NIAID Funds and Nature Publishes Doomsday COVID Viral Virulence-Enhancing Technology by Dr. Zheng-Li Shi: Call for Emergency Restrictions and Severe Penalties for Misuse

Dual-Use Dilemma... "Studying" Virulence Actually Means "Ability to maximize"... You maniacs...

As we have stressed in Popular Rationalism, the call for restricting gain-of-function (GoF) research, especially with respiratory pathogens, must be precise and targeted. Our advocacy is not for a wholesale ban on all GoF research but rather a focused, surgical prohibition on experiments that could amplify the transmissibility of respiratory viruses. This specificity acknowledges the legitimate scientific purposes of some GoF studies while urgently addressing the elevated risks posed by research that could lead to highly infectious respiratory pathogens. In the case of CVRs, the potential for misuse cannot be ignored, especially with a technology that could fundamentally alter viral entry efficiency.

We now have a new problem.

Chinese scientists have just given themselves new tools to understand—and manipulate—how viruses infect human cells. Among these is a new method introduced by Liu et al., who developed what they call "customized viral receptors," or CVRs. These artificial receptors are engineered to mimic the natural entry points viruses use to access cells. With these lab-created receptors, scientists can study viral infection in a controlled environment, observing how viruses latch onto cells, fuse with them, and initiate replication. By using CVRs, researchers can streamline the process of viral entry, allowing for detailed analysis of each step in infection without relying on natural cellular receptors.

On the surface, the creation of CVRs might seem like an unambiguous win for science, allowing researchers to better study infection without the risks posed by using live viruses. But this same tool, with its capacity to facilitate viral entry and spread, represents a dangerous new dual-use technology—one that could be exploited far beyond the realm of safe, ethical research. In the wrong hands, CVRs offer a way to engineer viruses with greater efficiency and potentially far higher infection rates. Scientists can manipulate viruses to be more infectious without even putting themselves at risk, all within the secure confines of a lab. This technology could fundamentally alter the way we think about biosafety and biosecurity, and the stakes could not be higher.

CVRs enable anyone with the right resources and know-how to experiment with virus infectivity and potentially pave the way for bioweapons research that is far safer for the researchers - but more dangerous for everyone else.

It is time for a sober examination of CVR technology. We must consider both its scientific potential and the very real risks it poses to public health and global security. This is a call to scientists, policymakers, and the public: we need a robust, enforceable framework to govern this technology before it moves beyond our control. Let us confront the reality of what this technology can do, not only to advance knowledge but also to threaten lives. The question is not whether we have the ability to restrict this technology—it is whether we have the will to do so before it is too late.

The Study

The Liu et al. study, co-authored by Zheng-Li Shi, tackled a fundamental problem in virology research: how to study the infectivity of viruses safely in a controlled environment. Their answer was a bold one. Rather than relying on natural cellular receptors viruses use to invade human cells, the researchers engineered synthetic versions—customized viral receptors, or CVRs—that mimic these natural entry points. These lab-made receptors are modular, meaning they can be tailored to interact with specific parts of viral proteins, creating a controlled, predictable pathway for virus entry into cells without (necessarily) studying replicating viruses.

The American scientists on the study, McCallum, Bowen, and Veesleron were funded by

• National Institute of Allergy and Infectious Diseases (NIAID) grants P01AI167966, DP1AI158186, and 75N93022C00036.

• Burroughs Wellcome Fund’s Investigators in the Pathogenesis of Infectious Disease Award

• University of Washington through the Arnold and Mabel Beckman CryoEM center.

• Howard Hughes Medical Institute, where Veesler serves as an Investigator.

• National Institutes of Health (NIH) via grant S10OD032290​

This sounds like a step toward safety. However, Liu and his team demonstrated that CVRs could facilitate nearly every crucial step in a viral infection. First, they enable what is known as “spike cleavage,” the initial split in a virus’s spike protein that prepares it for entry. Next, these CVRs guide the virus to fuse with a cell’s outer membrane, completing a sequence of steps that allows it to slip inside and release its genetic material. From there, using CVRs, the researchers showed that viruses could replicate in host cells—effectively spreading through lab cultures just as they would in the human body. This method provides a way to observe the entire infection process, from the virus’s first contact with a cell to its eventual spread, without needing a human receptor on a living cell.

The researchers argue that this innovation allows for greater control in studying dangerous pathogens and that CVRs open doors to study viruses that were previously difficult to propagate in a lab. For example, coronaviruses that lack well-understood natural receptors could still be studied using CVRs, allowing scientists to examine their behavior without needing human cell samples. They suggest this brings tremendous benefits in understanding how these viruses work and potentially in designing antiviral strategies.

But behind these advancements lies a darker, implicit potential. The researchers have developed a powerful tool for enhancing viral infectivity by creating artificial receptors that viruses recognize. The capability to control and amplify how effectively a virus enters and spreads in cells raises critical questions. The very design of CVRs enables researchers to sidestep many of the natural barriers that make viral infection a challenging process. And while this ability could accelerate research, it also offers a framework for potentially creating viruses that spread faster and more efficiently than their natural counterparts.

Our warnings in The Kennedy Beacon echo here, highlighting how gain-of-function techniques that manipulate viral entry pathways can bypass natural immune defenses. CVRs, with their ability to facilitate spike cleavage and enhance viral infectivity, offer a similar risk profile. This perspective underscores the critical ethical question: Have Liu et al. introduced technologies that, under the guise of scientific advancement, make it easier to exploit these mechanisms for harm? The ability of CVRs to sidestep normal immune responses heightens this concern, aligning with our cautionary stance on the dangers of manipulating viral infectivity without fully appreciating the broader implications.

The study by Liu et al. again highlights a tone-deafness on ethical responsibility. The creation of CVRs is not merely a new method; it is a technological leap that gives scientists unprecedented control over viral infectivity. In understanding this work, we must also confront the broader implications of giving researchers—and, by extension, the global scientific community—the tools to bypass natural infection processes. What began as a means to study infection may have set a foundation for something far more consequential and, potentially, far more dangerous.

Dual-Use Dilemma

A "dual-use dilemma" refers to a situation where scientific research, technology, or knowledge intended for beneficial purposes—such as advancing medicine, understanding pathogens, or developing public health strategies—also has the potential to be misused for harmful applications, such as creating biological weapons or enhancing the threat level of pathogens. This dilemma arises when the same tools, techniques, or insights contributing to scientific or medical progress can equally be repurposed to cause harm, often with devastating consequences.

The dual-use dilemma of CVR technology cannot be overstated. Dual-use research, by definition, involves work that can benefit society but can also be applied to harmful, even catastrophic, ends. This is where the creation of customized viral receptors becomes a double-edged sword. On one hand, the scientific community now has an unprecedented tool to study the details of viral infection. On the other, this same tool could be exploited to make viruses significantly more infectious or even deadlier, all within the safe confines of a laboratory.

Imagine a virus modified to become more contagious or better able to evade immune responses. With CVRs, researchers can manipulate these infection pathways without facing the infection risks themselves. For those involved in bioweapons research, this technology offers a way to safely explore dangerous alterations to viral structure and behavior without immediate danger to the scientists involved. The CVRs act as proxies, allowing researchers to test and perfect viruses with higher infection efficiency, greater replication rates, or adaptations that make them harder to neutralize—all of which could be weaponized if misused.

The implications are disturbing, especially when considered against historical examples of dual-use research gone awry. In the past, advancements in biotechnology have sometimes been co-opted for harmful purposes. During the Cold War, for instance, research in microbiology contributed to the creation of biological weapons designed for mass casualties. Today, as geopolitical tensions mount, the creation of CVRs presents a new set of opportunities for misuse, which are harder to detect and regulate because they operate under the banner of legitimate scientific research.

Some might argue that the risks are hypothetical and that there are no guarantees this technology will be misused. But history offers little reassurance. The mere existence of technology that can enhance viral infectivity introduces a dangerous potential. Now that this capability exists, it cannot be uninvented; the knowledge is out there, and the motivations for misuse—financial, political, or ideological—are as real as they have ever been.

The fact that CVR research does not inherently look like weapon development adds another layer of complexity. Customized viral receptors were ostensibly created for research and understanding. Yet, these benign goals can be easily subverted. In the wrong hands, what began as a tool for studying infection could quickly become a tool for amplifying it. It is precisely this dual-use potential that should alarm us. There is no easy way to monitor who uses CVR technology or for what purposes, and the existing regulatory frameworks were not designed to handle the quiet, controlled enhancement of viral infectivity.

As we have published earlier, lab accidents involving dangerous pathogens are far from rare. Between 2000 and 2021, 309 infections occurred in labs, with 51 pathogens escaping containment. These facts remind us that even the most stringent safety protocols cannot eliminate the inherent risks associated with such research. CVRs only amplify these risks by creating viruses with enhanced infectivity, placing lab workers and potentially entire communities at greater risk should containment fail.

When technologies like CVRs enter the equation, the risk is enhanced manifold. These risks are not hypothetical; they are grounded in history.

We must, therefore, now issue a stark warning that with CVR technology, we are on the brink of repeating these same mistakes and making new ones: A viral bioweapon can be made and never made to infect humans or human cell lines until its first deployment. In the wrong hands, the outcomes will be… not could be… catastrophic. This is a historical pattern that has been ignored to our detriment.

Ultimately, the dilemma of CVRs goes beyond science; it is a matter of global security. We face an uncertain future without a strict regulatory framework that acknowledges and addresses these dual-use risks. The CVRs are not merely an academic tool. They are a powerful means to enhance viral characteristics, and we must consider this fact soberly, acknowledging both the scientific promise and the shadow it casts.

Biosafety First

The biosecurity and biosafety risks associated with CVR technology demand urgent attention. History has shown us that no matter how stringent laboratory safety protocols are not foolproof. Accidents happen, and the results can be disastrous when they involve dangerous pathogens. Laboratories working with highly infectious agents, even those that follow the highest biosafety standards, have experienced containment failures that led to outbreaks. Between 2000 and 2021, there were hundreds of lab-acquired infections and instances of pathogens escaping containment. Each incident highlights the inherent risks of working with viruses capable of human infection—before introducing tools that make viruses even more adept at infecting human cells.

Customized viral receptors present a new level of biosafety challenge. By enabling viruses to bind to and enter cells more efficiently, CVRs effectively lower the threshold for what is needed to make a virus more infectious. It is one thing to work with naturally occurring viruses under strict biosafety protocols, but it is another to enhance their ability to infect cells. CVRs could enable a virus that might otherwise struggle to spread in human populations to acquire the efficiency it needs to propagate. This is not theoretical; it is a logical extension of the very purpose CVRs were designed for—to enhance viral entry for study. In the context of laboratory containment, a single breach could lead to the release of a virus engineered to be more infectious than it was in nature.

The potential fallout from such a release is even more troubling when considering the proximity of biosafety level 3 (BSL-3) and biosafety level 4 (BSL-4) labs to populated areas. Many of these high-containment facilities are located in or near major urban centers, putting millions of people within a relatively short distance of labs that handle the world’s most dangerous pathogens. BSL-3 labs, which work with microbes capable of causing serious and potentially lethal diseases through inhalation, are widespread. BSL-4 labs, which handle the most dangerous viruses—those that often have no treatment or vaccine and spread through the air—are fewer but still present in countries worldwide. Customized viral receptors complicate the biosafety landscape, adding layer of risk for every laboratory researching viral infectivity.

One must also consider the human factor. While biosafety protocols are designed to minimize risk, human error is an ever-present reality. In recent years, reports of lapses in laboratory protocols, improper handling of infectious agents, and failures in containment have made headlines, reminding us that even the best-laid plans are vulnerable to mistakes. With CVR technology, an error in protocol does not just risk exposure to a virus; it risks exposure to a virus with potentially enhanced infectivity. The consequences of even a minor breach could escalate rapidly, given the altered nature of viruses modified through CVR-assisted pathways.

The urgency to address these biosafety concerns is clear. Customized viral receptors may offer researchers valuable insights, but they also significantly burden laboratory safety. In an environment where containment is paramount, adding a mechanism to increase a virus’s infectivity may be another step too far. The fact that these tools exist should prompt the global scientific community to reconsider the protocols, locations, and oversight of any lab using CVRs to enhance viral infection. The risks are not only to those within the labs but to us outside them.

Accountability and Liability

Should a breach or release occur, who is responsible for the consequences? When scientists develop and use CVRs, they take on a moral obligation to ensure that this technology does not lead to harm. However, the complex chain of responsibility—from researchers to institutions and regulators to policymakers—makes accountability difficult to establish. If a lab accident were to result in the release of a virus enhanced through CVR technology, it would endanger public health and erode the very foundation of ethical research practices. Scientists, institutions, and governments would need to reckon with the fact that the pursuit of knowledge leads directly to harm.

The ethical and moral implications of CVR technology are clear: with great scientific power comes an even greater need for responsibility. Creating tools that can alter a virus’s infectivity is not a matter to be taken lightly. It requires a level of ethical rigor that matches the power of the technology itself—and we clearly do not have it.

Regulatory and Oversight Call to Action

As it stands, the current framework for overseeing high-risk virology research is woefully inadequate. The regulatory structure around gain-of-function research, where scientists intentionally enhance the properties of a virus, has long been controversial. Still, CVR technology brings new complexities that stretch beyond existing policies. The dual-use nature of CVRs—tools that can be exploited to increase viral infectivity and ease of spread—means that traditional oversight measures are insufficient. National policies vary widely, with some countries enforcing strict regulations while others have few safeguards. The result is an inconsistent global landscape, where high-risk research may proceed in one country while being restricted in another. This patchwork approach fails to account that pathogens do not respect borders. An escape or misuse in one country can quickly become a global crisis.

The probability that viruses evolving in nature will ever achieve the virulence that can be forced upon them in the lab is near zero. There is no need to see how deadly a virus might evolve in humans. Seeing if we can make vaccines against “most deadly” viruses is also not a relevant research question. Consider the ultimate virus: one that wipes out humanity, for which no sterilizing vaccine can be made. There. You have your answer. There is no need to enhance viral virulence. Period. Writing plainly? It’s quite stupid, in fact. Please quote us on that.

That research has no justification. Senator Rand Paul recently introduced a bill calling for stricter oversight of high-risk virology research, underscoring the urgent need for reform. This legislation proposes more stringent review processes, transparency requirements, and rigorous ethical evaluations for any work that could enhance viral properties in ways that may pose public health risks. Such oversight is a step in the right direction, especially as new technologies like CVRs emerge. However, domestic legislation alone is not enough. The scientific community and policymakers must push for international agreements that recognize the cross-border implications of biotechnologies like CVRs. Without coordinated global action, the risks posed by these technologies remain unaddressed.

In light of these challenges, we must call for a comprehensive, international moratorium on CVR research aimed at enhancing viral infection efficiency. A moratorium would allow time for a full assessment of this technology's risks, benefits, and ethical implications. It would provide a window to develop clear guidelines and protocols prioritizing safety and global health over scientific exploration. This moratorium should not merely pause research; it should set in motion a process to create robust guidelines that dictate how and under what circumstances CVRs can be used.

In addition to the moratorium, it is imperative to establish a framework for regulating this technology moving forward. Key components of this framework should include mandatory safety protocols for any lab working with CVRs, transparent reporting requirements to ensure that research details are open to scrutiny, and regular audits by independent biosecurity experts. These guidelines should also require an ethical review of each project’s potential dual-use applications, ensuring that scientists fully consider the consequences of their work before proceeding. Integrating these measures can create an environment where scientific progress aligns with public safety and moral responsibility.

Plus, it follows the old maxim: Don’t do stupid things that can wipe out humanity.

The scientific community must also uphold ethical standards by adopting research practices that minimize potential harm. Researchers should be held accountable for the risks their work may pose and prepared to operate under the strictest safeguards. Institutions and funding agencies must prioritize studies that pose minimal risk to public health and avoid supporting work that could be easily weaponized. Without this ethical commitment, the scientific community risks losing the trust of the public it aims to serve.

In conclusion, the promise of CVRs as a tool for understanding viral behavior must be weighed against their profound risks. We have seen, time and again, how technologies intended for good can be repurposed with disastrous results. This is not a matter of if but when; history has taught us that when the means to create harm exist, someone, somewhere, will try to exploit them. The time to act is now before these tools move beyond our control. We urge scientists, policymakers, and citizens alike to support comprehensive oversight and regulation of CVR technology. The cost of inaction is simply too high.

The call is clear: We must address the dual-use dilemma head-on, enforcing a moratorium on CVR technology with consequences on its use to enhance viral infectivity—intentionally or unintentionally—and supporting legislation like Rand Paul’s bill to strengthen oversight of gain-of-function and other high-risk virology research. Only by taking these steps can we hope to control the risks posed by technologies that could alter the nature of viral infections.

For the safety of our global community, we must act decisively, quickly, and with foresight. And let’s not be stupid.

Liu, P., Huang, M., Guo, H., McCallum, M., Si, J., Chen, Y., Wang, C., Yu, X., Shi, L., Xiong, Q., Ma, C., Bowen, J. E., Tong, F., Liu, C., Sun, Y., Yang, X., Chen, J., Guo, M., Li, J., . . . Yan, H. (2024). Design of customized coronavirus receptors. Nature, 1-9. https://doi.org/10.1038/s41586-024-08121-5

As Heston’s character quipped … “You maniacs!”