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[SANET-MG] GM safflower with human insulin
GM Safflower with Human Pro-Insulin
Regulators show cavalier disregard for the safety of threatened species
as well as human beings in proposed release of the GM pharm crop
Prof. Joe Cummins
This report has been submitted to the USDA on behalf of ISIS. Please
Proposed release of transgenic safflower shrouded in secrecy
USDA-APHIS conducted an Environmental Assessment (EA)  in response to
an application (06-363-103r), received from SemBioSys, Inc to field test
a transgenic safflower (Carthamus tinctorius) line 4438-5A that produces
human pro-insulin. The transgenic safflower was engineered to express an
oleosin-human pro-insulin protein exclusively in its seed. The field
site (<1 acre) is located on private property in Lincoln County, WA, and
will be surrounded on all sides by a 50 ft fallow strip. The exact
location of the site is withheld from the public; but the application
and risk assessment are open for public comment at
http://www.regulations.gov/fdmspublic/component/main until 23 July 2007.
Pro-insulin is the precursor to insulin, normally made in the beta cell
of the islets of Langerhans of the human pancreas. The protein is
synthesized in the endoplasmic reticulum (membrane stacks within the
cell), where it is folded and two sulphydryl (-SH) groups are oxidized
into a disulphide bond (-S-S-). It is then transported to the Golgi
apparatus (a special organelle) where it is packaged into secretory
vesicles, and processed by a series of proteases into mature insulin.
Mature insulin has 39 less amino acids; 4 are removed altogether, and
the remaining 35 amino acids - the C-peptide - are cut out from the
middle of the pro-insulin molecule; the two ends segments - the B chain
and A chain - remain connected by the disulphide bond formed earlier [2, 3].
A patent application  describes the genetic modifications for high
expression of human insulin in plants, including shortening the
C-peptide by four amino acids. The APHIS report  notes further that
the human pro-insulin has two amino acids removed for stability in
plants plus 11 C terminal amino acids added to ensure retention of the
protein in the endoplasmic reticulum of the plant seed cell. The
pro-insulin sequence was fused to the Arabidopsis oleosin gene, to be
exclusively expressed in seeds. Expression of the fused gene was
controlled by the phaseolin promoter and terminator sequences from
common bean. The bean promoter drives seed-specific transcription of the
synthetic pro-insulin. A selectable marker is regulated by the parsley
ubquitin promoter and terminator, and was deemed confidential business
information even though it is said to be the most commonly used
selectable marker in plants, and had been used in many previous field
trials . Animal feeding tests evaluating the toxicity of the neither
the synthetic pro-insulin nor the marker gene and its proteins were
included with the EA.
Site of release in area with threatened species
The area selected for the transgenic safflower field test releases -
“sagebrush steppe” - is dry and dominated by sagebrush. Resident animals
include the sage grouse, sage sparrows, loggerhead shrikes, and even the
once ubiquitous black-tailed hare or “jackrabbit”. According to
USAD/APHIS , the threatened species in the test area also include
bald eagle, pygmy rabbits, Columbian white tailed deer and grey wolf,
and the plant species Spalding’s catchfly and Ladies’ tresses. Pygmy
rabbits are the most threatened species, the Columbia pygmy rabbit feeds
mainly on sagebrush and its number may be as low as 30 or less. There
has been limited success in breeding the rabbits in captivity [5, 6].
The pygmy rabbit is likely to feed on the transgenic safflower seeds
with potentially detrimental (even fatal) consequences. The USDA/APHIS
report claims there will be no toxicity from ingesting seeds from the
transgenic safflower, from contact or from inhaling dust and debris .
Even if that were true - and there is evidence ignored by APHIS
suggesting that the ingested pro-insulin from transgenic safflower is
active (see below) - the disruption of the habitat of the pygmy rabbit
by human activities and transportation is likely to drive the threatened
animals to extinction. APHIS displays a cavalier disregard for the
threatened species, ignoring studies that do not support their conclusions.
Evidence of potential harm to threatened species ignored
There is at least one report showing that transgenic pro-insulin can
effectively reduce blood glucose in rats. Feeding a bracken fungus,
Ganoderma lucium, modified with a gene for human pro-insulin to diabetic
rats reduced their blood glucose ; presumably the modified fungus
cell wall and endoplasmic reticulum prevent rapid degradation of
pro-insulin, allowing the transgenic organism to deliver insulin to the
diabetic animal. Cholera toxin pro-insulin fusion proteins were produced
in lettuce and tobacco plants; and when powdered transgenic plant
preparations were fed to diabetic mice, oral tolerance to insulin was
produced, preventing the autoimmune degradation of insulin-producing
beta cells in the pancreas . Human insulin produced in Arabidopsis
seeds was activated by exposure to the common digestive enzyme trypsin
. The APHIS report presumes that human pro-insulin will be degraded
too rapidly for it to become activated when ingested by animals, but the
studies cited show that may not the case. Furthermore, functional
argenine peptides were found to enhance intestinal absorption of insulin
such peptides may be encountered commonly in anti-microbial peptides
. Seed debris may produce dust that contains human pro-insulin, and
it is worth noting that inhaled insulin is an available option for human
therapy . The APHIS report dismisses the possibility that inhaled
debris and dust from the transgenic safflower could be active, but
provides no experimental evidence to support that conclusion.
APHIS implies that wild animals would not be affected by human insulin
, but rabbits were among the animals first used in the discovery of
insulin, and continue to be used as experimental animals in current
studies on insulin action . Furthermore, birds  and snakes 
also respond to human insulin; and it is probably safe to say that all
of the threatened species, and human beings are potential victims of the
release of food crops modified to produce human insulin. The APHIS
report notes that grain crops surrounding the transgenic safflower plot
will provide a more attractive “free lunch” for birds and mammals than
the transgenic safflower; that is a fallacious and dangerous assumption
because the ‘free lunch’ will attract both foragers and predators to the
test site. Furthermore, the fallow strip around the test plot is
unlikely to discourage browsers such as rabbits that feed at night to
Safe haven for pharm crops but deadly for humans and wild life
Eastern Washington State is rapidly being transformed into a haven for
transgenic crops modified to produce pharmaceuticals. Along with
previous safflower field test releases, large plantings of humanized
barley are being tested. The exact locations of such tests are not
disclosed and people living near the test sites are unaware of the
potential hazards to their health. The impact of such developments on
threatened species is also ignored and dismissed by APHIS. The APHIS
report reads more like a public relations document for the company
rather than an independent critical evaluation of the company proposal.
This is potentially deadly for humans and wildlife, and the agency
should be held to public account.
1. USDA-APHIS Environmental Assessment In response to permit application
(06-363-103r), received from SemBioSys, Inc. for a field-test to produce
human proinsulin (line 4438-5A) in genetically engineered safflower
(Carthamus tinctorius) seeds U.S. Department of Agriculture Animal and
Plant Health Inspection Service Biotechnology Regulatory Services
06_363103r 06/22/2007 http://www.regulations.gov/fdmspublic/component/main
2. Wikipedia Proinsulin 2007 http://en.wikipedia.org/wiki/Proinsulin
3. Davidson, H. Proinsulin processing. Cell Biochemistry and Biophysics
2004 Supplement, 143-57.
4. Molony M, Boothe J, Keone R, Nykiforuk C and Van Rooijen. Method for
production of insulin in plants, 2005 US Patent 2005/0039235A1
5. Washington Department of Fish and Wildlife Pygmy Rabbit 1995
6. Hays D. Washington Department of Fish and Wildlife Washington Pygmy
Rabbit 2003 Recovery Plan Update addendum to 1995 above
7. Ni T, Hu Y, Sun L, Chen X, Zhong J, Ma H and Lin Z. Oral route of
mini-proinsulin-expressing Ganoderma lucidum decreases blood glucose
level in streptozocin-induced diabetic rats. Int J Mol Med. 2007, 20(1),
8. Ruhlman T, Ahangari R, Devine A, Samsam M and Daniell H. Expression
of cholera toxin B-proinsulin fusion protein in lettuce and tobacco
chloroplasts--oral administration protects against development of
insulitis in non-obese diabetic mice. Plant Biotechnol J. 2007, 5(4),
9. Nykiforuk CL, Boothe JG, Murray EW, Keon RG, Goren HJ, Markley NA and
Moloney MM. Transgenic expression and recovery of biologically active
recombinant human insulin from Arabidopsis thaliana seeds. Plant
Biotechnol J. 2006,:77-85.
10. Morishita M, Kamei N, Ehara J, Isowa K and Takayama K. A novel
approach using functional peptides for efficient intestinal absorption
of insulin. J Control Release 2007, 118(2), 177-84.
11. Guevara CA. Inhaled insulin for diabetes mellitus. N Engl J Med.
12. Barillas R, Friehs I, Cao-Danh H, Martinez JF, del Nido PJ.
Inhibition of glycogen synthase kinase-3beta improves tolerance to
ischemia in hypertrophied hearts. Ann Thorac Surg. 2007, 84(1), 126-33.
13. Remage-Healey L and Romero LM. Corticosterone and insulin interact
to regulate glucose and triglyceride levels during stress in a bird. Am
J Physiol Regul Integr Comp Physiol. 2001, 281(3), R994-1003.
Sidorkiewicz E and Skoczylas R. Effect of insulin on the blood sugar
level in the grass snake (Natrix natrix L.). Comp Biochem Physiol A.
1974, 48(3), 457-
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