Open Sources 2.0/Beyond Open Source: Collaboration and Community/Open Source Biology

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Open Sources 2.0

Andrew Hessel

Open source software (OSS) has played a central role in the growth of the Internet and increases in economic importance each year. It has rapidly changed the face of computing, with server side companies like Sun Microsystems, to end-user companies such as Adobe, to full platform/service companies like IBM incorporating open source into their offerings. With this success, open source is poised to diversify its influence. One experiment is open source biology (OSB), the idea that biological products such as drugs, vaccines, or pest-resistant crops, can be developed using open intellectual property (IP) models.

Academic science, like open source, supports the belief that knowledge evolves best when ideas, data, and methods are freely shared, and each contributor can build on the works of others. Universities have housed and promoted scientific thought for more than 1,000 years, creating a public commons. In contrast, alchemy is the forerunner of modern business. Today, with academic research a valuable economic good, weighing the societal benefits of freeing or protecting IP is a pressing challenge. In no scientific discipline is this more important than biology, central to all living things.

Commercial biotechnology was founded on the premise that strong IP protection was necessary. However, after nearly three decades, a sustainable industry has not yet been achieved. Public mistrust of the genetic technology persists. Now, with biology facing a paradigm shift, one where synthetic DNA will replace conventional manipulations, genetic engineering is converging with software engineering. OSB, guided by lessons from open software development, could result in a new, economically supportable route to biological products.

Contents

The Rise of Modern Biotechnology

The success of the Manhattan Project brought university research to national attention at the end of World War II. Recognizing the economic and defensive value of this work, the project's director, Vannevar Bush, produced a report for President Roosevelt titled "Science—The Endless Frontier," encouraging greater federal support for public research. This document led to the creation of both the National Institutes of Health (NIH) and the National Science Foundation (NSF), now the main agencies that support life science studies.

Through the late 1960s, biological science was conducted almost exclusively within academia and had few ties to business. The commercial value of biology was unrecognized. Drugs were chemicals—and pharmaceutical innovation had stalled in the absence of new targets. Chemistry and engineering, not biology, represented the majority of industry partnerships. Where university-industry relationships did exist, activity was generally low. Technology transfer occurred primarily via corporations hiring university graduates or academic consultants.

In the early 1970s, a new generation of life science companies began to appear, with some focused on developing DNA technologies. Although DNA was discovered in 1953, it had remained a curiosity of chemists. The amino acids (the fundamental building blocks of proteins) corresponding to genetic code were not determined until 1965, and few techniques existed to "read" or edit the chemical instructions. A breakthrough came in 1973 when biologists Stanley Cohen (Stanford) and Herbert Boyer (UCSF) developed a practical way to manipulate DNA constructs. Their method for recombinant DNA technology, published in the Proceedings of the National Academy of Sciences later that year, described how fragments of DNA could be directly cloned and expressed in other cells.

With recombinant techniques, snippets of the molecule could be "cut" from one genome and "pasted" into the DNA of another with enzymatic tools. Common microbes like the gut bacterium Escherichia coli could be transformed into miniature factories, able to make biochemical products difficult or impossible to synthesize using standard chemistries. DNA created an efficient way to develop biologicals, including vaccines, viral components, or even complex proteins like hormones or antibodies. Heavily touted in the scientific and popular media, genetic engineering created great expectations for the future.

News of this technology reached Neils Reimer, the director of Stanford University's patenting and licensing efforts. Earlier, Reimer had developed a novel IP capture scheme intended to grow licensing revenues. Under his plan, IP was solicited proactively, with any resulting royalties split equally (1/3 each) between the submitting researcher, the researcher's department, and the university. With scientists benefiting directly, IP submissions increased significantly. Pleased with the results, Stanford went on to create a formal IP development service, the University Office of Technology Licensing, one of the first dedicated technology transfer offices in the country.

Reimer recognized how attractive the new DNA technology would be to industry. Cohen gave his permission to proceed with a patent, but true to academic principles, disavowed any personal share of proceeds. Reimer's application to the U.S. Patent and Trademark Office (USPTO) became the center of scientific and public controversy. Apart from the safety of genetic engineering, concerns included opposition to the patenting of a general research method, questions over the patentability of life forms and genes (eventually affirmed by the Supreme Court in Diamond v. Chakrabarty), and how university commercial activities might threaten free inquiry. Complicating matters, government policies that addressed the ownership of inventions made using federal funds were vague.

Eventually, commercial interest outweighed safety and regulatory concerns, and U.S. patent 4,237,224 was granted to the two universities in December of 1980. Two other applications related to the technology, collectively known as the Cohen-Boyer recombinant DNA cloning patent, were also issued and describe some of the fundamental tools for the sciences of molecular biology and genetics.

Commercial biotechnology began with a handshake deal. In 1975, venture capitalist Robert Swanson met Boyer at a bar near the UCSF campus. Over drinks, they formed a plan to create a company to sell gene-based medicines. They incorporated Genentech (Genetic Engineering Technology) the following year, with each making an initial investment of $500 in the firm. Two years later, the company had successfully cloned and expressed the gene for human insulin, a remarkable achievement for the day. When Genentech shares soared at IPO in 1980, they initiated a wave of speculative activity that carried another dozen biotechnology firms to the market over the next 24 months.

The biotech boom quickly transformed the congenial, open world of biological research into a genetic gold rush. Overnight, academic scientists were thrust into the role of executives and businessmen. Naïve, brash, and fueled by VC cash, they competed against each other to identify and express medically important genes. Still skeptical of the technology, pharmaceutical companies watched from the sidelines as Genentech cemented its early lead, licensed insulin to Eli Lilly, and brought recombinant Human Growth Hormone to market independently in 1985. In less than a decade, a credible threat to established chemistry-based pharmaceuticals had emerged from nowhere.

In virgin commercial space, biotechnology grew rapidly, along with a host of supportive companies. Firms scrambled to identify and characterize new genes—potential drug targets and a scarce, nonrenewable resource—funneling millions into parallel research streams. With a new tool for dissecting cellular biochemistry that allowed the molecular basis of human disease and health to be explored with precision, academic research also flourished. Other genetic technologies soon followed in the wake of recombinant DNA, including polymerase chain reaction (PCR)—a method of amplifying minute amounts of DNA. The rate of innovation in life science moved closer to that of the semiconductor industry.

New legislation was created to streamline the transfer of IP between the public and private domains. Significantly, the Bayh-Dole act of 1980, drafted to encourage private investment for the commercial development of academic discoveries, allowed institutions to file patents on inventions resulting from federally funded research. Research became a new source of revenue for universities. Schools established or expanded technology transfer offices, which grew from 25 or 30 throughout the country in 1980 to more than 250 today, and began to actively seek commercially attractive ideas. Biology figured prominently in this search. According to recent statistics, currently 10 of the top 25 holders of U.S. DNA-based patents are universities, research institutions, or the U.S. government itself.

How to best manage biotech IP was an open question. With gene sequences potentially worth billions, and the validity of biotech patents untested, aggressive IP capture was encouraged, if only as a defensive measure. This position has been reinforced over time, and is now widely reflected in industry practices and statistics. According to a survey of biotech patenting trends published in the October 2004 issue of Nature Biotechnology, only 42 DNA-based patents were approved by the USPTO in 1981; by 2001, this figure had swollen to 4,463—although numbers have fallen back to roughly 3,500 since this peak. The Biotechnology Industry Organization (BIO) maintains that strong IP is essential not only to the success of biotechnology companies, but also to their survival.

Biotechnology delivered on its promise to bring new innovation and wealth. Today more than 200,000 people are employed directly by the industry, and companies have appeared to fill every technological and market niche. Biotechnology has led to many new medicines, diagnostics tools, and consumer products, including food, textiles, and enzymes. It has also stimulated new innovation in the traditional pharmaceutical and agricultural companies, all of which today incorporate biotechnologies into their research and development programs.

Universities also participated in the prestige and economic rewards of biotech. Biological research has blossomed throughout the academic world. By helping the first biotech startups get their footing, universities have formed close relationships with these now-established firms. These alliances were seeded in part by the nonexclusive licensing of Cohen-Boyer methods, eventually leading to more than 400 companies' purchasing rights. Licensing proved a rich source of university discretionary funds, with Cohen-Boyer alone returning about $250 million to UCSF and Stanford over the 17 years the patents remained in force.

Intellectual Property and Growing Challenges

Biotechnology now touches on virtually every facet of human culture and technological achievement and is a rising economic force throughout the world. All Western countries (and many developing ones) have specifically targeted life science as an engine of long-term economic growth. The public and scientific expectation for what biotechnology can or will accomplish has yet to peak, in part because the technology is still relatively complex and confined to professional circles.

Life science research has enjoyed healthy expansion within academia, supported in part by the NIH, whose annual budget increased from $3 billion in 1980 to over $27 billion in 2003. Reflecting this growth, the primary result of research—scientific publications—continues to mushroom. Pubmed, a journal database service maintained by the National Library of Medicine, adds 7,000 new science and medicine citations each week and now indexes more than 15 million listings from 18,000 journals. The volume of scientific data has driven scientists into increasingly fine specializations in an effort to remain current with recent literature.

The biotechnology industry has also enjoyed rapid expansion, fueled by pharmaceutical research and development (R&D) spending that climbed from $1.5 billion in 1980 to more than $20 billion in 2002. More than 1,450 companies now operate in the U.S.; those publicly traded have a market capitalization of about $300 billion. Industry revenues have increased from $11 billion in 1994 to almost $39 billion in 2003, mainly from the sale of drugs—a consumer market that continues to expand. The Congressional Budget Office (CBO) reported in 2003 that prescription drug expenditures rose at an inflation-adjusted rate of 14.5% between 1997 and 2002 to surpass $160 billion annually, outpacing all other health spending categories.

Yet, despite these strong results, biotechnology is not the picture of perfect health. In defiance of R&D spending trends, drug output has slowed over the last decade. Applications to the Food and Drug Administration (FDA), the agency responsible for evaluating new pharmaceuticals, fell from a high of 131 in 1996 to only 72 in 2003, while approvals of new molecular entities (NMEs) fell 60% over the same period, dropping from 53 to 21. Even with the growth observed in drug sales, the biotechnology industry as a whole remains in the red, recording $50 billion in losses since 1994. The top 50 companies account for the bulk of the industry's market capitalization and revenues.

While research seems to be thriving, development—in life science, a process exclusive to the commercial domain—is struggling. Although often grouped together as "R&D," research and development are actually very different processes. Research tends to be relatively unstructured and produces new observations, often summarized in scientific publications. It attracts free thinkers, explorers, and risk takers. In contrast, development attempts to transform a research discovery into a finished product, ready for sale. Drug development can take years to advance a molecule through the series of phased clinical trials (ranging from I to III) meant to determine basic safety, dosages, and efficacy necessary before seeking the FDA's approval for sale. Most drugs never exit this "pipeline." If they do, they enter an ongoing postmarket analysis (Phase IV) that in part monitors for rare or long-term effects. Development thus attracts careful, detail-oriented, process-driven individuals intent on minimizing risks.

Pushing a drug through development requires massive investment and commitment. Wyeth R&D president, Robert Ruffolo Jr., estimated in 2003 that R&D charges now range between $1.2 to 1.4 billion, while others place this figure anywhere between $400 million and $800 million. There is no way to be sure of the true cost, as companies closely guard these figures, which are used to justify new drug pricing. Whatever the exact numbers, the cost of drug development continues to rise at about 12% to 14% each year, well in excess of inflation. Given finite financial resources, the increasing cost of developing a new drug is the main bottleneck between promising research and new therapeutics. Only a small fraction of research, public or private, will ever enter the development pipeline.

IP practices contribute to this constriction. Only heavily protected molecules are likely to be backed by investors and developed. Competitive pressures have also fostered a secretive mindset and produced a mass of patent claims renowned for its complexity. This "thicket" impedes collaboration and materials transfer with other companies and universities, slowing R&D. IP sculpts the overall form of biotech companies. In an effort to reduce intellectual friction while retaining proprietary control, companies are driven to bring outside groups "in-house" through purchase or hire. In part, this has resulted in successive waves of merger and acquisition (M&A) activity, consolidating the biotech and pharma industries to produce giant, global organizations.

While sales and marketing efficiencies may result from consolidation, little proof that size only can yield R&D efficiencies remains scarce. Research cannot be mandated, at any price. Meanwhile, candidate drugs in development—although selected with the utmost care—may fail at any point in the pipeline. Given these risks, the ability to remain flexible and make unbiased decisions would seem crucial, but large R&D organizations can display considerable inertia and be hard to steer. Research may be slow to transfer to development, while failing projects in development may linger in the pipeline, burning cash. Industrial scientists also face intellectual isolation, with little exposure to ideas or peers outside company walls. Finding the right balance for successful research and development has been difficult for companies—one factor in why life commercial R&D has yet to demonstrate any clear economies of scale.

Meanwhile, expanding corporate bulk narrows the range of development choices that make economic sense. Large companies often set their sights on blockbusters—molecules with the potential to bring in $1 billion or more in annual sales. This makes the choice of what candidates to advance into development critical—a multibillion-dollar, multiyear commitment with risks and rewards different for each molecule. Even FDA approval for sale does not eliminate risk exposure, since drugs can be withdrawn if serious complications are discovered—an outcome certain to produce a flurry of class action lawsuits. Accordingly, the industry lobbies that strong IP is necessary for companies to recoup R&D costs, have cash to expand R&D activities, and also accumulate defensive legal reserves.

At the other end of the corporate spectrum, small biotech companies also struggle with IP. Nimble and highly motivated, most struggle to manage cash "burn" just to survive among the big industry players. They face not only high R&D costs, but also substantial legal fees, as they work to create new products or technologies. With limited cash and only a small number of patents in their IP portfolios, they produce little competitive pressure in the industry. Most remain speculative investments with almost no opportunity to independently market drugs. To persist, many companies form a symbiosis with big pharma, while others offer themselves as prey—innovative fodder for those with the resources to consume them.

Meanwhile, the richest and most plentiful source of low-cost innovation for companies—academic research—is fast drying up. Universities, while still friendly to commercial interests, better understand the value of their IP and have become shrewd negotiators. Technology transfer negotiations require more time—and end up costing much more money. In response to these complications, deals and collaborations with individual researchers have fallen out of favor, in preference to comprehensive "blanket" alliances. These sweeping arrangements, however, are much less attractive to the universities, particularly in the face of mounting reports of conflict of interest. The ideal economic balance for IP transfer from the public to private domain remains to be found.

The present drug development paradigm thus appears to suffer from economic challenges that have yet to be solved. Perhaps the most worrisome of these problems is the industry's failure, despite great internal effort, to decrease drug development costs. Without a turnaround in this metric, no reversal of drug output or consumer pricing trends can result—a mounting concern as Western society ages and demands more healthcare. Increasing tensions is the recall of several heavily marketed drugs that may have shown dangerous side effects even in early testing. Not only has this damaged consumer trust that companies will make safety the top priority, but it has also called in question the FDA's practices and relationship with industry. It has even forced a reevaluation of the financial risks and liabilities associated with large-market blockbuster drugs.

Open Source Biology

With present pharmacoeconomic trends unlikely to change in the immediate future, the path toward a sustainable drug industry remains as elusive. There is also a widening understanding that today's pharmaceutical companies—focused on disease management—may not have consumers' best interests in mind. Today there are few incentives for companies to improve any drug (at least until patent protection nears expiration) or to develop biological technologies that might lead to either prevention or cure.

In this light, some have begun to openly question whether there are other viable paths to drug development. At the heart of alternative routes is IP management. Since the passage of Bayh-Dole, scientists have been presented with two options for sharing research: publication; or patent and license with optional publication. The latter choice, heavily favored for discovery with commercial potential, has resulted in the current biotechnology industry. The alternative—open, unrestricted publication—has never been seriously considered a path to commercial development in the life sciences.

Now, open source, mainly used to develop computer software, has yielded strong evidence that open development may in fact be economically viable. OSS projects, including the Linux operating system and Apache Web Server, have become prominent examples that open strategies can result in robust, commercial-grade offerings. Open source has also emerged as an economic force, resulting in the formation of new companies like Red Hat, or adding revenues to the top line of others, like Sun and IBM. This success has encouraged speculation that similar results could be produced in biological development, if OSB could be made to work.

Recently, lawyers Stephen Maurer and Arti Rai and computational biologist Andrej Sali published a paper titled "Finding cures for tropical diseases: Is open source an answer?" to discuss how OSB might work. They suggest that OSB could organize many small research and development efforts toward the manufacture and testing of tropical disease drugs, reducing the final point-of-sale cost. Whether such a scheme would work in practice is unknown. However, there is no a priori reason why non-software products like drugs cannot be made using open source methods: it is not unreasonable that a community of open drug developers could produce open drugs. The unanswered question is whether, without IP, this development could be made economically sustainable enough to attract investors.

Any R&D effort, drugs or software, will consume resources that have real dollar costs. OSS developments are economically sustainable in part because these costs are kept very low. Geographic location, time zones, and physical facilities are not factors. Similarly, legal fees, product distribution costs, communication charges, and travel costs are also essentially zero. Few salaries are paid. OSS works because overhead is minimized while the aggregated value of donated developer time keeps growing over time. OSB faces a different economic reality. Any life sciences project, even an open source one, would come attached with physical constraints and very large costs. Laboratories are required. Millions of dollars of reagents, equipment, and testing are necessary. Realistically, before any OSB effort could yield a commercial product, the real dollar cost of biological R&D would need to be greatly reduced.

The Internet is helping to do this. The Web has already dropped the direct cost of doing scientific research, while also encouraging IP freedom. It has become an important repository for scientific information, much of it accessible openly and for free. Open access journal sites like the Public Library of Science (PLoS) and BioMedCentral now deliver peer-reviewed articles online at no charge and without copyright restrictions. Databases of DNA sequence data, human variation data, and, more recently, clinical trial results are available online. Sophisticated tools that link research datasets and support complex queries are beginning to appear. Science Commons, recently launched by the nonprofit Creative Commons, hopes to further interaction by making it easier for scientists, universities, and industries to share data and other IP. Overall, the Internet now allows most individuals, professionals or not, and even those in developing nations, free access to a wealth of high-quality scientific information. The main challenge for OSB to work, then, is to translate this research data into sustainable real-world open development projects.

New development strategies are beginning to emerge. Although not strictly open source, the company OneWorld Health appears to have found one successful path to reducing both IP and development charges. Based in San Francisco and billing itself as the first U.S. nonprofit pharmaceutical company, OneWorld assembles donated IP, expertise, and funds to further therapeutic development for diseases common in the Third World. It is working on drugs for malaria, leishmaniasis, and Chagas disease (a parasitic disease that can lead to heart failure), among others, and expects to launch its first product in 2005. However, while OneWorld's efforts are to be praised, its model is limited to drug molecules and markets not considered interesting to its proprietary partners.

The Biological Innovation for Open Society initiative (BIOS, http://www.bios.net), the brainchild of plant biologist Richard Jefferson, is also working to reduce the cost of biological development, and is willing to challenge proprietary groups to do so. Launched in 2004 and supported by a Rockefeller grant and technology from IBM, BIOS provides researchers with tools to share, manage, and navigate biotech IP, with an eye to facilitating open agricultural biotechnology. Keen on open source, Jefferson intends to create a patent commons and seed it with a broad method that allows plant researchers, public or private, to sidestep proprietary gene transfer technologies that restrict genetically modified (GM) crop development. Crops created with this community IP would be more affordable by growers throughout the world and be easier to manage than proprietary offerings. Meanwhile, the open patent commons would provide a defensive shield against proprietary challenges to their use.

Yet neither of these development models resembles the archetype OSS project, with an online platform, simple IP structure, and low overhead. For this reason, support is being found for a simpler model, a direct way for open source biology to follow in the footsteps of open software. The idea is to treat DNA, the foundation of virtually everything biological, for what it already is widely recognized in biology to be—a programming language. Virtually anything related to biology on this planet, living or not, can be reduced to this common denominator: a sequence of DNA bases that specifies its form and metabolism. DNA in a cell is no different from the 0s and 1s in a computer program. DNA is biological source code.

If OSS works, and DNA is software, don't reinvent: adapt. Allow genetic engineering to be done in the same way that software is engineered today, on computers with specialized software tools. In this way, OSB could closely parallel the strategies and, perhaps, realize the same advantages of open source software. Furthermore, since the DNA molecule can be a commercial product unto itself, and can direct biological synthesis of many bioproducts in vivo, circumventing the need for large production facilities, genetics can shorten the distance between research and development considerably. Because of these features, DNA code holds great potential to make OSB a reality, and also the possibility of developing a wide range of open biological products economically. Today a new science called synthetic biology is allowing researchers to move beyond mere speculation of this potential to practically test these ideas in reality.

Synthetic Biology and Genomic Programming

Since 1972, genetic engineering has been performed using the Cohen-Boyer recombinant techniques. These methods require DNA molecules to be extracted from cells and physically rearranged into new genetic designs—a process not unlike writing a letter "ransom note" style. Done in the lab, proficiency in this work typically requires an advanced degree with practical experience, a lot of equipment and reagents, and considerable time. Even relatively mundane procedures can take experienced technicians many months of tedious work, visible only by indirect methods. Compared to other modern engineering efforts—for example, microprocessor, aircraft, or building design, today performed in computer environments—genetic engineering remains a crude, manual process.

The emergence of synthetic biology (SB) changes everything. Founded on automated chemistries that permit long-chain DNA to be synthesized de novo, SB is a platform of software tools used to design and test artificial DNA molecules. It is an output device for bioinformatic software, and provides scientists with a way to write DNA sequences, not just read and comprehend them. The technology greatly lowers the barriers to genomic work: anyone with access to a computer can effectively create or edit DNA with exquisite precision. Overall, by transforming DNA into a biological programming language, SB represents the biggest improvement in genetic technology since Cohen-Boyer. It advances biological design into the digital age.

More than just bringing new speed and convenience to genetics, SB brings genetic scientists an alternative to unrestricted publication or patent. It is a creative tool, one that both proprietary companies and academic researchers will use to design DNA code. However, the technology brings an opportunity to reevaluate how the resultant IP should be protected. Today patent is used almost exclusively for biotech IP, including gene sequences—but synthetic biology makes new DNA designs into authored products like software. This type of IP is most often protected by copyright. Copyright would be inexpensive and easy to use, and would dovetail well with the application open source licenses, offering attractive IP benefits. However, without historical or legal precedent, there is no way to know how genetic copyrights would change R&D, or whether they would even be recognized as valid.

With the close similarity to software programming, synthetic biology gives OSB modeled after OSS a good chance of success. OSB could adapt the open source concepts, tools, licenses, and business models that already exist. Already, dozens of bioinformatic tools have been released under open source licenses, and software development platforms like SourceForge and Tigris could be easily modified to support DNA codewriting. Overall, for OSB based on SB to produce biological products, it would need to overcome only two main obstacles. First, it would need to attract an open developer community. Second, the genetic programs developed in the digital domain would need to be made affordably testable in real-world laboratories.

Open source synthetic biology will presumably find some support among genomic and bioinformatic scientists, many of whom currently release both data and tools openly on the Internet. However, Drew Endy, an assistant professor at MIT, is not taking any chances. He is actively seeding a new generation of biological programmers by teaching students how to build custom bacteria. Using presynthesized DNA dubbed "biobricks," or de novo code, Endy has created the biological equivalent of many electronic parts, including transistors, LEDs, and photosensors. Biobricks can be assembled in various ways to new create biological circuits, with bacterial cells the test breadboard. Biobricks form the foundation for MIT's multisite graduate student challenge, meant to encourage new synthetic designs and raise interest in synthetic techniques. The strategy is working: Endy's efforts have received wide attention in the technology press, and MIT's first conference on synthetics brought together more than 300 participants.

Endy is also a strong supporter of OSB, placing the biobricks standard registry in the public domain, a move he hopes will encourage others to use the technology and to share their own components. There is concern that unless an open ideology can be fostered, researchers might choose to patent each individual component, making biological programming a legal quagmire. Already, synthetic switches to turn genes on and off have been patented. Engineers Rob Carlson and Roger Brent, also early adopters of synthetic technologies, have warned of choosing a proprietary path and slowing innovation. In a white paper sent to DARPA, the advanced research agency of the U.S. military and an early backer of synthetic development, the pair argued that the development of a public domain "kernel" in synthetic biology could avert the negative consequences of having knowledge useful to the design of living organisms held proprietary. They maintain that biology conducted in an open manner would be, like open software, "robust and adaptive, providing for a more secure economy and country."

Great advantages could result if OSB can seed developer communities with keen interest in writing biological software. The sharing of genetic program designs openly should quickly lead to novel designs. The ability to engineer life on a computer desktop, not in a laboratory, should dissolve interdisciplinary boundaries and bring many new ideas into the biological sciences. Importantly, it allows genomic projects to aggregate and organize large numbers of developers. Online genomic development communities could blossom into virtual R&D organizations that dwarf those even of big pharma, yet be far more sustainable, open, and empowered. With inclusive membership and open data, "hobbyist" researchers—increasingly valuable contributors to astronomy, physics, and other sciences—would also enjoy the opportunity to participate meaningfully in collaborative genetic projects.

Meanwhile, the second obstacle to OSB producing a biological product, discovering inexpensive ways for genomic designs to be testable in the real world, is self-resolving. The per-base cost of long-chain DNA synthesis is dropping rapidly as commercial DNA providers compete for research customers. Today constructs that are viral size can be produced affordably. If current trends continue, human genome-size constructs will be realistic, both technologically and financially, by 2010. The economics of making commercial products with synthetics should become more attractive over time, if we can just learn how to write good code.

The Risk of Biological Hacking

Open source synthetic biology could result in a broad base of genomic skills in society and lead to low-cost gene-based commercial products. However, some people worry that convenient biological programming raises the chance that amateurs, hackers, or even terrorists will use the same tools to develop malicious genetic designs, either on purpose or by accident. While in silico genetic experimentation arguably poses little risk (the information remains within the digital domain), gaining access to synthetic DNA, or the equipment to make synthetic DNA, is not difficult, even for private individuals. The equipment for a functional DNA lab can be bought on eBay and would fit in a basement, kitchen, or garage. With the complete genomes for dozens of viruses publicly available—including Ebola, Marsburg, and SARS—a biological incident involving a synthetic virus may be a matter of when, not if. The proof of concept has already been demonstrated: in 2002, researchers at SUNY Stony Brook assembled an infectious synthetic poliovirus using mail-order DNA fragments.

The threat of a carefully engineered bioweapon unlike anything found in nature is thus real and significant. A CIA document titled "The Darker Bioweapons Future" published in 2003 cites a panel of experts that note "the effects of some of these engineered biological agents could be worse than any disease known to man." This panel also noted that genomics is entering "an explosive growth phase" and that "the resulting wave of knowledge will evolve rapidly and be so broad, complex, and widely available to the public that traditional intelligence means for monitoring WMD development could prove inadequate." These warnings make clear that the consequences of hacking DNA can be greater than those of hacking computer code. DNA programs, if they are chemically synthesized, will share physical reality with us. If released into the environment, the genetic information cannot be easily deleted or traced. Unwanted genetic distribution is already a problem in agricultural biotechnology, underscoring the fact that this is not a purely theoretical problem. Additionally, unlike in the digital world, nature cannot be "rebooted" if we make a serious mistake or encounter unexpected problems.

Yet, despite these concerns, synthetic DNA itself does not pose a new risk to society or the environment. Conventional laboratory methods of mutating and selecting organisms for enhanced pathogenicity have existed for decades, suggesting that those intent on using organisms for malicious purposes are probably already well equipped to do so. Genetic engineering is too powerful a technology to banish or outlaw, and it is already too late to suppress synthetic technologies: the underlying chemistries have been available for more than 20 years. Synthetic DNA will act mainly as an innovative accelerant, affecting all biotechnological applications, positive or negative. With synthetic technologies, the appearance of designer pathogens tuned to defeat our immune systems will not appear overnight, but we can no longer risk being complacent. For maximum safety, we need to broadly foster genetic awareness and skills in society, if only to better deal with rapidly evolving natural threats like SARS, Asian bird flu, or West Nile virus.

This makes the decision of whether to support OSB a critical one that extends beyond IP or economics. OSB may prove necessary as a means to assimilate the body of genetic information as a whole, an inherent advantage unlikely to be matched by more focused proprietary groups. No one company has the resources to understand the full complexity of DNA, the most difficult programming language for humans to comprehend. Because we didn't create the language or the computing environment, we must reverse engineer our understanding—taking systems apart one organism at a time, one cell type at a time, and finally one gene at a time. Putting all this data together again to get the big picture is like making a giant jigsaw puzzle. It requires cooperation, not fragmentation, to get perspective. By this rationale, the use of open genomics may bring far greater safety and security to synthetics. It should minimize fundamental design errors while also maximizing the responsive capability to unexpected challenges, including natural and engineered threats. Open computer software is also widely regarded as being more secure and more adaptive to threats than proprietary offerings.

Future Trends in Open Source Biology

Synthetic DNA appears poised to stimulate a new wave of genomic innovation, one closely aligned to software and using similar programming concepts. The decision of whether to support OSB will have long-term ramifications on the environment, the economy, and human health. There are thousands of biological products that could be designed collaboratively and produced inexpensively using open source synthetic DNA—including vaccines, proteins, and gene therapies. If sufficient resources can be identified to bring these products to market without transferring them to proprietary interests—for example, through open IP partnerships with generic drug manufacturers or HMOs, government loans, or the collection of personal donations—the commercial sale of first-run therapeutics at generic prices could result, and not just for tropical medicines.

While real-world data and experiences will have to be collected before any conclusions can be drawn, the economics of open development may prove very attractive for synthetic genetics. Nature lends some support to this idea. DNA is openly shared in the physical world. The molecule is able to cross easily between species and is surprisingly plastic even within species or individuals. Not only this, but the grammar and syntax of the genetic language have remained conserved across all species throughout evolution. Nature doesn't waste energy with needless complications. If has retained a common genetic language and supported free exchange because this was less expensive than any other alternative.

If OSS proves any guide, synthetic DNA code will evolve fastest in the digital domain if allowed to be free. Efforts are underway in the scientific community so that a fair test of this idea can be made. Allies are being sought in government, law, finance, industry, and the general public to marshal support for open biological development projects. The idea is alluring to many people, in part because of the increasing awareness, use, and approval of open source software. Just as open software now provides individuals with greater software choice, OSB may one day offer individuals another source of safe and affordable gene-based technologies, therapeutics, and other bioproducts.

While OSB may not be immediately attractive, and perhaps may even be threatening, to some biotechnology companies, the benefits may be very appealing to others, especially those with limited resources. Given how few biotechnology companies can successfully produce and market any product, the value of proprietary IP may be considerably overvalued in life science—especially when sufficient R&D opportunities exist to prevent competitive overlaps. Companies may find that switching to open source allows them access to public information, institutions, and a scientific community usable or unapproachable by their closed peers. Open companies are able to exchange ideas or materials on core technologies easily, without threatening development within their particular specializations.

In addition to encouraging and amassing shared biological innovation, the decision to support OSB could produce immediate cost savings or benefits. Researchers, whether in academia or open companies, would conserve valuable research time not writing patent applications, while retaining the ability to freely publish and profit (albeit nonexclusively) from their innovations. Open companies would reduce legal costs, freeing cash to further develop programs. Universities would also save money on IP maintenance while retaining the ability to commercialize life science innovations. Meanwhile, government agencies involved in IP—including the patent office, the FDA, and the courts—could find their workloads easier to manage if open source use grows. This will be particularly important with biotechnology IP if, as expected, synthetic leads to an acceleration of research discovery. In any case, the use of patent and strong IP would still remain available as an option if deemed more appropriate.

OSB could also appreciably shrink public distrust related to genetic development. The public is growing more aware of the issues that surround GM foods, genetic testing, stem cell technologies, gene doping, and gene therapies. While OSB will not solve the differences of opinion that make these topics controversial, open source ensures that each individual has equal access to information and also a voice in what products or technologies are developed. Open developments succeed because there is a demand for the product and sufficient community support, be it skill or money, to bring them to market. This shifts the agenda away from proprietary interests toward the needs and demands of consumers—a shift likely to be strongly supported by those requiring new drugs or therapeutics.

OSB also fits nicely with emerging trends in health and medicine. Pharmaceutical development is expected to grow increasingly personalized in the future, drawing on recognition that individual variation—genetic, environmental, and behavioral—plays a large role in human health and disease. Pharmacogenomic efforts are underway to allow better disease appearance prediction (facilitating preventative steps or treatments) and to determine how any particular patient will respond to a given drug. In time, therapies tailored to small patient subgroups, even individuals, will become favored—although present economic trends do not support this direction. Unable to make large-market drugs sustainable, personalized medicine cannot be accomplished by today's drug industry. However, gene-based medicine offers a tantalizing solution: change the informational content of each drug, not the drug itself. With DNA-based treatments, or gene therapies, the chemical entity remains the same, while the biological effects it can produce in cells changes. DNA may prove an efficient drug, inexpensive to make and modify, with a range of delivery options.

Synthetic design software, connected to an open, integrated dataset, could quickly evolve to facilitate the fabrication of custom health solutions for small populations or individuals. This capability will likely bring about large changes to the way drugs are currently tested in clinical trials: customized drugs could be tested only on the individuals for whom they were designed, who would presumably be agreeable to their use. New medicines could be quickly delivered to those in need. Even without broad clinical trials, gene-based drugs should prove very safe and reliable as test data is accumulated. Flaws with a genetic design would be excluded by software from happening again, and any complications would naturally be isolated to very small patient populations. Open source personalized medicine could also bring some legal relief to drug companies. With an open, software-based drug development system, class action lawsuits against synthetic drug manufacturers would be highly unlikely except in cases of outright negligence or fraud.

In summary, the concept of OSB is highly compelling. Focusing collaborative energies on the rapid and inexpensive development, synthesis, and testing of innovative biological products is a commanding vision. The potential of open genomics, with countless applications in medicine, agriculture, and environmental protection, is enormous—but so are the challenges to society. Familiar ideas and structures may need to be discarded before forward steps can be taken. Large changes in how scientific information is shared, new drugs are designed and tested, and knowledge is protected are sure to come. As we advance toward this future, tapped into a vast global web of information, we may find ourselves worrying much less about the ownership of old ideas and more about how to generate the next new one.

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