Question
Can you respond to the claims about promoters as well as association of Bt with ricin and anthrax in this article httprobynobrien.comgmosagmoscientistquestionstheirsafetyandpurpose
Submitted by: Cottonwolf
Answer
Expert response from Community Manager
Thursday, 15/10/2015 13:28
Thanks for your question. You asked about two topics, but the article makes several claims and I will comment on as many as possible. The blog’s author, Jonathan Latham, takes several opportunities to connect two dots because they are scary but stops short of painting the whole picture. Doing so is deliberate and leaves most wondering what the final image (the truth) really is. I find it curious that he would choose to raise these specific points about Bt. Simply because Bacillus thuringiensis (Bt) proteins (also referred to as Cry (crystal) proteins) have been used in agriculture since the 1920s for several production methods including plant biotechnology, organic farming and home gardening. As a consequence of the nearly 100 years of use, there exists a substantial history of safe use in humans and animals consuming Bt foods, derived from crops grown with Bt sprayed directly on or incorporated into them. Bt formulations are allowed in USDA certified organic production of vegetables and right up to harvest and often these are consumed by humans without cooking. But, just the ability to detect these-worse case residues is not informative of the safety. There is a history of safe use without a single documented health problem. For a more complete description of Bt proteins, and their safety and use, I refer you to an answer about Bt from my colleague, Michael Koch.
First, it is important to point out that biotech crops are rigorously tested for safety prior to commercialization. These tests include composition, toxicology, allergenicity, agronomic characteristics, effects on non-target organisms and environmental fate. These studies confirm that the use of Bt crops is as safe as conventional crops. Their safety is also supported by the numerous studies in the peer-reviewed scientific literature. Therefore the claim that the GMO risk assessment process is flawed is unsubstantiated. Furthermore, it is reckless to make claims like “…the experiments described within [regulatory submissions] are often very inadequate and sloppily executed. Scientific controls are often missing, procedures and reagents are badly described, and the results are often ambiguous or uninterpretable” while failing to provide even one credible example. In fact, no example was provided at all in direct support of this statement. Let me assure you that I work with hundreds of scientists and have personally seen many of these studies. They are professionally designed, executed and have significant oversight, probably at a level that far exceeds any study that Dr. Latham has witnessed. Questioning the “trustworthiness of the applicants and equally of the regulators” is an unfounded allegation that is unequivocally false.
GM crops are thoroughly tested and have a spotless safety record, to the tune of 18 years of commercially grown GM crops without a single documented safety issue. In fact, no food on the planet has been more thoroughly researched, tested and regulated. This process takes more than 13 years of molecular testing, field trials, and safety testing all to select the one plant with the precise and desired change. And it does not stop there. All this accumulated information is handed over to nearly 40 regulatory agencies from around the world that have made more than 2500 approvals. This all takes place in a very transparent process with an opportunity for the public to comment and raise any concerns they might have. By the way, any concern an agency might have must be sufficiently addressed by the applicant prior to final approval.
In response to the statement that “…Bacillus thuringiensis is all but indistinguishable from the well-known anthrax bacterium (Bacillus anthracis),” my first thought is if this is such a concern then all the more reason to choose the biotech version that uses a single protein over other applications that use the entire organism that is “all but indistinguishable” from anthrax. To be fair, while it is true that Bacillus anthracis, along with Bacillus cereus and Bacillus thuringiensis, are all members of the same genus, they have widely different phenotypes and effects ranging from beneficial (B. thuringiensis) to pathological (B. anthracis)2. To insinuate that because these bacteria share a species name means that they would similarly share a potential to be pathogenic is misleading. For instance, many are familiar with Streptococcus thermophilus, which is a commonly used probiotic. A species in the same genus is Streptococcus pyogenes, which causes strep throat, scarlet fever, and rheumatic fever and can result in the often deadly streptococcal toxic shock syndrome (e.g., the cause of death for Muppets creator Jim Henson). It is not their shared name that creates any link, but rather what is important are the other features/metabolism characteristics that they might share.
The assertion that Bt insecticides share structural similarities with ricin is another attempt to exploit a partial truth in an effort to mislead and create fear. This claim unquestionably needs to be, and can be, qualified. Cry proteins belong to a large family of proteins produced by Bacillus thuringiensis3. The many Cry proteins display clear differences in their amino acid sequences and are often classified based on shared sequences and structural similarities. In fact, many proteins have multiple domains that impart different functional capabilities to the protein. These domains are further defined by various structural motifs (pattern/repeats of amino acids) within them. One Cry protein named Cry35 contains a motif known to be a carbohydrate-binding domain. This motif is shared by numerous proteins, not just Cry proteins. An analogy for this is the tire of a car. All cars have tires which serve the same function but this in no way means that all the cars are the same. They share a common functional component, tires, to keep the car on the road. Nature does the same thing (no need to reinvent the wheel). This is why certain structural motifs are shared among proteins, including proteins with widely different functions. The ricin protein contains two domains, one is required for binding specificity (binds carbohydrates on the cell surface) and the other is responsible for its activity. The Cry35 protein I mentioned above is said to have a “ricin like” domain. This means that Cry35 has a domain (specifically a QxW motif) that is similar to the one in the ricin binding domain which binds carbohydrate structures on the surface of cells. However, this is a structural similarity which imparts a similar functional binding capability, like tires do for cars. Regarding Cry35, we are talking about one motif in one domain that is structurally similar to ricin which perhaps imparts a similar binding characteristic. It in no uncertain terms means that the two proteins share functionality. There is no clinical evidence that Bt proteins are toxic while there is a well-established clinical consequence for ricin. Furthermore, within your body, you make proteins that share certain motifs, yet they have very different functions. For example, the SH3 domain is about 60 amino acids long and found in nearly 300 different proteins, including adapter proteins involved in cell signaling, structural proteins and numerous enzymatic proteins like kinases. The SH3 domain facilitates protein-protein interactions which is a requisite feature for proper cellular function.4 The fact that it works so well means it is much more efficient for proteins to share an excellent motif versus the less efficient approach of making 300 different motifs serving the same purpose.
Latham references Mizuki et al., 2009 saying that Bt proteins are cytotoxic to human cells. I alluded to this above, but the Bt family is large and diverse and it would take considerable effort to adequately cover all of its complexities in this space. This is exactly why Latham chooses this topic, it is complex and the reader can be easily mislead and confused. In an effort to address this claim and for the sake of simplicity, the Bt protein family1 consists of Cry proteins which have anti-insecticidal applications and can be used in agriculture and another class called Cyt (cytolysins) proteins which are not insecticidal, are not used in agricultural application, but which do have cytotoxic characteristic and have been studied for their potential as anti-cancer agents. With this information in hand, lets now look at the study by Mizuki et al. which explores the ability of members of the Cyt family (not the same subset used for agricultural purposes) for their ability to kill cancer cells. This study is a preliminary (proof of concept) to demonstrate a novel therapeutic modality for the treatment of leukemia. From this study, the authors concluded that the group of proteins they tested “…exhibited no haemolytic activity and no insecticidal activity against dipteran and lepidopteran insects, but were highly cytocidal against leukaemia T cells and other human cancer cells…” which “…may lead to the use of B. thuringiensis for medical purposes.” Again, while this study used proteins from the same family they represent different proteins from the insecticidal proteins we are discussing. Conversely, when formulations containing whole Bt organisms are sprayed on veggies, these Cyt proteins come along for the ride. In biotech, only the specific Cry protein(s) is used.
Latham cites Bøhn et al (2014), a study that claims that soybeans routinely contain glyphosate residue. What the results really demonstrate is that glyphosate residues, while present, are well within established safety tolerances. Consequently, we are left with the primary conclusion that herbicide tolerant varieties of soy have measurable levels of glyphosate. This is totally expected and normal. The same would be true if you measured for pesticides used in other agricultural systems including organic and conventional, like the Cyt proteins discussed above. Therefore, the study provides no new data and falls well short of impacting the long standing safety of these crops.
Finally, the author states that GMOs contain a viral promoter and this represents another reason to be concerned. The origin of this claim is work done by Nancy Podevin and Patrick du Jardin, two researchers from the European Food Safety Authority (EFSA).5 Latham is inaccurate in claiming that the promoters “encode a large part of a small multifunctional viral protein” and that EFSA somehow “tried to bury their discovery.” In fact the results are published (reference provided) and the authors themselves do not agree with Latham’s assessment. The authors state that “it has been known for some years that a DNA sequence used to turn genes on and off (a gene switch) in some GM plants also forms the tail end of a virus gene in the Cauliflower mosaic virus.” The authors were studying to see if this gene segment could produce a viral protein fragment and concluded that “[n]o risks to human health were identified when this gene was present in GM plants.” Their complete response can be seen here.
Three products were specifically mention in the original allegations from Latham and Wilson, namely NK603, MON810, and 40-3-2. On page 4 of the paper by Podevin and du Jardin the authors state: “For short P35S sequences that overlap only with the D4 domain of P6 and for promoters that harbour an additional 35S enhancer that overlaps only with the D4 domain, it is unlikely that chimeric proteins will have unintended effects.” None of the three products evaluated contain a complete domain 4, therefore it is highly unlikely, if not impossible, for any of the three mentioned products to produce a truncated P6 protein. Furthermore, there are no bioinformatic or clinical (from consumption of cauliflower and related species) data to suggest that any such fragment would be either allergenic or toxic.
I think that just about covers most of the claims raised by Dr. Latham in his blog. I hope it provides you with a more complete and accurate picture about B. thuringiensis; whether we are talking about the whole organism or just the protein. What an amazing and safe tool Bt is, applicable to all types of agriculture including organic and GM.
4 T. Pawson, and J. Schlessingert, 'Sh2 and Sh3 Domains', Current Biology, 3 (1993), 434-42.
Answer
Expert response from Community Manager
Thursday, 15/10/2015 13:28
Thanks for your question. You asked about two topics, but the article makes several claims and I will comment on as many as possible. The blog’s author, Jonathan Latham, takes several opportunities to connect two dots because they are scary but stops short of painting the whole picture. Doing so is deliberate and leaves most wondering what the final image (the truth) really is. I find it curious that he would choose to raise these specific points about Bt. Simply because Bacillus thuringiensis (Bt) proteins (also referred to as Cry (crystal) proteins) have been used in agriculture since the 1920s for several production methods including plant biotechnology, organic farming and home gardening. As a consequence of the nearly 100 years of use, there exists a substantial history of safe use in humans and animals consuming Bt foods, derived from crops grown with Bt sprayed directly on or incorporated into them. Bt formulations are allowed in USDA certified organic production of vegetables and right up to harvest and often these are consumed by humans without cooking. But, just the ability to detect these-worse case residues is not informative of the safety. There is a history of safe use without a single documented health problem. For a more complete description of Bt proteins, and their safety and use, I refer you to an answer about Bt from my colleague, Michael Koch.
First, it is important to point out that biotech crops are rigorously tested for safety prior to commercialization. These tests include composition, toxicology, allergenicity, agronomic characteristics, effects on non-target organisms and environmental fate. These studies confirm that the use of Bt crops is as safe as conventional crops. Their safety is also supported by the numerous studies in the peer-reviewed scientific literature. Therefore the claim that the GMO risk assessment process is flawed is unsubstantiated. Furthermore, it is reckless to make claims like “…the experiments described within [regulatory submissions] are often very inadequate and sloppily executed. Scientific controls are often missing, procedures and reagents are badly described, and the results are often ambiguous or uninterpretable” while failing to provide even one credible example. In fact, no example was provided at all in direct support of this statement. Let me assure you that I work with hundreds of scientists and have personally seen many of these studies. They are professionally designed, executed and have significant oversight, probably at a level that far exceeds any study that Dr. Latham has witnessed. Questioning the “trustworthiness of the applicants and equally of the regulators” is an unfounded allegation that is unequivocally false.
GM crops are thoroughly tested and have a spotless safety record, to the tune of 18 years of commercially grown GM crops without a single documented safety issue. In fact, no food on the planet has been more thoroughly researched, tested and regulated. This process takes more than 13 years of molecular testing, field trials, and safety testing all to select the one plant with the precise and desired change. And it does not stop there. All this accumulated information is handed over to nearly 40 regulatory agencies from around the world that have made more than 2500 approvals. This all takes place in a very transparent process with an opportunity for the public to comment and raise any concerns they might have. By the way, any concern an agency might have must be sufficiently addressed by the applicant prior to final approval.
In response to the statement that “…Bacillus thuringiensis is all but indistinguishable from the well-known anthrax bacterium (Bacillus anthracis),” my first thought is if this is such a concern then all the more reason to choose the biotech version that uses a single protein over other applications that use the entire organism that is “all but indistinguishable” from anthrax. To be fair, while it is true that Bacillus anthracis, along with Bacillus cereus and Bacillus thuringiensis, are all members of the same genus, they have widely different phenotypes and effects ranging from beneficial (B. thuringiensis) to pathological (B. anthracis)2. To insinuate that because these bacteria share a species name means that they would similarly share a potential to be pathogenic is misleading. For instance, many are familiar with Streptococcus thermophilus, which is a commonly used probiotic. A species in the same genus is Streptococcus pyogenes, which causes strep throat, scarlet fever, and rheumatic fever and can result in the often deadly streptococcal toxic shock syndrome (e.g., the cause of death for Muppets creator Jim Henson). It is not their shared name that creates any link, but rather what is important are the other features/metabolism characteristics that they might share.
The assertion that Bt insecticides share structural similarities with ricin is another attempt to exploit a partial truth in an effort to mislead and create fear. This claim unquestionably needs to be, and can be, qualified. Cry proteins belong to a large family of proteins produced by Bacillus thuringiensis3. The many Cry proteins display clear differences in their amino acid sequences and are often classified based on shared sequences and structural similarities. In fact, many proteins have multiple domains that impart different functional capabilities to the protein. These domains are further defined by various structural motifs (pattern/repeats of amino acids) within them. One Cry protein named Cry35 contains a motif known to be a carbohydrate-binding domain. This motif is shared by numerous proteins, not just Cry proteins. An analogy for this is the tire of a car. All cars have tires which serve the same function but this in no way means that all the cars are the same. They share a common functional component, tires, to keep the car on the road. Nature does the same thing (no need to reinvent the wheel). This is why certain structural motifs are shared among proteins, including proteins with widely different functions. The ricin protein contains two domains, one is required for binding specificity (binds carbohydrates on the cell surface) and the other is responsible for its activity. The Cry35 protein I mentioned above is said to have a “ricin like” domain. This means that Cry35 has a domain (specifically a QxW motif) that is similar to the one in the ricin binding domain which binds carbohydrate structures on the surface of cells. However, this is a structural similarity which imparts a similar functional binding capability, like tires do for cars. Regarding Cry35, we are talking about one motif in one domain that is structurally similar to ricin which perhaps imparts a similar binding characteristic. It in no uncertain terms means that the two proteins share functionality. There is no clinical evidence that Bt proteins are toxic while there is a well-established clinical consequence for ricin. Furthermore, within your body, you make proteins that share certain motifs, yet they have very different functions. For example, the SH3 domain is about 60 amino acids long and found in nearly 300 different proteins, including adapter proteins involved in cell signaling, structural proteins and numerous enzymatic proteins like kinases. The SH3 domain facilitates protein-protein interactions which is a requisite feature for proper cellular function.4 The fact that it works so well means it is much more efficient for proteins to share an excellent motif versus the less efficient approach of making 300 different motifs serving the same purpose.
Latham references Mizuki et al., 2009 saying that Bt proteins are cytotoxic to human cells. I alluded to this above, but the Bt family is large and diverse and it would take considerable effort to adequately cover all of its complexities in this space. This is exactly why Latham chooses this topic, it is complex and the reader can be easily mislead and confused. In an effort to address this claim and for the sake of simplicity, the Bt protein family1 consists of Cry proteins which have anti-insecticidal applications and can be used in agriculture and another class called Cyt (cytolysins) proteins which are not insecticidal, are not used in agricultural application, but which do have cytotoxic characteristic and have been studied for their potential as anti-cancer agents. With this information in hand, lets now look at the study by Mizuki et al. which explores the ability of members of the Cyt family (not the same subset used for agricultural purposes) for their ability to kill cancer cells. This study is a preliminary (proof of concept) to demonstrate a novel therapeutic modality for the treatment of leukemia. From this study, the authors concluded that the group of proteins they tested “…exhibited no haemolytic activity and no insecticidal activity against dipteran and lepidopteran insects, but were highly cytocidal against leukaemia T cells and other human cancer cells…” which “…may lead to the use of B. thuringiensis for medical purposes.” Again, while this study used proteins from the same family they represent different proteins from the insecticidal proteins we are discussing. Conversely, when formulations containing whole Bt organisms are sprayed on veggies, these Cyt proteins come along for the ride. In biotech, only the specific Cry protein(s) is used.
Latham cites Bøhn et al (2014), a study that claims that soybeans routinely contain glyphosate residue. What the results really demonstrate is that glyphosate residues, while present, are well within established safety tolerances. Consequently, we are left with the primary conclusion that herbicide tolerant varieties of soy have measurable levels of glyphosate. This is totally expected and normal. The same would be true if you measured for pesticides used in other agricultural systems including organic and conventional, like the Cyt proteins discussed above. Therefore, the study provides no new data and falls well short of impacting the long standing safety of these crops.
Finally, the author states that GMOs contain a viral promoter and this represents another reason to be concerned. The origin of this claim is work done by Nancy Podevin and Patrick du Jardin, two researchers from the European Food Safety Authority (EFSA).5 Latham is inaccurate in claiming that the promoters “encode a large part of a small multifunctional viral protein” and that EFSA somehow “tried to bury their discovery.” In fact the results are published (reference provided) and the authors themselves do not agree with Latham’s assessment. The authors state that “it has been known for some years that a DNA sequence used to turn genes on and off (a gene switch) in some GM plants also forms the tail end of a virus gene in the Cauliflower mosaic virus.” The authors were studying to see if this gene segment could produce a viral protein fragment and concluded that “[n]o risks to human health were identified when this gene was present in GM plants.” Their complete response can be seen here.
Three products were specifically mention in the original allegations from Latham and Wilson, namely NK603, MON810, and 40-3-2. On page 4 of the paper by Podevin and du Jardin the authors state: “For short P35S sequences that overlap only with the D4 domain of P6 and for promoters that harbour an additional 35S enhancer that overlaps only with the D4 domain, it is unlikely that chimeric proteins will have unintended effects.” None of the three products evaluated contain a complete domain 4, therefore it is highly unlikely, if not impossible, for any of the three mentioned products to produce a truncated P6 protein. Furthermore, there are no bioinformatic or clinical (from consumption of cauliflower and related species) data to suggest that any such fragment would be either allergenic or toxic.
I think that just about covers most of the claims raised by Dr. Latham in his blog. I hope it provides you with a more complete and accurate picture about B. thuringiensis; whether we are talking about the whole organism or just the protein. What an amazing and safe tool Bt is, applicable to all types of agriculture including organic and GM.
4 T. Pawson, and J. Schlessingert, 'Sh2 and Sh3 Domains', Current Biology, 3 (1993), 434-42.
How Do GMOs Benefit The Environment?
