Using the Toolkit

Intellectual Property and Open Source Technology

We have explored the history and associated intellectual property (IP) issues that have surrounded zinc finger technology.

Because teams are trying to solve real-world problems, the vast majority of iGEM projects intersect with the IP landscape. Aside from its immediate relevance to our project, we argue that the story of zinc finger discovery, development, and commercialization presents a useful and enlightening case study of how IP affects the synthetic biology community.

Additionally, we wrote and sent a letter to multiple representatives regarding the conflict between IP and open source technology.

The History of IP and Open Source in Zinc Finger Technology

Discovered in 1985, zinc finger proteins have rapidly become a staple of gene therapy innovation. A cascade of research has transformed our understanding of the zinc finger domain from a natural transcription factor to a tool for highly specific genome alteration. As the zinc finger motif was domesticated and fused to DNA cleaving domains, its practical application through targeted gene alteration rose to the forefront of gene therapy research.

Seeking to harness zinc finger potential, researchers and entrepreneurs collaborated to form Sangamo Biosciences in 1995, which emerged as the sole commercial provider of the protein. Today, the Sangamo monopoly raises a variety difficult ethical and economic questions about intellectual property within the zinc finger field, and synthetic biology as a whole. As an open-source alternative to Sangamo’s proprietary system and commercial dominance, Keith Joung and others have published the OPEN system[5] of zinc finger creation. However, while the OPEN system and subsequent improvements are promising for massive zinc finger production, the methods are difficult and time-consuming to implement, and gaps remain in the list of available DNA binding targets.

Zinc Finger Historical Timeline

Discovery of the zinc finger protein

Jonathon Miller, A. D. McLachlan, and Sir Aaron Klug first identify the repeated binding motif in Transcription Factor IIIA and are the first to use the term ‘zinc finger.'
First crystal structure of a zinc finger

Carl Pabo and Nikola Pavletich of Johns Hopkins University solve the crystal structure of zif268, now the most-commonly studied zinc finger. This paved the way for construction of binding models to describe how zinc fingers bind to DNA, setting the foundation for future custom engineering of zinc finger proteins.
CEO Edward Lanphier founds Sangamo Biosciences

Edward Lanphier leaves Somatix Therapy Corporation and makes a deal for exclusive rights to the work of Srinivan Chandrasegaran of Johns Hopkins University who combined the Fok I nuclease with zinc fingers.
Srinivasan Chandrasegaran publishes work on fusing the Fok I nuclease to zinc fingers

By attaching nuclease proteins to zinc fingers, a new genome editing tool was created. The DNA-binding specificity of zinc fingers combined with the DNA-cutting ability of nucleases opened up possibilities for future research in gene therapy by allowing researchers to directly modify the genome though use of zinc finger nucleases.
Sangamo enters the public sector

In April 2000, five years after its founding, Sangamo Biosciences goes public offering 3.5 million shares at a starting value of $15 per share.
Sangamo patents zinc finger nuclease technology

Sangamo's patent, titled "Nucleic acid binding proteins (zinc finger proteins design rules)", ensures that any use or production of zinc fingers with attached nucleases is the intellectual property of Sangamo.
Rapid open source production of zinc finger nucleases becomes available

Researcher Keith Joung of Harvard University and Mass. General Hospital develops a method for making zinc finger nuclease proteins that bind to custom target sequences, utilizing a bacterial two-hybrid screening system to identify specific zinc finger binders to a DNA sequence of interest.
Zinc finger nuclease enters clinical trials

Sangamo and University of Pennsylvania begin clinical trials with a zinc finger nuclease designed to target the CCR5 gene and inhibit HIV. Success of this therapeutic could prove a significant advance for gene therapy.
Context-dependency improves open-source zinc finger engineering

Keith Joung publishes tables of zinc finger binding sites that account for context-dependent effects and can be rearranged to form custom zinc finger proteins that bind to a variety of DNA sequences. This greatly increases the ease of engineering novel zinc fingers based on the structures of previously characterized zinc fingers.
Harvard iGEM develops a novel method to engineer custom zinc fingers

Using novel integration of existing technologies, we have developed a rapid, comparatively low-cost, open source method for making thousands of custom zinc fingers by integrating MAGE, lambda red, and chip-based synthesis technologies. Our work greatly increases the ease of access to zinc finger technology for researchers worldwide.