Phase II clinical trials on children have been conducted with unapproved
experimental GM rice enhanced in pro-Vitamin A that has the potential to cause
birth defects and developmental abnormalities Dr. Mae-Wan Ho
and Prof. Joe Cummins
This report has been sent to the United States Food and Drug Administration
on behalf of ISIS
Announcing a new Report from ISIS. The most complete up-to-date summary of the dangers of GM agriculture in 52 pages. Buy Now, or download here
Clinical trials of unapproved, uncharacterized GM rice on children
More than 30 senior scientists and academics signed an open letter condemning
researchers at Tufts University (Boston) in the United States for carrying
out clinical trials of genetically modified (GM) ‘Golden Rice’ on children
 (Scientists Protest Unethical Clinical
Trials of GM Golden Rice). The scientists claimed that the trials were
in breach of the Nuremberg Code of Ethics brought in at the end of the Second
World War to prevent any repetition of the experiments conducted by Nazi scientists
including many on children.
The ‘Golden Rice’ in the trials (GR2) appears to be an experimental
collection of transgenic events still in the laboratory, uncharacterised
in terms of basic molecular genetics or biological and biochemical properties,
not tested pre-clinically on animals, or subjected to any other safety assessment.
Of the three studies listed on the US Clinical Trials website,
two involved children. The first, “Retinol Equivalence of Plant Carotenoids
in Children”  - a phase II trial to compare the vitamin A value of b-carotene
in oil capsule, spinach and Golden Rice - recruited 72 children 7 to 9 years
of age, and the start and finish dates were September 2004 and November 2005
respectively. The second study, with the same title and also a phase II trial
, recruited 72 children 6 to 8 years of age and registered start and finish
dates July 2008 and January 2009 respectively. No results are available for
either of the studies (as of 17 March 2009).
The third study , “Bioavailability of Golden Rice Carotenoids
in Humans”, listed as “ongoing, but not recruiting participants”, was a phase
I trial on 6 adults 40 to 70 years of age. The start date was August 2004,
and estimated completion date August 2008. Again, no results are available;
though an article in Science (25 April 2008)  mentioned “a recent,
soon-to-be-published study among healthy volunteers who ate cooked golden
rice, led by Robert Russell of Tufts University in Boston.”
All the studies were done in the United States, though it appears
that trials were also carried out and/or intended elsewhere.
The Golden Rice Project website  (accessed 17 March 2009),
stated that “Golden Rice has gone through many tests since it was first obtained”
Nine items are listed; but no feeding trial on animals among them. The final
two items are:
“8. Tests for beta-carotene bioavailability and bioconversion to retinol….with
deuterium-labelled Golden Rice fed to adults in USA and a small group
of children in China have been conducted. The former were highly successful
and the latter are being evaluated at present.
9. Feeding trials with human adults in China were carried out to measure
the effect of fat in the diet, on bioconversion and bioavailability.”
An Indian newspaper reported  that a clinical trial was cut
short in China in July 2008, when the government found that 24 children 6-8
years of age at a primary school in Henyan, Hunan, were to be used as guinea
pigs for a trial with Golden Rice. The trial was sponsored by Tufts University
and obtained approval from the US National Institute of Health, though not
from the Chinese government, which was alerted by Greenpeace. Greenpeace has
also warned the governments of Bangladesh, India, Indonesia, Philippines and
Vietnam against the risky trials. But at least three state-owned labs in India
are conducting research into Golden Rice: the Indian Agricultural Research
Institute in New Delhi, Tamil Nadu Agricultural University, and Hyderabad-based
Directorate of Rice Research.
Although Golden Rice was created by Ingo Potrykus at the Institute
of Plant Sciences in the Swiss Federal Institute of Technology and Peter Beyer
at the University of Freiburg some ten years ago , it has remained in the
laboratory since. Speaking to Science journal in April 2008 , Potrykus
bitterly blamed “2 decades of fear-mongering by organizations such as Greenpeace”
that has created a regulatory climate so burdensome that only big companies
can afford to get any GM products approved. Closer to the truth may be that
the product was never ready for commercial approval.
According to a recent report , a sample of the Golden Rice
grains was sent to Germany in 2001 for a feeding trial with mice. But when
the grains were tested for carotenoid content, the scientists were “surprised
to find it contained less than one percent of the amount expected.” After
the rice was cooked, this was reduced by another 50 percent, so the trial
In 2005, Syngenta made GR2  using the maize version of the
enzyme phytoene synthase that was transferred from daffodil. GR2 produced
up to 23 times the amount of carotenoids in the original Golden Rice, GR1.
But GR2 was not a transgenic variety based on a single
transformation event. On the contrary, it was explicitly stated that :
“The reported transgenic rice events [emphasis added] are experimental.”
There is no telling whether all the children or adults taking part in any
of the trials were given Golden Rice from the same GR2 event. The results
of the trials, as yet unreleased, could well be utterly worthless.
Syngenta was donating these GR2 events, via the Humanitarian
Project for Golden Rice, for further research and development (to institutes
across China, India, Philippines, Indonesia, Bangladesh and Vietnam) “through
license under certain conditions”, which include “being governed by the strategic
direction of the Golden Rice Humanitarian Board” Requests were to be directed
to Adrian Dubock, a previous employee of Syngenta.
Dubock helped Potrykus and Beyer work out a deal in which Syngenta
could develop Golden Rice commercially, but farmers in developing countries
who make less than US$10 000 a year could get it for free . Dubock retired
from Syngenta in 2007, but remains a member of the Golden Rice Humanitarian
Board, chaired by Potykus.
Golden Rice, an exercise in how not to do science
Golden Rice, genetically modified to make pro-vitamin A in the endosperm
(the grain remaining after polishing), was announced with great fanfare in
2000 as a cure for widespread vitamin A deficiency in developing countries.
The project had already cost US$100 million, funded by the Rockefeller
Foundation, the Swiss Federal Institute of Technology, the European Community
Biotech Programme and the Swiss Federal Office for Education and Science,
and could cost as much again to develop. It was tied up in at least 70 patent
claims on genes, DNA sequences and constructs, a problem only partly solved
in the “ground-breaking deal” worked out by Dubock (see above)..
Condemnation was swift and widespread, not least because it was
absurd to offer Golden Rice as the cure for vitamin A deficiency when there
are plenty of alternative, infinitely cheaper sources of vitamin A or pro-Vitamin
A, such as green vegetables and unpolished coloured rice (especially black
and purple varieties , which would be rich in other essential vitamins
and minerals, and hence much more nutritious. The UN Food and Agricultural
Organization (FAO) started a project in 1985 to deal with vitamin A deficiency
using a combination of food fortification, food supplements and general improvements
in diets by encouraging people to grow and eat a variety of green leafy vegetables.
One main discovery from the project was that the absorption of pro-vitamin
A depends on the overall nutritional status, which in turn depends on the
diversity of the food consumed .
The main cause of hunger and malnutrition in the Third World
is the industrial monocultures of the Green Revolution, which obliterated
agricultural biodiversity and soil fertility, resulting in ever-worsening
mineral and micronutrient deficiencies in our food. Golden Rice, like other
GM crops, is industrial monoculture only worse, and will exacerbate this trend,
as well as the destruction of agricultural land, and the impoverishment of
family farmers that also accompanied the Green Revolution  (see Beware the New "Doubly
Green Revolution", SiS 37).
GR1 was made with the standard ‘first generation’ genetic modification
techniques, using GM constructs that cause uncontrollable mutations and other
collateral damage to the host plant genome, with many unintended, uncharacterized
effects . In addition, the viral and bacterial sequences, including antibiotic
resistance marker genes, in the construct and in the vectors created for gene
transfer enhance horizontal gene transfer and recombination, the main route
to creating new pathogens and spreading antibiotic resistance.
GR2 represents an improvement in so far as antibiotic resistance
markers were no longer used, but still includes a medley combination of sequences
from plant pathogens Agrobacterium (used in a binary vector system)
and Erwinia uredovor, and from E. coli, inhabitant of the human
gut, which also contains pathogenic strains. We have highlighted the special
hazards of the Agrobacterium vector system since 2003  (Agrobacterium &
Morgellons Disease, A GM Connection?, SiS 38) (see below).
The main reason for Golden Rice was revealed in the unusually
long news feature article  accompanying the scientific publication 
which stated: “One can only hope that this application of plant genetic engineering
to ameliorate human misery without regard to short-term profit will restore
this technology to political acceptability.”
A detailed audit on the project  (The 'Golden Rice', An Exercise in
How Not to Do Science, ISIS Report) uncovered “fundamental deficiencies”
from the scientific and social rationale to the science and technology involved.
It was being promoted “to salvage a morally as well as financially bankrupt
agricultural biotech industry.” The situation has changed little since.
The phase II clinical trials of uncharacterized, unapproved,
experimental GR2 events on children, some of whom may indeed be suffering
from vitamin A deficiency, is morally inexcusable. GR2 has not been assessed
for safety, and there are reasons to suspect it is unsafe.
GMO safety in question
The biotech industry has consistently found genetically modified food and
feed ‘as safe as their conventional counterparts’, and regulators in the United
States and European Union have accepted this assertion overwhelmingly based
on studies carried out and interpreted by the industry  (GM
Food Nightmare Unfolding in the Regulatory Sham, ISIS scientific publication).
There is now a string of evidence that exposure of many species
of animals to a variety of genetically modified crops, and food and feed derived
from them, can cause illnesses and death, raising the distinct possibility
that genetic modification is inherently dangerous  (GM is Dangerous and Futile,
SiS 40). This is reinforced in results obtained in the most recent
The Austrian government commissioned long term studies showing
that mice fed GM maize hybrid (NK603xMON810) with combined glyphosate tolerance
and biopesticide Cry1Ab produced fewer and smaller litters with many genes
affected compared to controls  (GM Maize Reduces
Fertility & Deregulates Genes in Mice, SiS 41). At the same
time, the Italian National Institute of Research published a study showing
that GM maize MON810 fed to mice produced disturbances in the immune system
of the young and the old  (GM Maize Disturbs
Immune System of Young and Old Mice, SiS 41). In India, the first
independent assessment of the feeding study submitted by Monsanto and its
subsidiary Mahyco to the Indian regulatory authorities showed that Bt Brinjal
(aubergine) caused many changes in several species of animals including diarrhoea,
increased water consumption and decrease in liver weight in rats  (Bt
Brinjal Unfit for Human Consumption, SiS 41).
One major hazard inherent to GM organisms (GMOs) is enhanced
horizontal gene transfer and recombination  (Horizontal Gene Transfer
from GMOs Does Happen, SiS 39). This is considerably worse with
transgenic plants like Golden Rice (both GR1 and GR2) that have been created
using the Agrobacterium binary vector system, basically because the
Agrobacterium bacteria as well as the binary vector tend to persist
in the transgenic plants, providing a ready vehicle for further horizontal
gene transfer to all species that interact with the transgenic plant material,
including human cells. Agrobacterium is known to invade human cells. Horizontal
transfer of transgenic DNA into human cells has the potential to cause harmful
mutations including cancer. In general, horizontal transfer of transgenic
DNA facilitates the creation of new pathogens. The identification of Agrobacterium
sequences in patients with Morgellons’ Disease raises questions as to whether
the widespread use of Agrobacterium vectors in genetic modification
has indeed resulted in creating a new pathogen for humans .
Golden Rice particularly dangerous
In addition, the unbalanced enhancement of single nutrients in GM crops may
do more harm than good  (GM Crops and Microbes for Health or
Public Health Hazards? SiS 32). As David Schubert at the Salk
Institute for Biological Sciences La Jolla, California, in the United States
points out , plants possess the ability to synthesize between 90 000 and
200 000 nonessential small molecules, with up to 500 in one species. The enormous
repertoire is due in part to enzymes with very low substrate specificity,
which are unpredictably altered by mutations and pleiotropic effects associated
with GM technology. Furthermore, overdose of many single nutrients are known
to be toxic, vitamin A being a case in point. Schubert highlights the toxic
effects of retinoic acid and other metabolites of b-carotene, only a few of them can be identified
and measured in the current state of technology.
Golden Rice is enhanced in b-carotene, which on ingestion, is cleaved in
half to generate retinal for use in the visual cycle. Retinal is also reduced
to retinol, or oxidized to retinoic acid (RA), which interacts with highly
specific nuclear receptors. Essentially all of the biological activity of
retinoids, apart from vision, involves RA. While high concentrations of retinol
are toxic, RA is biologically active at concentrations several orders of magnitude
lower than retinol. Hence, Schubert states : “excess RA or RA derivatives
are exceedingly dangerous, particularly to infants and during pregnancy.”
RA is required for the development of the nervous system, both by directly
controlling nerve differentiation and by generating concentration gradients
that direct cell migration, embryonic segmentation, and development. Therefore,
RA and synthetic derivative of RA are teratogenic (able to cause birth defects).
They can accumulate in fat and plasma, becoming a risk factor for pregnancy
for up to 2 years following ingestion, and multiple low doses of retinoids
have greater toxicity than a single high dose.
Because of the type of biological functions controlled by low
levels of RA, any perturbation of its signalling pathways by plant-derived
RA receptor agonists or antagonists will have clinical consequences. “Could
the GM modifications used to enhance b-carotene synthesis create such compounds?”
(This question remains unanswered to this day.) Six hundred naturally occurring
compounds exist in the carotene family, and at least 60 can be precursors
to retinoids. “Therefore, plants have the potential to make many potentially
harmful retinoid-like compounds when there are increased levels of synthetic
intermediates to b-carotene as in
While all retinoids and derivatives are likely to be teratogenic,
good assays and information regarding the behaviour and teralogic activity
are available for only three: retinol, RA, and retinal. Therefore, at the
very least, “extensive safety testing should be required before the introduction
of golden rice as a food.”
Ye X, Al-Babili S, Kloti A., Zhang J, Lucca P, Beyer P. and Potrykus I.
Engineering the provitamin A (b-carotene) biosynthetic pathway into (carotenoid-free)
rice endosperm. Science 2000, 287, 303-5.
Then C. A critical look at golden Rice after nearly 10 years of development.
C Commissioned by Foodwatch in Germany, January 2009.
Paine JA, Shipton CA, Chaggar S, Howells RM, Kennedy MJ, Vernon G, Wright
SY, hinchliffe E, Adams JL, Silverstone AL and Drake R. Improving the nutritioinal
value of Golden Rice through increased pro-vitamin A content. Nature biotechnology
2005, 21, 482-7.
Frei M and Becker K. Fatty acids and all-trans-b-carotene are correlated
in different colored rice landraces. J Sci Food Agri 2005, 85, 2380-4.
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