implication being that this was because of the GM cotton. This claim makes really no sense.

The weight-of-evidence literature on insect-protected cotton is that Bt cotton farmers spray less insecticides, especially organophosphates (Multidecadal, county-level analysis of the effects of land use, Bt cotton, and weather on cotton pests in China; Bt cotton and sustainability of pesticide reductions in India; Impact of Bt cotton on pesticide poisoning in smallholder agriculture: A panel data analysis; Bt cotton cuts pesticide poisoning). If Bt cotton actually necessitated using more insecticides, then it might be reasonable to ask why would farmers plant Bt cotton?

Certainly there can be secondary pests that emerge when broad-spectrum insecticides are no longer sprayed on cotton, and there are some concerns with the development of resistance to Bt, especially given there were no refugia established in India as discussed in this article. But trade-offs exist with all pest control methods, and sometimes it seems that if there is a single trade-off associated with GM, and despite the documented benefits that are suggested by its widespread adoption, this tradeoff is used as a “gotcha” to dismiss all uses of this breeding method, in all situations. A common example is some weeds have developed resistance to glyphosate when used indiscriminately, therefore all GMOs are bad.

More generally the US National Academy of Sciences report on GM crops found “There is “reasonable evidence that animals were not harmed by eating food derived from GE crops,” and epidemiological data shows no increase in cancer or any other health problems as a result of these crops entering into our food supply. Pest-resistant crops that poison insects thanks to a gene from the soil bacterium Bacillus thuringiensis (Bt) generally allow farmers to use less pesticide. Farmers can manage the risk of those pests evolving resistance by using crops with high enough levels of the toxin and planting non-Bt “refuges” nearby.” This 800 plus page NAS study drew on hundreds of research papers to make generalizations about GE varieties already in commercial production.

Unfortunately Dr. Shiva made no reference to weight-of-evidence studies in her presentations, nor the consensus statements of scientific societies. Rather she frequently drew on anecdotes, appeals to “nature” and emotion, and an occasional reference to a selected subset of the scientific literature to support her points, including the much criticized and ultimately retracted highly-controversial 2012 Seralini study (subsequently republished in a different journal) to suggest GMOs and glyphosate were associated with tumors in rats, and a 2014  Sri Lankan paper that posed an untested hypothesis that glyphosate was responsible for chronic kidney disease of undetermined causes (CKDu). A systematic 2018 review and meta-analysis “found little evidence that pesticides were the main cause of CKDu in Central America.”

During the Sunday workshop, Dr. Shiva stated that “I am not an agricultural scientist. I am not a toxicologist. I am just in deep love with the Earth.” This was met with approving nods and applause by the Santa Cruz audience. By setting up this dichotomous framing – that scientists with a deep understanding of agriculture and toxicology are somehow not in love with the Earth, her message seemed be to distrust expertise and science, and rather side with people who profess “a deep love of the Earth”. My land grant colleagues spend careers trying to use science to develop approaches to decrease the environmental impact of agriculture to help both the earth and humanity. If agricultural scientists and public sector toxicologists are the enemy to be despised or ignored, then I fear for the future of food production.

Students from Stanford University invited Dr. Shiva to speak at that University the Thursday (1/23/2020) prior to her appearance at Santa Cruz . Following the controversy regarding that event, the student group “Students for a Sustainable Stanford” (SSS)  wrote in their campus newspaper:

“We recognize that Dr. Shiva has made many incendiary statements in her career. Some of them are untrue. For example, she has argued that farmer suicides in India have doubled since the introduction of Bt cotton, and that GMOs are unsafe to consume. She referenced these points during the lecture. These stances are not supported by the scientific literature, and our organization does not endorse them. Do these statements delegitimize Dr. Shiva’s entire platform? Should she be denied the microphone because some of her statements have been disproven?” No. SSS believes that we can invite a controversial speaker to campus and provide a platform for her insights on environmental justice and community-based activism, without sponsoring every statement she makes.” (emphasis added)

That argument is interesting, as it suggests that speakers on campus should not be required/expected to present 100% factual information. Rather, it excuses the misinformation that it is well-known the paid speaker will present as “not sponsored”. But I question how does the audience, mostly with little agricultural background or expertise, discern which parts of the talk are “unsponsored untruths”, and which parts are “sponsored insights on environmental justice and community-based activism”? Could a similar argument be made that Dr. Andrew Wakefield should be invited to discuss his discredited contention that vaccines cause autism? I am reminded of the old adage, ‘You are entitled to your opinion. But you are not entitled to your own facts.’ I wonder, does sponsoring a speaker known to spread misinformation on university campuses serve the public good?

More generally, I am not sure that rationale would fly too well at faculty recruitment interviews, “Well 80% of what the candidate said was true but the remaining 20% about “pick your controversial polarizing scientific topic” [climate change not happening/ vaccines causing autism/the earth being flat/GMOs being unsafe to consume/evolution being a conspiracy] are stances not supported by the scientific literature, and this university does not endorse those fabrications as fact, but the candidate has a big public following so they seem like an acceptable hire.”

As an educator, I have a pretty simple expectation for speakers on university campuses, irrespective of their subject matter area. And that is they should not intentionally mislead people with anecdotes that are not supported by the scientific literature, or spread misinformation that they know to be false.  And if I suspect this might be a problem, I would pair them with a public sector subject matter expert who could challenge any unsupported statements with evidence. That does not seem like a very high bar to me. And in my opinion, when it comes to encouraging community-based activism around shifting agricultural production practices in the face of climate change, that expectation for evidence is doubled because of the dramatic real world implications of ill-advised shifts based on incorrect information.

This is part 1 of a 1, 2, 3 part BLOG series on this January 2020 two-day event featuring Dr. Vandana Shiva at UC Santa Cruz

In late January, 2020 I attended two events at UC Santa Cruz, a sister campus to UC Davis, and also where my tuition fees go to pay for the (presumably fact-based) education of my “banana slug” son who is a senior there. It was therefore with some concern that I read that Vandana Shiva had been invited to speak on campus. Dr. Shiva has been a polarizing figure in the genetically modified (GMO) foods discussion, as detailed by Michael Specter. But I personally had never heard her speak and as a scientist and someone who is trying to understand why the GMO debate has become so polarized, I decided to sign up and listen closely to what Dr. Shiva had to say, both at her Saturday evening lecture, “Vandana Shiva In Conversation”, and the following all day event entitled “Poison-Free, Fossil-Free Food and Farming.”

The Saturday night lecture, to a very receptive and supportive crowd, conversed on a range of topics, from empowering women farmers to the importance of nutritious food, the impact of climate change on food production systems, and the importance of seed banks.  Hard to find fault with any of those topics, in fact I agreed with Dr. Shiva on a number of her points. There was a lot of disparaging of “industry” and billionaires, especially Bill Gates despite his philanthropy, and much demonization of globalization and colonization.

As an agricultural scientist I took issue with the lack of evidence to support some of the overly optimistic anecdotes that were given regarding the productivity of different organic and agroecological production systems, because if they really were so much superior it makes little sense as to why would ALL farmers, as astute business owners, would not rapidly employ such production systems. Perhaps it is more complicated than was suggested.

The contention that organic production systems outcompete conventional systems is not supported by the weight-of-evidence in the peer-reviewed literature, and is one of the reasons that less than 1% of US farmland is under organic production.  But it was when discussing anything related to GMOs, Monsanto, patents and especially glyphosate (Round-up) that things (perhaps as might be expected) went totally off the rails. I will get into a couple of the specifics of that for those who are interested in fact-checking in part 2  (Sponsoring Falsehood) and part 3  (Rounding Up Fear) of this BLOG series.

The next day a group of very like-minded people discussed collective action ways to move California agriculture to “poison free” and “fossil-free”, meaning avoiding the use of all synthetic pesticides and fertilizers. California is a large agricultural producer, the largest state in the nation. Although the speakers talked a lot about social justice and empowering farmers, there were no California farmers or farm workers, those who would presumably be most likely be impacted by the proposed changes, represented on the panel of speakers.

Crop loss to different factors in the absence of effective controls

There was discussion about the need for farm-workers to be paid a living wage, but little discussion of what removing all pesticides and fertilizers might mean for those same farm-workers in terms of their job duties, or the economic sustainability of the farms that provide their employment. In other words, there was NO discussion of what trade-offs might result from this re-envisioning of the entire agricultural production system in California.

In the course of my job I interact with California farmers and ranchers, some conventional and some organic, and others somewhere in between to meet certain value-added program requirements (e.g. “never ever”, “non-GMO”). I watch how farmers under different production systems handle the nutrient needs of their crops, and control pests; be they disease-causing microbes, hungry insects, or moisture-seeking weeds.  Chicken manure from conventional chicken houses systems is composted and used as fertilizer on organic production systems, conventional almond hulls provide a good source of nutrients for dairy cows precluded from GMO-feed, and farm-workers control weeds in production systems that do not allow to use synthetic herbicides using tillage, propane flame throwers, and manual hoeing as pictured below.

California farm workers hand weeding an organic crop in the San Joaquin Valley

India, where Dr. Shiva lives, with its population of 1.27 billion people, employs 59% of the country’s total workforce in Agriculture. Seventy percent of its rural households still depend primarily on agriculture for their livelihood, with 82 percent of farmers being small and marginal. It is also home to a quarter of the world’s hungry people and anemia affects 50 percent of women and 60 percent of children in the country. There are certainly good reasons to be concerned about improving both food security and the productivity of agriculture in that country.

However, California agriculture is not comprised of small subsistence farms. It is an agricultural powerhouse.  California’s 77,100 farms and ranches received a total of $50.13 billion for their output in 2017 with combined commodities representing 13.4 percent of the U.S. total. California’s leading crops are fruits, nuts and vegetables. Over 27 percent of California’s 77,100 farms generated sales over $100,000, greater than the national average of 19.9 percent. The average farm size in California is 328 acres, which is below the national average of 444 acres. These are large enterprises to manage and farm, and the challenges facing California farmers are likely quite different to those of a small holder, subsistence farmer. What might California agriculture look like if synthetic pesticides and fertilizers were banned?

Back in 1840, workers in the agriculture industry made up 70% of the American workforce. Today farmers and ranchers themselves make up only 1.3% of the employed US population, totaling around 2.6 million people. Part of this urban transition has been enabled by the use of synthetic herbicides in agriculture. According to the author of an article entitled The Value of Herbicides in U.S. Crop Production, “By controlling weeds effectively, herbicides do the work of 70 million laborers.” In that article it is stated that “the problem of controlling weeds without herbicides has been cited numerous times as the single biggest obstacle to crop production that organic crop growers encounter.” USDA reports on strawberry, carrot, cotton, and processing tomato concluded that national production would decline by 30%, 48%, 27%, and 20%, respectively, without the use of herbicides and with the substitution of likely alternatives.

More generally, it has been estimated that without pesticides, 70% of the world food crop would be lost; even with pesticide use, 42% is destroyed by insects and fungal damage. According to one study, “Dispensing with pesticides would require at least 90% more cropland to maintain present yields. Dispensing with fertilizer would require at least 400-600 Mha additional cropland (in addition to the ~1,400 Mha currently grown).

“The consequence of less-efficient agriculture will be the elimination of wilderness that by any measure of biodiversity far exceeds that of any kind of farming system.”

Anthony Trewavas, Fellow of the Royal Society, University of Edinburgh, Scotland

There was a real sentiment in the room that all pesticides were “poisons”, and that no amount of pesticide (or inorganic fertilizer) was acceptable. And all of this seemed to be based on the premise that agriculture today is using ever increasing amounts of more toxic (poison) pesticides. The figure below on pesticide use in U.S. Agriculture from 1960-2008 , from a 2014 report from the USDA ARS, states “Average chronic toxicity declined, as toxic products applied to cotton (such as DDT and toxaphene) and to corn (such as aldrin) were banned (particularly in the 1970s and early 1980s). Other factors affecting toxicity were the use of less toxic insecticides, such as carbaryl and chloropyrifos, the introduction of pyrethroids, the use of malathion in the boll weevil eradication program, and the use of Bt [insect-protected, genetically engineered] cotton since 1996.

Figure from Fernandez-Cornejo, Jorge, Richard Nehring, Craig Osteen, Seth Wechsler, Andrew Martin, and Alex Vialou. Pesticide Use in U.S. Agriculture: 21 Selected Crops, 1960-2008, EIB-124, U.S. Department of Agriculture, Economic Research Service, May 2014.

Persistence fell during the 1970s after the bans of DDT and aldrin, then increased during the 1980s and early 1990s (in part with the use of high-persistence products such as metolachlor and pendimethalin); persistence has declined in recent years, reflecting the rapid increase in glyphosate use. Glyphosate has low chronic toxicity (a high chronic score) and relatively low persistence relative to the herbicides that it has replaced. As the NRC (2010) report states, glyphosate “is biodegraded by soil bacteria and it has a very low toxicity to mammals, birds, and fish.”

There was none of this type of evidenced-based data presented at this all-day event. Let alone data that documented that GMO crops had actually decreased insecticide use, especially organophosphate insecticides including in India, and allowed the use of less toxic herbicides. Unfortunately, non-Bt cotton refuges were rarely planted in India, which increased selection pressure for Bt-resistant pink bollworms thereby reducing the effectiveness of Bt cotton in that country, and highlighting the importance of integrated pest management, a term I did not hear mentioned at this conference.

I was disappointed that at a public university event on agriculture there were no public sector toxicologists to present objective facts and data on pesticide use in agriculture, integrated pest management specialists, or California farmers present to discuss potential trade-offs,  and what poison-free, fossil-free California agriculture might mean for their farms, their workers, their families and their livelihoods. The discussion did not reach beyond a simplified dichotomous framing of good versus evil, and was a missed opportunity to have the more nuanced discussion that such a weighty and important topic deserves. But things got much worse at the all day event entitled “Poison-Free, Fossil-Free Food and Farming” as detailed in the final part Rounding Up Fear of this 3-part BLOG.

(*****This series of 4 BLOG posts (1,2,3,4) is extracted from my paper from the Proceedings of the Range Beef Cow Symposium XXVI, November 18-20, 2019. Mitchell, NE. pages 37-49.*****)

Nobody is selling it yet, at least as far as cultured meats go, because no one has reduced the production  to a commercial scale. But the concept is being sold hard.

In October 10, 2019 a Jerusalem biotechnology company Future Meat Technologies announced it will establish the world’s first cultured meat pilot production facility, “producing GMO-free meat cultivated directly from animal cells on a commercial scale”.  According to an Israeli press article “The company plans to establish the facility south of Tel Aviv and begin operations next year. The expansion of research and development efforts come after the start-up secured $14 million in a Series A funding round. The company plans to introduce hybrid products into the market, combining plant proteins for texture with cultured fats to create the aroma and flavor of meat. While existing costs are $150 per pound of chicken and $200 per pound of beef, it aims to market its hybrid products at a “competitive cost level” from its pilot production facility by 2021.”

According to the June 2019 report by consulting firm A.T. Kearney, they predict that “In 20 years, only 40% of global meat consumption will still come from conventional meat sources”. They posit that “Cultured meat will win in the long run. However, novel vegan meat replacements will be essential in the transition phase”. In their estimation by 2040, cultured meat will make up 35 percent of meat consumed worldwide, while plant-based alternatives (e.g. Impossible, Beyond Burger) will compose 25 percent.

Projected breakdown of global meat production by 2040 according to a June 2019 A. T. Kearney Analysis.

By 2040 the FAO predicts there will be 402 million metric tons (MMT) of land-based meat consumed worldwide (169 MMT chicken, 143 MMT pork, 90 MMT beef). That does not include eggs (98 MMT), fish (200 MMT), or milk (1,051 MMT). The total of animal-based products in 2040 is therefore predicted to be 1751 MMT (compared to 1430 in 2020) as illustrated in the feature image. Doing the back of the envelope math and assuming that only the 402 MMT of land-based meat production (i.e. not the sizable milk, fish and eggs production) is replaced with “quarter pounders” of alternative sources as predicted in the image above, that would equate to [(.25 x 402 MMT) X (1,000,000,000/0.1133981)] which would be approximately 886,258,235,367 plant-based burgers, and (.35 x 402 MMT)X(1,000,000,000/0.1133981) which would be approximately:

One trillion, two hundred forty billion, seven hundred & sixty-one million, five hundred and twenty-nine thousand, five hundred & fourteen (1,240,761,529,514) cultured meat burgers annually by 2040. That is a big ask in 20 years for an industry that does not yet have a single product on the market!

As with all ‘disruptive innovations’, there is a need to consider the pros and cons of the system that is being proposed as compared to the existing system. There will always be tradeoffs, some good, some bad. There are positive externalities associated with ruminants such at the ecosystem services they provide when they graze rangeland.  Grazing ruminants are embedded in the definition of rangelands—“a natural ecosystem for the production of grazing livestock and wildlife.” Grasslands and their associated biodiversity frequently evolved with large hoofed herbivores; well-managed, herbivorous grazing by ruminants maintains rangeland health.

Ruminants also provide manure, transportation, the livelihoods and food security of an estimated 1.3 billion livestock keepers. Small ruminants – sheep and goats – produce only about 4% of global animal-source protein. However, they are a very important source of such protein in the developing world as they are able to upcycle plants that are inedible for humans into high quality animal-souce foods. THAT is the magic super-power of grazing ruminants. The rumen’s microbial population can transform inedible grasses and other cellulose-based forages into energy. Additionally ruminants produce more than just hamburgers. Milk is by far the most consumed animal-source food globally, and dairy animals also produce both milk and meat.

https://cfpub.epa.gov/ghgdata/inventoryexplorer/

Mattick et al. (2015) writes of cultured meat, “These energy dynamics may be better understood through the analogy of the Industrial Revolution: Just as automobiles and tractors burning fossil fuels replaced the external work done by horses eating hay, in vitro biomass cultivation may similarly substitute industrial processes for the internal, biological work done by animal physiologies.” Meaning external energy sources will be used to replace the work of the biological processes that take place in the cow. The authors continue with this train of thought, “That is, meat production in animals is made possible by internal biological functions (temperature regulation, digestion, oxygenation, nutrient distribution, disease prevention, etc.) fueled by agricultural energy inputs (feed). Producing meat in a bioreactor could mean that these same functions will be performed at the expense of industrial energy, rather than biotic energy.” Cultured meat would replace  a biotic system with a fermentation factory powered by industrial energy. The abstract of their paper concludes:

“While uncertainty ranges are large, the findings suggest that in vitro biomass cultivation could require smaller quantities of agricultural inputs and land than livestock; however, those benefits could come at the expense of more intensive energy use as biological functions such as digestion and nutrient circulation are replaced by industrial equivalents. From this perspective, large-scale cultivation of in vitro meat and other bioengineered products could represent a new phase of industrialization with inherently complex and challenging trade-offs.”

Mattick, et al. 2015. Anticipatory Life Cycle Analysis of In Vitro Biomass Cultivation for Cultured Meat Production in the United States. Environ Sci Technol 49(19):11941-11949.

In summary, cultured meat is a term used to describe imitating a range of animal products from animal cells grown in a bioreactor. Although there is a lot of venture capital and celebrity investor buzz around this technology, there is no company that is currently selling cultured meat. There are a number of unknowns about the feasibility of culturing animal tissues at scale, and the true environmental impact of using energy to replace the biological functions carried out by the body of an animal (harvesting forage for energy and growth, waste removal, fighting off disease etc.). Growing animal cells efficiently and keeping contaminants out of the system and end product requires attentive management and innovation, whether meat is produced in a biotic system that is powered by solar energy and the physiology of a cow, or an industrial system using electricity and a bioreactor to produce cultured meat in a manufacturing plant.

(*****This series of 4 BLOG posts (1,2,3,4) is extracted from my paper from the Proceedings of the Range Beef Cow Symposium XXVI, November 18-20, 2019. Mitchell, NE. pages 37-49.*****)

When it comes to cultured meat, venture capital funds are funding startups in California, Israel and the Netherlands. Some of the first work in this area was done by Mark Post at Maastricht University in the Netherlands to produce the proof-of-concept burger  featured at the August 2013 £250,000 (US $330,000) lab-grown burger unveiling event in London. According to an article by Mouat and Prince, “Before the hamburger event, the mystery benefactor that financed the burger was unknown. Later it was revealed that the funder was Google co-founder Sergei Brin (Net Worth: $53.8 Bn). The event was simulcast on the web and included a celebrity chef live-cooking the burger, a three-person tasting panel, and a live studio audience . At this event, Post estimated that if the process can be scaled up it would take 10–20 years to produce ‘beef,’ likely still at relatively high cost (Murray, 2018).

Memphis Meats made meatballs from cultured meat at $18,000 per pound in 2016. Somewhat ironically given the environmental footprint of airplane travel, Virgin Airlines founder Richard Branson (Net Worth: $3.8 Bn) joined Bill Gates in financing cultured meat leader Memphis Meats in part of a $17 million fundraising round in 2017.

“There is no doubt that the association of this iteration of biological technology with super-rich celebrity investors and venture capital is significant”  (Mouat and Prince, 2018).

Ground beef is not the only product that is being attempted in cell-based culture. There are a number of companies springing up making everything from ice-cream to egg whites to cowless milk. In 2014 Perfect Day (Muufri prior to August 2016) was offered USD$2 million in seed money from Horizons Ventures. According to Mouat and Prince (2018), one of the partners at Horizons Ventures, Li Ka-shing ‘loves disruptive innovations and sees it as kind of predictive lenses into the future. He loves to meet and geek with the founders and CEOs of companies within our disruptive portfolio, to understand their concepts and missions’. Horizons Ventures have also invested in Facebook, Spotify, Skype, Modern Meadow (lab-grown leather for disrupting the $90 billion per year leather industry). There has also been some state investment in these technologies (Stephens, 2015).

A list of the companies I could find is in Table 2 using data from this list maintained at Cell based tech (https://cellbasedtech.com/lab-grown-meat-companies) among other media sources – along with their location and the product they are trying to mimic.

Table 2: Listing of companies formed to produce cellular animal-based products, and their location. Estimates of total capital raised is listed when known.

New Harvest, a 501(c)(3) research institute accelerating breakthroughs in cellular agriculture, collects and directs charitable donations and grants in the industry. Next to venture capital funds, large corporations such as Cargill, Merck, Google, UBS, and PHW Group have invested in these companies. Cargill invested in Memphis Meats. The sum of total capital raised in Table 2 is well north of USD$400 million. The Good Food Institute, a non-profit that promotes plant-based and cultured meat alternatives to meat, dairy, and eggs; estimated that in the five years leading up to 2018, USD$17.1 billion had been invested in plant-based food; with a further USD$73.3 million in cell-based meat companies.

Mouat and Prince (2018) use the term biocapitalism to describe the investment in cultured meat. They reflect that fundraising for companies trying to produce animal-free food – depends to varying extents on “a venture capital industry with a culture that celebrates ‘disruption’; a set of biotechnical materials and relations that are being pacified into a marketable object; an existing community of concern worried about the effects of animal agriculture; and the construction of ethical agency for animal-free food to solve the problems that this community is so concerned with. It is all of these things that enable value to be leveraged off the biological material that makes up animal-free food, and so constitutes it as biocapital.

(*****This series of 4 BLOG posts (1,2,3,4) is extracted from my paper from the Proceedings of the Range Beef Cow Symposium XXVI, November 18-20, 2019. Mitchell, NE. pages 37-49.*****)

The start-to-end environmental footprint – called a life cycle assessment (LCA) – of cultured meat at large scale is not available as no group has yet achieved this feat. I have tried to summarize the literature on the basis of kg of final product (Table 1), but note there are differences in a kg milk versus a kg of beef, and even a two-fold difference in the assumptions made as to the protein content of cultured meat. It is therefore close to impossible to do an apples to apples comparison. The values vary dramatically depending upon the assumptions made, and the boundaries of the LCA.

The functional unit (i.e. metric of the comparison) matters – whether kg carcass weight, kg product, kg of nutritional value (e.g., protein), and then of course the quality of that protein or food source. Changes in the functional unit (FU) alters the results quite dramatically, and therefore, the development of a FU which would reflect the complete integrative nutritional function of meat substitute is needed. It is obvious that meat substitutes have different nutritional profiles and, therefore, nutritional value. At the same time, different aspects of nutritional quality (protein and amino acid content, vitamins, fat and fatty acids, micronutrients etc.) vary in different proportion in meat substitutes. Therefore, it is necessary to develop a complex nutritional value estimate, which would reflect the qualities of meat and meat substitutes for further studies.

Table 1. Carbon Footprint CO2-eq, land use (m2), and energy use (MJ) per kg product for different products in a number of different studies. *Qantis (https://quantis-intl.com/).

In looking at Table 1, some general rules always apply: the carbon footprint per kg product increases as you go from one trophic level to the next (i.e. plants to animals that eat plants), and from single stomach (monogastric) animals (e.g.,  chickens/pigs) to ruminants (e.g., cattle and sheep). However, ruminants can eat forage that monogastrics, humans included, cannot. Ruminants consume byproducts (e.g. distiller’s grains) and crop residues (e.g. almond hulls) that would otherwise go to waste or into landfills.

Eighty-six  (86%) of the global livestock feed dry matter (DM) intake consists of feed materials that are not human edible. Producing 1 kg of boneless meat requires an average of 2.8 kg human-edible feed in ruminant systems and 3.2 kg in monogastric systems (Mottet et al., 2017).

It should also be noted that land use numbers in Table 1 do not differentiate between arable land, and land that has no other human food purpose. Many ruminants graze marginal land, or crop residues, and convert that otherwise inedible forage into milk and meat. Conversely, cellular meat will require the provision of food grade nutrients supplied directly to the cells growing in the bioreactor, and waste streams will need to be disposed of following production of the cultured product. The LCA of this aspect of cellular meat remains unknown.

It is worth noting that the very favorable cultured meat LCA (Tuomisto and Teixeira de Mattos, 2011), oft-cited by proponents of cultured meat, was funded by New Harvest, a non-profit research institute accelerating breakthroughs in cellular agriculture, and has been especially criticized for assuming cultured mammalian meat will be able to be grown using  cyanobacteria hydrolysate as the nutrient and energy source for muscle cell growth, as this medium is more commonly used for yeast cells; and for ignoring the environmental impacts of growth factors and vitamins, as the cells cannot grow without these supplements and they are both difficult to isolate and synthesize.

The functional unit (FU) of the alternative meat discussion to date has been, oddly enough, hamburger patties, ground beef.

As  mentioned previously, the FU used as the comparator can dramatically alter the sustainability metrics of any system (lb carcass weight is different to lb edible meat, and lb protein, and lb of animal source food) – especially if the comparators differ nutritionally.

An average weight steer (1,300 lb) produces an 806 lb carcass which yields 639 lb edible beef, of which 38% is ground beef (i.e.  62% is not!). Primal cuts are obviously more valuable than ground beef, and the by-products of beef (including hides, offal, blood, tallow, bones, and bone meal) which represent approximately 11.7% of the value of a carcass are not factored into many LCA analyses. There are also offal products such as beef tongue and tripe, favorites of many ethnic communities, which are unlikely to be replicated via cell culture technology.

According to the FAO, global animal agriculture is estimated to account for 14.5% of anthropogenic GHG emissions which can be broken down into beef (5.9%), cattle milk (2.9%), pork (1.3%), buffalo milk and meat (1.2%), chicken meat and(1.2%), and small ruminant milk and meat (0.9%) (FAO).

Nationally agriculture accounts for 9% emissions, slightly less than 4% is animal agriculture. https://cfpub.epa.gov/ghgdata/inventoryexplorer/

In the United States, all of agriculture is responsible for 9% of the US GHG emissions (US EPA). Fossil fuel-based energy is responsible for over 80% of total US GHG emissions, as compared to slightly less than 4% from animal agriculture. To put this in perspective, it has been estimated that eliminating ALL of US animal agriculture would decrease US GHG by 2.6%, but would also create a food supply incapable of supporting the US population’s nutritional requirements .

LCA REFERENCES

Lynch, J. and R. Pierrehumbert. 2019. Climate Impacts of Cultured Meat and Beef Cattle. Frontiers in Sustainable Food Systems 3(5).

Mattick, C. S. 2018. Cellular agriculture: The coming revolution in food production. Bulletin of the Atomic Scientists 74(1):32-35.

Mattick, C. S., A. E. Landis, B. R. Allenby, and N. J. Genovese. 2015. Anticipatory Life Cycle Analysis of In Vitro Biomass Cultivation for Cultured Meat Production in the United States.  Environ Sci Technol 49(19):11941-11949.

Mottet, A., C. de Haan, A. Falcucci, G. Tempio, C. Opio, and P. Gerber. 2017. Livestock: On our plates or eating at our table? A new analysis of the feed/food debate. Global Food Security 14:1-8.

Nijdam, D., T. Rood, and H. Westhoek. 2012. The price of protein: Review of land use and carbon footprints from life cycle assessments of animal food products and their substitutes. Food Policy 37(6):760-770.

Tuomisto, H. L., M. J. Ellis, and P. Haastrup. 2014. Environmental impacts of cultured meat: alternative production scenarios. Pages 8-10 in Proc. Proceedings of the 9th international conference on life cycle assessment in the agri-food sector.

Tuomisto, H. L. and M. J. Teixeira de Mattos. 2011. Environmental Impacts of Cultured Meat Production. Environmental Science & Technology 45(14):6117-6123.