When the World Health Assembly declared smallpox eradicated in 1980, many technologies used to study, alter, or create pathogens were new, considered science fiction, or had yet to be imagined. In the years since, as these technologies have improved or been created, they have become essential to developing new tools against smallpox and understanding similar health threats.

These innovations, however, are a double-edged sword: Although pathogen research can help the world prepare for future pandemics, working with the variola virus that causes smallpox raises the risk of reemergence, whether accidental or intentional. To counter risk responsibly, the global community should adopt a proactive approach and collaborate to better detect, respond to, and prevent a potential outbreak or biological attack. The world needs improved diagnostics, vaccines, and therapeutics—known as medical countermeasures (MCMs)—to be ready if the dangerous variola virus were to resurface, as well as strong enough health systems to deliver them.

Even though the World Health Organization has overseen essential research with live variola virus in the United States and Russia, the world continues to debate whether these research samples should be destroyed. Real and perceived risks associated with emerging technologies, from artificial intelligence to synthetic biology, are intertwined with concerns about nations or substate actors that might seek to reintroduce native or modified smallpox. The COVID-19 pandemic and multicountry mpox spread have further underscored the need to prepare for outbreaks.

A Great Global Health Success

Before smallpox was eradicated in 1980, the infectious disease killed between 300 and 500 million people worldwide in the 20th century

In a consensus study report, the Future State of Smallpox Medical Countermeasures, published in March, a committee convened by the National Academies of Sciences, Engineering, and Medicine considered the risks and benefits of smallpox research. The report explores both the potential of emerging technologies—including gene editing, genome synthesis, and other techniques advanced by the power of artificial intelligence—to contribute to future risks, as well as the vital opportunities for those technologies to strengthen the response to a potential outbreak. The report emphasizes two pillars of readiness and response: enabling the development of improved MCMs and expanding system-level capabilities to deliver those countermeasures efficiently.

The Emerging Technology Paradox

Emerging technologies are enabling more people to access and practice increasingly sophisticated research. For example, viral genome synthesis, a topic among Nobel laureates two decades ago, can now be studied by undergraduates. As biotechnology capacities become easier and more available, individuals with diverse backgrounds—not just established and vetted scientists—can become enabled to act unilaterally. If ignored, the promulgation of advancing tools and capacities contributes to real and perceived risks of biosafety lapses and bioterrorism.

Leaders should evaluate how future generations can be protected from biological threats

That situation raises several hypotheticals for the global community to consider. In a potential world in which anyone anywhere might access any toxin or pathogen, leaders should evaluate how future generations can be protected from biological threats. Given more available technology, scientists need also to consider that anyone anywhere could produce any infectious disease diagnostic, treatment, or vaccine on demand. In this case, specific emerging biotechnologies could be carefully and strategically explored, developed, and deployed to make obsolete many of the risks associated with emerging biotechnology overall.

Maintaining a stockpile of premade MCMs that address a single strain or variant of a pathogen, such as the smallpox vaccine, is critical to responding to a potential outbreak. However, stockpiles could ultimately be overwhelmed or worked around in an era of increasingly agile and decentralized capacities and distributed risks. To secure such a future, entirely new approaches need to be developed, including commensal microbes using persistent infectious disease surveillance platforms, brewing-based approaches to update medical countermeasures based on evolving threats, or bioengineered bacteria-based novel vaccine platforms that do not need ancillary inputs that can be affected by supply chain strains. Such distributed capacities could be included in public health and biodefense networks to complement what stockpiles alone can offer, but their development and deployment will require strategic investment and leadership.

Actions for Health System Readiness and Response

Our current health-care and public health systems may need to change profoundly, not only to respond to new ways in which a threat from variola could present but also to maximize the public health gains from those technological advances. If the threat of smallpox can arise from more places than secure laboratories, disease surveillance systems will need to become more geographically dispersed and data sharing will need to be strengthened to ensure rapid and accurate identification of suspicious cases. Additionally, a more intricate network of interconnected public health infrastructure, built on principles of equity and global collaboration, is crucial for swift and effective response. This interconnectedness will enhance situational awareness and facilitate a coordinated international effort to contain any potential outbreaks.

The Smallpox Eradication Gap

While successful, the campaign against smallpox reached low- and middle-income countries last, as evidenced by the year each country reported its final case

Similarly, a public health system that is well funded, equitable, and better integrated with health-care delivery is better poised to take advantage of synthetic biology–related advances in diagnostic, vaccine, and treatment development and manufacturing. Such a system has greater capacity to leverage knowledge gained from artificial intelligence–powered study of pathogen transmission, evolution, and adaptation. As new MCMs are developed, the speed at which they can be deployed at the site of an outbreak—whether by delivery or on-site manufacture—will be crucial to controlling a new infectious threat. At the same time, lifesaving technologies must gain public trust and acceptance while being allocated fairly.

Global Cooperation and Equity

The eradication of smallpox in 1980 is a testament to the power of global public health collaboration, a sentiment the World Health Assembly underscored in its declaration of eradication of the disease:

[The Assembly] calls this unprecedented achievement in the history of public health to the attention of all nations, which by their collective action have freed mankind of this ancient scourge and, in so doing, have demonstrated how nations working together in a common cause may further human progress.

More than 40 years later, the call to action has not changed. Enabling technologies can help proactively adapt new biotechnologies in the face of novel or reemerging pathogens. These technologies, however, should not benefit the few yet leave most at risk. Collaborations and partnerships among nations and organizations to develop and deploy next-generation smallpox and orthopoxvirus MCMs should be expanded to better support international sharing of benefits. New strategies will also require a balance between expansion of access to emerging tools with improved biosecurity and biosafety capacities.

Robust public health systems, functioning as the foundation of biosecurity, are essential to harnessing the full potential of emerging biotechnologies and ensuring a future free from the threat of smallpox and, potentially, other infectious diseases that have long plagued humankind.

Medical personnel prepare smallpox vaccines. — Medical personnel prepare smallpox vaccines, in Jerusalem, on January 2, 2003. REUTERS/Yossi Zamir

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