Golden Rice

in Bio-Technology

Methode

Collected By,

P. Arunkumar M.Sc

Originally

WAEA Invited Paper Session

Coordinating Science and Technology

In the Agricultural Biotechnology Revolution

Information Pathways

in Biotechnological Innovation:

The Research Demand for Intellectual Property

Steven Buccola and Yin XiaAgricultural and Resource Economics

Oregon State University

Terri LomaxProgram for the Analysis of Biotechnology Issues

Oregon State University

Virus-resistant PapayaPapaya, a tropical fruit high in vitamins C & A, is an important food crop worldwide.and the 2nd largest export crop in Hawaii.

A virus, papaya ringspot potyvirus (PRSV), was discovered in Hawaii in the 1940’s and had wiped out papaya production on Oahu by the 1950’s.

The papaya industry moved to the Puna district on the Big Island of Hawaii.

PRSV was discovered in Puna in 1992, by late 1994, PRSV had spread throughout Puna and many farmers were going out of business.

Virus-resistant Papaya

Transgenic Non-transgenic

In anticipation of a new virus outbreak, scientists at Cornell, began a project to develop transgenic virus-resistant papaya in 1986.

Papaya transformation was greatly facilitated by the recent invention of the “gene gun” at Cornell.

The coat protein of the virus was engineered into papaya to confer resistance, similar to a vaccine.

Funding: USDA

TransgenicNon-transgenic

Golden Rice• Millions of people suffer from vitamin A deficiency, which leads to blindness and increased susceptibility to diseases.

• Half of the world’s population eat rice as their staple food, but rice grains do not contain vitamin A or its immediate precursors.

• UNICEF predicts that improved vitamin A nutrition could prevent 1-2 million deaths each year among children aged 1-4 years.

• Humans can make vitamin A from carotenoids, the yellow, orange, and red pigments of plants.

Golden Rice Scientists from Swiss and German universities have engineered two genes from daffodil and one bacterial gene into rice to produce provitamin A.

GGPP

Phytoene

Lycopene

beta-Carotene= provitamin A

Phytoene synthase (psy)

Phytoene desaturase (crtl)

Lycopene ß-cyclase (lcy)

(daffodil)

(daffodil)

(bacteria)

Provitamin A biosynthesis pathway

Funding: Rockefeller Foundation,Swiss Federal Institute Of Technology,European Community Biotech Program

Plasmid vector

Vector cutwith EcoRI

Donor DNA

Donor DNA cutwith EcoRI

Donor DNA fragments

Add DNA ligase

Introduce intoE. coli

Tetracycline-resistantBacterial colony fromtransformed cell

Transformed cell

Plasmids

Recombinant DNA

Selectable antibiotic resistance marker

The bacterium that causes crown gall disease in plants has a natural vector for transformation of desirable traits from one plant to another.

Plant Gene Transfer via Agrobacterium

T-DNA

There are Two Major Methods of Plant Gene Transfer

Agrobacterium tumefaciens

plasmid DNA

Plasmid DNA is cut open with an enzyme.

chromosomalDNA

A specific gene is “cut out” of thedonor DNA using the same enzyme.

New gene isinserted intothe plasmid.

Plasmid is transformedinto Agrobacterium.

When mixed with plantcells, Agrobacteriumduplicates the plasmid.

The new gene is transferredinto the chromosomal DNAof the plant cell.

When the plant celldivides, each daughtercell receives the newgene, giving the wholeplant a new trait.

Plant Gene Transfer via biolistics (“gene gun”)

Biolistic bombardment(gene gun)

Transformation of Agrobacterium

Cloned Gene in Vector DNA Molecule

Protoplast transformationfollowed by cell wall regeneration

Agrobacterium-mediatedtransformation of plantcell

Migration and integration of gene into nucleus

Plant cells grown in

tissue culture

Regeneration ofgeneticallymodified plantfrom tissueculture

Golden Rice Gene ConstructsI-SceI KpnI I-SceI

LB Gt1p psy nos! 35Sp tp crtl nos! RB

LB

I-SceI

35Sp Gt1p RB

I-SceIˆSpeI

35S! aphIV 35S! Icy

Virus resistant Papaya Construct

35Sp nos!PRSV coatprotein

nptII GUS

Selectable Markers

Biotechnology Research

Principal elements of a bioengineering project:

• Organism to be modified• Attributes to be altered in the organism

Discoveries needed in a bioengineering project:

• Genes transmitting the intended attributes• Promoters and Terminators• Protein-targeting mechanisms• Selectable markers• Vectors• Transformation and Regeneration methods

These discoveries are equivalent to fitting parts together into a sub-assembly, then fitting together

the sub-assemblies.

Walking Through a Laboratory Step

• The scientist must decide whether to design experiments using publicly-held or privately-held (IP) methods and lab products. We will call these methods or products technologies.

• Most privately-held technologies are like kits, fashioned for particular settings and imperfectly used in others.

• Some publicly-held technologies are also kits. Others are invented by the scientist herself, to adapt to her own project.

• Rational technology choice requires the scientist to develop an expectation of the number of laboratory trials that will be needed until the assembly is complete.

The expected number of laboratory trials depends on:

• Inherent difficulties of the organism to be modified (Org)

• Inherent difficulties of the attributes to be altered (Attr)

• Mean proximity of the available technologies to the project objectives (Prox)

Definitions

U, T : number of lab trials expected to be needed with publicly-

and privately-held technologies, respectively, until success is achieved

: probability that the privately-held technology will be successful, ()

: price of the t th privately-held technology (license negotiation plus royalty costs)

Expected IP price is then :

The Trial Expectation Functions are:

Research Cost Function

Total research cost consists of

i. equipment and scientist time

ii. number and expected prices of licensed IP

Ex Ante Minimum Research Cost is

Ex Ante Cost in Input Space

Shephard’s lemma gives the optimal demand for equipment and scientist time.

Total ex ante cost thus can be written in terms of conventional factor demands and IP cost as :

Recovering the primal technology from the dual

1. An iso-innovation line is constructed by recording, for each publicly or privately-held technology selected, the number of sub-technologies embedded in it.

2. Because these technology uses are cost-minimizing, they are functions of relative prices, project difficulty, and technology proximity.

The technology demand functions are

Public technology use U can be observed only by close inspection of laboratory processes.

Private technology use T is available from any “Freedom-to-Operate” study.

Private Technologies

Used

Public Technologies

Used

Iso-Innovation

Line

Technology Choice in Biotechnology Research

IP Success Rate in Current Project

Effectiveness of Privately-Held Intellectual Property

IP’s Proximity to Current Project

High -Powered IP Path

Low -Powered IP Path

Minor Crop

Major Crop

Minor Crops Likely Have Flatter Iso-Innovation LinesPublic

Technologies Used

Private Technologies

Used

Hypotheses

• Iso-innovation lines involving more difficult organisms or attributes lie above those involving less difficult ones.

Golden Rice’s iso-innovation line lies above VR-Papaya’s.

• Iso-innovation lines are flatter if they involve organisms or attributes more distant from current IP.

New patented innovations in the vicinity of a research project will steepen its iso-innovation line.

Golden Rice’s iso-innovation line is steeper than VR-Papaya’s.

• Declining IP prices induce weaker substitution into privately- held IP as a project moves closer to current private technology.

IP use in VR-Papaya would have responded less to IP market improvements than in Golden Rice.

The supply of IP technology is lower for minor crops and for those grown in poor countries. Thus, elasticity of demand for IP in minor and poor-nation crops will be greater than in major or developed-nation crops.

• Declining IP prices encourage scientists to tackle more difficult, higher-payoff projects.

Examples: Projects targeting food quality attributes far from the plant’s biosynthetic pathways, requiring the manipulation of groups of genes rather than a single gene.

Hypotheses, con’t.

• Impacts of IP prices on IP use are greater for projects in the private sector, since publicly employed scientists are motivated only weakly by project cost.

IP costs are relevant only if the public scientist plans to market his innovation. Most public scientists still prefer to publish than to market.

• Acquiring intellectual property reduces the negotiation portion of IP cost, shifting equilibrium toward the southeast on the iso-innovation line. Privately-held technology use rises at the expense of publicly-held technology.

Use of the gene gun in VR-Papaya development.

Hypotheses, con’t.

Model Virtues

Our model captures many of the features of biotechnology research:

1. Its building-block nature

Projects are completed by way of an assembly process.

2. Its risk

Scientists make decisions in the face of ex ante probabilities of trial success.

3. The cumulation of its discoveries

As technology supply rises, its mean proximity to other projects rises also, reducing the cost of these other projects.

Model Virtues, con’t.

4. Its susceptibility to quantum leaps

Success-rate functions shift upward (trial numbers U and T

decline) when fundamental advances are discovered.

5. The dual character of its costs: laboratory and intellectual property.

Because of bioscience’s cumulative structure, technologies

more successful in a given project are not necessarily more

expensive: quality and price are not necessarily related in

the laboratory.