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Future directions for agricultural biotechnology

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Title: Future directions for agricultural biotechnology


1
Future directions for agricultural biotechnology
  • Dr. Kirstin Carroll
  • Outreach in Biotechnology Program
  • Oregon State University

2
Lecture Outline
  • What is biopharming?
  • Why use plants?
  • Current and evolving regulation
  • What are the risks and concerns?

3
What is biopharming?
The use of agricultural plants for the production
of useful molecules for non food, feed or fiber
applications. (also called molecular farming,
pharming, or biopharming)
4
What is biopharming?
The use of agricultural plants for the production
of useful molecules for non food, feed or fiber
applications. (also called molecular farming,
pharming, or biopharming) Plants are already
grown to produce valuable molecules, including
many drugs. Biopharming is different because
the plants are genetically engineered (GE) to
produce the molecules we want them to.
5
Plant Products
  1. Plant derived pharmaceuticals (non-GE)
  • Over 120 pharmaceutical products currently in use
    are derived from plants. Mainly from tropical
    forest species (e.g. Taxol from Yew trees)

6
Plant Products
  1. Plant-derived pharmaceuticals (non-GE)

2. Plant-made pharmaceuticals (PMPs) and
industrial products (PMIP) (GE)
  • Industrial products
  • proteins
  • enzymes
  • modified starches
  • fats
  • oils
  • waxes
  • plastics
  • Pharmaceuticals
  • recombinant human proteins
  • therapeutic proteins and pharmaceutical
    intermediates
  • antibodies (plantibodies)
  • vaccines

7
Strategies for Biopharming
  • Plant gene expression strategies
  • Transient transformation
  • adv. quick and easy production
  • disadv. small amount of product, processing
    pblms
  • Stable transformation
  • adv. use for producing large quantities of
    protein, stability and storage
  • disadv gene flow - outcrossing w/native species
  • Chloroplast transformation
  • adv. reduce gene flow through pollen
  • disadv. protein not stable for long periods of
    time therefore complications w/extraction/processi
    ng times

8
Strategies for Biopharming
  1. Plant gene expression strategies

2. Location of transgene expression
  • Protein quantity and preservation
  • Whole plant
  • adv. - an obtain large amts of protein
  • disadv. - problems w/preservation
  • examples - tobacco, alfalfa, duckweed
  • Target specific tissues (e.g. seed, root)
  • adv. - high amts of protein in seed/root,
    long-term storage capability.
  • examples soy, corn, rice, barley

9
Strategies for Biopharming
  1. Plant gene expression system

2. Location of trans-gene expression
3. Selection of plant species and characteristics
  • Mode of reproduction self/outcrossing
  • Yield, harvest, production, processing

10
Why use plants?
Advantages Cost reduction - scalability (e.g.
Enbrel ) - low/no inputs - low capital
cost Stability - storage Safety - eukaroytic
production system - free of animal viruses (e.g.
BSE)
Disadvantages Environment contamination - gene
flow - wildlife exposure Food supply
contamination - mistaken/intentional mixing
w/human food Health safety concerns - Variable,
case-specific
11
Industrial products on the market
  • Avidin by Sigma
  • transgenic corn
  • traditionally isolated from chicken egg whites
  • used in medical diagnostics
  • GUS (b-glycuronidase) by Sigma
  • transgenic corn
  • traditionally isolated from bacterial
  • sources (E.Coli)
  • used as visual marker in research labs
  • Trypsin by Sigma
  • transgenic corn
  • traditionally isolated from bovine pancreas
  • variety of applications, including
    biopharmaceutical processing
  • first large scale transgenic plant product
  • Worldwide market US120 million in 2004

12
Industrial products close to market
13
Plant-made Pharmaceuticals (PMPs)
  • Plant- made vaccines (edible vaccines)
  • Plant-made antibodies (plantibodies)
  • Plant-made therapeutic proteins and intermediates
  • Unlike PMIPs, no PMPS are currently available on
    the market

14
Plant-made Vaccines
  • Edible vaccines
  • Advantages
  • Administered directly
  • no purification required
  • no hazards assoc. w/injections
  • Production
  • may be grown locally, where needed most
  • no transportation costs
  • Naturally stored
  • no need for refrigeration or special storage

15
Plant-made Vaccines
  • Examples of edible vaccines under development
  • pig vaccine in corn
  • HIV-suppressing protein in spinach
  • human vaccine for hepatitis B in potato

16
Plantibodies
  • Plantibodies - monoclonal antibodies produced in
    plants
  • Plants used include tobacco, corn, potatoes, soy,
    alfalfa, and rice
  • Free from potential contamination of mammalian
    viruses
  • Examples cancer, dental caries, herpes simplex
    virus, respiratory syncytial virus

17
Plantibodies
Dental Caries MAb expected to reach the market
soon MAb directed against genital herpes
estimated to reach market within 5
years (Horn et al, 2004)
GE Corn can produce up to 1 kg antibody/acre
and can be stored at RT for up to 5
years. Humphreys DP et al. Curr Opin Drug
Discover Dev 2001 4172-85.
18
Plant made Pharmaceuticals
  • Therapeutic proteins and intermediates
  • Blood substitutes human hemoglobin
  • Proteins to treat diseases such as CF, HIV,
    Hypertension, Hepatitis B..many others

19
Plant made Pharmaceuticals

To date, there are no plant-produced
pharmaceuticals commercially available
Patient advocacy groups American Autoimmune
Related Diseases Association Arthritis
Foundation Cystic Fibrosis Foundation
20
Current Pharm Companies
21
Current Pharm Companies
  • LEX System
  • Lemna (duckweed)

Kentucky Tobacco Research and Development Center
  • trangenic tobacco
  • PMPs and non-protein substances (flavors and
    fragrances, medicinals, and natural insecticides)
  • Controlled Pharming Ventures
  • collaboration w/Purdue
  • transgenic corn
  • converted limestone mine facility

22
Current Pharm Companies
  • biomass biorefinery
  • based on switchgrass.
  • used to produce PHAs in green tissue plants for
    fuel generation.

23
Examples of Current Research
  • Genetically engineered Arabidopsis plants can
    sequester arsenic from the soil. (Dhankher et al.
    2002 Nature Biotechnology)
  • Immunogenicity in human of an edible vaccine for
    hepatitis B (Thanavala et al., 2005. PNAS)
  • Expression of single-chain antibodies in
    transgenic plants. (Galeffi et al., 2005 Vaccine)
  • Plant based HIV-1 vaccine candidate Tat protein
    produced in spinach. (Karasev et al. 2005
    Vaccine)
  • Plant-derived vaccines against diarrheal
    diseases.(Tacket. 2005 Vaccine)

24
Risks and Concerns
  • Environment contamination
  • Gene flow via pollen
  • Non-target species near field sites e.g.
    butterflies, bees, etc
  • Food supply contamination
  • Accident, intentional, gene flow
  • Health safety concerns
  • Non-target organ responses
  • Side-effects
  • Allergenicity

25
U.S. Regulatory System (existing regulations)
USDA
FDA
EPA
Field Testing -permits -notifications Determinati
on of non-regulated status
Food safety Feed safety
Pesticide and herbicide registration
26
Breakdown of Regulatory System Prodigene
Incident 2002
2001 Field trails of GE corn producing pig
vaccine were planted in IA and NE. 2002 USDA
discovered volunteer corn plants in fields in
both IA and NE. Soy was already planted in NE
site. 500,000 fine 3 million to
buy/destroy contaminated soy
27
USDA Response to Incident
  • Revised regulations so that they were distinct
    from commodity crops
  • Designated equipment must be used
  • At least 5 inspections/yr
  • Pharm crops must be grown at least 1 mile away
    from any other fields and planted 28 days
    before/after surrounding crops

28
Current Evolving Regulations
  • FDA/USDA Guidance for Industry on Plant-Made
    Pharmaceuticals Regulations
  • November 2004 Draft Document
  • Other challenges
  • Industrial hygiene and safety programs these
    will depend on the activity of the protein, route
    of exposure.
  • Difficulty in obtaining relevant data because of
    high species-specificity.
  • (Goldstein, 2005)

29
Biopharming field trials in the US
www.ucsusa.org
Since 1995 300 biopharming plantings The USDA
receives/reviews applications for permits for
biopharm trials.
30
Biopharming field trials in the US
www.ucsusa.org
US Pharma Crop Database
http//go.ucsusa.org/food_and_environment/pharm/in
dex.php?s_keywordXX
31
Biopharming in Colorado
32
Biopharming in N.Carolina
33
The 2005 Oregon Biopharm Bill
34
Biopharm opposition
  • Main concern is containment.
  • Opponents want
  • a guarantee of 0 contamination of the food
    supply.
  • full disclosure of field trials, crop, gene,
    location, etc.
  • an extensive regulatory framework

35
Suggested Safeguards for biopharm operations
  • 1. Physical differences
  • e.g. purple maize, GFP
  • 2. Sterility
  • male sterile plants
  • terminator technology
  • 3. Easily detectable by addition of 'reporter
    genes
  • e.g. PCR markers

36
Suggested Safeguards for biopharm operations
  • Use chloroplast expression system
  • will help increase yield
  • will eliminate potential gene flow via pollen
  • disadv. technically difficult (Chlorogen
    Company)
  • 5. Complete disclosure of DNA sequences
  • Legislate for administration

37
Alternatives to biopharming?
  • Use only traditional drug production systems
  • microbial, yeast and fungi
  • mammalian cell culture
  • Use only fully contained production systems
  • plant cell cultures
  • hydroponics (rhizosecretion)
  • greenhouses
  • Use non-food crops
  • tobacco
  • hemp/cannabis

38
Economics
The expectation is for lower production costs
however there is no evidence that pharming will
produce cheaper, safe drugs. Moreover, there
are unknown costs associated with containment,
litigation and liability, production..others?
39
Future directions for agricultural biotechnology?
Science has developed genetically enhanced crops
and has/can develop plant-made industrial and
pharmaceuticals crops. The extent to which these
crops will be further developed for commercial
and/or humanitarian use will ultimately depend
on..
Public perception of risk
Regulation
40
Discussion Questions Do you think nutritionally
enhanced plants should be developed even though
there are oral supplements available? Why or why
not? Do you support the development of pharm
crops? Do you feel that the potential benefits
of pharm crops are worth the potential
risks? What are your thoughts on using food vs.
non-food crops as phactories for pharmaceutical
or industrial protein production?
41
Linkage Discussion Questions In the lecture on
sustainability, Proebsting painted a picture that
all of conventional ag is so out of whack in its
water/energy/soil effects that biotechs benefits
are, by implication, irrelevant.  Is that what he
meant?  Do you agree or disagree with this basic
view?  Why or why not?  In the lecture on
organic ag, Stone showed the many ways in which
farmers can work to improve soil quality and
reduce energy use.  The list of excluded
practices aside, in what ways are the goals of
organic ag the same or different from
conventional and other sustainable forms of ag? 
The first generation of GMO crops are often
cited as having benefits for farmers and seed
companies but not for consumers/public.  In what
ways is this true or false? 
42
Potrykus painted a picture of a regulatory
system so out of whack that GMO crops with huge
potential benefits for the poor and ill are held
up to the same or a greater degree as are crops
whose main beneficiaries might be agribusiness or
the developed world.  Do you agree?  What should
a smart system look like?  How would it compare
to the system in use for conventionally bred
crops?  Genetic pollution is often cited as
unmanageable and thus a reason not to completely
exclude biotech crops in entire countries or
states.  But toxicology teaches us that the dose
makes the poison (thus, by analogy its not a
pollutant in consequence unless it is above a
given threshold).  Should adventitious presence
be called pollution/contamination at all?  When? 
How should it be dealt with by society? 
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