FORUM: Science & Society

A golden opportunity, squanderedHenry I. Miller

Hoover Institution, Stanford University, Stanford, CA 94305-6010, USA

Update

Even when used to make products of negligible risk andthat contribute significantly to public health, recombinantDNA technology (a.k.a. ‘genetic modification’, or GM)applied to agriculture has a tough row to hoe. ‘GoldenRice’, which has been enriched by the addition of genesthat allow rice to synthesize b-carotene (the precursor ofvitamin A) in its edible endosperm, has endured resistancefrom activists and a decade of imposing and gratuitousobstacles to regulatory approval. This is an ominous pre-cedent for other ‘biofortified’ foods made with recombinantDNA technology.

The announcement in November 2008 by a group ofmulti-national European scientists that they had producedan extraordinary new, recombinant DNA-modified tomatovariety garnered a great deal of media attention world-wide. This variety, which contains two snapdragon tran-scription factors, boasts deep purple skin and flesh andcontains levels of antioxidants threefold greater than itsunmodified parent. Most important, when fed to highlycancer-susceptible mice, the tomatoes significantlyextended the life span of the animals [1].

These tomatoes are a so-called functional food, one for-tified or enhanced with something that confers healthbenefits. This is not a new idea: for more than 80 years,iodine has been added to table salt to prevent hypothyroid-ism and goiter (see http://www.iccidd.org/pages/protecting-children/fortifying-salt/history-of-salt-iodization.php).Newer functional foods, including eggswith enhanced levelsof omega-3 fatty acids to reduce the incidence of heartdisease and probiotic yogurt with extra bacteria to aiddigestion, are becoming more common.

The announcement of the enhanced-antioxidant tomatoreceived wide attention from the press and scientific com-munity, but an equally momentous achievement of plantgenetic modification that is almost a decade old has beenlargely ignored. That innovation is ‘Golden Rice’, a collec-tion of new rice varieties biofortified, or enriched, by theintroduction of genes that enable the edible endosperm ofrice to produce b-carotene, the precursor of vitamin A (seehttp://www.goldenrice.org). (It is converted in the humanbody, as needed, to the active form.)

Why are these new varieties so important? After all,most physicians in North America and Europe never see asingle case of vitamin A deficiency in their professionallifetimes. The situation is very different in many develop-ing countries, however. Vitamin A deficiency is epidemicamong poor people whose diet is comprised largely of rice(which contains neither b-carotene nor vitamin A) or othercarbohydrate-rich, vitamin-poor sources of calories.

Corresponding author: Miller, H.I. (miller@hoover.stanford.edu).

0167-7799/$ – see front matter � 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2008.11.004 Available online 29 January 2009 1

In developing countries, 200–300 million children ofpreschool age are at risk of vitaminAdeficiency, which canbedevastating and even fatal. It increases susceptibility tocommon childhood infections such as measles and diar-rheal diseases and is the single most important causeof childhood blindness in developing countries. Everyyear, �500 000 children become blind as a result of vita-min A deficiency and 70% die within a year of losing theirsight (see http://www.cdc.gov/nccdphp/dnpa/immpact/micronutrient_facts.htm).

Why not simply supplement children’s diets with vita-minA in capsules or add it to some staple foodstuff, thewaythat we add iodine to table salt? It’s a good idea in theory,except that neither the resources – hundreds of millions ofdollars annually – nor the infrastructure for distributionare available.

Recombinant DNA technology offers a cheaper and morefeasible solution: Golden Rice, which, after the insertion oftwo genes coding for phytoene synthase (psy) and phytoenedesaturase (crt I), is able to accumulate b-carotene in theendosperm, the edible portion of the genetically alteredrice grains (see http://www.goldenrice.org/Content2-How/how1_sci.html). The concept is simple: although rice plantsdo not normally synthesize b-carotene in the endospermbecause of the absence of two necessary enzymes of thebiosynthetic pathway, they domake it in the green portionsof theplant.Byusing recombinantDNAtechniques to insertthe two genes that express these enzymes, the pathwaybecomes functional and the rice grains accumulate thera-peutic amounts of b-carotene. Golden Rice and theenhanced-antioxidant tomatoes are examples of what hasbeen called the ‘second generation’ of plants developed withrecombinant DNA technology – those that provide consu-mer-directed benefits, as opposed to plants that offer onlyimprovements in agronomic properties.

GoldenRice offers the potential tomake contributions tohuman health and welfare as historic as those made by thediscovery and distribution of the Salk polio vaccine. Withwide use, it could save hundreds of thousands of lives ayear and enhance the quality of life for millions more. Butone aspect of this shining story is tarnished. Intransigentopposition by anti-science, anti-technology activists –

Greenpeace, Friends of the Earth and a few other radicalgroups – has provided already risk-averse regulatorspolitical ‘cover’ to adopt an overly precautionary approachthat has stalled approvals.

There is absolutely nothing about Golden Rice thatshould require endless case-by-case reviews and bureau-cratic dithering. As the journal Nature editorialized in1992, a broad scientific consensus holds that ‘the samephysical and biological laws govern the response of organ-

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Update Trends in Biotechnology Vol.27 No.3

isms modified by modern molecular and cellular methodsand those produced by classical methods. . . . [Therefore] noconceptual distinction exists between genetic modificationof plants and microorganisms by classical methods or bymolecular techniques that modify DNA and transfergenes.’ [2]

Putting it another way, government regulation of fieldresearch with plants should focus on the traits inherent inthe host plant and in the introduced genes that might berelated to risk-invasiveness, weediness, toxicity and soforth – rather than on whether one or another techniqueof genetic manipulation was used.

In spite of its vast potential to benefit humanity – andnegligible likelihood of harm to human health or theenvironment – a decade after its creation Golden Riceremains hung up in regulatory red tape with no end insight (see http://www.goldenrice.org/Content2-How/how4_regul.html). Lactoferrin and lysozyme produced in recom-binant DNA-modified rice by ‘biopharming’ (which isoften cited as the ‘third generation’ of recombinant DNA-modified plants) and used to treat children with diarrheahas endured similar regulatory delays (see http://www.washingtontimes.com/news/2004/jul/05/20040705-095035-5659r/).

If Golden Rice had been created with conventionaltechniques of genetic improvement (which is not possiblefor technical reasons), it would have required 2–3 years tobreed relevant local varieties and to produce seed fordistribution. Because all plants produce high amounts ofcarotenoids, their presence in rice will not introduce anynew substances into the environment or provide anyadditional selective advantage in the field. b-carotene isalready present in the food supply and is, in (U.S.) regu-latory terms, ‘Generally Recognized As Safe’, or GRAS (seehttp://www.cfsan.fda.gov/�dms/gras-ov.html); as such, itwould not require a pre-market governmental review.Cancer-preventing tomatoes, take notice.

In contrast to plants modified with recombinant DNAtechnology, those constructed with less precise techniques,such as hybridization or mutagenesis, generally are sub-ject to no government scrutiny or requirements (or opposi-tion from activists) at all. That absence of scrutiny applieseven to the numerous new plant varieties that haveresulted from ‘wide crosses’, hybridizations that movegenes from one species or genus to another across whatused to be thought of as natural breeding boundaries. (Onearguable exception is Canada, where regulations are, intheory, triggered by whether a trait in a given species is‘novel’, but the reality is that recombinant DNA-modifiedorganisms there are subjected to a far higher standardthan those crafted with conventional technologies.) Itshould be noted that the commonly cultivated and con-sumed varieties of rice – all of which have been developedwith conventional techniques – are the product of widecrosses [3] and, therefore, are ‘transgenic’ by any reason-

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able scientific definition. However, these constructions areless precisely crafted, less well characterized and lesspredictable than recombinant DNA constructions. Thus,we have a situation in which for more than two decades thedegree of regulatory scrutiny (and therefore, the time andexpense required for the development of new varieties) hasbeen inversely proportional to the perceived degree of risk.This is absurd.

Regulators and activists are not the only villains of thepiece. Themedia – and even scientific journals (see Ref. [4])– have been undiscriminating and overly tolerant of themisrepresentations and distortions of anti-biotechnologyactivists, and politicians have opposed recombinant DNAtechnology for reasons of trade protectionism.

Judith Rodin, the President of the Rockefeller Founda-tion, announced in October 2008 that her organization willprovide funding to the International Rice Research Insti-tute to shepherd Golden Rice through national regulatoryapproval processes in Bangladesh, India, Indonesia andthe Philippines (see http://www.rockfound.org/about_us/speeches/101708food_prize.shtml). Although this is pre-sumptive good news, what is really needed is a multi-faceted, aggressive effort to reform regulation so thatnew genetic constructions will be able to succeed even ifthey do not enjoy the patronage of a powerful benefactor.Employing a laboratory metaphor, the regulatory travailsof Golden Rice are analogous to a positive control in thelaboratory that doesn’t work: in other words, if we cannotmove this product expeditiously through the regulatorylabyrinths and into the rice-cookers of the developingworld, then the application of recombinant DNA technol-ogy to biofortified foods is truly ‘cooked’.

In an April 2008 editorial in the journal Science, NinaFedoroff, an eminent plant geneticist at PennsylvaniaState University who is currently serving as senior scien-tific advisor to the U.S. Secretary of State, wrote: ‘A newGreen Revolution demands a global commitment to creat-ing a modern agricultural infrastructure everywhere, ad-equate investment in training and modern laboratoryfacilities, and progress toward simplified regulatoryapproaches that are responsive to accumulating evidenceof safety. Do we have the will and the wisdom to make ithappen?’ [5]

The Golden Rice story makes it clear that the answer is,not yet.

References1 Butelli, E. et al. (2008) Enrichment of tomato fruit with health-

promoting anthocyanins by expression of select transcription factors.Nat. Biotechnol. 26, 1301–1308

2 Anonymous (1992) U.S. biotechnology policy. Nature 356, 1–23 Goodman, R.M. et al. (1987) Gene transfer in crop improvement. Science

236, 48–544 Miller, H.I. et al. (2008) Is biotechnology a victim of anti-science bias in

scientific journals? Trends Biotechnol. 26, 122–1255 Fedoroff, N. (2008) Seeds of a perfect storm. Science 320, 425