Gigi Kwik Gronvall

Clustering Class I MHC Modulates Sensitivity of T Cell Recognition

T cell recognition of peptide-MHC is highly specific and is sensitive to very low levels of agonist peptide; however, it is unclear how this effect is achieved or regulated. In this study we show that clustering class I MHC molecules on the cell surface of B lymphoblasts enhances their recognition by mouse and human T cells. We increased clustering of MHC I molecules by two methods, cholesterol depletion and direct cross-linking of a dimerizable MHC construct. Imaging showed that both treatments increased the size and intensity of MHC clusters on the cell surface. Enlarged clusters correlated with enhanced lysis and T cell effector function. Enhancements were peptide-specific and greatest at low concentrations of peptide. Clustering MHC class I enhanced recognition of both strong and weak agonists but not null peptide. Our results indicate that the lateral organization of MHC class I on the cell surface can modulate the sensitivity of T cell recognition of agonist peptide.

The FDA animal efficacy rule and biodefense.

VOLUME 25 NUMBER 10 OCTOBER 2007 NATURE BIOTECHNOLOGY The difficulty Nature Biotechnology encountered in finding accurate information about BioShield and BARDA underlies the communications gap concerning US biodefense. Clearly, what officials at the Office of the Biomedical Advanced Research and Development Authority (OBARDA) are aware of and what information seeps out into the outside world (and to those in industry) are two entirely different things. The Acambis smallpox vaccine that the FDA’s VRBAC acted on in May of this year and approved in September was the live attenuated vaccine (ACAM2000), not the modified vaccinia Ankara as we wrongly stated. We still remain perplexed, however, as to why US officials did not award MVA smallpox vaccine a stockpile supply contract when Acambis already received contracts from the National Institutes of Allergy and Infectious Diseases to develop MVA as a smallpox vaccine for immunocompromised subjects (around 10% of the population). This seems like the right hand not knowing what the left hand is doing. Clearly the decision was a surprise to Acambis; the loss of a potentially billion dollar contract contributed to the departure of the CEO, a 40% slump in share price and a cut in the workforce. Our description of the Hollis Eden debacle erroneously stated the company had a contract, whereas it only had responded to a Request for Proposal (RFP) for radiation countermeasures. We apologize to our readers and OBARDA for this error. Either contract or RFP, however, the criticism of poor communication by the government still stands. We also thank Vanderwagen for clarifying the lack of an indemnity clause in the final Pandemic and All-Hazards Preparedness Act—although this means, of course, that BioShield is even less enticing to companies than we originally thought. We still are somewhat in the dark about the indemnity provision in the Emergency Preparedness Act of 2005, which appears to apply only to pandemic flu, part of BARDA’s purview. So does the indemnity clause only pertain to part of BARDA’s programs? With regards to the US government’s exemption from FOIA under the Act, it seems very likely that officials will find many situations where they regard information must be kept secret if the definition is: “to safeguard non-public technical information deemed to reveal significant vulnerabilities of existing public health defenses, generated during countermeasure or product advanced research and development.” Overall, we remain convinced that the US government needs to do a much better job disseminating information about BioShield and proactively communicating its goals for BARDA and BioShield with companies. Although we welcome the appointment of an interim director, this is hardly the answer to providing clear leadership.

U.S. Medical Countermeasure Development Since 2001: A Long Way Yet to Go

The U.S. government has taken significant steps toward developing and acquiring vaccines, drugs, and other medical countermeasures (MCMs) to protect and treat the population after a biological attack. In contrast to 2001, there is now a procedure for the Department of Health and Human Services (HHS) to develop, license, and stockpile MCMs for civilian use. Another major accomplishment is smallpox preparedness: There is now an adequate supply of vaccine for every person in the U.S., and there is an alternative vaccine meant for immunocompromised people and those with close contact with them. In spite of these and other accomplishments, the U.S. government MCM effort has been criticized by federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts who state that the efforts lack central leadership and accountability and that the pace of progress has been slow. A clear operational strategy for using MCMs, which would guide their development and acquisition, is also lacking. In this article, we review key areas of progress made since 2001 to develop and acquire MCMs, and we summarize what we judge to be the most critical and often mentioned areas where improvements are needed.

Everywhere You Look: Select Agent Pathogens

The United States regulates more than 80 human, animal, and plant pathogens as part of the Select Agent Program, imposing strict controls on access by U.S. researchers and laboratories. However, almost all of these pathogens are also found in nature. The map at the end of this article (see supplementary material at http://www .liebertonline.com/doi/suppl/10.1089/bsp.2011.0321/suppl_ file/Supp_Data.pdf) depicts the countries in which select agent pathogens caused disease between January 1, 2009, and October 31, 2010. Although pathogen security measures justifiably have been strengthened since 2001, the widespread natural occurrence of these pathogens indicates an inherent limitation of the regulations.

Biosecurity Implications for the Synthesis of Horsepox, an Orthopoxvirus

This article examines the biosecurity and biodefense implications resulting from the recent creation of horsepox virus, a noncirculating (extinct) species of orthopoxvirus. Here we examine the technical aspects of the horsepox virus synthesis and conclude that orthopox synthesis experiments currently remain technically challenging-and will continue to be so, even once this work is published in the scientific literature. This limits potential misuse by some types of nefarious actors. We also examine the implications of one stated purpose for the recreation of horsepox virus: the development of a smallpox vaccine. If the development is successful, it could take advantage of US government incentives for the priority FDA review of medical countermeasures (MCMs) against biosecurity threats. However, if this case leads to the determination that this incentive is counterproductive for security, the newly created priority review voucher program should be more clearly defined or limited based on need. Limiting the program could have costs that require further consideration, however, as general incentives for biodefense medical countermeasure development are required for MCMs to be available. Finally, while the recreation of horsepox virus was not technically trivial, nor was it cell-free, this experiment was a de facto demonstration of already-assumed scientific capabilities. The ability to recreate horsepox, or smallpox, will remain no matter what policy controls are put into place. It will be impossible to close off all avenues for nefarious misuse of gene synthesis, or misuse of biological materials more broadly. As a result, we advocate for the implementation of policy, regulations, and guidance that will make illicit recreation harder, more burdensome, more detectable, and, thus, more preventable without having sweeping negative consequences for the research enterprise. As part of our biosecurity efforts, we must also encourage and enable scientists to participate actively and to do all they can to safeguard their technical fields from irresponsible or illicit actions.

Assessing the bioweapons threat

Is there a foundation of agreement among experts about risk? The U.S. government (USG) has taken steps intended to diminish the likelihood of misuse of research—in one recent action, declaring a funding moratorium on gain-of-function studies on influenza until a risk-benefit analysis can be conducted (1). The analysis is expected to examine biosafety concerns, the potential for such research to produce a biological weapons agent, and the possibility that publication may lower barriers to bioweapons development (1). To analyze the security risks of biological research, however, it is first necessary to determine the likelihood that bioweapons will threaten national security and to what degree legitimate research is at risk of misuse. This type of assessment is fraught with uncertainty.

Antimicrobial Resistance Is a Global Health Emergency

Leading experts have declared that the end of the age of antibiotics is imminent and that this development could undermine the foundation of much of modern medicine and public health.1,2 Since antibiotics were first introduced into clinical practice some 80 years ago, microbes have been evolving ways to resist these drugs, but in recent years this problem of antimicrobial resistance (AMR) has been rapidly getting worse.1 It is estimated that there are at least 2 million cases per year of AMR infection in the United States directly resulting in at least 23,000 deaths.2 In many nations around the world, the problem of AMR is worse than in the US. For example, rates of gram-negative resistance reach over 25% in parts of southern Europe, and all 6 regions of the World Health Organization (WHO) include countries that are reporting more than a 50% incidence of resistance of Klebsiella to third-generation cephalosporins.3,4 There are no reliable estimates of the number of cases globally, largely because surveillance is incomplete; however, fragmentary evidence suggests that the problem is much worse in many developing countries.1 These infections occur in nearly all medical settings. A substantial percentage of childhood ear infections, urinary tract infections, community-acquired pneumonias, sexually transmitted infections, and wound and skin infections are caused by pathogens that have evolved resistance to one or more antibiotics to which they were previously sensitive. For example, all WHO regions report countries with rates of resistance to penicillin exceeding 50% in community-acquired pneumococcal infections, and half of the WHO regions have countries wherein the rate of gonorrhea resistance to third-generation cephalosporins exceeds 50%.4

Options for Synthetic DNA Order Screening, Revisited

Gene synthesis providers affiliated with the International Gene Synthesis Consortium (IGSC) voluntarily screen double-stranded DNA (dsDNA) synthesis orders over 200 bp to check for matches to regulated pathogens and to screen customers. Questions have been raised, however, about the continuing feasibility and effectiveness of screening. ABSTRACT Gene synthesis providers affiliated with the International Gene Synthesis Consortium (IGSC) voluntarily screen double-stranded DNA (dsDNA) synthesis orders over 200 bp to check for matches to regulated pathogens and to screen customers. Questions have been raised, however, about the continuing feasibility and effectiveness of screening. There are technical challenges (e.g., oligonucleotides and tracts of DNA less than 200 bp are not screened) and corporate challenges (e.g., the costs of screening are high, but other costs are dropping, so screening is an increasing portion of operating costs). In this article, we describe tangible actions that should be taken to (i) preserve the effectiveness of DNA order screening as a security tool and (ii) develop additional mechanisms to increase the safety and security of DNA synthesis technologies. Screening is not a perfect solution to DNA synthesis security challenges, but we believe it is still a valuable addition to security, and it can remain effective for some time.

A new role for scientists in the Biological Weapons Convention.

Moves are afoot that could make individual scientists, not just governments, accountable under international and national bioweapon legislation.

Safety, security, and serving the public interest in synthetic biology

This article describes what may be done by scientists and by the biotechnology industry, generally, to address the safety and security challenges in synthetic biology. Given the technical expertise requirements for developing sound policy options, as well as the importance of these issues to the future of the industry, scientists who work in synthetic biology should be informed about these challenges and get involved in shaping policies relevant to the field.