IP and Open Source Technology | Letter to Representatives
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 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.
Harvard iGEM and Human Practices
Where does our project stand in this complex and contentious history?
The objective of our project was to provide an open-source, "reduced-to-practice" method for zinc finger production through the novel application and integration of technologies. This method allows for the rapid creation of custom zinc fingers in a high-volume fashion for targeting novel binding sequences. This, in turn, has enabled us to fill gaps of undiscovered zinc finger binders in the OPEN and CoDA database and other open-source zinc finger databases. Most importantly, our open-source BioBrick materials, detailed protocols, and software tools greatly increase the accessibility of zinc finger technology and help to overcome the prohibitively high price tags of the present market.
We aim to increase the accessibility of our method, which can in turn be applied by others to the generation of novel biological interactions beyond zinc fingers. We wish to share our data and results with the community, highlighting our successes and failures to collectively advance our knowledge of designing novel biological interactions. In addition, we seek to openly address pertinent ethical and legal concerns surrounding the impact of intellectual property in synthetic biology, and to open a dialogue to raise awareness about these issues.
No "Finger" Pointing
A Case Study in Intellectual Property and Open Source Alternatives
The Harvard iGEM team aims to open discussion and raise awareness of the future impacts of intellectual property rights on synthetic biology research. We seek to provide an objective view of the existing relationships between intellectual property and open-source content. Our concern is particularly for the necessity of balance in intellectual property rights and the promotion of open-source technology for optimal benefit to all.
iGEM & IP
The questions raised by this case study are of particular importance for synthetic biology, which has historically placed great emphasis on an open-source nature. iGEM in particular has placed great value on this history. The Registry of Standard Biological parts and the concept of BioBricks are fundamental examples: characterized, standardized parts are available to on the registry website to anyone with Internet access. In fact, IP questions are relevant for many of the technologies developed and used in the competition.
Zinc finger intellectual property is held predominantly by a single commercial research institution, unlike many other areas of research where intellectual property is distributed across a wide variety of interested parties. This institution, Sangamo Biosciences Inc., is a clinical stage biopharmaceutical company which focuses on zinc finger production for clinical applications. Sangamo has acquired most of the patent rights for the exclusive production and use of zinc finger proteins as DNA-modifying molecules. The result is an imbalance in the legal rights to research zinc fingers and their related medical applications which has notable consequences.
Implications of Monopoly
First, researchers outside of Sangamo may be less motivated to research zinc finger technology because there is less of a foreseeable reward with patent rights blocking any prospect of earning a profit from patenting new technology. Even if there is no profit motive involved, it is impossible to do open source research using purchased zinc fingers, as licensing and high costs inhibit effective research.  The cost of purchasing a single zinc finger protein from Sigma® Life Science (licencing partner with Sangamo) is prohibitively high - up to $15,000 for a single functioning zinc finger nuclease, which only work as pairs  - limiting the possibilities for significant outside research.
Second, Sangamo is able to monopolize the zinc finger market and intellectual capital: this means that they become a powerful, specialized research institution with the ability to potentially achieve progress at a faster pace than multiple individual institutions. Specialization naturally allows Sangamo to make progress more efficiently than individual researchers. Centralization also brings specialized researchers together under one roof for effective collaboration without having to cross communication barriers that exist between multiple isolated institutions.
These two effects act in opposite directions from the perspective of making intellectual progress for humanity. Thus we arrive at the central question: Does the Sangamo zinc finger monopoly augment the positive effects of research benefits for humanity and profit for individual researchers? Is the Sangamo research monopoly more beneficial to all involved parties?
In Favor of Opening the Field
Imbalance of Research Benefits
The economic consequences of monopoly have been posed by some as a clear negative consequence of the Sangamo phenomenon. In a single-actor monopoly, standard economic theory predicts that the rational market actor will sell at the profit-maximizing price. This price, however, does not necessarily maximize social benefit especially since monopolistic trade results in deadweight loss . In other words, this means that the collective world production of societal benefits - such as medical treatments - potentially decreases in order to maximize profit for Sangamo.
Lack of transparency in the field inhibits outside research while promoting Sangamo’s internal research. Technology that otherwise would have been available for use by many researchers is concealed behind Sangamo's large patent portfolio. Therefore, Sangamo passively impedes outside research by removing the opportunities for advancement and dissemination of protocols.
Risk of Centralization and Failure
Another problem with the monopolistic model arises when the company fails: when it fails to make scientific progress, and the whole field suffers. Recently, Sangamo Biosciences’ lead drug candidate has flunked its biggest test yet in clinical trials, and the company said this morning [October 3 2011] that it’s time to move on to other programs.[Sangamo] said today that SB-509 failed in a study of 170 patients that randomly assigned patients with diabetic neuropathy to a new drug or a placebo."  If concerns of IP violation discouraged other researchers from working on comparable zinc finger-based treatments for that disease, there is now nothing to show for years of work, and the disease remains untreatable from a gene therapy approach.
Two Sides to Every Story: Benefits of IP
Intellectual Property Security
However, others have argued that concentrating intellectual property in a single company has actually promoted innovation and progress in the field . Monetary incentive to conduct research is undoubtedly a key driving force for scientific progress. What scientist or institution would invest in research without at least a chance of returning profit? Lack of protection of intellectual property rights and thus profit would diminish the sense of security and equality that the U.S. patent system currently provides. In fact the U.S. patent system was first instated to encourage openness of knowledge. Sangamo's large patent share gives the impression that intellectual property rights block future research incentive. In fact without intellectual property rights zinc finger research (and Sangamo) may not even exist today.
Centralization Boosts Efficiency
By bringing leaders in the field together, Sangamo might allow zinc finger researchers to be more productive through close collaboration than they otherwise would have been working individually. Furthermore, specialization in zinc finger technology minimizes costs of production that individual researchers would otherwise face. From the perspective of consumers purchasing zinc fingers, valuable time and negotiation costs may be saved by working with one company rather than many.
Conclusion: Striking a Balance
The ultimate goal of both Sangamo and other researchers is to make progress in scientific innovation while gaining profit from intellectual property. Naturally both Sangamo and other science researchers will tend to maximize personal profit; however, we suggest that the optimal scenario would maximize both scientific progress and the collective profit gained by each research actor.
The Harvard iGEM Proposition
An optimal resolution can be achieved only by a proper balance between intellectual property right regulation and open source technology; therefore we propose that there be an investigation into the current status of the zinc finger intellectual market with respect to the social and private profit-maximizing values. Currently the market lies heavily in favor of maximizing the private profits for Sangamo and the chance that this is the overall profit-maximizing equilibrium is therefore lessened. Only by properly informing the scientific community of the implications of imbalance between intellectual property rights and open source technology can we hope to achieve the most efficient research conditions for the future of synthetic biology research.
One way to do this would be to follow the model of the European Union. In most European countries, patent laws "include a 'research exception' which permits use of a patented invention for experimental purposes without infringing the rights of the holder. Additionally, there are further exceptions such as those in respect of private and non-commercial use."  In the United Kingdom, specifically, "those acts which do not constitute an infringement are set out in Section 60(5) of the Patents Act 1977." How can the United States remain competitive in the long-term with countries who allow for academic research without fear of infringement - and have done so for the past 30 years?
A research exception could provide the needed balance between IP and research: companies could maintain their profitability, while scientists could use the best methods and ideas in their academic research, without fear of litigation.
For more information on Harvard iGEM's Human Practices activism,
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8. Luke Timmerman. Sangamo Fails Diabetic Neuropathy Study, Falls Back on HIV, Other Programs. Xconomy, 10/3/11.