Standards for synthetic biology
Jonathan B. Tucker is helping to track the emerging field of synthetic biology in writing “Double-Edged DNA: Preventing the Misuse of Gene Synthesis” (Issues, Spring 2010) in addition to his 2006 article coauthored with Raymond Zilinskas, “The Promise and Perils of Synthetic Biology” (The New Atlantis). Although the current article effectively states the reasons why a voluntary approach to managing synthetic genomics can be effective, several statements require clarification, consideration, or correction.
As early as 2006, Tucker identified and assessed the two main options for screening synthetic nucleic acid orders to address the potential risk posed by the commercial availability of synthetic genetic sequences of concern: (1) requiring U.S. suppliers under the penalty of law to implement mandatory screening, or (2) relying on the due diligence of U.S. providers to prevent malicious uses of their products by voluntarily implementing screening for pathogenic sequences. These options have also been considered by the U.S. government, and the issue is revisited by Tucker in the current article.
Upon extensive consultation with industry and on behalf of a broad interagency working group, on November 27, 2009, the U.S. Department of Health and Human Services (HHS) released the draft report Screening Framework Guidance for Synthetic Double-Stranded DNA Providers. The primary goal in developing guidance for synthetic double-stranded DNA providers is to minimize the risk that unauthorized individuals or individuals with malicious intent will gain access to toxins and organisms that are of concern because they were created or modified with nucleic acid synthesis technologies, while at the same time minimizing any negative effects on the conduct of research and business operations. In the document, sequences of concern are identified as those unique to Select Agents and Toxins (and, for international orders, sequences unique to pathogens and toxins on the Commerce Control List). The draft document offers guidance to providers of synthetic genomic products regarding the screening of orders so that these orders are filled in compliance with current U.S. regulations and to encourage best practices in addressing potential biosecurity concerns. Providers also may implement additional safeguards if they deem necessary (“The U.S. Government acknowledges that there are synthetic nucleic acid sequences from non-Select Agents or Toxins that may pose a biosecurity concern. Synthetic nucleic acid providers may choose to investigate such sequences as part of their best practices”).
In order to be effective, risk mitigation should be international in scope and dependent in part on the willingness of the research community to do their own diligence and patronize only companies that have screening procedures in place. In developing the draft guidance, the U.S. government took into consideration not only the best practices in the industry but also the need to promote screening universality by considering the ease of integration, with minimal cost and within existing protocols, for U.S. companies, U.S.-based firms operating abroad, and international companies.
Tucker indicates that “one currently unresolved issue is whether gene-synthesis companies should supply synthetic DNA to researchers who lack an institutional affiliation.” The draft guidance released by HHS indicates that the “lack of affiliation with an institution or firm does not automatically indicate that a customer’s order should be denied. In such cases, the U.S. government recommends conducting follow-up screening.”
With regard to recommended sequence-screening methodologies, Tucker notes that critics of the Best Match approach state that Best Match is “weaker than either industry standard because it cannot detect genetic sequences of pathogens and toxins of biosecurity concern that are not on the Select Agent List.” We believe that the quoted language illustrates a common misunderstanding about Best Match, specifically the confusion between the screening methodology (the how) with what one hopes to identify (the what).
In the Best Match approach, sequence orders are screened against a comprehensive and publicly available database of all known nucleotide sequences, such as GenBank, and the identity of the top match is determined. For example, the Best Match might be to a sequence from a Select Agent, such as Bacillus anthracis, or to a non-Select Agent, such as Escherichia coli. In the draft guidance, it is recommended that providers use this approach to flag sequences unique to Select Agents and Toxins. However, Best Match could be used to identify sequences from any number of lists or curated pathogen databases. Therefore, the statement that Best Match cannot be used to identify non-Select Agent and Toxin sequences is inaccurate. In fact, the Best Match–plus method described by the author could be achieved by simply using the Best Match approach to screen for any sequence unique to a Select Agent or Toxin or to a sequence contained in the curated pathogen database suggested by the author, without using the two-step process proposed. Thus, identical results could be achieved by simply using an (automated) Best Match approach that is set up to identify sequences from Select Agents and sequences in a curated database. When any hits are identified, further follow-up screening by human experts would occur. As such, Best Match could easily be adapted by providers to identify sequences from Select Agents or non-Select Agents, if desired.
Tucker generally focuses on the critiques of the Best Match approach and does not mention that key benefits of Best Match were noted at the January 11, 2010, American Association for the Advancement of Science (AAAS) meeting. As noted by one attendee and reiterated in public comments, Best Match “automatically adapts to new sequences entered in GenBank … and is adaptable to completely synthetic genes.”
Tucker also presents the views of an attendee at the AAAS meeting, who indicated that by endorsing the Best Match approach, the screening standards in the industry will be downgraded. In fact, industry providers such as Integrated DNA Technologies and Blue Heron Biotechnology, which helped lead industry efforts to implement voluntary screening methodologies in the absence of any specific government guidance, indicated (as summarized in Nature, December 4, 2009) that it is inaccurate to assert that “the government guidelines are less rigorous and far-reaching than industry’s already-adopted standards.” Additionally, this view implies that companies who have led the way in voluntarily developing high screening standards are now eager to reduce those standards.
Tucker notes that “the draft U.S. government guidelines are widely considered inadequate.” In fact, a number of media sources have noted broad support for the U.S. government guidance. Specifically, in Microbe, vol. 5, no. 4, it is noted that “Although [AAAS meeting] participants identified several specific concerns and offered HHS several ways to address them, in general members of this industry niche and their counterparts at universities support the HHS set of voluntary recommendations,” based on information from Gerald Epstein of AAAS, who helped to organize the January AAAS workshop. Additionally, in the December 2009 Nature article referenced above, Damon Terrill of Integrated DNA Technologies stated that “The approach recommended in the draft government guidelines in fact produce[s] exactly the information we need to ensure safety and security in the real world of gene synthesis.”
Deliberations within the U.S. government to consider potential changes to the draft guidance are ongoing, but no final decisions have been made. In addition to the comments presented at the AAAS meeting, there are a number of other considerations, including formal public comments submitted in response to the Federal Register Notice and existing federal regulations. Finally, the U.S. government is also considering (as stated by Tucker and Zilinskas in their 2006 article) “how best to guide synthetic biology in a safe and socially useful direction without smothering it in the cradle.”
Jonathan Tucker paints a vivid picture of how U.S. officials write biosecurity regulations. But as Tucker explains, that’s only half the story. The real news is how a small group of European companies [the International Association Synthetic Biology (IASB)] wrote their own standards and then pushed 80% of the industry to follow their lead. Security experts have long urged industry to practice self-governance. Here, finally, they got their wish. What have we learned?
The first and most surprising lesson is that private standards can be tough. The IASB’s Code requires human screeners to investigate every gene shipped to customers. Satisfying this requirement is far more costly—but also more effective—than the government’s Best Match algorithm. As Tucker points out, the United States may yet upgrade Best Match to include human screening. If it does, industry will have led the way.
The second lesson is that the private standard-setting is remarkably swift and decisive. Here, we should recall that the IASB’s Code had a competitor. In August 2009, two of the industry’s largest companies (DNA 2.0 and Geneart) announced what they called a fast and cheap alternative. Within three months, however, they had dropped the idea and replaced it with a Harmonized Protocol that echoes the IASB Code. Why the quick turnaround? Economics. Gene synthesis is a volume business where companies survive by keeping their customers happy. And big customers hate controversy. When “fast and cheap” became too controversial, even its authors decided to dump it. Compare this with conventional regulation, where debates typically drag on for years.
The third lesson is that private standards have teeth. Tucker is right to ask whether rogue companies could earn a profit by defying industry standards. But what is the market? No sensible company would risk losing its customer base for one or two terrorist orders, particularly when the “terrorists” may actually be “red teams” from a business rival or the media. Moreover, the synthetic gene market, unlike national law and most treaties, is inherently global. This means that the business case for adopting standards in Iowa is more or less identical in Shanghai. The fact that two Chinese companies have already signed the IASB’s Code surely confirms this. It’s also a safe bet that still more Chinese companies would have joined the Code but were confused by the U.S. government’s failure to write a Best Match requirement that includes human screening. This is still another reason to fix Best Match.
The final and most troubling lesson is that the government has so far refused to say which private standards it prefers. But standards wars are rough-and-tumble affairs, and their outcomes are unpredictable. If officials prefer one proposed standard over another (and they usually do), then they have an obligation to say so publicly. Nor is there any legal or ethical obstacle to prevent this. Officials routinely criticize companies for raising prices and overpaying CEOs. Why should inadequate biosecurity practices be any different?
The private standards story is just beginning. Indeed, the IASB has said that it wants to extend the concept by launching a shared threats database [the Virulence Factor Information Repository (VIREP)] and other industry-wide collaborations. Shrewd government engagement can strengthen and shape these ventures.
It’s not as if we have not been investing in girls who call the developing world home. Reams of annual reports attest to well-meaning efforts on the part of many. And that includes investments in health and education, the focus of the pungent clarion call offered by Miriam Temin, Ruth Levine, and Sandy Stonesifer in the spring 2010 Issues. What sets “Start with a Girl: A New Agenda for Global Health” apart is the contextual filter through which girls are viewed. No longer should girls (and especially adolescent girls) be viewed only as children deserving of all we can offer. Girls of today are and must be thought of as the women of tomorrow.
It is the women of the developing world, separate and distinct from their male counterparts, who are broadly and rightly viewed as holding the key to progress. Simply put, without investing in women, and hence in girls, little meaningful change for the better can be anticipated in arenas as diverse as education, economic growth and productivity, climate change, and even national security. It is no accident that the 2009 rollout of an expanded version of “Start with a Girl” at the Washington, DC–based Center for Global Development was headlined by Melanne S. Verveer, the first-ever U.S. Ambassador-at-Large for Global Women’s Issues.
Investing in women is investing in today. Investing in girls is investing in tomorrow. We need to hear that at a time when much global attention is mostly directed at the women of the developing world, a focus galvanized by the ever-intractable tragedy of maternal mortality and morbidity affecting low- and middle-income countries. We need to do both: Invest in tomorrow as well as today. In this context, “Start with a Girl” is doing us a great service by reminding us of the seemingly obvious but all too often forgotten importance of prevention when girls are still girls.
Investing in girls is an unassailable imperative. However, the global health system has not yet fully grappled with translating advocacy into action. Making the case is one thing. Implementation is quite another. As the authors acknowledge, “the commonly identified roots of the problem are factors that are difficult to change.” Alas, vaccination alone will not reverse deeply ingrained gender norms rooted in a long-standing Gordian knot replete with religious, social, and cultural overtones. Progress is inevitable. It is just that overnight progress is unlikely. Recall the seminal importance of the 20th century to the well-being of women in the developed world. Let’s hope that the 21st century is as kind to the women and girls residing in less fortunate places on this planet of ours.
Miriam Temin, Ruth Levine, and Sandy Stonesifer offer a valuable analysis of the ways in which the systematic marginalization of adolescent girls can have a detrimental impact on society as a whole. As the authors note, this is most strongly experienced in the developing world, where there are some 600 million girls between the ages of 10 and 19 who disproportionately lack adequate access to education, health care, and decent employment.
The authors point out that the international community has historically failed to match its rhetoric with the kinds of actions that would actually improve the lives of adolescent girls worldwide. Sadly, they are right. For the most part, adolescent girls’ issues have been largely neglected; reproductive health education or even things as basic as providing girls-only toilets in schools have remained in the margins of national economic development strategies, if included at all. For their part, donors have also not been particularly attentive to the needs of adolescent girls.
But this is rapidly changing. The international community is now on the verge of making adolescent girls the center point of development strategies. For example, at the recent Commission on the Status of Women meeting at the United Nations (UN), the heads of six key UN agencies (the International Labor Organization, UNESCO, UNFPA, UNICEF, UNIFEM, and the World Health Organization) unveiled a strategy document that, for the first time, places the interests of women and girls at the heart of the development agenda. The plan was issued under the auspices of the newly formed UN Adolescent Girls Task Force, of which these six agency heads are members. It commits them to support efforts to educate adolescent girls, improve their health (including their reproductive health), keep them free from violence, promote their economic and social development, and better monitor their progress, so policies can be developed “to advance their well-being and realize their human rights.”
Part of the reason why adolescent girl issues are moving to the forefront of the international community’s discussion on development can be attributed to the upcoming 2010 Summit to review progress on achieving the UN Millennium Development Goals. These goals were adopted by 191 world leaders in 2000 as targets for global development; they include reducing child mortality, cutting poverty, stopping the spread of HIV/AIDS, and achieving universal primary education by 2015.
For many of the reasons outlined by Temin, Levine, and Stonesifer, leaders are now realizing that progress on the Millennium Development Goals cannot be sustained unless the needs of girls are addressed directly. The connection between fulfilling our obligations to girls and achieving many of the Millennium Development Goals is becoming firmly entrenched in UN circles.
As always, civil society has an important role to play. Aligned with the UN’s renewed focus on adolescent girls, the UN Foundation has launched a campaign called Girl Up to harness the enthusiasm and entrepreneurial spirit of U.S girls as advocates for their counterparts in the developing world.
The authors deserve praise for so thoroughly articulating the linkages between the lives of girls and the overall welfare of their communities. The rest of the world, finally, is beginning to catch on.
Miriam Temin, Ruth Levine, and Sandy Stonesifer issue a call to action for the international community to finally “walk the talk” of its numerous reports on the importance of helping adolescent girls experience healthy transitions to adulthood. Rather than focusing on the individual behavioral interventions that target girls, the authors direct our attention to the underlying social determinants of girls’ poorer health and education outcomes in societies around the world. They highlight the need for attention to the social factors affecting girls’ lives and well-being, such as societal gender norms that make girls vulnerable to infection with HIV and gender-based violence. They also critique the education systems that fail to retain girls through secondary school and thereby hinder the positive impact that girls’ education can have on population health.
The authors provide helpful examples of projects in Latin America and sub-Saharan Africa that have successfully worked to change local gender inequalities between young men and women (in Brazil) or that have enhanced girls’ social networks and successful school participation (in Ethiopia). Although the authors emphasize the importance of including boys and men in the effort to improve girls’ health and well-being, additional social science research is needed on the effectiveness of intervening with younger children (including boys). For example, interventions with younger children could prevent the negative impacts of gender inequalities on older adolescent girls’ and women’s health and economic futures; this may be more effective than trying to undo social norms already formed. Using an interdisciplinary perspective, policymakers, researchers, and practitioners need to recognize the gendered dynamics of girls’ everyday experiences and to implement structural and environmental changes in girls’ school and community environments.
The authors highlight the need to support girls in becoming their own advocates; they emphasize how girls who speak up for their own health and well-being are the most effective agents of social change. The importance of this final point cannot be overstated and could be enhanced by identifying successful interventions around the world where girls’ voices and recommendations are already being successfully incorporated into interventions and government policy. In January 2005, when UNICEF and the International Water and Sanitation Center brought together Ministers of Education and schoolgirls from across low-income countries to speak about how the onset of menses was disruptive to school participation, the girls’ articulate explanations convinced the predominantly male ministers of structural gender discrimination in schools that was hindering the closing of the gender gap in education (Carol Watson, UNICEF, personal communication). As a 12-year-old representative from Nigeria noted at the meeting, “It is no longer a cliché that any long-term development goal without the involvement of children and young people, who are the future-oriented generation, is not a positive step.” (Oxford Roundtable, 2005, p. 28). This holds true for meeting all of the girls’ health goals called for in this article.
Promoting the health of young women means supporting the agency of young women and working with young men and women to reduce gender inequalities. “Start with a Girl” is a valuable roadmap for this effort.
To innovate, educate
In June 2009, the Pew Research Center conducted a survey of more than 1,000 randomly sampled American adults. Each participant took a brief quiz testing their science knowledge including one question that asked whether or not lasers work by focusing sound waves (they don’t). More than half of those surveyed got the question wrong, and no single demographic group scored better than 66%.
Many approaches to stoking innovation in the United States focus on R&D funding or other advanced options. Within education, most attention is paid to increasing the number of Americans graduating from college with a STEM-related degree. Yet this ignores a fundamental truth about the innovation agenda: Developing economic strength based on a foundation of innovation is only as good as a nation’s capacity to implement what is yielded from R&D. As such, enhancing individual capacity for understanding math and science across the entire spectrum of our society is necessary to drive the nation into an era of global competitiveness.
The truth is that modern manufacturing facilities require that workers understand innovations such as lasers or the complex computers and space-age fuel cells used in today’s automotive industry. Math and science education is crucial to instilling the ability to critically analyze and problem solve, two of the vital skills that all employers increasingly demand and decreasingly find in their workers. Although many people point to the growing “green economy” as the way to reduce the employment rates, many U.S. companies are forced to outsource production of products such as solar panels because such a large proportion of the nation’s workforce has only a high school diploma or less. Skilled workers are becoming increasingly difficult to find.
In their article “United States: A Strategy for Innovation” (Issues, Spring 2010) Diana Farrell and Thomas Kalil describe the U.S. export control systems as being “rooted in the Cold War era of more than 50 years ago.” If this line were applied to public education, it would vastly understate just how archaic the system has become. We cannot expect to foster a love of math and science in our children when our classrooms continue to exclude higher levels of learning from the curriculum. We cannot expect students to pursue STEM-skilled careers—at any level—when we consider career technical education and work-based learning opportunities to be a lesser educational experience.
The Carnegie-IAS Commission on Mathematics and Science Education recently outlined many necessary changes to the education system in its report The Opportunity Equation. These foundational reforms include: the establishment of clear, common math and science standards; improving math and science teaching; and redesigning schools to deliver excellent and equitable math and science education. In support of these reforms, the U.S. Chamber of Commerce’s Institute for a Competitive Workforce is mobilizing its grassroots network to support policies that develop a STEM-capable workforce.
Ultimately, we must foster a culture that makes math and science desirable. That may eventually be achieved through the nation’s classrooms, but the work begins with modern public policy that recognizes education as the cornerstone of innovation and economic development.