LANCET - GMO foods

16 October 1999

A Hot Potato (Editorial)

Effect of diets containing genetically modified potatoes expressing 
Galanthus nivalis lectin on rat small intestine
(Stanley W B Ewen, Arpad Pusztai)
Differential binding of the insecticidal lectin GNA to human blood cells
Brian Fenton, Kiri Stanley, Steven Fenton, Caroline Bolton-Smith)
Adequacy of methods for testing the safety of genetically modified foods
Harry A Kuiper, Hub P J M Noteborn, Ad A C M Peijnenburg)

3 July 1999

Health Risks of Genetically Modified Foods (Letter, Peter Lachmann)

Health Risks of Genetically Modified Foods (Letter, Alan D B Malcom)

Health Risks of Genetically Modified Foods (Letter, Carl B Feldbaum)

Health Risks of Genetically Modified Foods (Letter, H Schellekens)

Health Risks ofGenetically Modified Foods (Eric Brunner, Erik Millstone )

29 May 1999

Health Risks of Genetically Modified Foods (Editorial)





Lancet - Saturday 16 October 1999

A hot potato

'publication of a paper after substantial review and revision provides a report that deserves further scientific attention'

Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine.

This week, The Lancet publishes the results of Stanley Ewen and Arpad Pusztai's experiments on the effects of genetically modified (GM) potatoes on laboratory rats (p 1353), together with a report on the possible effects of GM foods on human blood cells by B Fenton and colleagues (p 1354). This issue also contains Commentaries on these two Research Letters by Richard Horton (p 1312) and by Harry Kuiper and colleagues from the Netherlands State Institute for Quality Control of Agricultural Products (p 1313).

In publication of these papers, The Lancet aims to make constructive progress in the debate between scientists, the media, and the general public about the safety of GM foods.

Lancet - Saturday 16 October 1999

Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine

Stanley W B Ewen, Arpad Pusztai


Diets containing genetically modified (GM) potatoes expressing the lectin Galanthus nivalis agglutinin (GNA) had variable effects on different parts of the rat gastrointestinal tract. Some effects, such as the proliferation of the gastric mucosa, were mainly due to the expression of the GNA transgene. However, other parts of the construct or the genetic transformation (or both) could also have contributed to the overall biological effects of the GNA-GM potatoes, particularly on the small intestine and caecum.

See Commentaries by Horton and Kuipers et al

Genetically modified (GM) plant products are becoming increasingly common in the human food-chain, yet in contrast to the general acceptance of the need for the biological testing of novel foods and feedstuffs, few studies have been carried out on the possible effects of GM products on the mammalian ut mucosa. GM potatoes expressing a snowdrop lectin (Galanthus nivalis agglutinin [GNA]) under the CaMV35s promoter have been developed to increase insect and nematode resistance.1 GNA was selected for insertion into potatoes because the initial effect of this mannose-specific lectin on the rat small bowel has been shown to be minimal,2 and because its binding to mannose present on the epithelial surface of rat jejunal villi is demonstrable only after feeding for 10 days.

We compared the histological indices of the gut of rats fed potato diets containing GM potatoes, non-GM potatoes, or non-GM potatoes supplemented with GNA, to find out whether GNA gene insertion had affected the nutritional and physiological impact of potatoes on the mammalian gut.

ELISA analysis confirmed that the expression level of GNA in raw GM potatoes was 25·4 µg/g dry matter; the concentration was decreased to 4·9 µg/g after boiling for 1 h. Six rats were randomly allocated to each group, and were fed diets containing either raw or boiled GNA-GM potatoes, parent potatoes (Desiree), or parent-line potatoes supplemented with 25·4 µg/g GNA for 10 days. All potato diets were isocaloric and contained an average of 6% protein. Histological samples of stomach, jejunum, ileum, caecum, and colon were taken 10 days after the start of feeding.

The samples, each 2 cm in length, were opened along the antimesenteric border. The serosal surface was allowed to adhere to card for 3 min and was then fixed in 10% neutral buffered formalin for 18 h at 20°C. Paraffin sections (4 µm) were stained with haematoxylin and eosin, and mucosal thickness (stomach) or crypt length (jejunum, ileum, caecum, and colon) was measured by video-image analysis. Intraepithelial lymphocytes are equally distributed in all parts of the small intestine, and are known to increase when non-specific intestinal damage occurs.

Thus, to assess potential damage, intraepithelial lymphocytes were counted in eight jejunal villi from each of the six rats fed diets containing GNA-GM potatoes or parent potatoes, both raw and boiled. No such measurements were made for the group fed parent potatoes spiked with GNA because dietary GNA or other lectins do not induce lymphocyte infiltration. GNA binding to the jejunum and ileum was measured by elution with 0·1 mol/L mannose, followed by ELISA.

The presence of GNA in the diets, irrespective of whether originating from GNA-GM potatoes or from parent-potato diets supplemented with GNA, was associated with significantly greater mucosal thickness of the stomach when compared with parent-potato diets (table 1). This effect was observed with both raw and boiled potatoes. Crypt length in the jejunum of rats fed on raw GNA-GM potato diets was significantly greater than in those given parent-line or parent-line plus GNA potato diets. However, the increase in jejunal crypt length was not seen in rats fed boiled GNA-GM potatoes (table 1). GNA had no significant effects on the ileum, but rats fed boiled potatoes had shorter ileal crypts than rats given respective raw potato diets.

Rats fed boiled GNA-GM potatoes had significantly thinner caecal mucosae than rats given boiled parent potatoes, with or without GNA supplementation (table 1). Intraepithelial lymphocyte counts per 48 villi were 7·6 (SD 2·7) in rats fed on boiled parent potatoes, compared with 10·3 (3·3) in rats fed boiled transgenic potatoes (p<0·01). With raw potato diets, the intraepithelial lymphocyte counts were again significantly different: 5·3 (2·0) and 9·3 (2·6) in parent and GM potatoes, respectively (p<0·01). Peyer's patches appeared normal in all rats. GNA binding in the jejunum and ileum was about the same, irrespective of whether spiked GNA potatoes or GM potatoes were fed (table 2). Measurement of GNA binding by immunocytochemistry also showed a similar pattern.2


Table 1: Effect of raw and cooked parent, parent+GNA, and GNA+GM potatoes on histological indices of rat gut

Mean (SD) crypt length (µm) and
difference between treatments*


Statistical analysis
(p) **


Interaction (p) **


Parent vs Parent+GNA




Parent vs

Effect of GNA


Effect of


Trans x cook

Stomach (B=boiled, R=Raw)























Jejunum (B=boiled, R=Raw)

























Ileum (B=boiled, R=Raw)

























Caecum (B=boiled, R=Raw)

























Colon (B=boiled, R=Raw)






0·65 0·878 0·002 0·181 0·231 0·001













Data are the means of six animals calculated from five observations for each. GNA×cook=interaction between GNA and cooking; Trans×cook=interaction between transformation and cooking.

**  By Student's t test.
** By multivariate analysis with Tukey's test.

We suggest that the promotion of jejunal growth was the result of the transformation of the potato with the GNA gene, since the jejunum of rats was shown to be stimulated only by GM potatoes but not by dietary GNA (table 1), in agreement with a previous study in which the dietary GNA concentration was 1000-fold higher than the one used in this study.2

Thus, we propose that the unexpected proliferative effect was caused by either the expression of other genes of the construct, or by some form of positioning effect in the potato genome caused by GNA gene insertion. Because caecal thickness was similar in rats given boiled parent potatoes in the presence or absence of spiked GNA, we suggest that the decrease in caecal mucosal thickness seen in rats fed boiled GM-potato diets was the consequence of the transfer of the GNA gene into the potato.

Caecal mucosal thickness in rats given raw potato diets was significantly higher than in those given the corresponding boiled potatoes. Thus, the main effect of boiling was to decrease mucosal thickness; this binding was fully in line with expectations. The raw parent-line potato diets supplemented with GNA were associated with a significantly thinner caecal mucosa than that of rats given parent-line potato diets. A similar trend was also observed in rats fed raw GNA-GM potatoes, but the difference did not reach significance (table 1).

Table 2: GNA binding to the jejunum and ileum of rats given diets containing GNA-GM potatoes or parent potato diets spiked with GNA


Raw potato


Boiled potato


GNA intake (µg)





Mean (SD) bound GNA (µg)      


0·37 (0·27)

0·25 (0·21)

0·05 (0·04)


0·28 (0·15)

0·44 (0·25)

0·17 (0·08)

0·07 (0·02)


5·04 (2·67)

2·23 (0·63)

0·78 (0·35)

0·20 (0·17)


5·79 (2·71)

3·04 (0·60)

1·20 (0·49)

0·32 (0·17)

On the morning of day 10, rats were given 1·5 g allocated diet and were killed 2 h later. After dissection, oesophagus, pylorus, and ileocaecal junction were clipped, and small intestine was washed thoroughly with saline. Small intestine was cut into three segments: jejunum (first 20 cm), ileum (last 20 cm), and remainder. Tissues were homogenised with phosphate-buffered saline containing 0·1 mol/L mannose, and solutions were used for determination of GNA content by competitive ELISA.

As expected, colonic crypt lengths were generally higher in rats given raw potato diets than in those given boiled potatoes, except for animals fed GNA-supplemented raw or boiled potato diets, between which there was no significant difference. Feeding rats on diets containing GM potatoes, irrespective of whether raw or boiled, had no significant effect on colonic crypt length compared with that in animals fed the corresponding parent-line potatoes (table 1). Rats fed on GNA-supplemented parent potatoes had significantly shorter colonic crypt lengths than those fed on parent potatoes of GNA-GM potatoes; the reason for this finding is not clear.

In conclusion, the stimulatory effect of GNA-GM potatoes on the stomach was mainly due to the expression of the GNA transgene in the potato. By contrast, the potent proliferative effect of raw GNA-GM potatoes on the jejunum, and the antiproliferative effect of boiled transgenic potatoes on the caecum can be attributed only partly to GNA gene expression. Other parts of the GM construct, or the transformation, could have contributed to the overall effects.

Once bound, GNA is internalised by endocytosis;2 some other component of the construct in the GNA-GM potato or its expressed gene product might also be able to penetrate and affect the rat mucosal cells in a similar manner. The growth-promoting effect of raw GNA-GM potatoes in the jejunum, evident as crypt hyperplasia, is probably due to a direct stimulatory effect on crypt cells; the increase in T lymphocyte infiltration may be important in the elimination of damaged enterocytes.3

The possibility that a plant vector in common use in some GM plants can affect the mucosa of the gastrointestinal tract and exert powerful biological effects may also apply to GM plants containing similar constructs, particularly those containing lectins, such as soya beans or any plants expressing lectin genes or transgenes.

This study was supported by Scottish Office: Agriculture, Environment, and Fishery Department (grant number FF 818).

1 Gatehouse AMR, Down RE, Powell KS, et al. Transgenic potato plants with enhanced resistance to the peach-potato aphid Myzus persicae. Ent Exp Appl 1996; 79: 295-307.

2 Pusztai A, Ewen SWB, Grant G, et al. Relationship between survival and binding of plant lectins during small intestinal passage and their effectiveness as growth factors. Digestion 1990; 46 (suppl 2): 306-16.

3 Marsh NM, Ensari A. The gut associated lymphoid tissue and immune system. In: Whitehead R, ed. Gastrointestinal and oesophageal pathology. 2nd edn. Edinburgh: Churchill Livingstone, 1995: 201-25.

Department of Pathology, University of Aberdeen, Aberdeen AB25 2ZD, UK (S W B Ewen FRCPath, A Pusztai PhD)

Correspondence to: Dr Stanley W B Ewen (e-mail:

Lancet - Saturday 16 October 1999

Differential binding of the insecticidal lectin GNA to human blood cells

'publication of a paper after substantial review and revision provides a report that deserves further scientific attention'

Brian Fenton, Kiri Stanley, Steven Fenton, Caroline Bolton-Smith

Evidence of snowdrop lectin binding to human white cells supports the need for greater understanding of the possible health consequences of incorporating plant lectins into the food chain.

See Commentaries by Horton and Kuipers et al

There is interest in the possible use of lectins to protect food plants from attack by insects. Many of these carbohydrate-binding proteins agglutinate vertebrate red blood cells. The lectin peanut agglutinin (PNA) also binds to the Thomsen-Friedenreich antigen on the surfaces of some human colon cells. After eating peanuts, PNA has been detected in the blood after 1 hour1 and individuals who express this antigen have increased rates of colonic cell division, with possible health implications.2 PNA does not appear to be under consideration in an insecticidal role. Galanthus nivalis (snowdrop) agglutinin (GNA) is however under consideration and transgenic plants expressing GNA have been constructed.3 GNA recognises terminal 1-3-linked mannosyl residues.

The distribution, abundance, and microheterogeneity of this structure on human glycoproteins is largely unknown, particularly for membrane-bound receptor proteins. Although the conventional view is that mammalian intestinal cells possess no free mannose residues, and therefore cannot bind GNA, there have been reports of dietary effects of GNA in rats, including hypertrophy of the small intestine.4 GNA is highly resistant to digestion, and tests on human cells suggest that GNA can cause increase in mitosis. Although mitogenic stimulation requires both lectin binding and activation of appropriate cell-surface receptors, poorly mitogenic lectins can act in synergy with other compounds to increase mitotic indices. In addition, GNA could react with other receptors and block their normal function in at least some tissues and in at least some individuals.

We examined proteins isolated from human buffy coats and red blood cells taken on three different occasions from six healthy individuals (aged more than 60 years) for their reactivity with GNA. Sodium dodecyl sulphate polyacrylamide gel electrophoresis and western blot procedures were used to transfer proteins onto a nitrocellulose support matrix.5 This procedure was followed by detection with commercially available biotinylated lectins and alkaline phosphatase linked to streptavidin. Our results show that human white blood cells have many proteins that strongly bind to GNA (figure). This binding was partially inhibited in the presence of mannose. Red blood cells showed little reactivity with GNA which was consistent with the lack of agglutinating activity of GNA for human erythrocytes and also indicated that blood group variation was not an issue.

Lane 1 molecular weight markers; lanes 2-7 individuals
1-6 buffy coats; lanes 8-13 RBCs; lane 14 ribonuclease A (not mannosylated; negative control); lane 15 ribonuclease B (mannosylated; positive control)

These data strongly suggest that human glycosylation pathways in white cells are capable of synthesising substantial quantities of terminal mannose moieties that interact with GNA. Furthermore the reaction appears to vary (indicated by arrows). This work highlights the need for a much greater understanding of the interactions between plant lectins and human glycoproteins before they can be safely incorporated into the food chain.

1 Wang Q, Lu-Gang Y, Campbell BJ, Milton JD, Rhodes JM. Identification of intact lectin in peripheral venous blood. Lancet 1998; 352; 1831-32.

2 Ryder SD, Jacyna MR, Levi AJ, Rizzi PM, Rhodes JM. Peanut ingestion increases rectal proliferation in individuals. Gastroenterology 1998; 114: 44-49.

3 Down RE, Gatehouse AMR, Hamilton WDO, Gatehouse JA. Snowdrop lectin inhibits development and decreases fecundity of the glasshouse potato aphid (Aulacorthum solani) when administered in vitro and via transgenic plants both in laboratory and glasshouse trials. J Insect Physiol 1996; 42: 1035-45.

4 Pusztai A, Kininx, J Hendriks H, et al. Effect of the insecticidal Galanthus nivalis agglutinin on metabolism and the activities of brush border enzymes in the rat small intestine. J Nut Biochem 1996; 7: 677-82.

5 Fenton B. Clark JT, Wilson C, McBride J, Walliker D. Polymorphism of a 35-48kDa Plasodium falciparum merozoite surface antigen. Mol Biol Parasitol 1989; 34: 79-86.

Scottish Crop Research Institute, Invergowrie, Dundee, UK (B Fenton PhD, K Stanley BSc), and Nutrition Research Group, Cardiovascular Epidemiology Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK (S Fenton MSc, C Bolton-Smith PhD)

Correspondence to: Dr Caroline Bolton-Smith

Lancet - Saturday 16 October 1999

'Genetically modified foods: "absurd" concern or welcome dialogue?

Richard Horton

"The attempt of single-interest groups, supported by the tabloid press and now by others who should know better, to declare this whole [genetically modified] technology as dangerous and immoral is sad for the UK, but is also absurd".1 So wrote the president of the UK's Academy of Medical Sciences, Peter Lachmann, after The Lancet criticised Arpad Pusztai for announcing the results of his experiments with genetically modified (GM) potatoes on television. Lachmann had less to say about the journal's additional and equally important concern--namely, that those in government, the food industry, and science had badly miscalculated the level of public anxiety about this new biotechnology.2

Richard Sykes, chairman of GlaxoWellcome, also marginalised the public's concern. In his presidential address to the British Association for the Advancement of Science on Sept 13, 1999, he noted that "It is now very possible that the outcomes of the present anti-GM food campaign will be detrimental to this country. It will lead to a failure to develop new UK companies based upon the technology developed here, loss of technical expertise as funding by major international companies is withdrawn, and disadvantage for British agriculture". This state of affairs was even more starkly summed up by Roger Gosden, the scientist acclaimed for the first successful ovary graft, who is emigrating from the UK to Canada in a blaze of publicity about the brain drain, who said that "With all the fuss over GM food and so on, it is difficult to be a scientist in Britain. One does not feel proud of being a scientist any longer".3

The trigger for much of this despondency was the public debate that followed Pusztai's television revelations. The data on which this media furore was founded are published for independent assessment in this week's issue of The Lancet, 18 months after their first public release. The Research Letter by Stanley Ewen and Pusztai was received by the journal towards the end of 1998. Since then, it has been peer reviewed by six specialist advisers--a nutritionist, a human pathologist, a veterinary pathologist, an agricultural geneticist, a plant molecular biologist, and a statistician--who had several requests for clarification about the design of the study, the laboratory methods used, and the statistical tests applied. Some advised rejection; others encouraged us to go ahead and publish. The authors revised their letter three times to try to meet our reviewers' criticisms. The Royal Society's own internal review of the Pusztai data had led to the damning verdict that the study "is flawed in many aspects of design, execution, and analysis and that no conclusions should be drawn from it". So why publish the paper?

The answer lies partly in a February, 1999, statement from the UK's chief scientific adviser, Robert May.4 While criticising the researchers' "sweeping conclusions about the unpredictability and safety of GM foods", he pointed to the frustration that had dogged this entire debate: "Pusztai's work has never been submitted for peer review, much less published, and so the usual evaluation of confusing claim and counter-claim effectively cannot be made". This problem was underlined by our reviewers, one of whom, while arguing that the data were "flawed", also noted that, "I would like to see [this work] published in the public domain so that fellow scientists can judge for themselves . . . if the paper is not published, it will be claimed there is a conspiracy to suppress information". Publication of Ewen and Pusztai's findings is not, as some newspapers have reported,5 a "vindication" of Pusztai's earlier claims. On the contrary, publication of a paper after substantial review and revision provides a report that deserves further scientific attention. Such wider appraisal begins in this week's Lancet with the commentary by Harry Kuiper and colleagues .

Once the sketchy details of these data had been revealed last year, several respected scientists and scientific institutions called for more careful government scrutiny of research into GM food. For example, the Royal Society's own statement on GM plants6 recommended that "any further increase in the number of antibiotic-resistant micro-organisms resulting from transfer of antibiotic-resistance markers from GM food should be avoided". The report supported labelling of foods containing GM material (a practice introduced last month in the UK) and threw its weight behind the idea of "an over-arching body or 'super-regulator'" to oversee all government advisory bodies on GM technology. The Royal Society also recommended further research into alternative markers to antibiotic-resistance genes, the impact of virus-resistant and insect-tolerant plants on the ecosystem, and the unpredictable genetic effects resulting from gene insertion into a GM plant.

These concerns were echoed in Robert May's 1999 statement,4 which concluded that "there can be questions of health and safety associated with some GM foods, particularly if we introduce genes coding for production of toxins against certain kinds of pests". The Chief Medical Officer of England, Liam Donaldson, together with May, wrote that although "There is no current evidence to suggest that the GM technologies used to produce food are inherently harmful . . . nothing can be absolutely certain in a field of rapid scientific and technological development.7 Donaldson and May urged the UK government to develop a comprehensive research strategy into GM food technology, including study of its potential effects on health.

These responses reflect an appropriately cautious approach towards the science of genetic modification. They reflect the real concern expressed by both "single- interest groups" and a wider public. These anxieties may seem odd, even irrational, given that GM foods were introduced in the USA without any sign of consumer anxiety. Why? Because Europe now lives in a post-BSE (bovine spongiform encephalopathy) age, one in which society has learned that the epidemic of BSE was brought on by unchecked industry-driven changes in farming practices and that the denials of risk by government and scientific authorities were worthless. That concern is now spreading beyond the UK. Recognition of this deeply ingrained public scepticism about food technology has led Monsanto to rethink its entire GM-food strategy.8,9

The comments by Lachmann, Sykes, and Gosden are therefore disappointing because they reflect a failure to understand the new, and apparently unwelcome, dialogue of accountability that needs to be forged between scientists and the public. Risks are not simply questions of abstract probabilities or theoretical reassurances. What matters is what people believe about these risks and why they hold those beliefs. Ewen and Pusztai's data are preliminary and non-generalisable, but at least they are now out in the open for debate, as are the results, also published in today's Lancet, of Brian Fenton and colleagues. Only by welcoming that debate will the standard of public conversation about science be raised. Berating critics rather than engaging them--and criticising reports of research, as the Royal Society did with the Pusztai data, before those data were reviewed and published in the proper way--will only intensify public scepticism about science and scientists.

The Lancet, London WC1B 3SL, UK

1 Lachmann P. Health risks of genetically modified foods. Lancet 1999; 354: 69.

2 Editorial. Health risks of genetically modified foods. Lancet 1999; 353: 1811.

3 Dobson R. Medical stars pack their bags. Independent on Sunday Sept 26, 1999: 16.

4 May R. Genetically modified foods: facts, worries, policies, and public confidence. London: Office of Science and Technology, 1999.

5 Lean G. Smeared GM expert vindicated. Independent on Sunday Oct 3, 1999: 1.

6 Royal Society. Genetically modified plants for food use. London: Royal Society, September, 1998.

7 Donaldson L, May R. Health implications of genetically modified foods. London: Department of Health, May, 1999.

8 Quinn S. Monsanto rethink welcomed. Guardian Sept 27, 1999: 4.

9 Finn G. Monsanto's U-turn on "terminator gene" seeds. Independent Oct 5, 1999: 1.

Lancet - Saturday 16 October 1999

Adequacy of methods for testing the safety of genetically modified foods

Harry A Kuiper, Hub P J M Noteborn, Ad A C M Peijnenburg 

An issue that has been prominent in the current debate on the health risks of genetically modified (GM) foods is whether there are adequate methods of testing for the safety of these foods. One view is that the safety assessments of these foods are not as rigorous as those for new chemicals or drugs. Today's Lancet carries two Research Letters reporting work on the potential risks to human health of the lectin Galanthus nivalis agglutinin (GNA), a compound that may be useful in protecting food plants from attacks by insects. These letters raise issues about the design of studies on safety.

Stanley Ewen and Arpad Pusztai report that, when fed to rats, GM potatoes containing the GNA lectin have proliferative and antiproliferative effects on the gut. They suggest that several of these effects are due to alterations in the composition of the transgenic potatoes, rather than to the newly expressed gene product. However, data on the composition of the different diets are not reported in the letter. Pusztai has released some of these details on the internet ( ). These details indicate that the content of starch, glucose polymers, lectin, and trypsin and chymotrypsin inhibitors in GM potatoes differed from that of the parental line. Unfortunately, these differences have not been examined further by analysis of an extended range of lines, for evidence on whether these differences are attributable to the genetic modification or to natural variations. Another shortcoming of the study is that the diets were protein deficient; they contained only 6% protein by weight. There is convincing evidence that short-term protein stress and starvation impair the growth rate, development, hepatic metabolism, and immune function of rats.1,2

Ewen and Pusztai say that the significant differences between diet groups in variables such as mucosal thickness or crypt length are evidence of the biological effects of the GM foods. Such a claim is easy to make but difficult to prove, because no consistent patterns of changes were observed in the study. Ingestion of potatoes may be associated with several adaptive changes in the gut because of the low digestibility of raw or partly refined potato starch. In rats caecal hypertrophy is a common response to short-term feeding of various poorly digestible carbohydrates, such as raw potato starch.3,4 A physiological response of this nature is probably of little toxicological significance. Dose-response studies would have helped in the assessment of consistency of response.

The experiments done by Ewen and Pusztai were incomplete, included too few animals per diet group,5 and lacked controls such as a standard rodent diet containing about 15% protein (lactalbumin) as a balanced source of aminoacids6 and a test diet with potatoes containing an "empty" vector. Therefore the results are difficult to interpret and do not allow the conclusion that the genetic modification of potatoes accounts for adverse effects in animals. Similar criticisms of this work have been made by the Royal Society ( st_pol54.htm ).

In the second Research Letter, Brian Fenton and colleagues provide data that indicate strong binding of GNA to human white blood cells in vitro. Binding per se of a lectin does not automatically imply cell activation. Nevertheless, such findings emphasise the need for further studies. Attention should not be confined to the gastro-intestinal tract, but should also be paid to the bioavailability of these compounds and their potential toxic effects once they have entered the systemic circulation. Such investigations will be of paramount importance for future generations of GM foods (see below). An extensive toxicological study of this type has been done with a GM tomato containing an insecticidal protein derived from Bacillus thuringiensis.7

What about the adequacy of existing test methods and strategies for the assessment of the safety of GM foods? Internationally agreed strategies for the evaluation of the safety of transgenic food crops with improved agronomic properties have been drawn up. The assessments have consisted of the characterisation of the new gene products, identification of alterations in concentrations of nutrients and known toxicants, and evaluation of the potential allergenicity of the gene product and of the implications of gene transfer between plants and the gut microflora of animals or human beings.8 The first approach to safety assessment is a comparative one--ie, a new food is compared with a conventional product that long-term experience has shown to be safe (concept of substantial equivalence).9 The data so far indicate that GM crops with agronomic advantages that have been introduced into the environment do not differ from the traditionally grown crops except for the inserted traits.

Safety testing will have to be adjusted for the "second generation" of food plants, which are modified to improve food-quality traits--eg, to raise the nutritional value of the proteins, to increase concentrations of oils low in saturated fats or of novel carbohydrates, or to fortify the foods with micronutrients or antioxidants. These must undergo extensive toxicological and nutritional assessment with a combination of in-vitro and in-vivo techniques as required for novel foods in general.10

Particular attention must be given to the detection and characterisation of unintended effects of genetic modifi-cation. Inferences about such effects can no longer be based solely on chemical analysis of single macronutrients and micronutrients and known crop-specific antinutrients or toxins. New methods have been developed to screen for potential alterations in the metabolism of the modified organism by analysis of gene expression (monitored by microarray technology, mRNA fingerprinting), by overall protein analysis (proteomics), and by secondary metabolite profiling.11,12 Depending on the outcome of these studies, further toxicological and nutritional studies may be needed.

In summary, methods to assess the safety of GM foods that are already on the market are adequate, but the future generation of such foods will need a wider range of tests covering both toxicological and nutritional endpoints. The studies must be designed carefully because of the complexity of foods.13 This complexity means that the adoption, as recently proposed,14 of an approach used for pesticides and food additives--the establishment of an "acceptable daily intake"--is inappropriate. Results of studies into GM foods should be interpreted with caution and presented to the scientific community in sufficient detail.

RIKILT (National Institute for Quality Control of Agricultural Products), Wageningen University and Research Centre, Wageningen, NL-6700 AE, Netherlands

1 Konno A, Utsuyama M, Kurashima C, Kasai M, Kimura S, Hirokawa K. Effects of a protein-free diet or food restriction on the immune system of Wistar and Buffalo rats at different ages. Mech Ageing Dev 1993; 72: 183-97.

2 Le Moullac B, Gouache P, Bleiberg DF. Regulation of hepatic transthyretin messenger RNA levels during moderate protein and food restriction in rats. J Nutr 1992; 122: 864-70.

3 Walker R. Some observations on the phenomenon of caecal enlargement in the rat. In: Gali CL, Paoletti R, Vettorazzi G, eds. Chemical toxicology of food, vol 3. Amsterdam: Elsevier/North-Holland Biomedical Press, 1978: 339-48.

4 Lopez HW, Coudray C, Bellanger J, Younes H, Demigne C, Remesy C. Intestinal fermentation lessens the inhibitory effects of phytic acid on mineral utilization in rats. J Nutr 1998; 128: 1192-98.

5 OECD guideline for testing of chemicals 407. Repeated dose oral toxicity--rodent 28-day or 14-day study, adopted May 12, 1981. Paris, OECD.

6 Committee on Animal Nutrition, Board on Agriculture, National Research Council.Nutrient requirements of laboratory animals, 4th edn. Washington: National Academy Press, 1995: 23.

7 Noteborn HPJM, Bienenmann-Ploum ME, van den Berg JHJ, et al. Safety assessment of the Bacillus thuringiensis insecticidal crystal protein CryIA(b) expressed in transgenic tomatoes. In: Engel K-H, Takeoka GR, Teranishi R, eds. Genetically modified foods: safety issues. ACS Symposium Series 605, Washington DC, 1995: 134-47, 1995.

8 FAO/WHO. Joint FAO/WHO Expert Consultation on Biotechnology and Food Safety, Rome, 1996.

9 OECD. Safety evaluation of foods derived by modern biotechnology: concepts and principles. Paris: OECD, 1993.

10 Regulation (EC) no 258197 of the European Parliament and the council. Official J European Communities 1997 no L43, 1-7.

11 Van Hal NLW, Vorst O, Van Houwelingen AMML et al. The application of DNA micro-arrays in gene expression analysis. J Biotechnol (in press).

12 Noteborn HPJM, Lommen A, Van der Jagt RC, Weseman JM, Kuiper HA. Chemical fingerprinting for the evaluation of unintended secondary metabolic changes in transgenic food crops. J Biotechnol (in press).

13 OECD. Food safety evaluation. Paris: OECD, 1996.

14 Millstone E, Brunner E, Mayer S. Beyond "substantial equivalence". Nature 1999; 401: 525-26.

Lancet - Saturday 3 July 1999

Health Risks of Genetically Modified Foods

Peter Lachmann  

Sir--It is profoundly depressing to follow the public debate on genetically modified (GM) crops. As the passion of the arguments increase, their scientific content diminishes correspondingly. It is a sad day for UK medicine when first the BMA and then The Lancet, in your May 29 editorial ,1 align themselves with the tabloid press in opposition to the Royal Society and the Nuffield Council on Bioethics. It is also disturbing and unusual for an editorial in The Lancet to be factually so inaccurate.

I imagine the first paragraph refers to maize made resistant to stem boring insects. This crop is not sterile and there is no difficulty in planting the GM seeds. The "Gene Use Restriction Technology", called the "terminator gene" by the press is so far merely a patent claim and has not yet been produced. This device to prevent the formation of fertile seed from a GM crop, would also prevent the spread of the inserted gene to other plants. Surprisingly, this idea has found no favour with the opponents of GM organisms who concentrate entirely on the rights of the farmer to save seed.

Farmers currently have to use new seed with the conventionally bred F1-hybrid crops that are increasingly used worldwide, because F1-hybrid seeds do not produce F1 progeny. Their yield is so much higher that, in many cropping systems, F1-hybrids are highly advantageous.

There is no experimental evidence nor any plausible mechanism by which the process of genetic modification can make plants hazardous to human beings. Individual introduced genes may not be a great idea. For example, the use of a nut protein to enhance the protein content of a cereal may be a hazard to people who are allergic to nuts, but this danger would be the same if the nut protein were simply added to the cereal. The practice of leaving antibiotic-resistant markers in the GM plant has attracted criticism from the Royal Society among others since there is a hypothetical risk that antibiotic resistance could spread to gut flora.

The Scottish Crop Research Institute initiated an entirely sensible study to see whether lectins which make some plants unpalatable to insects could be intro-duced into other plants for the same purpose. The study used potatoes only to make the experimentation easier. These particular potatoes were never intended to be developed as a food crop. Some assessment of the transgenic pota-toes was made at the Rowett Institute. One of their scientists announced on television last autumn that feeding these transgenic potatoes to rats had caused abnormalities of organ growth and had damaged their immune systems. These remarks were seized upon by the tabloid press and engendered an hysterical reaction that has not died down. The Royal Society produced a careful peer review of all the avilable data on this work and concluded that the experi-ments were badly designed, poorly carried out, and inaccurately inter-preted. Your editorial 's comment that it is impertinent of the Royal Society to review the data because they may not be in their final form is incomprehensible. A scientist invites expert scrutiny by making his work public through the media and the worldwide web.

One reason for welcoming GM technology is that intensive agriculture, on which the world's food supply now depends, is in the long term both unsustainable and potentially harmful. It is unsustainable because it relies on the consumption of fossil fuels and consumes more energy than the food produces. The high levels of nitrogen and phosphate fertilisers used are a potential hazard to human health when these ions appear in the water supply. There are also potential concerns about the residues of pesticides and herbicides. Any technology that may enable better yields to be obtained with less external input should be welcomed.

It is also an illusion that there ever was a time when the food supply was entirely safe. All those who, in previous centuries, died of ergot poisoning and those who still develop liver disease from aflatoxin in their food are forgotten, especially by the enthusiasts for organic farming. Bacterial food poisoning always was a serious problem.

It is wrong to regard the introduction of resistance to insects or herbicides as the only long-term goals of genetic manipulation. This is the "horse-less carriage" stage of development of this new technology. Looking rather further into the future, other goals include developing plants that can grow in saline-polluted soil, a major issue in some parts of the world. Similarly, it may be possible to develop plants that need less water input. Finally, there is the pros-pect of developing plants with an in-creased efficiency of the photosynthetic process itself. If this efficiency could be increased several fold agriculture would be able to meet not just the food but also the energy needs of the world.

The attempt of single interest groups, supported by the tabloid press and now by others who should know better, to declare this whole technology as dangerous and immoral is sad for the UK, but is also absurd. 300 million Americans and a billion Chinese eat genetically modified food with neither ill effects nor hysteria. On the world scale, what happens in the UK may not be of overwhelming importance. However, what this campaign of vilification does to the science base and the prosperity of the UK may be serious.

The Academy of Medical Sciences, London SW1Y 5AH, UK

1 Editorial. Health risks of genetically modified foods. Lancet 1999; 353: 1811.

Lancet - Saturday 3 July 1999

Health Risks of Genetically Modified Foods

Alan D B Malcom   

Sir--Your editorial 1 on genetically modified (GM) crops would never have passed the rigorous refereeing which you normally use for the contents of the rest of your journal. Of course the motive behind the commercial production of anything is added shareholder value. No farmer is compelled to buy any seed from any company. They can always continue to use traditional crops if they feel it is to their benefit. Farmers are just as driven by the profit motive as anybody else, whether in developing countries or not. There are many parts of India where cotton farmers have gone bankrupt through insect depredation, whereas North American cotton growers are now able to guarantee increased yields of cotton accompanied by a 70% reduction of chemical-based insecticides.

Although antibiotic-resistance markers are used for some plant biotechnology products to "select" for the presence of a desired trait, the antibiotic markers in these products were selected on the basis of their frequent occurrence in nature, their efficacy as a marker, and the limited clinical importance of the antibiotics which they inactivate. The potential effect on human health of these markers is carefully evaluated during the safety assessment regulatory review process in the UK and other countries. Further, it is recognised that the increased frequency of bacterial resistance to antibiotics is mainly attributable to the widespread use and misuse of antibiotics in human and veterinary applications, not to genetically modified crops. Experts and regulatory bodies that have assessed the probability that antibiotic markers used in genetically modified plants will impact antibiotic efficacy have concluded that this likelihood is remote. Nonetheless, alternative markers should be and are being developed for use in future genetically modified crops.

It is unusual for the Royal Society to take a judgment on an independent scientist's unpublished data. Unfortunately, it was clear that the mythology surrounding these experiments was having a major impact on public perception of this technology. Although the data were not refereed by the usual channels, they had been made available to the world via the internet. It was therefore perfectly appropriate that any scientist or group of scientists should comment on the false conclusions being drawn.

The British Medical Association did not need to recommend a moratorium on the commercial planting of GM crops. Such a moratorium already exists. No permission for commercial planting has been given nor will it be given until ACRE is satisfied on the various issues which have been widely discussed.

Of course the Government should take an interest in any possible health risks associated with any new food and indeed this is exactly the role which the Advisory Committee on Novel Foods and Processes takes. Nobody, however, has been able to identify any potential health risk associated with consumption of lecithin, or soya oil, or soya starch obtained from a GM crop, compared with traditional crop. In the absence of any hypothesis, the design of a sensible experiment is impossible.

It is not true that the population of the USA had been eating genetically modified ingredients. The ingredients they have been eating have not been modified in any way whatsoever. It is the crops from which the ingredients were derived that have been modified. There has not been one example of any identifiable medical condition induced in the 250000000 Americans who have consumed such material during the past 3 years.

Alan D B Malcom

Institute of Biology, 20 Queensberry Place, London SW7 2DZ, UK

1 Editorial. Health risks of genetically modified foods. Lancet 1999; 353: 1811.

Lancet - Saturday 3 July 1999

Health Risks of Genetically Modified Foods

Carl B Feldbaum    

Sir--Your May 29 editorial 1 misleads readers by saying biotechnology companies and government officials "have paid little evident attention to the potential hazards to health of genetically modified foods". You ignore thousands of scientific studies, environmental risk assessments, and the field trials undertaken worldwide before the com-mercial introduction of transgenic crops.

Before the approval of the first transgenic Bacillus thuringiensis (BT) corn in the USA, the Department of Agriculture (USDA) conducted an environmental assessment in 1995 that analysed data on risks to insects beneficial to agriculture and other non-target insects as risks to endangered organisms--from bobwhite quail to certain species of butterflies. Tests to find out if endangered aquatic organisms were threatened examined the impact of BT corn pollen blown into water. The USDA concluded the data showed no significant potential to adversely affect organisms other than the targeted pest that destroys corn.

Scientific inquiry, however, has not ended there. Researchers continued to examine transgenic corn, such as scientists who explored the impact on beetles, flower bugs, and lacewings, all of which feed on corn borers. These predators also eat corn pollen. In a paper published in April 1997, the researchers reported they found no detrimental effects on the beneficial insects. In fact, they observed more of them in BT corn fields than in non-BT corn fields.2

As for the safety of transgenic corn and other biotech crops in food, the US Food and Drug Administration (FDA) undertook its own exhaustive studies and concluded in 1992 and again in 1995, "It is not aware of information that would distinguish genetically engineered foods as a class from foods developed through other methods of plant breeding".3 The fact is, the FDA observed, because recombinant DNA techniques are used to introduce only one or a few genes into a crop, agricultural scientists avoid a major difficulty of conventional cross hybridisation, which is the multiple introduction of undesirable genes.

Results of all studies by the USDA, FDA, and the Environmental Protection Agency--the three US agencies charged with monitoring biotech crops and foods--are produced with public input and available for perusal when completed.

A 1996 report from the Food and Agricultural Organisation of the United Nations and WHO also explored in depth the safety of foods derived from biotech crops. Those two groups concluded: "Food safety considerations regarding organisms produced by techniques that change the heritable traits of an organism, such as recom-binant DNA technology, are basically of the same nature as those that might arise from other ways of altering the genome of an organism, such as conventional breeding."4 The report also noted, "The presence in foods of new and introduced genes per se was not considered to present a unique food safety risk."

It is one thing for The Lancet to urge caution in introducing genetically modified foods. Everyone agrees continued vigilance is necessary. It is an egregious error, however, for you to imply potential health hazards have been overlooked by industry and regulatory agencies. In doing so, it dismisses decades of dedicated scientific work that clearly proves otherwise.

Biotechnology Industry Organization, Washington, DC 20006, USA

1 Editorial. Health risks of genetically modified foods. Lancet 1999; 353: 1811.

2 Pilcher CD, Obrycki JJ, Rice ME, Lewis LC. Preimaginal development, survival, and field abundance on insect predators on transgenic Bacillus thuringiensis corn. Environmental Entomology April 1997; Vol. 26, no 2, 446-54.

3 FDA's policy for foods developed by biotechnology contained in the proceedings of the American Chemical Society Symposium, series no. 605, 1995, by Maryanski JH, Strategic Manager for Biotechnology. Centre for Food Safety and Applied Nutrition, FDA.

4 Biotechnology and food safety, report of a joint consultation of the food and agricultural organisation of the United Nations and WHO, Rome, Italy, 30 September to 4 October 1996.

Lancet - Saturday 3 July 1999

Health Risks of Genetically Modified Foods

H Schellekens

Sir--As chairman of the Dutch Committee on Genetic Modification (COGEM), the main adviser to the government in our country on the safety of genetic modifications, I and others stand accused in your editorial of May 29 1 of badly mishandling important health issues.

The safety of genetic modification is a serious topic and the quality of the decision-making process can only improve by the input from as many sources a possible. However, these contributions should be based on the data collected by the cautious step-by-step approach during the 20 years of genetic modification. Although uncer-tainties remain, there is no reason to ignore the information that is available. Your editorial fails to make a continuing argument against the opinion of the US Food and Drug Administration that genetic modification does not constitute a risk in itself.

Phenotypic characteristics such as the presence of an antibiotic resistance in plants may be considered harmful, but you ignore the reports and other scientific evidence on this topic. It would for example, be interesting to know your reaction to the criteria used by the Dutch COGEM to assess the risks of antibiotic resistance gene in crops. Our approach is based on the assumption that antibiotic resistance may spread from plants to microorganisms.

You also fall short of supporting the moratorium on introduction of genetically modified crops, as advocated by the British Medical Association and other organisations. In my opinion there is at present no rationale for a moratorium. Those who argue in its favour have to formulate the specific reasons why and what they want to achieve. They have to quantify the current risks and to what extent these risks have to be reduced to be acceptable and to terminate the moratorium.

Learned societies and journals, mainly in the UK, seem to have lower scientific standards with regard to the genetic modification of plants than other topics. If the assumption is correct that the reasons for this unbalanced approach lie outside science, there is more at stake than the future of genetic modification of plants.

Dutch Committee on Genetic Modification, 2912 BH Nieuwerk, Netherlands

1 Editorial. Health risks of genetically modified foods. Lancet 1999; 353: 1811.

Lancet - Saturday 3 July 1999

Health Risks of Genetically Modified Foods

Eric Brunner, Erik Millstone

Sir--Peter Mitchell and Jane Bradbury's May 22 news item (p 1769)1 reports the Royal Society's judgment that Arpad Puztai's study on the potential toxic effects of genetically modified (GM) potatoes is "flawed in many aspects of design, execution and analysis and that no conclusions should be drawn from it". The society rightly says that research scientists should expose their new results to peer review before releasing them.

The episode at the Rowett Research Institute highlights just how important the integrity of the peer-review process is to the maintenance of high standards in science. Our experience1 with trial data on recombinant bovine somatotropin (rBST, an injectable hormone which raises milk yield in dairy cows) suggests that increased vigilance, perhaps through some mechanism of formal audit, may be needed to preserve such standards.

In that case, official regulatory authorities accepted the manufacturer's unpublished analysis. We previously identified the shortcomings in this analysis, and did our own, but we were unable to publish it because the company concerned withheld consent. Here the peer-review process was compromised, partly by the pressures on the existing regulatory process and partly by the requirement for commercial scientists to deliver the product to market. In general, if preapproval studies are not published, any questionable conclusions may go unchallenged. Put another way, if applicants are able to argue successfully that disclosure would cause commercial harm, then peer scrutiny may be restricted.

A process that bears the hallmarks of these difficulties led to the approval of rBST for farm use by the US Food and Drug Administration in 1994. rBST is unlicensed in Canada and the European Union. The company seeking to market this productivity aid gave us data from eight randomised controlled trials. We did a meta-analysis and found evidence for a pro-mastitic effect due to rBST. The report was sent to the company and to a UK peer-review journal. Although our report passed the peer review, the company refused permission for its publication on the basis that the trial investigators would soon submit their own analysis for publication. In the following 3 years, no such report appeared. We resubmitted our paper to a US journal and then to another UK journal. On each occasion the paper received peer approval but could not be published because the company alleged they had copyright over our analysis of their data. We were eventually able to publish our findings as a response to a public accusation of plagiarism by a company representative, but only after FDA approval for rBST had been given.

There is no method of recourse in such situations. We therefore support the recent recommendation contained in the first report of the Commons Select Committee on Science and Technology2 for further openness in the regulatory process in the UK and elsewhere for new foods, with the rapid publication of papers and data (http://www.publications.parliament. cm199899/cmselect/cmsctech/286/ 28602.htm; accessed June 10, 1999).2 This approach would substantially strengthen the peer-review process.

*Department of Epidemiology and Public Health, University College London Medical School, London WC1E 6BT, UK; and Science Policy Research Unit, Sussex University, Brighton

1 Millstone EP, Brunner EJ, White IR. Plagiarism or protecting public health. Nature 1994; 371: 647-48.

Lancet - 29 May 1999

Health risks of genetically modified foods


Crops genetically modified to have reduced susceptibility to pests are promoted as a solution to low food yields in developing countries. The motive of these promoters is profit, not altruism. Monsanto, one of the largest developers of genetically modified crops, has developed a grain that gives an improved crop and is sterile, so instead of keeping back some seeds for the next year's sowing, farmers must return to the supplier for more.

In view of this unbridled commercial approach to genetic modification, it is perhaps not surprising that companies have paid little evident attention to the potential hazards to health of genetically modified foods. But it is astounding that the US Food and Drug Administration has not changed their stance on genetically modified food adopted in 1992 ( ). They announced in January this year, "FDA has not found it necessary to conduct comprehensive scientific reviews of foods derived from bioengineered plants . . . consistent with its 1992 policy". The policy is that genetically modified crops will receive the same consideration for potential health risks as any other new crop plant. This stance is taken despite good reasons to believe that specific risks may exist.

For instance, antibiotic-resistance genes are used in some genetically modified plants as a marker of genetic transformation. Despite repeated assurances that the resistance genes cannot spread from the plant, many commentators believe this could happen. Of greater concern is the effect of the genetic modification itself on the food. Potatoes have been engineered with a gene from the snowdrop to produce an agglutinin which may reduce susceptibility to insects. In April last year, a scientist, Arpad Pusztai, from the Rowett Research Institute in Aberdeen, UK, unwisely announced on television that experiments had shown intestinal changes in rats caused by eating genetically engineered potatoes. He said he would not eat such modified foods himself and that it was "very, very unfair to use our fellow citizens as guineapigs".

A storm of publicity overtook Pusztai. He was removed from his job, a sacrifice that did not quell public alarm in the UK or in Europe. Last week (May 22, p1769 ) we reported that the Royal Society had reviewed what it could of Pusztai and colleagues' evidence and found it flawed, a gesture of breathtaking impertinence to the Rowett Institute scientists who should be judged only on the full and final publication of their work. The British Medical Association called for a moratorium on planting genetically modified crops. The UK Government, in accordance with national tradition, vacillated. Finally, on May 21 the Government came out with proposals for research into possible health risks of genetically modified foods.

Shoppers across Europe had already voted with their feet. By the end of the first week in May, seven European supermarket chains had announced they would not sell genetically modified foods. Three large food multinationals, Unilever, Nestlé, and Cadburys-Schweppes followed suit. The Supreme Court in India has upheld a ban on testing genetically modified crops. Activists in India have set fire to fields of crops suspected of being used for testing. The population of the USA, where up to 60% of processed foods have genetically modified ingredients, seem, as yet, unconcerned.

The issue of genetically modified foods has been badly mishandled by everyone involved. Governments should never have allowed these products into the food chain without insisting on rigorous testing for effects on health. The companies should have paid greater attention to the possible risks to health and of the public's perception of this risk; they are now paying the price of this neglect. And scientists involved in research into the risks of genetically modified foods should have published the results in the scientific press, not through the popular media; their colleagues, meanwhile, should also have avoided passing judgments on the issue without the full facts before them.