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The United States (US) Food and Drug Administration (FDA) finally allows sale of fast-growing genetically engineered AquAdvantage salmon. Many people are asking about the impacts of the fish on human health and the environment. We have answers to these questions thanks to two independent sets of regulatory processes, one in Canada and one in the United States. This AquAdvantage Regulatory Timeline Infographic displays some of the key steps in the regulatory process.

Find information about safety of the fish for human health and for the environment in Fast-growing genetically engineered salmon approved.

Detailed AquAdvantage Regulatory Timeline

Detailed information for the AquAdvantage Regulatory Timeline Infographic can be found below. Parts of the timeline are adapted from Chronology of AquAdvantage® Salmon and AquaBounty Technologies.

• 1989 – Initial development of fast-growing genetically engineered salmon begins.
• 1992 – AquaBounty establishes the AquAdvantage salmon (AAS) line.
• 1995 – AquaBounty starts an Investigational New Animal Drug file with FDA’s Center for Veterinary Medicine to pursue development of AquAdvantage salmon.
• 2003 – AquaBounty submits its first regulatory study for a New Animal Drug Application to the FDA.
• 2008 – The FDA inspects AquaBounty’s hatchery in Prince Edwards Island as an authorized production site for AAS eggs, and has no adverse findings. AquaBounty begins construction of a land-based aquaculture facility in Panama.
• 2009 – AquaBounty Technologies submits its final regulatory study to the FDA. The FDA releases Guidance 187 for evaluation of genetically engineered animals. The FDA inspects the Panama facility for production of AAS for import into the US, and has no adverse findings.
• 2010 – AquaBounty receives section complete letters from the FDA on all seven parts of the New Animal Drug Application. The FDA convenes a public meeting of the Veterinary Medicine Advisory Committee to review its findings. They conclude the genetically engineered salmon is indistinguishable from Atlantic salmon, is safe to eat, and that it poses no threat to the environment under its conditions of use. FDA also holds a public hearing about GMO salmon, accepts comments, then responds to public comments.
• 2011 – The FDA consults with the National Marine Fisheries Service and the US Fish and Wildlife Service. Both agencies concur that AAS does not pose a threat to the environment. Environmental groups submit a petition to the FDA asking them to slow or stop approval of GMO salmon (which FDA subsequently rejects).
• 2012 – The FDA releases a draft Environmental Assessment with a preliminary Finding of No Significant Impact. A 60-day public commentary period, later extended to 120 days, begins. The FDA inspects AquaBounty’s hatchery in Prince Edwards Island, and has no adverse findings. AquaBounty submits a request to Canadian regulatory agencies to sell AAS.
• 2013 – The public comment period on the draft Environmental Assessment concludes in April, and FDA responds to public comments. The Canadian Science Advisory Secretariat (CSAS) releases their Environmental and Indirect Human Health Risk Assessment, which determines that AAS does not pose a risk to the environment. Environment Canada authorizes AquaBounty to produce AAS eggs for commercial sale.
• 2014 – AquBounty submits labels to the FDA for review.
• 2015 – FDA determines that Executive Order 12114, “Environmental Effects Abroad of Major Federal Actions” does not apply to fast-growing genetically engineered salmon. Environmental groups submit a petition to the FDA asking them to deem genetically engineered salmon an unsafe food additive (which FDA subsequently rejects). FDA approves AquBounty’s New Animal Drug Application and labels, with conditions on where and how the salmon may be raised. FDA also issued guidance on labeling genetically engineered salmon.
• 2016 – Health Canada approves AAS for use as a human food. The Canadian Food Inspection Agency determines that AAS may be used in livestock feed. The FDA issued an import alert that “prevented the introduction or delivery for introduction into interstate commerce of food containing GE salmon, including their eggs.” This blocks AquaBounty from commercializing AAS in the US.
• 2017 – AquaBounty submits a Supplemental New Animal Drug Application for a new rearing facility in Indiana. AquaBounty announces they sold 5 tons of AAS filets in Canada. The Organisation for Economic Co-operation and Development (OECD) publishes a Consensus Document on the Biology of Atlantic Salmon, which provides background information about Atlantic salmon that might be useful in regulatory assessments.
• 2018 – FDA approves AquaBounty’s supplemental application, releasing an updated approval letter, appendix with conditions, a Supplemental Environmental Assessment, and a Supplemental Finding of No Significant Impact. AquaBounty announces they sold 5 tons of AAS filets in Canada.
• 2019 – In response to new regulations about Bioengineered Labels, FDA revises its draft guidance on labeling genetically genetically engineered salmon to state that labeling will not be required, but that they support voluntary labeling (GM food labeling is also not required in Canada, unless the food has a significant nutritional change or a health risk). FDA deactivates the import alert they issued in 2016. Finally, AquaBounty may sell the previously-approved genetically engineered salmon in the US, import eggs from their Canadian facility, and raise AAS in their FDA-approved, land-based facility in Indiana.

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• Citation: Anastasia Bodnar. AquAdvantage Salmon Regulatory Timeline. Version 1.0. Biology Fortified, Inc. Mar 12, 2019.
• Permissions: Biology Fortified is making this infographic available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone may download, republish, and use this infographic in its original form for non-profit educational use. Please attribute us when you use this infographic, link back to this page whenever possible, and do not modify the infographic without permission from Biology Fortified.
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In their article Introduction to GMOs, SciMoms Layla Katiraee and Anastasia Bodnar answer many questions that people have about products of biotechnology, commonly known as genetically modified organisms or GMOs. They start with the basics: What is a GMO? Why do they exist? What crops are genetically modified and what traits do they have? Then, the SciMoms delve into the hard questions: Are GMOs safe? Are they tested? What studies have been done? Read the full article at the SciMoms website.

SciMoms created a helpful infographic, shared here with permission as part of Biology Fortified’s infographic collection.

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• Citation: Layla Katiraee, Anastasia Bodnar. SciMoms Guide to GMOs. Version 1.0. SciMoms. Jan 23, 2019.
• Permissions: SciMoms is making this infographic available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use. Please attribute them to us when you use them, and do not modify them without permission from SciMoms.
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For more information, see Virologist Alma Laney’s detailed article on How virus resistance works in GMOs.

Plant viruses can be serious pathogens in crops as they can cause anywhere from minor losses to total crop failure. Viruses can be transmitted to crops in a number of ways ranging from contaminated tools to seed and pollen infections. But the primary mechanism of virus transmission is by arthropod vectors^1,2 such as mites and insects. Because of the speed of infection and the devastation that crops can suffer, farmers focus on preventing the introduction of these viruses, which can slow or reduce its spread. However, one of the best strategies is to engineer resistance to the viruses themselves.

How does it work?

Genetically engineered plant virus resistance induces two different forms of resistance and one of the methods can use two different approaches.

• Early on, virologists transformed plants with the complete virus coat protein gene, which forms the shell of the virus to protect the genetic material. It was found in the case of Tobacco mosaic virus (TMV), that over-expression of the coat protein gene led to virus resistance because the excess coat protein interfered with the ability of the virus to complete its lifecycle and move systemically in the plant³.
• Later research uncovered that the the RNA silencing (RNAi) can induce resistance to plant viruses. In plants, the RNAi pathway serves as a type of immune system to target pathogens⁴, including viruses. There are multiple ways that the RNAi pathway can be triggered:
• dsRNA: In plants and animals, most RNA is single-stranded. However, the majority of the described plant viruses have RNA genomes and one of the byproducts of viral replication is double-stranded RNA (dsRNA)⁵. This dsRNA is very stable and triggers the RNAi pathway. Some genetically engineered crops that utilized the complete coat protein also triggered the RNAi pathway, and it was found that in some cases the secondary structure of the RNA produced regions with dsRNA that could trigger RNA silencing in plants⁶.
• Short hairpins: The discovery that short dsRNA segments could trigger RNAi led to the use of constructs that generate a hairpin cassette that forms into dsRNA⁷. Early uses of virus-derived transgenic resistance used entire genes; however, with advances in our understanding of the RNAi pathway, many researchers have adopted the hairpin cassette method. This allows for the targeting of multiple viruses and/or viral genes⁸, which minimizes the chances of the targeted virus developing resistance.

What crops are modified?

• Papaya resistant to Papaya ringspot potyvirus (PRSV): This product saved the papaya industry in Hawaii as PRSV makes fruit unmarketable and eventually kills infected trees⁹. The virus spreads quickly and attempts to introgress resistance to PRSV from wild relatives failed for decades, leaving papaya growers with the only strategy of moving their operations to another island. Each time they moved, there was a short reprieve, but the virus eventually made it to that area. By the time PRSV made it to the last papaya growing area in Puna, Hawaii, the transgenic was ready and the industry was saved.
• Summer squash: There are two different transgenic events for virus resistance in summer squash:
  • ZW-2010, targets Zucchini yellow mosaic potyvirus (ZYMV) and Watermelon mosaic potyvirus (WMV)
  • CZW-311, targets Cucumber mosaic cucumovirus (CMV)in addition to ZYMV and WMV.
• Crops in development: There are multiple crops in development, the most notable are Cassava with resistance to Cassava mosaic disease (CMD)¹² and Cassava with resistance to Cassava brown streak disease (CBSD)¹³, to their potential impact to food security in several African nations.

Conclusions

Virus-derived transgenic resistance holds great promise in sparing growers and consumers the costs of losses due to virus infection. Furthermore, this technology has saved at least one crop, papaya grown in Hawaii, and holds the potential to grant those in developing nations food security by preventing losses in staple crops. Some of the other benefits of this approach to controlling plant viruses is that it reduces sprays that were used to control the arthropod vectors, while not altering how the crops are grown. One of the main challenges is that resistance to one strain of virus may not give strong resistance to other strains, so the evolution of new virus strains must be closely monitored.

References

1. Leitner et al., 2015. Arthropod Vectors and Disease Transmission: Translational Aspects. PLoS Neglected Tropical Pathogens 9(11):  e0004107. DOI: 10.1371/journal.pntd.0004107
2. Whitfield et al., 2015. Insect vector-mediated transmission of plant viruses. Virology Volumes 479–480: 278–289 DOI: 10.1016/j.virol.2015.03.026
3. Beachy, 1999. Coat-protein-mediated resistance to tobacco mosaic virus: discovery mechanisms and exploitation. Philos Trans R Soc Lond B Biol Sci 354:659-664. DOI: 10.1098/rstb.1999.0418
4. Obbard et al., 2009. The evolution of RNAi as a defence against viruses and transposable elements. Philos Trans R Soc Lond B Biol Sci 364(1513): 99–115. DOI: 10.1098/rstb.2008.0168
5. Weber et al., 2006. Double-Stranded RNA Is Produced by Positive-Strand RNA Viruses and DNA Viruses but Not in Detectable Amounts by Negative-Strand RNA Viruses. Journal of Virology. 80(10): 5059–5064. DOI: 10.1128/JVI.80.10.5059-5064.2006
6. Lindbo and Falk, 2017. The Impact of “Coat Protein-Mediated Virus Resistance” in Applied Plant Pathology and Basic Research. Phytopathology 107(6): 624-634 DOI: 10.1094/PHYTO-12-16-0442-RVW
7. Jia et al., 2007. A strategy for constructing and verifying short hairpin RNA expression vectors. J RNAi Gene Silencing 3(1): 248–253. PMCID: PMC2737214
8. Lambeth et al., 2010. A direct comparison of strategies for combinatorial RNA interference. BMC Molecular Biology 11:77. DOI: 10.1186/1471-2199-11-77
9. Gonsalves et al., 2004. Transgenic Virus Resistant Papaya: From Hope to Reality for Controlling Papaya Ringspot Virus in Hawaii. APSnet Features. Online. DOI: 10.1094/APSnetFeature-2004-0704
10. Fuchs and Gonsalves, 1995. Resistance of Transgenic Hybrid Squash ZW-20 Expressing the Coat Protein Genes of Zucchini Yellow Mosaic Virus and Watermelon Mosaic Virus 2 to Mixed Infections by Both Potyviruses. Nature Biotechnology 13: 1466 – 1473 DOI: 10.1038/nbt1295-1466
11. Tricoll et al., 1995. Field Evaluation of Transgenic Squash Containing Single or Multiple Virus Coat Protein Gene Constructs for Resistance to Cucumber Mosaic Virus, Watermelon Mosaic Virus 2, and Zucchini Yellow Mosaic Virus. Nature Biotechnology 13: 1458 – 1465 DOI: 10.1038/nbt1295-1458
12. Chellappan et al., 2004. Broad Spectrum Resistance to ssDNA Viruses Associated with Transgene-Induced Gene Silencing in Cassava. Plant Molecular Biology 56: 601-611 DOI: 10.1007/s11103-004-0147-9
13. Ogwok et al., 2012. Transgenic RNA interference (RNAi)-derived field resistance to cassava brown streak disease. Molecular Plant Pathology 13: 1019-1031 DOI: 10.1111/j.1364-3703.2012.00812.x

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• Citation: Layla Katiraee, Alma Laney, Karl Haro von Mogel, Anastasia Bodnar. Virus Resistance. Version 1.0. Biology Fortified, Inc. Jul 28, 2017.
• Permissions: Biology Fortified is making these infographics available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use by anyone, in multiple formats. Please attribute them to us when you use them, and do not modify them without the permission of Biology Fortified, Inc.
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How does it work?

Bt proteins are produced by bacteria found in the soil, called Bacillus thuringiensis. The bacteria kill the insect using these proteins, and then colonize the insect’s remains. Each Bt protein, also known as a Crystal or “Cry” protein, can affect a narrow spectrum of hosts, which makes them well-suited to put into plants to fight insects that are crop pests, while not significantly affecting insects that do not eat the plants. These proteins are extensively tested before being genetically engineered into the crop.

In the bacteria, the proteins are not dissolved due to a certain section of the protein which allows it to condense into a crystal. For the protein to work properly in plants, this must be removed. The versions engineered into plants are truncated (shortened) to remove these regions and allow the Bt protein to dissolve in the cell.

Each Bt protein has a similar mechanism of action, but Cry1Aa provides a good window into how these proteins work. To be active, several copies of the Bt protein must be linked together in a specific way. Processing by the caterpillar’s digestive system is what allows this to happen.  The end result of this processing is that several copies of this protein link up to form the active toxin. The toxin is then passed to a transporter protein, which the toxin uses to settle into the gut and pop the cells.

When enough of the Bt proteins pop the cells, holes form in the gut. These holes allow the contents to spill out, and bacteria in the gut enter and colonize the body. This eventually causes the death of the insects.

This process requires specific receptor proteins on the surface of the gut cells, and different Bt proteins are specific for receptors from different kinds of insects. This makes the Bt proteins very specific for certain kinds of insects, such as caterpillars or beetles, while not affecting other kinds of insects or other animals such as humans.

What crops are modified?

Corn was the first commercialized crop engineered to produce Bt, followed by Bt cotton which represent the two most widespread applications of this trait. Bt soy has also been approved in South America, while Bt Brinjal (eggplant) is currently approved in Bangladesh. Bt rice is under development. Bt-producing potatoes have been produced, but are not currently commercialized.

Which insects are targeted?

The insects that feed on these crops vary around the world, and Bt crops control different pests in each location. Western Corn Rootworm and Pink Bollworm are considered worldwide pests, but there are other, major pests that are included in this list. The list is not exhaustive.

• Corn:
  European Corn Borer
  Corn Earworm (also attacks cotton and soy; has different common names on these plants)
  Fall Armyworm
  Western Corn Rootworm
• Soy:
  Soybean Looper
  Velvetbean Caterpillar
• Cotton:
  Pink Bollworm
  Corn Earworm (Cotton bollworm, AKA Helicoperva zea)
• Eggplant:
  Brinjal Fruit and Shoot Borer
• Potato: (not commercialized)
  Colorado Potato Beetle

Benefits

Growers have seen benefits from Bt crops in the form of decreased loss of their crops due to insect feeding, but also increased quality of their crops as measured by mycotoxin reduction.

Bt corn has increased the yields for farmers by reducing insect pressure. This has reduced the need for broad spectrum pesticide sprays. Pests such as European Corn Borer and Western Corn Rootworm which were once key pests have declined in importance as Bt crops have been adopted. As a result, the use of broad-spectrum insecticide sprays has declined for Bt crop growers.

Many of the insects that feed on crops also introduce fungi which can produce mycotoxins that cause some rather serious health effects. Although many management strategies have been devised to combat these mycotoxins, Bt crops provide an additional measure of protection by preventing feeding insects from introducing them. The exact level of reduction depends on many factors, both environmental and biological, but the reduction is economically significant for many mycotoxins. Furthermore, Bt crops are compatible with biological control programs which target mycotoxin producing fungi.

Challenges

With any pest control measure, resistance can become an issue because management puts evolutionary pressure on a pest to evolve. Bt growers use a strategy called “high-dose/refuge” (H-D/R) which combines crops that produce a high enough dose of Bt to kill the insects with “refuge” plantings of non-Bt crops to maintain populations of non-resistant insects that will breed with any resistant insects that evolve. This strategy has been generally successful, but has been hampered by lack of refuge planting among growers. Current measures to solve the problem involve incorporating the refuge in the bag, although how effective this is compared to the standard refuge is unclear. In areas of the world where the refuge strategy has not been enforced, resistance to some Bt proteins has emerged, and newer varieties with multiple “stacked” Bt proteins increase effectiveness and slow resistance.

Although Bt has reduced the need for broad-spectrum insecticide sprays, this lack of pesticide also creates challenges for growers. Some minor pests were controlled by these sprays, and narrow-spectrum control methods allow these pests to rebound. In many regions, these pests include Plant Bugs (Hemiptera: Miridae), Stink bugs (Hemiptera: Pentatomidae), and Thrips. For many of these pests transgenic control options are also possible, although their biology will present additional challenges for the development of biotech crops.

The issues of resistance and replacement are not unique to Bt crops, and these have been documented in other types of control programs.

References

• Abbas, H. K., Zablotowicz, R. M., Weaver, M. A., Shier, W. T., Bruns, H. A., Bellaloui, N., … & Abel, C. A. (2013). Implications of Bt traits on mycotoxin contamination in maize: overview and recent experimental results in Southern United States. Journal of agricultural and food chemistry, 61(48), 11759-11770.
• Catarino, R., Ceddia, G., Areal, F. J., & Park, J. (2015). The impact of secondary pests on Bacillus thuringiensis (Bt) crops. Plant biotechnology journal, 13(5), 601-612.
• Cullen, E. M., Gray, M. E., Gassmann, A. J., & Hibbard, B. E. (2013). Resistance to Bt corn by western corn rootworm (Coleoptera: Chrysomelidae) in the US corn belt. Journal of Integrated Pest Management, 4(3), D1-D6.
• Lu, Y., Wu, K., Jiang, Y., Xia, B., Li, P., Feng, H., … & Guo, Y. (2010). Mirid bug outbreaks in multiple crops correlated with wide-scale adoption of Bt cotton in China. Science, 328(5982), 1151-1154.
• Marvier, M., McCreedy, C., Regetz, J., & Kareiva, P. (2007). A meta-analysis of effects of Bt cotton and maize on nontarget invertebrates. science, 316(5830), 1475-1477.
• Pardo-Lopez, L., Soberon, M., & Bravo, A. (2013). Bacillus thuringiensis insecticidal three-domain Cry toxins: mode of action, insect resistance and consequences for crop protection. FEMS microbiology reviews, 37(1), 3-22.

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• Citation: Layla Katiraee, Joe Ballenger, Karl Haro von Mogel, Anastasia Bodnar. Insect Resistance: Bt Traits. Version 1.0. Biology Fortified, Inc. Feb 14, 2017.
  
• Permissions: Biology Fortified is making these infographics available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use by anyone, in multiple formats. Please attribute them to us when you use them, and do not modify them without the permission of Biology Fortified, Inc.
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Proper experimental design is the foundation of any scientific publication. However, a study is not so easy to plan, particularly when it includes methods that are expensive or that use tools that are hard to find. To make things more complicated, many studies are performed as part of a Master’s or Doctoral thesis, and the investigator gains skills and knowledge throughout the course of the experiment. By the time the study is done, the investigator sees parts she would have done differently.

Studies that involve animals are especially complex, since you cannot “redo” a failed experiment as easily as you can with in vitro or in silico assays. Criticisms by reviewers and editors can seldom be addressed during the peer review process: if an editor or reviewer identifies a flaw in an animal feeding study, it often cannot be redone due to resource constraints.

Poorly designed GMO feeding studies abound, quite possibly due to these difficulties in performing any animal feeding study. Such studies are often used by people who claim GMO are dangerous. It can be difficult to determine if a study has been properly designed and performed. We’ve put together a list to help you navigate through the messy world of GMO feeding studies.

Evaluating GMO Feeding Studies

1. Feed Analysis
   • The nutritional content of feed given to both control and treatment animals must be analyzed to determine if there are any differences other than the GM trait. If the feeds aren’t as identical as possible, any difference observed between the treated animals and controls cannot be attributed exclusively to the GM trait.
   • Many papers have shown that the environment has a strong impact on nutrient and mineral content in crops, so a failure to perform this analysis is a critical flaw in any GM feeding study. Anti-nutrient content, and toxin-producing fungi and bacteria must be analyzed as well.
   • For example, the paper “The Comparative Effects of Genetically Modified Maize and Conventional Maize on Rats” observed differences in organ size and other parameters between the rats fed a diet with GMOs and controls, however, without analysis of the feed we don’t know if the differences are due to the GM trait. Maize has natural variation in sugar content, protein content and other nutrients which could have given rise to the observed differences, rather than the Bt-trait to which the authors attributed the observed differences.
2. Feed Source
   • The feed that is provided to control and treated animals must be as similar as possible and should be isogenic. This means that the GM feed is the same variety as the control, with the exception of the introduction of the genetically engineered trait.
   • A well designed study will have the control and GM feed grown in the same field and in the same year, to minimize variability caused by the environment.
   • Often times, a failure to use similar feed sources can be a fatal flaw, such as in the paper “Feeding Study with Bt Corn (MON810: Ajeeb YG) on Rats: Biochemical Analysis and Liver Histopathology“, where the authors had identified nutritional differences in the GM feed but do not describe normalization of the nutrients in the feed provided to the animals nor do they provide information on how the crops were grown, if pesticides were used, or other important factors. Consequently, the observed differences between the control rats and the GM-feed rats cannot be attributed exclusively to the transgenic protein in the diet.
3. Controls
   • The control and treated animals must be kept and treated in the exact same way, with the exception of the presence of the transgenic protein and gene in the feed. This ensures that any differences observed between the animals can be attributed exclusively to the feed, not the environment or the conditions under which the animals were kept.
   • For example, the paper “Biological impact of feeding rats with a genetically modified-based diet” identifies tissue changes in rats fed a diet of GM soy and corn, however the controls were fed a diet of wheat when they should have been fed a diet of non-GM soy and/or corn. Therefore, the two groups were not treated equivalently.
4. Statistics
   • The proper statistical tests should be used throughout the study. For example, in the paper “A Comparison of the Effects of Three GM Corn Varieties on Mammalian Health“, the authors jump from one statistical test to another without explaining why a new statistical test is being used, suggesting that the authors may have been fishing for significance.
   • A well designed study must consider statistical power during the design phase. The authors must consider in advance what metrics they will be measuring and how much the measurement fluctuates in healthy subjects to determine how many animals they need in their study. For example, Seralini’s study examining the toxicity of GM-maize and Round-Up was found not to have a large enough sample size to make relevant conclusions.
5. Relevance
   • There’s natural variation in any species. For any given trait, there’s a range for what’s considered “normal”. The types of mice and rats used for feeding studies have less variation because they are inbred, but there’s still variation for most traits. As such, any difference observed between the controls and the animals given GM feed must be explained within the context of natural variation for the species.
   • Statistically significant differences are not necessarily biologically relevant. This point is intertwined with statistical power. If you take two groups of animals and take enough measurements, you are bound to find a measurement that is different between the two groups. As such, it is important to address the question: is the measured difference biologically relevant?
   • The European Food Safety Authority defines biological relevance as “an effect considered by expert judgement as important and meaningful for human, animal, plant or environmental health. It therefore implies a change that may alter how decisions for a specific problem are taken.” The EFSA also points out that the magnitude of the effect must be considered when examining biological relevance.
   • As an example, the paper “A three generation study with genetically modified Bt corn in rats: Biochemical and histopathological investigation” finds “minimal” differences between GE-fed and control animals in several measurements. The paper concludes that despite these minor differences, “long-term consumption of transgenic Bt corn throughout three generation did not cause severe health concerns on rats.” However, the findings from this paper are often taken out of context as an example of harm.
6. Reproducibility
   • If a study finds a difference between GM-fed and control animals, studies that repeat the experiment should observe the same difference. In contrast, if a similar study has been done in the past and didn’t see the observed difference, the authors should address the discrepancy and propose a hypothesis on why their results are different.
   • For example, three different studies have examined the impact of Round-Up Ready Soy feed on goats and their kids. None of their conclusions are the same (see here, here, and here – note that one of these has been retracted).

When are animal feeding studies useful?

Several years ago, the European Commission funded the GRACE project (GMO Risk Assessment and Communication of Evidence). The goal of the project is to review the literature to find evidence of benefits and harms of GM crops, and to determine which types of studies are best suited for GMO risk assessments. Their most recent publication investigates whether animal feeding studies are useful.

In contrast with reviews that found 90-day feeding studies to be sufficient, the GRACE project concluded that in most cases 90-day feeding studies do not provide any additional information over non-animal testing. “GRACE data support the scientific reasoning that only in case a trigger is available from the initial molecular, compositional, phenotypic and/or agronomic analyses, feeding trials with whole food/feed may provide an added scientific value for the risk assessment of GM crops. Thus, feeding trials might be considered, provided that the study design can be tailored to the posed safety concern.”

GRACE’s conclusions are similar to the idea that most healthy people do not need to undergo regular medical testing. When large numbers of people (or animals) are tested, some differences will be detected simply due to random chance – even when there is no underlying concern. To avoid the risk of false positives, there must be some initial concern to trigger the additional tests. For example, doctors only recommend that pregnant women undergo amniocentesis if there is some risk factor, such as concerning results from another test. Similarly, GRACE recommends that animal feeding studies are not necessary unless there is some risk factor, such as a compositional difference.

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• Citation: Layla Katiraee, Anastasia Bodnar. GMO Feeding Studies. Version 1.0. Biology Fortified, Inc. Jan 14, 2016.
  
• Permissions: Biology Fortified is making these infographics available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use by anyone, in multiple formats. Please attribute them to us when you use them, and do not modify them without the permission of Biology Fortified, Inc.
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To help educate people about the many methods that are used to generate new traits in plants, Biology Fortified has created an infographic on six different crop modification techniques, with examples of crops generated with each method.

Six Crop Modification Techniques

1. Traditional Crossbreeding
   For millennia, traditional crossbreeding has been the backbone of improving the genetics of our crops. Typically, pollen from one plant is placed on the female part of the flower of another, leading to the production of seeds that are hybrids of the two parents. Then, plant breeders select the plants that have the beneficial traits they are looking for to go on to the next generation. Apple varieties such as the Honeycrisp apple were developed in this way – thousands of hybrid trees were made, grown, and tested to find just one great new variety with a combination of genes that has never existed before. Modern plant breeding often uses genetic markers to speed the selection process, and may incorporate genes from wild varieties and closely-related species. Here are some videos about the different techniques that plant breeders use. Crossbreeding can only make use of desirable traits if they are in the same or closely-related species, so additional techniques have been developed to create new traits for plant breeders to use.
2. Mutagenesis
   In nature, new traits often arise through spontaneous mutations. In the past century, this process has been mimicked by scientists, who have used mutating chemicals (such as ethyl methanesulfonate) or radioactivity to generate random mutations in plants, and subsequently screening for new or desired traits. For more information on mutagenesis, please view this post.The Ruby Red and the Star Ruby varieties of grapefruits were developed using ionizing radiation. The mutations that they carry give these fruit their characteristic deep red color. This article from the New York Times provides many additional examples of crops that have been developed using this technique.
3. Polyploidy
   Most species have 2 sets of chromosomes: one set inherited from each parent. This is known as diploidy. Polyploidy is the occurrence of more than 2 sets of chromosomes. It can occur naturally, but polyploidy can also be induced through the use of chemicals. This crop modification technique is usually used to increase the size of fruits or to modify their fertility. For example, the seedless watermelon has 3 sets of chromosomes and is created by crossing a watermelon with 4 sets of chromosomes with another watermelon that has 2 sets, making a sterile watermelon with 3 sets of chromosomes, much to the delight of picnic lovers throughout the globe. Potato species also have many different number of chromosome copies, and potato breeders commonly have to change the copy number of their varieties to breed new traits into them (More on this process here).
4. Protoplast Fusion
   When sperm cells in pollen combine with the ova in the ovaries of a flower, this is a fusion of two cells into one. Protoplast fusion is an artificial version of this process. Beneficial traits can be moved from one species to another by fusing the protoplasts (‘naked’ cells without the cell walls that give plants their structure) together and growing a plant from the newly fused cell. One of the most commonly used traits that has been developed with this process is the transfer of male sterility between species. If you have a male sterile plant, you can more easily make hybrid seeds – especially for plants that have small flowers and are difficult to cross. Male sterility was introduced to red cabbage from daikon radishes, making it easier to produce hybrid seeds of this crop.
5. Transgenesis
   Transgenesis is the process by which you introduce one or more genes into an organism from another organism entirely. This usually involves handling and modifying the DNA itself in a test tube, and then packaging it to insert it into the new organism. There are several ways to introduce the new gene or ‘transform’ a plant such as biolistics (the “gene gun”), using Agrobacterium – a naturally occurring organism that inserts DNA into plants, or by using electricity – a process called electroporation. Transgenic plants have been generated with many useful traits, some of which have been commercialized. For instance, papayas were transformed with a gene from the virus that infects the plant to make it resistant to the virus. Other traits include insect resistance, herbicide tolerance, and drought tolerance, and more. The creation of these ‘transgenic’ crops works even though the genes can from from any other species because the genetic language is universal to all life on this planet. Genes that originated from the same species can be called ‘cisgenic’ or ‘intragenic’. For more information, see this paper.
6. Genome editing
   Genome editing consists of using an enzyme system to change the DNA of a cell at a specified sequence. There are different systems that can be used for genome editing, the most promising of which is the CRISPR-Cas9 system (for more information on genome editing and how it works, please view this post). The sulfonylurea (SU) herbicide tolerant canola was developed to enable farmers to better control weeds and to enable crop rotation. The crop was created using a patented genome editing system known as Rapid Trait Development System (RTDS). You could conceivably edit the genome of any crop to alter any gene you wanted, from introducing new genes to restoring ‘natural’ alleles from the ancestors of our crops.

Each of these methods have similarities and differences, and some work better for some traits rather than others. Each of them modifies the genetic makeup of the plant in order to combine useful traits together to improve agriculture. All of them have examples that are being grown on farms and are producing benefits, all can be patented in one way or another, and all of them can have unintended consequences.

However, socially and politically the products of these methods are treated very differently. The fact that the changes that these techniques introduce do not line up with how they are treated when it comes to debates over the regulations for health and environmental safety, and political debates about labeling has come to be known as the “Frankenfood Paradox.” For instance, transgenesis produces far fewer changes and unintended consequences than mutagenesis (see this article), while mutagenesis is generally accepted and ignored in political discussions.

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• Citation: Layla Katiraee, Karl Haro von Mogel. Crop Modification Techniques. Version 1.0. Biology Fortified, Inc. Jul 17, 2015.
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Do scientific studies on the safety of consuming genetically engineered or GMO foods come to different conclusions if they are funded by government, industry, competing industries, or nonprofit organizations?

On August 25, 2014 the first data from the GENetic Engineering Risk Atlas (GENERA) project was released, and it can help us answer this question. According to these results, the conclusions of the almost 200 studies that tested this issue from the 400 randomly selected to be a part of the GENERA beta test, the studies largely agree irrespective of funding sources. For more information, see the GENERA beta test announcement.

Biology Fortified collaborated with the Genetic Literacy Project on creating this infographic based on the data from GENERA. Visit the GENERA website and search the atlas.

About the data

Safety for Consumption

Studies in GENERA were read and their outcomes were rated for four categories of risk: Efficacy, Equivalence, Safety for Consumption, and Safety for the Environment. The safety for consumption category includes studies that assess various aspects of the safety of consuming genetically engineered crops or products derived from them. These include feeding studies, allergenicity assessments, and studies that examine the impact of nutritional intervention with GE approaches.

Broadly, this category answers the question: Are genetically engineered crops safe to eat?

Each study is rated with the same terminology: Positive effect, no effect, mixed, and negative effect.

• Positive effect For safety for consumption studies, a positive effect means that the researchers concluded that the GE approach was safer or more healthful than non-GE crops and approaches.
• No effect For safety for consumption studies, no effect means that the researchers concluded that the GE approach was as safe or healthy as non-GE crops and approaches.
• Mixed For safety for consumption studies, a mixed result means that the researchers did not clearly conclude whether the GE approach was more or less safe or healthy than non-GE crops or approaches, and/or the data was a mixture of positive, negative, and/or neutral results.
• Negative effect For safety for consumption studies, a negative effect means that the researchers concluded that the GE approach had a detrimental impact on the safety or healthfulness of the food.

Generally in this category, positive and no effects are considered desirable outcomes, negative effects are undesirable, and mixed effects speak to the difficulty of interpreting data.

Funding Sources

Funding sources for each study were also categorized as to whether they came from government sources, various industries and NGOs, individuals, and unknown sources. Authors who did not disclose complete funding information were contacted to fill in the missing information. The following are the definitions for the categories of funding types.

• government The funding came from a national or state government agency, granting program, or state university.
• industry: same The funding came from a private biotechnology company that develops genetically engineered plants for commercialization, or develops traits for licensing to other companies. This also includes farmers and companies that produce and sell genetically engineered foods.
• industry: competing The funding came from a private company that competes for market share against biotechnology companies, farmers, food producers or retailers that sell genetically engineered foods. This also includes companies that develop products intended to replace or augment the performance of a GE crop.
• industry: other The funding came from a private company that does not appear to have a specific commercial interest in the sale of genetically engineered crops, nor in the sale of competing products.
• NGO: independent The funding came from a non-governmental organization (NGO), usually a non-profit organization, which is not affiliated with does not appear to be significantly funded by the biotechnology industry or any competing industry.
• NGO: same industry aligned The funding came from an NGO which is affiliated with and/or significantly funded by the biotechnology industry, which would indicate a financial dependence on that industry.
• NGO: competing industry aligned The funding came from an NGO which is affiliated with and/or significantly funded by a competing industry, which would indicate a financial dependence on that industry.
• individual The funding came from an individual person or an unincorporated association of individuals, or was self-funded.
• not reported This means that the funding source was not reported in the body of the study and that we were unable to reach the study authors for clarification.
• unknown This means that the funding source was not reported in the body of the study, and that we were able to reach the study authors but they were unable to recall or find information about the specific funding for that study.
• refused to disclose This means that the funding source was not reported in the body of the study, and that we were able to reach the study authors but they refused to disclose the source of funding.

About this infographic

Each study was grouped according to both their conclusions for safety and their funding types.

Columns: Studies are arranged according to their conclusions for the safety of consuming GMOs by humans or animals (rodents, pigs, cattle, sheep, goats, birds, fish, water buffalo, etc)

Rows: Each row represents studies that were funded by the same category of funding sources. These are also color-coded to make them easier to interpret.

The size of each circle is based on the number of studies with the same types of funding sources and the same conclusions. Therefore, the relative number of studies in each position can be seen visually with both the relative size of the circle and the number inside (or next to) each circle.

How to interpret this chart: It can be seen clearly that a similar pattern of study conclusions exists in each funding category. Studies that find that GMOs are as safe as non-GMO foods vastly outnumber the studies that find differences, and most differences are positive, with a small minority finding negative conclusions.

This infographic will be updated as more data becomes available from the GENERA project.

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• Citation: XiaoZhi Lim, Karl Haro von Mogel. The scientific literature on the safety of GMOs for consumption. Version 1.0. Biology Fortified, Inc. Aug 25, 2014
• Permissions: Biology Fortified is making these infographics available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use by anyone, in multiple formats. Please attribute them to us when you use them, and do not modify them without the permission of Biology Fortified, Inc.

What countries fund research on genetically engineered crops? Is it mostly funded by the US government?

On August 25, 2014 the first data from the GENetic Engineering Risk Atlas (GENERA) project was released, and it can help us answer this question. The research is worldwide, and while concentrated in developed nations, some developing nations have contributed significantly to our understanding of these crops. For more information, see the GENERA beta test announcement.

Biology Fortified collaborated with the Genetic Literacy Project on creating this infographic based on data from GENERA.

Visit the GENERA website and search the atlas here.

About this infographic

Each study in GENERA was analyzed for its source(s) of funding, which were categorized by type, such as government, various industries, NGOs, and individuals. Only studies that were solely funded by government sources were included in this graphic. The country that this funding originated from was also gathered for GENERA.

The size of each circle is based on the number of studies funded by each country. Therefore, the relative number of studies in each position can be seen visually with both the relative size of the circle and the number inside (or next to) each circle. Because many studies were funded by individual European countries as well as from agencies of the European Union as a whole, one circle was created for Europe, with the numbers for each source listed.

This infographic will be updated as more data becomes available from the GENERA project.

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• Download jpg
• Download PDF with links
• Citation: XiaoZhi Lim, Karl Haro von Mogel. Map of government-funded GMO studies around the world. Version 1.0. Biology Fortified, Inc. Aug 25, 2014
• Permissions: Biology Fortified is making these infographics available under a Creative Commons Attribution-NonCommercial-NoDerivatives License. Everyone is free to download, republish, and use these infographics (images, slides) in their original form for nonprofit purposes. We are providing these graphics for non-profit educational use by anyone, in multiple formats. Please attribute them to us when you use them, and do not modify them without the permission of Biology Fortified, Inc.