Introduction

Since 1997, California-based Ventria Bioscience has conducted outdoor field tests of rice genetically engineered with modified human genes to produce artificial versions of human milk proteins that have antimicrobial and other drug-like properties. Ventria hopes to market the rice-extracted pharmaceutical proteins for use in oral rehydration solutions to treat diarrhea, and as nutritional supplements in yogurt, granola bars, performance drinks and other products.
Ventria was blocked from growing its rice in California (2004) and Missouri (2005) by farmers and food companies concerned about contamination of their products with the company’s pharmaceutical proteins, which have not been approved by the U.S. Food and Drug Administration (FDA). Ventria recently sponsored an experiment in Peru in which its rice-grown pharmaceutical proteins were fed to Peruvian infants suffering from severe
diarrhea. Reports that two infants who participated in the experiment developed allergies, and that some parents did not give informed consent to the experiment, led to an official government inquiry. Ventria is now seeking permission from the U.S. Dept. of Agriculture (USDA) to grow up to 3,200 acres of its pharmaceutical rice in Kansas, which would be the world’s largest planting of a genetically engineered (GE) pharmaceutical crop to date.
So-called “pharma crops” such as Ventria’s rice represent an experimental and highly controversial application of biotechnology. Concerns that unapproved drugs could enter the food supply were confirmed in 2002, when 500,000 bushels of soybeans contaminated with pharma corn in Nebraska had to be seized and destroyed. Unapproved genetically engineered (GE) crops have contaminated the food supply numerous times before and since. In the past year, unapproved GE rice twice contaminated commercial rice supplies, causing export market rejection and substantial loss of income to rice farmers. USDA has been heavily criticized for its failure to properly regulate or even keep track of GE and pharma crop field tests, including a scathing report from its own Inspector General in 2005. Finally, Ventria’s Vice President Delia Bethell admitted that its pharma rice could enter the commercial rice supply in a 2003 petition to the FDA.

Potential human health impacts

Two of the pharmaceutical proteins in Ventria’s rice are genetically engineered versions of the human milk proteins lactoferrin and lysozyme. According to infant nutrition experts, “…the commercial production of milk proteins using recombinant technologies [i.e. genetic engineering] may produce unintended and unexpected side effects,” such as allergic reactions. In addition, infants are more vulnerable than adults to adverse nutritional and environmental influences, which can disrupt development of rapidly growing organs and systems. Adverse events in infancy can have long-term effects that are not immediately
detectable, but can be irreversible. Infants and young children are 3-4 times more likely to have food allergies than adults, and sick infants are even more vulnerable than healthy ones. Specific potential effects that require more rigorous evaluation include:

Aggravated Infections: While human lactoferrin has antimicrobial properties, it paradoxically poses the potential hazard of exacerbating infections by certain pathogens capable of using it as a source of needed iron. Such pathogens include bacteria that cause gonorrhea and meningitis, as well as the H. pylori bacteria implicated in causing ulcers and certain forms of stomach cancer. According to Dr. Eugene Weinberg of Indiana University, human lactoferrin “might not be a successful therapeutic agent for H. pylori and, indeed,
could intensify the infection.”

Allergenicity: Ventria’s rice-expressed lysozyme and lactoferrin have two characteristics of proteins that cause food allergies: resistance to digestion and to breakdown by heat. Its lactoferrin has two further allergenic characteristics, structural similarity to known food allergens (lactoferrin from cows and chick ovotransferrin) and plant-type glycosylation. These allergenic characteristics may explain why noted food allergist Steve Taylor stated that the FDA would not approve rice-grown lactoferrin.”

Autoimmune Disorders: Pharmaceutical proteins generated by inserting human genes into plants, bacteria or other mammals are usually different than their natural human counterparts. These differences may cause the body to perceive them as foreign, resulting in potentially dangerous immune system responses. Antilactoferrin antibodies are correlated with markers of disease activity in rheumatoid arthritis and systemic lupus erythematosus. Careful study is required to determine whether rice-expressed lactoferrin or lysozyme could cause such potentially dangerous reactions.

FDA refuses to approve ventria’s pharmaceutical proteins

Ventria has thus far evaded FDA’s new drug review process by requesting the FDA to grant its proteins “generally recognized as safe” (GRAS) status as food additives. The FDA has properly taken no action on these requests. Significantly, Ventria’s GRAS petition for lactoferrin languished at the FDA for two years before Ventria withdrew it in November
2006. FDA’s letter announcing the withdrawal of the petition alludes to “complex scientific issues” regarding Ventria’s lactoferrin, suggesting that the agency has unanswered safety questions. Another company’s recombinant human lactoferrin is currently undergoing
FDA’s new drug review process as a potent anticancer drug, underscoring the need for stringent review of Ventria’s recombinant proteins as drugs.

Ventria’s pharmaceutical proteins may be used in unregulated “medical foods”

Ventria intends to market its pharmaceutical proteins as additives to oral rehydration solution (ORS) to treat diarrhea. ORS falls into an unregulated category known as “medical foods” that have been associated with adverse health impacts, including deaths, as well as fraudulent health claims. Ventria must not be permitted to exploit this loophole in FDA regulation.

Questionable experimentation on peruvian infants

In 2002, a Ventria collaborator stated that Ventria’s rice-derived lactoferrin (rhLf) would have to be tested on rats and infant rhesus monkeys before any human testing. However, a search on the comprehensive medical database PubMed reveals no such published studies of rice-derived rhLf on rats or monkeys. It is unclear whether such research has been conducted but remains unpublished, was published in some obscure
journal, or whether Ventria and its collaborators chose to forego animal experiments and proceed directly tothe trial on Peruvian infants. At least one mother whose infant was enrolled in the Peruvian experiment and subsequently developed allergies reports that she was “deceived” in that she was not informed that the treatment was experimental and involved compounds from transgenic rice. The researchers observed the infants in the experiment for only 14 days, far too short a period to detect any adverse consequences of Ventria’s compounds.
The authors of a paper on the Ventria-sponsored Peruvian experiment violate basic scientific protocol by not reporting the results for each of the three groups tested. By improperly combining the results for two distinct treatment groups, the authors may have
exaggerated the benefit (if any) of Ventria’s compounds in treating diarrhea.

Ventria’s rice a diversion from proven, cost-effective ways to treat diarrhea

Diarrheal mortality in infants and young children has been reduced from about 4.6 million deaths in 1980 to 1.5 to 2.5 million deaths a year today, one of the greatest medical achievements of the 20th century. This reduction in diarrheal deaths is due to a number of effective prevention measures—including improved sanitation facilities and drinking water supplies, improved hygienic practices, use of disinfectants, and more optimal breastfeeding as well as widespread introduction of oral rehydration therapy.
Ventria’s CEO Scott Deeter admits that foundation support would be necessary to make oral rehydration solutions (ORS) containing his company’s proteins — which would likely be more expensive than existing ORS formulations — widely available. Even if Ventria’s proteins eventually do prove safe after proper testing, governmental or private foundation aid would be more cost-effectively spent on the proven measures mentioned above, which are not adequately funded. In addition, Ventria intends to market its proteins as
nutritional supplements in performance (sports) drinks, granola bars, yoghurt and similar products for wealthy consumers in developed countries. This raises the question of whether premature experimentation on Peruvian children has been conducted primarily
to obtain market approval for these more profitable applications.

Conclusion

Genetically engineered, pharmaceutical rice is not the answer to diarrhea. The bioactive proteins in Ventria’s pharma rice may exacerbate infections or cause allergies or autoimmune disorders. They have apparently not been adequately tested on animals. A Ventria sponsored experiment on sick Peruvian infants was marked by lack of informed consent, incomplete presentation of data, and reports of adverse reactions in several study participants.
Ventria has failed to obtain FDA approval of its pharma rice or pharmaceutical proteins, despite four petitions to the FDA since 2003. Meanwhile, USDA is poised to allow Ventria to grow thousands of acres of pharmaceutical rice in Kansas, despite ample evidence
of unapproved genetically engineered crops entering the food supply and extremely deficient USDA regulation. Ventria’s officers and promoters have likened the company’s
rice to the “Holy Grail,”25 reminiscent of many past promises that pharma crops would deliver “miracle cures.” Yet despite outdoor field tests dating back to 1991, not a single pharma crop-produced drug has received FDA approval or saved a single life. Ventria’s rice-grown drugs are not only unproven, they are not needed. Effective and inexpensive measures to prevent and treat diarrhea have already saved millions of lives, and could save millions more with adequate funding.

Recommendations

  1. Reject field test permit:The U.S. Dept. of Agriculture is urged to reject all permit applications for cultivation of pharmaceutical-producing food crops, including Ventria’s application for cultivation of pharmaceutical rice in Kansas and other states.
  2. Reject GRAS additive review: The U.S. Food and Drug Administration is urged to reject applications to approve Ventria’s rice-expressed, recombinant human milk and blood proteins in the context of the GRAS (“generally recognized as safe”) food additive review process.
  3. Moratorium on further human experimentation: Ventria and its collaborators are urged to refrain from further human experimentation with Ventria’s recombinant human lactoferrin or lysozyme except in the context of the U.S. Food and Drug Administration’s new drug review process.
  4. Bar use of pharma rice compounds in “medical foods”: In view of the drug-like properties and potential hazards of Ventria’s recombinant proteins, the FDA is urged to bar use of Ventria’s recombinant human lactoferrin or lysozyme in unregulated products marketed as “medical foods.”
  5. Fund inexpensive and cost-effective to address diarrheal disease: Private and governmental public health funders are urged to invest in provision of safe water, sanitation facilities and other proven, cost-effective measures to reduce diarrheal morbidity.

This article has been extracted from the paper: “A Grain of Caution: A Critical Assessment of Pharmaceutical Rice”, by the Center for Food Safety. You can see the whole work in pdf format by clicking this link.

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