Human Lactoferrin Biopharming in New Zealand: Scientific Risk Assessement (2008) | BCH-VLR-SCBD-103308 | Biosafety Virtual Library Resources | Biosafety Clearing-House


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Human Lactoferrin Biopharming in New Zealand: Scientific Risk Assessement
Heinemann, J.A. School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
Centre for Integrated Research in Biosafety (INBI)   BCH-ORG-SCBD-16293-5
  • Academic or research institute
Constructive Conversations, University of Canterbury
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Animals but especially plants and microbes are a source of a significant proportion of our medicines
and industrial compounds. Arguably, their cultivation and preservation for this purpose is nothing
new. However, the emergent genetic engineering of plants and animals to be used as recombinant
biofactories for the production of therapeutic or industrial chemicals warrants thorough hazard
identification and risk evaluation. Unlike the  use of transgenic, or genetically modified,
microorganisms for this purpose, plants and animals cannot be contained to the same degree at
commercial scales of production. This report will  focus on the risks to human health and the
environment of using transgenic plants and animals as biofactories for recombinant human lactoferrin
(rhLf). The economic and social implications are detailed in other reports in this series (Goven et al.,
2008, Kaye-Blake et al., 2007).
Transgenic organisms including plants and animals are being designed to produce pharmaceuticals,
such as recombinant proteins that are secreted in milk. Presently, there are pre-commercial
developments of rice plants and cows that can express rhLf. Transgenic sources may be harnessed to
reduce costs and the potentials for undesirable contaminants.
Transgenic “biofactories” producing pharmaceutical products (e.g., PMPs: plant-made
pharmaceuticals) and industrial chemicals (e.g., PMIPs: plant-made industrial products), or foods of
altered nutritional value, also can pose special risks to human and animal health. Pharmaceutical
compounds have profound physiological effects. Molecules with these attributes are unlikely to act
solely in the manner sought by clinicians. Human lactoferrin (hLf) is a protein with several known,
distinct functions and others that remain only partially understood. The expression of this compound
outside of its normal species and tissue ranges for  the lifetime of transgenic organisms occupying
different environments, creates a new combination of potentially undesirable outcomes. These will be
identified and discussed as far as possible.
Human lactoferrin
is a whey protein found in human milk. It binds iron (Fe) and other metals, such
as aluminium, chromium, cobalt, copper, gallium, magnesium and zinc. Fe-binding activity is
associated with lactoferrin’s broad-spectrum anti-bacterial effects and is sufficient on its own to
explain its activity as a bacteriostatic antibiotic for many bacteria. A derivative of the molecule, called
lactoferricin, is bactericidal. That is, it is sufficient to kill certain bacteria through its effects on their
membranes. Beyond this, lactoferrin has anti-viral, anti-fungal, immunomodulatory and antioxidant
properties, demonstrated activity against some tumours, and other physiological roles.
Several structural characteristics of the protein are particularly relevant to a safety assessment. First,
the protein has secondary structures that could be important for predicting its potential to aggregate,
and form a general cytotoxin (i.e., a compound that  kills cells). Second, the protein is normally
glycosylated. This affects predictions of its potential to be an allergen.
RhLf may be used as a human medicine both in acute infections and as a prophylactic. It may also
have uses as a veterinary medicine. Expression in animals and plants may affect microbes that
normally inhabit these organisms and those that  cause diseases in them. Because rhLf has speciesspecific effects on bacteria and viruses, its expression at agricultural scales may have implications for
the development of resistance to lactoferrin and possibly other important antibiotics (e.g.,
aminoglycoside antibiotics) in pathogens of plants, animals or humans because of both the scale and diversity of non-target organisms exposed. In  addition, some bacteria that cause disease use
lactoferrin to acquire iron from their environments and thus specifically thrive in its presence.
Lactoferrin has a tendency to aggregate and form amyloid fibrils. Any protein that makes amyloids
may be infectious even if it does not cause known diseases such as those caused by prions (amyloid
fibrils of other proteins). The tendency of a protein to form fibrils can be influenced both by its
concentration and its biophysical environment. Both of these variables are uniquely affected when a
protein is made in a genetically modified organism (GMO). The implications of fibrils are their
potential infectious transmissibility and health implications for the GMO.
Lactoferrin and especially rhLf may create new risks to people or animals susceptible to developing
oral sensitivity to this potential allergen. Formation of autoantibodies to lactoferrin is a common
observation in patients suffering from a number of diseases, although the relevance to the diseases or
their complications has not been established. The propensity of humans to develop immune responses
to bovine and goat milk suggests that the reverse might also be true, and this would be a potential
welfare issue for animal biofactories. Finally, the possible effects of rhLf on wildlife that feed on
biofactories are unknown.
An intriguing property of lactoferrin is that  it binds DNA, and transports DNA into cells with
lactoferrin receptors. Lactoferrin binds specific DNA sequences that are expected to occur by chance
at reasonably high frequencies in mammalian and plant genomes. These sequences also are important
for gene expression regulation in the presence of lactoferrin, making lactoferrin a transcription
regulator. Bacteria that import lactoferrin may also be able to acquire the DNA to which it is bound,
thereby increasing horizontal gene transfer.
Some risks of rhLF are unique to, or highly pronounced by, its production in plant or animal
biofactories because biofactories increase both the scale of exposure to non-target organisms and the
diversity of non-target organisms exposed. To determine the actual implications of plant or animal
biofactories of rhLf will require regulatory authorities to recognise each of these potential harm
pathways and either evaluate the possibilities of harm management or ask for relevant new research.
In sum, the most immediate risk factors of producing rhLf in transgenic plants or animals derive from
the protein’s toxic effects on microbes, fungi and viruses, and its potential to elicit an immune
response in people when it is derived from GMOs. The potential of rhLF to aggregate into amyloid
fibrils and to act as a gene transfer agent are poorly understood risk factors but they are both possibly
of profound importance. Long-term studies will be required to better understand these risks.
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pharma animals, LMOs