Help us map the synthetic genomics industry

Synthetic genomics may be the most common dual-use biotechnology today. The ability to construct double-stranded DNA from scratch enables a better understanding of protein structure and function, and the development of new vaccines, speeding up the process of biological engineering. However, these technologies also have the potential to allow people with nefarious intentions access to toxins and pathogens that would be otherwise difficult to acquire.

With each passing year, synthetic biologists are becoming more adept at designing novel structures and functions from DNA, RNA, and proteins—the basic building blocks of biology. The Central Dogma of molecular biology is that DNA is transcribed into RNA, which is then translated into proteins (4). Proteins then perform a variety of functions inside and outside the cells. They can join together to build the cytoskeleton of the cell, break down molecules to produce the energy the cell needs, and much more. However, proteins can be also used to synthesize toxins such as cyanide salts and aflatoxins. Proteins can also themselves be toxins, such as ricin or Botulinum toxin.

These approaches even confer the ability to create viruses from scratch. In the past, DNA synthesis was a key step of the de novo (i.e., from scratch) synthesis of poliovirus, the 1918 influenza virus, and most recently horsepox virus. While the synthesis of an infectious virus requires a high degree of technical expertise, access to DNA was a bottleneck. For a ‘booted’ virus to be infectious, its synthesized DNA must have as few errors as possible. While benchtop synthesizers make it easier to synthesize double-stranded DNA without having to order a sequence from a gene synthesis company, this method typically leads to too many errors to make a long genetic sequence with high enough accuracy.

This potential threat can be reduced if gene synthesis providers screen their orders. Therefore, in 2010, the US department of Health and Human Services published the Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA. This guidance recommends that companies screen both the customer and sequence of any gene synthesis order to ensure its legitimacy (13). However, since the publication of the HHS guidance, the gene synthesis industry has quadrupled in size, and the number of providers doubled. This once US-based industry is now growing, and is projected to keep growing, particularly in the Asia-Pacific region, where it was almost absent when the HHS guidance was written (14).

Here at the Johns Hopkins Center for Health Security we are currently mapping the gene synthesis industry in order to understand which changes are necessary for the future of the HHS guidance. We are searching for gene synthesis companies and cataloguing them based on their laboratory locations, the reach of their shipments, and the breadth of their screenings. We have published here a work-in-progress map with the hope of receiving feedback from the public and gene synthesis companies and ensuring the information we collected is correct.

If you would like to add a gene synthesis company to this map, or if you can verify information about a gene synthesis company’s laboratory locations, shipping, or screening protocols, please email Noga Aharony at naharon1@jhu.edu. We are assembling this information for publication, and will be making further recommendations regarding gene synthesis order screening.

Moving the needle on infectious disease control investment

In mid-June, the National Academies of Science, Engineering, and Medicine held a workshop called “Understanding the Economics of Microbial Threats”, bringing together economic and public health subject matter experts to discuss the economics of infectious disease emergencies. Discussion topics were diverse, ranging from preparing for the next pandemic to tackling antimicrobial resistance.

An inability to control a deadly outbreak substantially affects regional and global stability. The 2014 Ebola outbreak cost resource-constrained Sierra Leone, Guinea, and Liberia almost $3 billion, and contributed to longer term reductions in GDP.  Outbreaks burden communities both through associated direct costs of preventing and treating illness, and the resulting longer term reduced labor productivity and health consequences.

Dr. Tom Inglesby, our Center’s director, was a workshop panelist and described challenges and important considerations for optimizing responses to global catastrophic biological risks (GCBRs). An ideal response to these large-scale pandemics is multifaceted, requiring substantial planning, stockpile maintenance, non-pharmaceutical interventions (e.g., closing schools), and flexibility to account for unique pathogen attack or mortality rates. Strengthening resources to address GCBRs is critical. Though scientists and governments have historically focused on other catastrophic risks like nuclear threats, the consequences of inadequately preparing for the next pandemic could be immense, as we demonstrated in the Center’s recent Clade X exercise.

Despite consensus in the health economics community that infection control is important, these messages often do not resonate with other key stakeholders. As Workshop Chair Dr. Peter Sands articulated, economic policymakers rarely fully consider the financial burden of microbial threats. A contributing factor to this, Dr. Martin Meltzer explained, is that future pandemics are inevitable but unpredictable, appearing anywhere between once every 10 to 60 years. This time range makes the necessary investment in infection control often unpalatable to policymakers who prefer shorter-term solutions with clear outputs that can be achieved within terms or election cycles. Furthermore, the way in which modeling results are sometimes communicated can sometimes backfire. Some speakers cited that “trillion-itis”, or the tendency for modelling results to express potential findings in terms of billions and trillions, can make these issues appear too challenging to address. Communicating economic findings in compelling, transparent, and easily digestible ways is critical.

One of the most discussed topics was antimicrobial resistance (AMR). A clear threat to global health security, AMR has received increasing attention from governments, industry, and academia-- but finding solutions remains daunting.  A key issue is that pharmaceutical investment in antibiotics is generally not as profitable as other drugs because antimicrobial prescriptions are usually for acute issues and are restricted to reduce future drug resistance. Executives from major pharmaceutical stakeholders including Merck, Pfizer, and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) discussed potential strategies they believe could address this issue.  While many government-led incentives are designed to “push” industry to increase investment through initial R&D benefits, speakers cited the need for “pull incentives” that enable companies to view antibiotic development as a truly profitable long-term venture. Similar suggestions were stated in a recent World Economic Forum report. Ensuring market exclusivity, fostering public-private partnerships such as CARB-X, or structuring reimbursement mechanisms so that profits aren’t based on total use were also proposed as important future directions. Conversely, some participants acknowledged that solutions to incentivize industry can be politically challenging because they often result in resource-limited governments paying for-profit companies more for their products. Ensuring transparency, trust, and empathy for the complexities of these issues were cited as important considerations to tackle AMR. 

The valuable discussions and research presented in this two-day workshop served as an instrumental stepping stone for future progress in understanding and addressing the economic issues of infectious disease.

House Energy & Commerce Subcommittee Hearing on Public Health and Biopreparedness: Observations

Strengthening our national health security has been an enduring, bipartisan objective of the federal government for many years. Prompted in part by infectious disease threats like Ebola, Zika and this past year’s particularly severe seasonal influenza, Congress has used the reauthorization of a key piece of health security legislation as a moment to take stock. The Oversight and Investigations Subcommittee of the House Committee on Energy and Commerce recently called a hearing on the federal government’s ability to respond to natural and intentional infectious disease threats. The conversation mostly centered around pandemic influenza and the development of medical countermeasures for biological attacks.

There were four expert witnesses representing the primary responding HHS components:

  • Dr. Rick Bright – Director of BARDA and Deputy Assistant Secretary of ASPR
  • Dr. Anne Schuchat – Principal Deputy Director, CDC
  • Dr. Anthony Fauci – Director, NIH NIAID
  • Rear Admiral Denise Hinton – Chief Scientist, FDA

There were several important comments and opinions shared during the hearing, but the main takeaways points that I gleaned were as follows:

  1. There was a significant amount of focus on preparing for an influenza pandemic, particularly in terms of detection and response. There were a lot of questions directed towards the NIH and FDA representatives on this topic. They both emphasized the importance of inter-agency collaboration to speed up the clinical trial process.
  2. There is bipartisan support for the reauthorization of the Pandemic and all Hazards Preparedness Act (PAHPA), which will provide funding and resources to combat emerging infectious disease threats.
  3. Concern was expressed by committee members over the transfer of the Strategic National Stockpile (SNS) from the CDC to the Assistant Secretary for Preparedness and Response (ASPR). Representatives from both agencies reassured committee members of ongoing communication efforts to ensure a smooth transition.

The transfer of the SNS was a topic of concern because of the outsized importance of the SNS during public health emergencies. The SNS is a critical component of the U.S. preparedness response efforts. Proper management of the SNS is necessary for the rapid and organized distribution of medical countermeasures to the effected populations. Witnesses from ASPR and CDC reaffirmed the dedication of their respective organizations to ensure a smooth transfer with minimal consequences of new management. Dr. Bright said, “We have several working groups working very close with CDC and ASPR to evaluate various components of the stockpile transfer.” This sentiment was confirmed by Dr. Schuchat who followed up, “We are well on the way to a seamless transition.”

Many questions about the development of medical countermeasures and getting those products rapidly in to the market were directed towards the witnesses from NIAID and the FDA. Dr. Fauci of NIAID made several references to the promising avenue of multiplex point-of-care diagnostic tests that are capable of detecting multiple different viruses in one test with one sample. These tests would revolutionize response efforts to disease outbreaks, particularly in resource-poor settings. Dr. Fauci seemed enthusiastic about the technology, saying that “multiplex is a very important tool of the future now for detecting outbreaks.” Dr. Fauci also discussed Phase II trials for an Ebola vaccine and ongoing work to develop a universal influenza vaccine; although he admitted that such a product is still years away.

Re-authorizing PAHPA would be an important step in increasing the capacity of the United States to protect its own citizens and the global community from infectious disease threats. The original act was signed into law in 2006 and was re-authorized in 2013. A current reauthorization is being undertaken by Congress under the title of the Pandemic and All-Hazards Preparedness and Advancing Innovation Act (PAHPAI). PAHPAI will continue to support important preparedness efforts such as funding the development and stockpiling of vaccines, therapeutics and medical devices that will be needed during an emergency and enabling local, state, and federal public health agencies to rapidly respond to infectious disease emergencies. In his opening statements, Chairman Mr. Harper said, “Passage of PAHPA’s reauthorization would not only provide critical certainty for public health agencies and industry partners, it would also bring about some much needed reforms.” In general, committee members appeared supportive of re-authorizing PAHPA.

To Identify Pandemic Pathogens, Diagnose Every Case

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Of the roughly 1,400 bacterial, viral, protozoan, and fungal pathogens that are known to infect people, only a few have demonstrated the potential to cause a “sudden, extraordinary, widespread disaster beyond the collective capability of national and international governments and the private sector to control” – what my colleagues and I define as ‘Global Catastrophic Biological Risks’ (GCBRs). The members of this infamous club include some of humanity’s greatest scourges, including plague, smallpox, and pandemic influenza. While the current threat posed by these pathogens has been attenuated somewhat due to the modern infectious disease armamentarium (e.g., basic sanitation and hygiene, vaccines, and modern medical care), these and other pathogens nevertheless have the potential to cause mass death and the chaos and suffering that would inevitably follow.

In response, governments and health authorities have attempted to bound the problem by compiling both formal and informal lists of the pathogens most likely to cause severe epidemics or pandemics. Notable examples include the WHO’s R&D Blueprint and the CDC’s Bioterrorism Agents list. While these lists serve important planning or regulatory functions, they also can inhibit a comprehensive understanding of the biological threat landscape. As the 2009 emergence of the pandemic H1N1 influenza virus in Mexico (rather than Southeast Asia) and the importation of Zika virus to the Americas demonstrate, surprise has been the norm.

We believe this stems, in part, from list-based thinking. That’s why we were so pleased to see WHO include “Disease X” in this year’s update of the R&D Blueprint, as a reminder of the importance of constant vigilance and preparedness. This theme will feature prominently in the Clade X tabletop exercise that our Center is conducting this week.

For the past several months, my colleagues and I have been working to identify some common characteristics of pandemic pathogens. We hope our findings will spur more nuanced assessments of biological threats. I encourage you to check out our recently released final report.

There is one major finding from that report I want to highlight here.

The fact is, the vast majority of illnesses and deaths from infectious causes are never definitively diagnosed. This is true regardless of where in the world care is rendered. Instead, clinicians primarily rely on constellations of signs and symptoms, what are called ‘syndromes’, to whittle down the list of things that could conceivably cause the illness. While far less labor intensive than tracking each and every case down to its root cause, this aspect of medical practice makes it far more likely that index cases or clusters of known or unknown pathogens will go unnoticed.

We believe that clinicians the world over should be making routine use of classical clinical microbiology, clinical applications of next-generation sequencing, and point-of-care molecular diagnostics that are starting to become available. That information, once gleaned, should be rapidly and seamlessly transmitted to public health authorities. This improved flow of information would dramatically boost our ability to identify pandemic pathogens in a timely fashion.

Modernizing epidemiology through outbreak science

By Caitlin Rivers, PhD, MPH

I’m excited to announce that with support from the Open Philanthropy Project, my colleagues and I at the Johns Hopkins Center for Health Security will be working over the next eighteen months to develop a plan to develop an Outbreak Science Initiative to support the US government in responding to infectious disease outbreaks. The program would formally integrate the nation’s top disease outbreak scientists into federal response operations, where they could produce the forecasts, models, and analyses that decision makers need to allocate resources, compare interventions, and assess progress on outbreak containment. This capability would improve our ability to respond to outbreaks quickly and effectively.

We coin the term “outbreak science” to mean a subfield of epidemiology that uses infectious disease modeling, data science and visualization, and modern data practices for outbreak response. The goal of outbreak science is to connect public health decision makers with the most current data and analytics necessary to determine how best to contain outbreaks. Although this type of expertise has been influential in several major epidemics, it is often tapped by response officials in sporadic, ad hoc, and pro bono partnerships. There is currently no formal mechanism for public health officials to reliably and quickly access experts who can produce the models and analyses necessary to inform decision making.

The use of outbreak science during the 2014-2015 Ebola response is illustrative of the value of outbreak science. One influential model published by the Centers for Disease Control and Prevention forecast a worst-case scenario of more than one million cases if the epidemic continued unabated. It’s widely acknowledged that the CDC model galvanized the international response that ultimately contributed to control of the epidemic. However, CDC is one of just two groups in government with embedded outbreak science expertise. Most of the other models used during the outbreak, including those used to forecast case counts and monitor containment, were produced by academics with no formal connection to the response. They worked without guidance about the public health questions that needed answering, without official data sets, and without compensation. They also had to put their results in academic journals instead of in the hands of decision makers.

Conversely, decision makers without outbreak science support had no choice but to act without full analysis of the current and future state of the outbreak. This lack of adequate situational awareness potentially contributed to the late identification of funerals as superspreading events, and to the overdue surge of hospital beds. The disconnect between public health decision makers and modeling expertise limited the timeliness and applicability of most of the models produced during the Ebola outbreak, and reduced the effectiveness of the response. An outbreak science program would aim to close this critical gap in future public health events by formally integrating the best outbreak scientists into outbreak response operations to enable faster control of epidemics.

An Unwelcome “Newcomer” to the United Kingdom

Today, British Prime Minister Theresa May announced that a “Novichok” agent was used in the poisoning of Sergei Skripal and his daughter in Salisbury, England. This announcement is highly significant because the use of one of these agents points to a very sophisticated operation using next-generation chemical weapons.

That the word “Novichok” was used publicly could also be highly consequential, as it has a very specific meaning and history. The word “Novichok” roughly translates to “newcomer” and reflects the special nature of this class of nerve agents developed and manufactured in the former Soviet Union. Very little information on them is available generally or in the medical literature.  

In general, nerve agents work by interfering with neurotransmission through the inhibition of acetylcholinesterase, the enzyme that breaks down the neurotransmitter acetylcholine. The continued presence of acetylcholine in the neuromuscular junction leads to perpetual muscle contractions. The result is a recognizable clinical syndrome characterized by salivation, lacrimation, urination, diarrhea, pinpoint pupils, and seizure-like activity. Death arises from paralysis of respiratory muscles. As nerve agents, the “Novichok” agents would be expected to operate in this manner. There are antidotes for standard nerve agents that can be beneficial if given in time.

Familiar nerve agents include VX, sarin, soman, and tabun. “Novichok” agents appear to differ in a few key ways. First, they are deadlier - reportedly up to 10 times more lethal than VX.  Second, the production of "Novichok" agents can be more readily concealed from weapons inspectors, according to a Soviet chemist who worked with them. Other properties, such as improved ease of handling and the ability to evade standard chemical detection equipment, penetrate personal protective equipment, and resist treatment efforts have also been suggested in the fragmentary literature. 

As more information emanates from these cases in England, attention to clinical details of the resulting illnesses and their treatment will be essential to understanding the nature of these deadly agents and how to best counteract their effects. Additionally, because this appears to be the first confirmed deployment of a “Novichok” agent with more than a dozen people potentially exposed, there is a pressing medical and public health need to have all clinically relevant information about these agents that may be possessed by government entities disseminated to healthcare professionals immediately.

This latest use of a chemical warfare agent follows the 2017 assassination of Kim Jong-nam - the half-brother of North Korean dictator Kim Jong-un - in a Malaysian airport. In that case, a binary preparation of VX nerve agent was directly applied to the victim’s face. The US recently imposed additional sanctions on the DPRK in response. 

The use of chemical weapons is internationally prohibited by the Chemical Weapons Convention (CWC), to which 98% of the nations of the world are signatory. Though there is speculation that “Novichok” agents were designed to circumvent the CWC, any chemical used to cause harm is treated as a weapon, and their use is banned under the treaty. The UK government, the Organization on the Prohibition of Chemical Weapons (OPCW), and other national security agencies will need to investigate this particularly serious violation of the CWC.

[Note: This post has been updated from its original version]  

FY2019 Health Security Funding Outlook: Quick Take Based on President's Budget Request

By Crystal Watson, Tara Kirk Sell, and Matt Watson

With the release of the President’s Budget Request this week, we now have a glimpse into White House priorities and recommendations for major health security programs. While a detailed analysis will be forthcoming in our annual health security funding article, here is what we know so far:

Centers for Disease Control and Prevention (CDC): There should be a big change at CDC as the Strategic National Stockpile program is moved from its long-time home in the Office of Public Health Preparedness and Response (OPHPR) over to the Assistant Secretary for Preparedness and Response (ASPR). The Public Health Emergency Preparedness (PHEP) Cooperative Agreement program at CDC would receive a $5 million increase above the estimated FY2018 Continuing Resolution (CR) level, while CDC Preparedness and Response would be cut by $20 million, Influenza Planning would get a slight boost, and Emerging and Zoonotic Infectious Diseases programs would be cut by $60 million.

  FY2017 FY2018 FY2019
  (actual) (estimated CR) (budget)
Centers for Disease Control and Prevention (CDC)      
Public Health Emergency Preparedness (PHEP) Cooperative Agreements 658.5 655.5 660.0
CDC Preparedness and Response Capability (includes BioSense) 161.5 160.7 140.0
Strategic National Stockpile (SNS) 573.9 571.1 ---
Influenza Planning and Response 187.2 171.4 180.0
Emerging and Zoonotic Infectious Diseases 575.7 568.3 508.3

Office of the Assistant Secretary for Preparedness and Response (ASPR): As the new home for the SNS, ASPR’s budget would increase by over $575 million in FY2019. Other programs in ASPR would remain relatively flat, with the Hospital Preparedness Program (HPP) at $255 million (compared to $253 million estimated for FY2018), BARDA receiving about $2 million more than FY2018, and BioShield getting a $3 million increase. Pandemic influenza funding (split between ASPR and the Office of Global Affairs) would increase to a total of $250 million (almost $50 million more than in FY2018).

  FY2017 FY2018 FY2019
  (actual) (estimated CR) (budget)
Assistant Secretary for Emergency Preparedness and Response (ASPR)      
Medical Reserve Corps 6.0 6.0 4.0
Operations 30.9 30.9 31.0
Biomedical Advanced Research and Development Authority (BARDA) 510.0 508.0 512.0
Project BioShield 509.0 507.0 510.0
Strategic National Stockpile (SNS) --- --- 575.0
Preparedness and Emergency Operations 25.0 24.0 27.0
National Disaster Medical System (NDMS) 50.0 50.0 50.0
Hospital Preparedness (HPP) Grants (includes ESAR-VHP) 254.0 253.0 255.0
Policy and Planning 15.0 15.0 15.0
Pandemic Influenza (funded between ASPR and OGA) 72.0 112.0 250.0

Department of Homeland Security (DHS): The major development at DHS is creation of the new Countering Weapons of Mass Destruction (CWMD) Office and reorganization of health-security related programs from across the Department into CWMD. This office was created in December 2017 with the purpose of elevating the CWMD mission within the Department, and providing a centralized office for WMD-related programs. This Office will encompass programs and operations from a number of other parts of the Department, including the Domestic Nuclear Detection Office (DNDO), which will transfer all of its functions to the new CWMD Office; the Office of Health Affairs, which will transfer all of its functions; and the Science and Technology Directorate, which will transfer some of its functions to CWMD. A deeper dive into these budgets will be helpful in understanding what programs were moved, defunded, or kept in place. On initial review, here is what we know:

In total, CWMD’s proposed budget is $429.3 million in FY2019, including:

  • $209.3 million for Mission Support and Capability and Operations Support
    • Of which, $51.8 million will be for Biological Support, primarily for bio-detection (BioWatch)
  • $74.9 million for Procurement, Construction, and Improvements (primarily for radiological detection equipment)
  • $80.4 million for Research and Development (primarily for RN detection)
  • $64.7 million for federal assistance to federal, state, local, tribal, and territorial partners

For the Science and Technology Directorate, there is a proposed cost-sharing agreement for the National Bioforensic Analysis Center (NBFAC) within National Biodefense Analysis and Countermeasures Center (NBACC), where the FBI would assume operational costs for NBFAC (which is about 40% of NBACC’s total operational costs). In addition, S&T is proposing to transfer responsibility of the National Bio and Agro-Defense Facility (NBAF) Operations in its entirety to the US Department of Agriculture (USDA).

Global Health Security Agenda: Funding for the Global Health Security Agenda in the FY2019 budget would include $59 million designated GHSA funding out of a $109 million budget in the Global Disease Detection line at CDC, and $72.5 million in repurposed Ebola supplemental funds at US Agency for International Development (USAID). GHSA funds for CDC would be on top of any unexpended Ebola supplemental funding at CDC, which expires in FY2019 for that agency.

More to come in our comprehensive Federal Funding for Health Security analysis, published annually in Health Security.

The problem of horsepox synthesis: new approaches needed for oversight and publication review for research posing population-level risks

By Tom Inglesby

In summer 2017, a team of Canadian scientists revealed that they had synthesized the horsepox virus in a lab at the University of Alberta, and planned to publish their research. I and others expressed strong concern about the work at that time, and we have opposed its publication. 

Today, the science journal PLOS ONE published this research online, so it is now globally available. The horsepox researchers acknowledged that this work may lower the bar for other scientists interested in synthesizing smallpox. Before its eradication from nature in 1980, smallpox was humanity’s greatest infectious disease killer. Almost none of the global population in 2018 has effective immunity, and smallpox vaccine supplies are available only to protect a small fraction of the world. There are only two declared smallpox repositories, one in the United States and one in Russia. Any research that reduces the challenges of synthesizing smallpox de novo outside these repositories—as this work does—should be off limits unless, perhaps, there were to be extraordinary benefits that make the risks worth taking.

This work does not carry such extraordinary benefits. As Greg Koblenz has articulated in his paper on this issue, there is not a compelling case that governments will need or use this virus to develop a new and improved smallpox vaccine. Another justification made by the horsepox researchers was that it is important to demonstrate the feasibility of synthesizing smallpox de novo. But creating a new extraordinary risk (i.e., instructions for how to simplify smallpox synthesis) to show that the risk is legitimate is a dangerous path. In any event, relevant members of the science community have widely agreed that smallpox synthesis has been technically feasible for many years now. What this new research does is show the global scientific community how to synthesize orthopox viruses in an efficient way, to overcome technical challenges, and to employ techniques developed by one of the leading orthopox labs in the world.

Now, with this research published and accessible to the world, those of us who are deeply concerned about it should consider what is needed to prevent future events with such potential harmful impact. This horsepox synthesis research work has exposed serious flaws in how governments oversee research that has profound potential population-level adverse consequences. The University of Alberta research team admitted that regulatory authorities “may not have fully appreciated the significance of, or potential need for, regulation or approval of” their work. Clearly, fundamental changes need to be made. 

The most important locus of control should be whether specific research is approved and funded in the first place. When scientists are considering the pursuit of research that has the potential to increase highly consequential national population-level risks, national authorities and leading technical experts on those issues should be part of the approval process. When there are highly consequential international population-level implications, international public health leaders should also be involved. When researchers put forth claims about potential benefits of this work to justify extraordinary risks, those claims ought not be accepted without discussion; those claims should instead be examined by disinterested experts with the expertise to validate or refute them.

If research posing potential population-level risks does get performed without such high level national or international scrutiny, or without a disinterested examination of the benefits, publishers should have clear guidance from governments and a process for engaging with governments in the decision-making process regarding publication. That kind of system is not in place in the United States or elsewhere. Journals are now often on their own, in some cases with the help of a dual-use research committee that is comprised of individual scientists who may or may not have full understanding of the potential risks or the claims of benefits of the underlying research being published.   

We need to turn what we’ve learned from this damaging situation into actionable policies aimed at strengthening preparedness and global health security. The first step is changing the oversight and approval process for experiments that have potential to create highly consequential population-level risks. We also need a coinciding publication review system for such research with the scientific and government input necessary to avoid publishing research that increases risks to global populations.   

Is Captain America a Biological Weapon?

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As part of my trip to attend the 2017 Meeting of States Parties to the Biological and Toxin Weapons Convention (BWC), I attended a pre-meeting workshop hosted by the Malaysian and American Permanent Missions to the United Nations. This workshop provided a forum to discuss relevant bioweapons nonproliferation, preparedness and response efforts for deliberate and naturally occurring outbreaks and epidemics, international collaboration mechanisms, and the future of the Biological and Toxin Weapons Convention (BWC) leading up to the Meeting of States Parties. During one presentation on the security considerations for advances in genome editing, an interesting question was posed that reframed my perspective on the BWC:

Does the BWC adequately address genetic modification of higher order organisms?

Article I of the BWC states (emphasis added):

Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or otherwise acquire or retain:

(1)  microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes;

(2)  weapons, equipment or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict.

Written in the early 1970s, the BWC text is intentionally vague, providing it the flexibility to address emerging and unforeseen threats (eg, prions), but this vagueness leads to questions regarding its scope, especially in the context of higher order organisms—ie, complex organisms such as plants, animals, and humans.

Until this workshop, essentially the entirety of the several years during which I have been paying attention to the BWC, Article I seemed fairly straightforward to me. Beyond toxins (which the BWC explicitly states that it covers), I had always assumed that Article I covered bacteria, viruses, and fungi. Seems pretty obvious, right? Basically, just the things that can intentionally infect humans, animals, or plants in order to directly or indirectly cause harm to target populations.

But what if there is no infection, per se? What if the “biological agent” isn’t a pathogen at all, but rather, a human, animal, or plant? What if the affected individuals are volunteers rather than victims?

Using a fictional example to illustrate these issues, let’s look at the classic superhero Captain America. Captain America underwent some form of human enhancement as part of a US military program that transformed him from tiny weakling Steve Rogers into, well, Chris Evans for the sole purpose of battling Nazis in World War II. Under Article I, normal, naturally occurring pathogens would fall under “microbial or other biological agents,” so it would follow that modified versions of these pathogens would also qualify. But normal humans, animals, and plants do not seem to count as “other biological agents” in the context of the BWC, but what about enhanced or modified versions like Captain America or, perish the thought, the accidentally enhanced Teenage Mutant Ninja Turtles? Have we been unwittingly cheering for bioweapons this whole time?

The two principal tenants of Article I are that (1) the BWC specifically addresses biological organisms (as opposed to chemical or nuclear) AND (2) that the organism is used for purposes other than peaceful or protective (ie, for offensive or hostile purposes). The second part is pretty easy; if you have ever read a Captain America comic book or seen a Captain America/Avengers movie, it should be obvious that Captain America was designed for and utilized in an offensive capacity in combat. The first tenant, however, is a little less straightforward. Captain America is certainly a biological organism, but there is no explicit text in Article I that differentiates him from a normal human. Normal humans have been employed in military combat and other forms of violence for the entirety of our existence, but surely, they would not be regulated under the BWC. On the other hand, Captain America clearly is not a normal human, posing the question:

Does the deliberate modification of a human genome change this distinction in the context of the BWC?

The Captain America scenario raises a number of other questions with respect to how a bioweapon might be employed. In this case, Steve Rogers enthusiastically volunteered to be enhanced. Traditional bioweapons scenarios likely involve the victim population being harmed through direct infection or via secondary effects of infecting their animals and/or food sources rather than the attacker voluntarily being “infected” him/herself and posing no risk of infection to the target population. And speaking of “infected,” Captain America wasn’t ever really infected with a biological agent in the traditional sense; his biological makeup was simply modified through some targeted biological/radiological process, but there was no pathogen involved (to my knowledge, anyway; I’m not a superhero expert).

Would this biological/radiological process be regulated under the BWC, and if so, would Captain America then be considered to be a “[weapon], equipment or other means of delivery”? Additionally, there are numerous mechanisms available to enhance higher order organisms, ranging from improving performance through drugs or supplements to deliberate modification of the genome. Some infections can also potentially alter biological traits of higher order organisms, further blurring the line between infection and modification. In one timely example, mosquitoes infected with naturally occurring Wolbachia bacteria exhibit poorer transmission of vectorborne diseases like dengue and Zika.

The tools required to modify the biological traits of higher order organisms, to varying degrees, are rapidly increasing in number, capability, and availability. Considering the potential for these tools, and the resulting organisms, to be utilized for offensive purposes, explicit discussions are needed to ensure that all States Parties have a common understanding of the BWC’s scope and, in turn, adhere to the same norms with respect to the use of advanced biology and biotechnology and genetically modified organisms of all kinds.

The incredible pace of advancement in biology and biotechnology and its impact on the ability to deliberately modify the genomes of higher order organisms necessitates that these types of questions be addressed proactively rather than reactively. The ability to utilize tools such as CRISPR-Cas9 to treat genetic diseases seems to be just over the horizon. In fact, the US FDA recently approved the first directly applied gene therapy to treat blindness caused by an inherited genetic mutation. Scientists have also produced animals with excessive muscle mass using these types of tools, research that could potentially lead to treatments genetic disorders such as muscular dystrophy. If these techniques were utilized to enhance similar properties in normal, healthy humans—or other properties that could provide an advantage in combat—it could essentially result in the creation of super-soldiers, real-life versions of Captain America. In another example, genetically modified mosquitoes have already been employed to reduce local mosquito populations and, therefore, incidence of vectorborne diseases such as Zika and chikungunya. A release of modified bees or other insects in an agricultural area could result in substantial risk to food and economic security in the affected country or region due to the release of a genetically modified higher order organism.

The 2017 BWC Meeting of States Parties succeeded in its mandate to agree upon a program of work for the remainder of the intersessional period before the next Review Conference in 2021. The agreed-upon agenda includes an annual Meeting of Experts that provides for 8 days each year dedicated to substantive discussion about technical and policy issues surrounding:

  • International cooperation and assistance in the context of BWC Article X (2 days)
  • Review of developments in science and technology potentially relevant to the BWC (2 days)
  • Strengthening national implementation of the BWC (1 day)
  • Requesting and providing international assistance, response, and preparedness for deliberate biological incidents in the context of BWC Article VII (2 days)
  • Institutional strengthening the of the BWC—eg, legally binding verification mechanisms (1 day

The two days of discussion about emerging science and technology will be critical to ensuring that the BWC adequately addresses the potential risks posed by a broad range of dual-use science capabilities, but discussion at this level (ie, national delegations) is not sufficient to fully address the risks potentially posed by this kind of research.  As these capabilities become more prolific, it is increasingly likely that they will be utilized—for public health purposes (eg, vector control), military purposes (eg, human enhancement), or otherwise.  Explicit discussion is required in fora such as the BWC to ensure that all States Parties understand and agree on the extent to which these techniques and/or the resulting organisms are regulated by the BWC so that all States Parties adhere to the same established norms, particularly when the issue at hand is technology with potential military applications.

Course of Conversation: Infectious Disease Threats to Global Health Security

Jennifer Nuzzo, DrPH, a senior scholar at the Johns Hopkins Center for Health Security, teaches the Infectious Disease Threats to Global Health Security elective as visiting faculty in the department of environmental health and engineering at the Johns Hopkins Bloomberg School of Public Health. The course will be offered for the first time in spring 2018.

In the following Q&A, Jennifer explains what students should expect from her course and why the material is so valuable to future public health leaders.

What are the learning objectives of your Infectious Disease Threats to Global Health Security course?

 Jennifer Nuzzo, DrPH

Jennifer Nuzzo, DrPH

My goal for this course is to help students understand why infectious disease threats pose a risk to the security of nations. As we have seen in recent years with events like the Zika epidemic, the Ebola epidemic in west Africa, and prior to that SARS and MERS, emerging infectious diseases keep popping up and causing harm to public health as well as to economies. We want to explore what the specific impacts of these events are, and what public health practitioners can do to ensure that nations are ready to prevent them—or, if they can’t prevent them, to mitigate them when they occur.

We think this is relevant because we’ve seen an increase in the frequency of emerging infectious disease events. Unfortunately, that means public health professionals will likely be involved in one of these events at some point in their career. It’s valuable for public health students to understand the consequences not only so they can improve response, but also so they can convey to political leadership in a convincing way the importance of preparedness and appropriate resource allocation.

Who should take the course?

Every public health student should take this class. One of the themes of the class we’re going to explore is that increasingly we’re seeing that all public health is global health, so anyone who’s interested in US public health has to recognize that disease threats can start abroad and have impacts at home.

Folks who want to focus on improving public health globally, even if you’re interested in routine public health conditions like HIV or TB, or non-communicable diseases, that work can be jeopardized if a large-scale epidemic emerges.

How do infectious diseases threaten global health security?

Emerging infectious diseases threaten global health security in myriad ways. They have the immediate effect of impacting health, causing illness and potentially death, but there are secondary and tertiary effects on societies, on the ability of people to be able to work and provide for their families, and threats to economies—particularly when measures are taken like closing boarders or shutting down travel and trade.

There are also political effects. How a society responds to these threats, whether that response is effective, can impact public confidence in government.

Subject matter aside, what’s unique about this course?

We’re going to spend some time talking about the broader themes and political dimensions of public health events, more than students experience in their other classes. The foundation public health education gives students the methods to describe infectious disease events and the tools to respond to them. This is essential, obviously. I hope to build on those themes with a multi-faceted approach to the infectious disease problem: you need to know what strategies work and what strategies don’t; you need to know the consequences of making the wrong decisions and what the wrong decisions are; and you need to know how to interface with political leadership so policymakers are supportive of what needs to be done and don’t undermine the overall response.

In addition, I want the class to be highly relevant to the world that we’re living in. I’m committed to tailoring the material in the course to the events that we are witnessing in the world. As new events occur, we will incorporate that into our class and encourage students to interpret the world around them as it’s currently happening.

What’s the most important key takeaway for students?

Understanding how health is important for broader societal goals like improving economies and strengthening the defense of countries. Public health professionals have a role to play in the security of nations and protecting economies, and I want to help them understand what that role is so they can then make stronger arguments for the value of investing in public health.

What got you interested in work on the prevention of infectious diseases?

When I graduated with a Master of Public Health in 2001, I took a job in New York City as an epidemiologist. Shortly after the attacks of Sept. 11, what had previously been a small component of my job—maintaining a surveillance system that had a potential application to bioterrorism—became a large part of the focus of my job. It was that event that particularly underscored for me the interdependency between health and security.

Since then, my colleagues and I at the Johns Hopkins Center of Health Security have worked every day to demonstrate to political leaders that health is a vital component of national security.

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Jennifer Nuzzo can be reached by email at jnuzzo1@jhu.edu and on Twitter at @JenniferNuzzo.