Transgenes for tea?John Heritage

School of Biochemistry and Microbiology, University of Leeds, Leeds, LS2 9JT, UK

So far, no compelling scientific evidence has been found

to suggest that the consumption of transgenic or

genetically modified (GM) plants by animals or humans

is more likely to cause harm than is the consumption of

their conventional counterparts. Despite this lack of

scientific evidence, the economic prospects for GM

plants are probably limited in the short term and there

is public opposition to the technology. Now is a good

time to address several issues concerning GM plants,

including the potential for transgenes to migrate from

GM plants to gut microbes or to animal or human tis-

sues, the consequences of consuming GM crops, either

as fresh plants or as silage, and the problems caused by

current legislation on GM labelling and beyond.

Despite qualified approval for the commercialization ofGM crops for human food and animal feed purposes in theUnited Kingdom, granted in March of this year [1], large-scale industrial research in this area has been severelycurtailed. The reasons for this curtailment are the poorcommercial prospects in Europe for the technology ratherthan scientifically based opposition. In the EuropeanCommunity, vocal opposition to GM technology in agri-culture has been evident for years (A report to theEC Directorate General for Research from the project‘Life Sciences in European Society’ QLG7-CT-1999-00286,http://europa.eu.int/comm/public_opinion/archives/eb/ebs_177_en.pdf), as has been well illustrated by theNational GM Public Debate [Genetic Modification (GM)Public Debate (2003) GM Nation? The findings of thenational debate, http://www.gmnation.org.uk/docs/gmnation_finalreport.pdf] which was held in the Uni-ted Kingdom during 2003.

There were three strands to the National GM PublicDebate: a public consultation (http://www.gmnation.org.uk/docs/gmnation_finalreport.pdf), a review of the econ-omic consequences of commercializing GM crops [UKCabinetOfficeStrategyUnit (2003) Fieldwork:weighingupthe costs and benefits of GM crops, http://www.number-10.gov.uk/su/gm/downloads/gm_crop_report.pdf] and a reviewof the science underpinning the technology [GM ScienceReview Panel (2003) GM Science Review First Report: Anopen review of the science relevant to GM crops and foodbased on interests and concerns of the public, http://www.gmsciencedebate.org.uk/report/pdf/gmsci-report1-full.pdf].The science review found no evidence for harm in theintroduction of transgenic plants as food or feed. Theeconomic review concluded that none of the situationsexaminedwas entirely good or bad: each required a trade-off

Corresponding author: John Heritage ( j.heritage@leeds.ac.uk).Available online 25 November 2004

www.sciencedirect.com 0167-7799/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved

between costs in some areas and benefits in others,necessitating value judgements to be made weighing thepros and cons of introducing transgenic plants as food orfeed.Thepublic consultation foundthatpeople in theUnitedKingdomare generally uneasy aboutGM food and feed, andthat themore thatpeople engagewithGMissues, theharderare their attitudes and the deeper are their concerns.

Opposition to agricultural applications of GM plants isnot universal. The growth of insect-resistant plants hasseen the crystal toxin of Bacillus thuringiensis trans-formed from a foliar insecticide with limited practicalapplications to a toxin engineered into ‘Bt crops’ that, atthe turn of the millennium, were being grown on 11.4million hectares worldwide [2]. By 2003, the latest year forwhich figures were available at the time of writing, thearea devoted to cultivation of these Bt crops had risen to12.2 million hectares worldwide, and the total global areasupporting the growth of transgenic plants for food or feedpurposes had grown to 67.7million hectares [Global statusof commercialized transgenic crops (2003) ISAAA BriefsNo. 30-2003l http://www.isaaa.org]. It has been arguedthat inserting the gene encoding the crystal toxin ofB. thuringiensis into target plants where only pests willconsume the toxin is more environmentally friendly thanis spraying the toxin widely across fields and therebyexposing insects that do no damage to plants, as well asthose that do, to the toxin.

In this article, I focus on the potential for transgenes tomigrate from GM plants to gut microbes and/or to animalor human tissues. In addition to exploring the conse-quences of consuming fresh GM plants, I discuss the issueof ensilage and the problems caused by current legislationon GM labelling and beyond.

Cause for concern?

Despite the absence of scientific evidence showing thatpotential harm to human or animal health is associatedwith the commercialization of GM plants (http://www.number-10.gov.uk/su/gm/downloads/gm_crop_report.pdf),the UK economic review revealed that any economicbenefits from the application of this technology are likelyto be limited, at least in the short term (http://www.number-10.gov.uk/su/gm/downloads/gm_crop_report.pdf).Furthermore, many people in Great Britain are uneasyabout the use of GM plants for food or feed purposes, andthe more these people engage with the topic, the morehardened become their attitudes (http://www.gmnation.org.uk/docs/gmnation_finalreport.pdf).

But are there reasons for concern? One area ofparticular public concern is the potential for the insertedgenes to migrate from GM plants to microbes in the guts of

Opinion TRENDS in Biotechnology Vol.23 No.1 January 2005

. doi:10.1016/j.tibtech.2004.11.004

Opinion TRENDS in Biotechnology Vol.23 No.1 January 200518

the animals or humans who consume the GM material;another is the possibility that these genes might associatewith animal or human tissues. I consider these issues below.

The potential for gene flow in the gut and beyond

There has been considerable interest in the report thatforeign DNA consumed in food is not degraded completelyin the mouse intestinal tract [3]. When mice were fed onmaterial containing DNA from bacteriophage M13mp18,DNA fragments of 976 bp were detected in the blood-stream for up to 8 h after feeding. By fluorescent in situhybridization (FISH) analysis, about 1 in 1000 peripheralwhite blood cells were found to be carrying bacteriophageDNA in the test mice, whereas none was found in thecontrols. Bacteriophage DNA was observed in gut epi-thelial cells, in the Peyer’s patches, in liver cells, and inlymphocytes and macrophages found in the spleen [3].

More recent studies using various foreign DNA sourceshave confirmed that DNA sequences are taken up from thediet of humans, food animals and laboratory rodents, andthat increasing the concentration of bulky dietary fibrematerial accelerates the passage of food through thegastrointestinal tract, speeding up the clearance of foreignDNA from the gut [4]. If foreign DNA is capable oftransferring from a food source into the tissues of ananimal that eats the test material, could transgenesincorporated into GM plants that are used for food orfeed purposes do the same?

GM foods and feeds are not a homogenous group andrange from plant material that is consumed fresh andunprocessed to pure chemical compounds, such as sucrose,that are derived from GM plants. For pure compounds inwhich there is no trace of the GM event, there is clearly nopotential for gene flow; however, the same might not betrue for GM food or feed material that undergoes little orno processing. Both high temperature and low pH reducethe survival of DNA in food and feed, and these effects areadditive [5,6].

The physical nature of DNA affects its chances ofsurvival during its passage through the gut. In a studyusing gnotobiotic rats, plasmid DNA was recoveredthroughout the intestinal tract of the rats. Furthermore,the DNA recovered retained the ability to transformelectrocompetent Escherichia coli cells [7], indicating thatnot only had it survived passage through the digestivetract but it had remained biologically active. This distinc-tion between the detection of total DNA and DNA thatretains biological activity is important because the abilityto transform cells is a crucial step in potential gene flowand it is a property that is lost before the ability to amplifytarget DNA from samples is lost [8,9]. In vitro modelstudies have confirmed that transgenes in some GM foodscan survive passage through the small intestine [10].

Gene transfer events to the microflora of the intestinaltracts of animals and humans eating GM plants involvingtransgenes are likely to be very rare events. Indeed,searching for them might be likened to seeking needles inhaystacks. In this area of research, however, a recentpublication stands out. Netherwood et al. [11] examinedthe fate of transgenic DNA in food given to humanvolunteers. Food containing significant amounts of GM

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soya was fed to people who had had an ileostomy, anoperation in which the ileum is passed through the wall ofthe abdomen to form an artificial anus so that the contentsof the gut at this point can be collected with ease. The fateof transgenic DNA in the ileostomy fluid of volunteers wasexamined. Although Netherwood et al. [11] concluded thatgene transfer events did not occur during the feedingexperiment, three of the seven volunteers showed evi-dence of low-frequency gene transfer events from GM soyainto the small bowel microflora that had occurred beforethe experiment began.

Transgenic DNA fragments could be amplified frombacteria cultivated in liquid culture from the ileostomyfluid at the outset of the experiment. Furthermore,bacteria containing the transgene template could bedetected after six serial passages in broth culture.Intriguingly, these bacteria were not recoverable onconventional solid growth media, making further studiesin this area challenging, although it is likely from thework reported so far that the bacteria are obligatelysymbiotic facultative Gram-positive bacteria [11]. Nether-wood et al. concluded that these DNA transfer events fromtransgenic plants to gut microflora are highly unlikely toalter gastrointestinal function and thus do not pose a riskto human health. This is a view with which I agreecompletely [12].

“.these DNA transfer events from transgenicplants to gut microflora are highly unlikely to altergastrointestinal function and thus do not pose a riskto human health.”

The problem of antibiotic resistance marker genes

It is not only the potential for transfer of transgenes thatrequires consideration when contemplating the commer-cialization of GM plants for food or feed purposes. What isencoded by the DNA might be also significant. In thiscontext, DNA sequences that encode traits that have thepotential to harm health require active deliberation. It isunlikely that DNA sequences that encode increasedbacterial virulence will be incorporated into GM plantsdestined for food or feed usage; however, another area ofpotential concern is the inclusion of DNA sequences thatencode antibiotic resistance.

In Europe, the use of such markers is being phasedout and so the associated issues will take on a lessersignificance. Elsewhere in the world, the use of antibioticresistance markers in GM plants has caused less concernon the basis that, first, there is already a very highprevalence of bacteria resistant to antibiotics in thegastrointestinal tracts of the humans and animals thatare likely to consume GM plant material; and second, thevery low probability of gene transfer from GM plantmaterial to the gut microflora is unlikely to have any effecton the overall prevalence of resistance.

This issue has also been the subject of recent reviews,which have concluded that the likelihood of antibioticresistance genes escaping from GM plants and transform-ing gut bacteria with antibiotic resistance is slight andthat the consequences are negligible given the level ofresistance already present in bacteria associated with

Opinion TRENDS in Biotechnology Vol.23 No.1 January 2005 19

humans [13,14]. I have previously commented that themost significant threat to the continued use of antibioticscomes from their use and misuse in humanmedicine, but Ialso retain my concern that everyone must take respon-sibility to ensure that the spread of antibiotic resistancegenes is minimized [15].

There is another aspect of research pertaining to thepresence of antibiotic resistance genes in GM plants thathas received scant attention. The administration of anti-biotics might have a profound effect on the microflora ofthe gut [16] and provides a selective pressure forresistance to antibiotics among bacteria exposed toantimicrobial compounds. It is not known what effectsthe administration of antibiotics has on the potential forgene flow to humans or animals that consume GM plantmaterial containing DNA that encodes antibiotic resist-ance. Does the administration of antibiotics to humansor animals feeding on transgenic plant material increasethe chance that antibiotic resistance markers, or indeedother transgenic DNA, will transfer to the gut microflora?We do not know.

Would silage research lead to pastures new?

Much of the maize crop grown in northern Europe is usedto make silage. If GM plants are used for this purpose,then there is the potential for gene flow from the GM plantmaterial, either to the bacteria responsible for ensilage orto the microflora of animals fed on silage. Because thelactic acid bacteria responsible for silage production canact as opportunist pathogens, the potential problemscaused by the ensilage of transgenic plant material donot come directly from the food chain but might arise if thebacteria from silage production were to cause infection inhumans working with or animals fed on silage material.

Most of the studies published on ensiled GM crops havefocused on the nutritional qualities of this feed material,and none has shown a difference between GM crops andtheir conventional counterparts with respect to feedquality [17,18]. High molecular weight DNA survives theensilage process and whole gene sequences are present inmaize silage [6]. Large fragments of transgenic DNA arenot recoverable by PCR in the rumen fluid of sheep fed onGM maize silage, although the same target can beamplified from the rumen fluid of animals fed on GMmaize grains [8]. Shorter DNA sequences (211 bp) can berecovered from the rumen fluid of sheep fed on maizesilage for up to 3 h after feeding. More recently, thepersistence of large- or medium-sized fragments of plantDNA was found to be dependent not only on the timespent in the rumen but also on the copy number of thetarget gene [19].

The fate of transgenic DNA during silage productionhas received little research interest. Silage is a productof mixed microbial fermentation, in which lactic acidbacteria form the predominant flora [20]. Among theseflora are enterococci, which might act as opportunistichuman pathogens. Furthermore, these bacteria arenaturally competent for genetic transformation. Conse-quently, ensilage provides an environment in which highmolecular weight DNA from GM plants is in closeproximity to a diverse population of bacteria, some of

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which are both competent for natural transformation andopportunistic human pathogens. It is perhaps surprisingthat so little attention has been paid to the potential forgene flow during the ensilage of GM plant material.

Wider issues: labelling what is and what is not GM

The debate on using GM plants for food or feed purposesgoes much wider than just scientific arguments. InEurope, strong lobbying by pressure groups is beingmanifested in an increase in legislation regarding theuse of GM crops for food and feed purposes. In a recentarticle [21], Derek Burke, founder chairman of the UKAdvisory Committee on Novel Foods and Processes,argues cogently against an extension of legislation withrespect to GM food. A similar argument has been madewith respect to the mandatory labelling of GM foodsin Canada [22].

The European Commission are enacting legislationthat requires all food made with products from GM plantsto be so labelled. This applies to food ingredients thatcontain no traces of transgenic protein or DNA. Thereason underpinning the legislation is that consumersshould be offered informed choice. Those who wish to buyGM foods are free so to do; but people who wish to avoidconsuming GM plants will also have this freedom. In myview, this legislation is unworkable because someone whofails to label Bourbon whiskey distilled from GM maizewill have committed the same offence as someone who failsto label GM sweetcorn. In the latter crop, both transgenicDNA and protein will be readily detectable; in the former,no trace of the transgenic event will be found. In bothcases, however, failure to label the product as ‘GM’ willmean that a fraudulent act will have been perpetrated.This situation is to be deprecated; it will be much easier toprove the latter case than the former.

Another consequence of such labelling legislation isthat producers who wish to avoid prosecution might welllabel any feed that could contain GM material as so doingto avoid prosecution, even if there is nothing of GM originin the product. The precedent for the precautionaryprinciple in labelling is the ‘may contain nuts’ label thatwarns people with peanut allergies. Where does this leavethe consumer’s right to informed choice?

“.this legislation is unworkable because someonewho fails to label Bourbon whiskey distilled fromGMmaize will have committed the same offence assomeone who fails to label GM sweetcorn.”

Beyond labelling.The issue of labelling is even more complex than I haveoutlined above. So far, the products of animals fed on GMplants, including meat, milk and eggs, have been exemptfrom being labelled as containing GM material. The sameexclusion is likely to apply also to honey from bees thathave visited GM plants. Is this exclusion justified? Thisquestion is pertinent, particularly in light of the resultsobtained when mice were fed bacteriophage DNA(see above) [3]. Neither fragments of transgenic DNAnor the proteins encoded by transgenes have been foundin poultry meat or eggs, although plant-specific DNA

Opinion TRENDS in Biotechnology Vol.23 No.1 January 200520

sequences have been found in the muscles, liver, spleenand kidneys of broiler chickens and laying hens [23].Several studies using pigs or cattle have reported similarfindings in animal tissues: a lack of transgenic DNA, butthe presence of multicopy plant DNA sequences, particu-larly those derived from chloroplast genomes [24–30].

Notably, these studies have detected only short frag-ments of target DNA, which disappear from tissues onprolonged fasting, suggesting that these sequences areunlikely to integrate permanently into the host DNA [31].Foreign DNA has typically not been found in eggs or milk,but there has been a report of faint signals in milk testedfor the presence of chloroplast DNA [32]. When workingwith milk samples and when PCR is used to detect targetDNA, care must be taken with the integrity of the samplesto ensure, for example, that they are not contaminatedwith food components or with airborne feed particles thatmight carry the target DNA sequences [33].

The observation that small fragments of multicopyDNA sequences derived from food or feed sources might befound in the tissues of animals is not confined to plants,and studies have not been confined to animals. A recentpublication reports the use of nested PCR to detect thetransient presence in blood samples of rabbit mitochon-drial DNA in two healthy male volunteers after theconsumption of cooked rabbit [34]. Although these studiespose further questions relating to the control of DNA inour diets, they show that the uptake of DNA derived fromfood or feed material is a natural process that relates, atleast in part, to the copy number of the DNA that isdetected. It is not clear whether the failure to detect food-derived DNA that is typically present in low copy numberis due to its absence in the tissues of the animals orhumans who have consumed it or to the insensitivity ofcurrent assay systems. Whatever the answer to thisquestion is, it has consequences for future trends inplant biotechnology.

Although there are compelling reasons for exploitingplastid transformation systems relating to the expressionof multiple copies of transgenes, there is an increasedlikelihood that DNA fragments associated with transgenicevents will be detected in the tissues of animals or humanswho eat such plants and this will have to be taken intoaccount in any risk assessment process. This underlinesthe need for risk assessment to be made on a case-by-casebasis, although – given that the size of DNA fragmentstypically reported in these studies is small – it is unlikelythat a significant threat to human or animal health willbe posed by such constructs if they are used for food orfeed purposes.

Concluding remarks

Although many studies have examined the fate of trans-genic DNA from GM plant material in its passage throughthe gastrointestinal tract, most have concentrated on thedetection of DNA per se rather than on the detection ofDNA that retains its biological activity. Although it ismore challenging to study the latter, only when the fate ofbiologically active DNA is studied will we gain insight intogene flow as opposed to the passage of DNA. Muchevidence indicates that DNA derived from the diet can

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be detected in animal and human tissues irrespective ofwhether the subjects consume GM plants. In general,however, the targets detected are too small to carry wholegenes. Although the prospect of gene flow from GM plantsduring digestion is often cited as a cause for concern, thereremains no scientific evidence to show that the presence oftransgenes in our food and feedstuffs poses a threat tohuman or animal health.

Herein I have identified areas in which knowledgecould be extended and that deserve active research tofurther our understanding of issues that are of publicconcern. Even with the phasing out in Europe of the use ofantibiotic resistance markers, the need to study the effectsof antibiotic challenge on the potential for gene flowremains a challenge. The potential for ensilage of trans-genic crops also warrants further study. The apparenttransfer of plant transgenes to the microflora of the ileum,as reported by Netherwood et al. [11], is another area thatis worthy of more attention. Gene flow seems to occur intobacteria that are not recoverable as discrete colonies onthe solid media tested, but that are nevertheless capable ofgrowth in liquid culture. Netherwood et al.’s study waslimited in that no information was obtained regardingthe nature of the DNA identified in the gut bacteria.Work has begun to address this issue and should besupported strongly.

AcknowledgementsI thank several colleagues who have commented critically on mymanuscript.

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Free journals for dev

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