Stephen M. Maurer

Finding Cures for Tropical Diseases: Is Open Source an Answer?

The Tropical Disease Initiative will be a Web-based, community- wide effort where scientists from the public and private sectors join together to discover new treatments

The economics of synthetic biology

Mol Syst Biol. 3: 117 Ten years ago, genetic engineering was limited to cutting and pasting DNA from existing organisms. Todays biologists can write down gene sequences that have never existed anywhere, place an order over the Internet, and receive the desired DNA by return mail. The new science of synthetic biology dreams of a day when blueprints for new life forms can be designed as easily as computer chips. Practitioners argue that the key is to create libraries of standard gene sequences (‘parts’) that reliably perform simple functions like encoding an enzyme or building a protein that detects light. This strategy is potentially powerful: the electronics industry already uses similar libraries to create ultra‐complex objects like computer chips and software (Endy, 2005). The technological benefits of introducing electronic methods into biology seem clear. The economic consequences are more ambiguous. Many electronics and software industries feature a dangerous ‘winner‐take‐all’ or ‘tipping’ dynamic, in which an initial frontrunner becomes steadily more entrenched over time. Microsofts rise to power is an obvious example. Significantly, tipping dynamics do not always lead to monopoly. In fact, many outcomes are possible: The eventual winner can be open (Apache) or proprietary (Windows), technically superior (Web) or suboptimal (VHS). Historically, these outcomes have emerged more or less at random from rough‐and‐tumble contests in the market. Synthetic biologists can and should do better. Which of the many possible outcomes is most likely to deliver a world of plentiful, high quality, and affordable parts? Now is surely the time to ask. Academic scientists still control the lions share of synthetic biology projects, resources, and expertise. Potentially, this gives them important leverage over how industry evolves. But that will change. One company (Amyris Technologies, see below) is already using synthetic biology to make a parts‐based organism. Other companies …

Science's neglected legacy.

Large, sophisticated databases cannot be left to chance and improvisation.

Parts, property and sharing

1095 overcharge for its IP. Second, many types of cross-licenses (for example, per-unit royalties) tend to generate higher prices for consumers. This is because higher royalties push up each company’s costs and therefore prices. This can happen even where payments cancel out so that no firm earns a net royalty. The existence of these problems suggests the importance of cutting the number of licensing transactions that firms face wherever possible. In principle, this could be done by making standard biological parts unpatentable. Legislatures and courts, however, are highly unlikely to do this. Furthermore, this would also reduce incentives to innovate2,4. Traditional private-sector solutions based on patent pools—perhaps with zero royalties— seem more promising5–9. Here, the main difficulties are getting contributors to agree on terms and writing agreements that do not exclude competitors in violation of the antitrust laws10. An ASCAP-style clearinghouse comes to dominate the rest. In principle, the dominant parts can be owned by one firm (as is true of Windows, for example), fragmented across many owners (mobile telephony standards), or owned by no one (Linux). We argue that Linux-style openness in synthetic biology is desirable and, to a significant extent, feasible.

A Kernel for Open Source Drug Discovery in Tropical Diseases

Background Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private–public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues—open source drug discovery—has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such “kernels”. Methodology/Principal Findings Here, we use a computational pipeline for: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. Conclusions/Significance The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.

Open Source Research — the Power of Us

Academic and industrial scientific research operate on powerful and complementary models, consisting of some mix of competitive funding, peer review, and limited inter-laboratory collaboration. Enormous successes have arisen from both models. Yet there are clear failures to deliver results in certain areas, such as the provision of drugs for some of the most prevalent of human diseases. Is there a mechanism of research that is not wholly dependent on funding for its operation nor on traditional peer-reviewed articles for its propagation? Open source methods have delivered tangible benefits in the computer science community. We describe here efforts to extend these principles to science generally, and in particular biomedical research. Open source research holds great promise for solving complex problems in areas where profit-driven research is seen to have failed. We illustrate this with a specific problem in organic chemistry that we think will be solved substantially faster with an open source approach.

Chapter 5 Open Source Software: The New Intellectual Property Paradigm

Open source methods for creating software rely on developers who voluntarily reveal code in the expectation that other developers will reciprocate. Open source incentives are distinct from earlier uses of intellectual property, leading to different types of inefficiencies and different biases in R&D investment. Open source style of software development remedies a defect of intellectual property protection, namely, that it does not generally require or encourage disclosure of source code. We review a considerable body of survey evidence and theory that seeks to explain why developers participate in open source collaborations instead of keeping their code proprietary, and evaluates the extent to which open source may improve welfare compared to proprietary development. 1 Both authors can be contacted at 2607 Hearst Ave, MC 7320, Universtiy of California, Berkeley, CA 94720-7320, USA. Emails: smaurer@berkeley.edu, scotch@berkeley.edu. We thank the Toulouse Network on Information Technology for financial support, and Terry Hendershott for thoughtful comments. This paper is forthcoming in T. Hendershott, ed., Handbook of Economics and Information Systems, Amsterdam: Elsevier.

Open Source Drug Discovery: Finding a Niche (or Maybe Several)

Despite their novelty and importance, open source methods have been largely been limited to software. However, scholars have long suggested that it would be logical to organize at least one other field - drug discovery - using open source principles. This paper reviews todays relatively tentative attempts to organize open source biology collaborations and argues that more ambitious projects are feasible. Five specific projects are proposed and analyzed in detail. The article concludes by examining the special legal problems of writing open source licenses in the patent-dominated field of biology.

Harmonizing biosecurity oversight for gene synthesis

volume 28 number 1 january 2010 nature biotechnology converge on a uniform (and hopefully high) standard. In principle, there are two ways to accomplish this. The first and most familiar method is government regulation. In late 2006, the US government’s National Science Advisory Board for Biosecurity (Washington, DC) asked the federal government to prepare formal guidance on how gene synthesis companies should screen incoming orders4. Shortly afterward, the US government convened a formal interagency task force to develop this vision into formal guidelines. However, there is also a second path: private agreement. In April 2008, Europe’s leading gene synthesis industry trade association, the IASB, hosted a meeting in Munich where leading companies from the United States and Europe discussed what they could do to improve biosecurity at the grassroots level5. Participants quickly agreed to develop a new code of conduct. By mid-2008, both industry and government were hard at work developing screening standards. As it turned out, the private track was slightly faster. IASB produced a first draft “Code of Conduct for Best Practices in Gene Synthesis” in late 2008, which members continued to comment on into the first half of 2009. In keeping with the practice at most companies, this Code of Conduct required commercial gene synthesis providers to compare incoming orders against GenBank and use human experts to determine what the closest GenBank matches encoded. If the GenBank match was problematic—most notably, if it encoded a protein associated with virulence—members would have to conduct additional customer investigations before filling the order. On November 3, IASB held a meeting in Cambridge, Massachusetts, USA, to produce the final text of IASB’s Code2. In the course of these discussions, participants agreed to narrow the draft Code so that members would only have to investigate sequences that corresponded to known pathogens. (The compromise was based on a judgment that current technology is incapable of making threats from the DNA found in other organisms.) Seven companies, including standards—despite their strong substantive similarities—also present an important choice. This is because the IASB standard was developed openly in public meetings, whereas the IGSC standard was written behind closed doors by five large companies. For better or worse, the winning standard will almost certainly have a profound impact on future transparency both within the gene synthesis industry and in its dealings with the wider public. Since 1999, when suppliers started making DNA to order, industry observers understood that artificial DNA could potentially be used to ‘resurrect’ pathogens such as smallpox that are no longer found in nature, build genetically engineered weapons similar to those pursued by the Soviet Union in the 1980s or exploit the new science of synthetic biology to create artificial pathogens. Within a few years, most gene synthesis companies had developed and implemented programs to screen incoming orders for security threats. Most companies did this by comparing customer-submitted sequences against GenBank (http://www.ncbi.nlm. nih.gov/Genbank/). They then paid human experts to determine whether the closest homologs encoded functions that could be used to make weapons. Where the answer was problematic, companies would conduct a further investigation to make sure that the customer existed, had a legitimate use for the DNA and had thought through any safety or biosecurity issues. Today, most current and proposed screening protocols follow this same basic structure. The problem is that each DNA synthesis company imiplements this system differently. This means that across the industry, practices are highly nonuniform, with a few firms paying relatively little attention to biosecurity. Things would be better, industry observers agreed, if companies could be persuaded to To the Editor: As highlighted in your December issue, commercial gene synthesis companies routinely sell long strands of made-toorder DNA to researchers around the world. Observers have long speculated that individuals, terrorist organizations and governments could potentially use this DNA to create pathogens and other biosecurity threats. Last November, two separate industry groups—the International Association Synthetic Biology (IASB) and the International Gene Synthesis Consortium (IGSC)—issued competing standards1,2 specifying the precautions that companies should take before they provide artificial DNA to customers. So far, roughly a dozen gene synthesis companies in the US, Europe and China have promised to follow one or the other of these standards. More recently, the US Department of Health and Human Services has similarly announced its own draft ‘Framework Guidance’ recommending steps that commercial gene synthesis providers should take to screen incoming orders3. Readers who follow private sector ‘standards wars’ will immediately recognize that the current situation is unstable and only one of these three standards is likely survive in the long term. Furthermore, the prevailing standard will almost certainly set security policy in this area for many years. As we explain below, the choices are profound. On the one hand, the US government’s draft Guidance embraces an automated ‘Best Match’ approach that defines threats based on how closely they resemble the so-called Select Agent list. We argue that this procedure is clearly less capable (but also less expensive) than either private standard, both of which require human experts to investigate gene function any time a customer sequence resembles a pathogen or toxin found in government’s enormously larger Genbank database. On the other hand, the two private Harmonizing biosecurity oversight for gene synthesis c o r r e s p o n d e n c e

Coping with change: intellectual property rights, new legislation, and the human mutation database initiative.

In 1996, the European Union issued a directive requiring member states to protect databases against unauthorized copying. Similar legislation is currently being considered and will probably be enacted in the US. Such database legislation 1) will almost certainly increase existing pressures on human mutation databases to commercialize, and 2) could inadvertently make human mutation data harder to acquire and use. Strategies for minimizing these difficulties are discussed. Alternatively, a nonprofit, community‐wide “depository” could probably support itself by selling sophisticated bioinformatic products to the private sector. The proposed depository would offer substantially similar databases to academic and government users at little or no cost. Hum Mutat 15:22–29, 2000.