Viruses (And People) Play A ‘Signaling Game’ With Strangers And Dangers

By Deborah Borfitz

March 31, 2021 | Mathematically speaking, the cytokine storm seen with severe COVID-19 and the out-of-control behavior of QAnon conspiracy theorists are not really all that different, according to Bud Mishra, a professor at New York University's Courant Institute of Mathematical Sciences. Both invoke a stranger-danger “signaling game” that would also explain how messenger RNA (mRNA) and transfer RNA (tRNA) came to be cellular co-occupants some three and half billion years ago.

The signaling game utilizes two well-known types of mimicry—"Batesian,” which involves deception, and “Müllerian,” based on a common interest between organisms—to achieve a goal or gain an advantage, he explains.

In human society, people form cooperative mimicry rings with similar and familiar others and pay a heavy cost for the affiliation, says Mishra. The Batesian mimickers may be spotted and ejected from the ring but can be frequent intruders if their approach is cheap and therefore easy to repeat.

At the cellular level, the game is “just a struggle between information-carrying molecules,” Mishra says. “They are trying to figure out how to interact with each other to optimize their utility... which may be to make more copies of themselves.”

The goal is persuasion between sender and receiver in the signaling game only when utilities are aligned—the U.S. and Canada, for example, or digestion-aiding gut microbes and probiotics, Mishra says. People, unlike bats, would be harmed by a symbiotic relationship with SARS-CoV-2 and so the objective is instead durable herd immunity to the virus.

Steve Massey, a biologist at the University of Puerto Rico who collaborates with Mishra, says he is particularly intrigued by the analogy his colleague makes between human and molecular mimicry behavior. “The type of cooperative mimicry humans display is a degree more complex than the classical Müllerian mimicry shown by biomolecules, in that each member of the ring both sends and receives signals."

The unknowns on the molecular level are where the struggle ends and if the virus has unwanted “alignment utility” with individuals of different genotypes, says Mishra.

New technology under development called Nanomapping, the focus of a commercial entity Mishra co-founded in 2016 with Jason Reed, associate professor in the department of physics at Virginia Commonwealth University, will explore genomics data to find out. Similar approaches have already been used to understand who gets sicker with COVID-19 and who gets mildly affected.

Mishra says he has been “obsessed” with improving genome technologies for years now, and his focus currently is on atomic force microscopy using CRISPR-Cas9 as a programmable nanoparticle. His research team has also started an online group named “cure COVid for Ever and for All” (aka RxCOVEA) to confront some of the issues raised by the COVID-19 pandemic.

The group is focused on immune systems biology and using models in biochemical labs to better understand the variable impacts of the virus—including asymptomatic disease and long-haul symptoms—and how to effectively personalize treatment regimens, Mishra says.

The Adversarial Chase

Based on the signaling game, the emergence of SARS-CoV-2 variants is not unexpected. An article newly published in the Journal of the Royal Society Interface (DOI: 10.1098/rsif.2020.0689) showcases a mathematical model producing a range of blueprints of how mimicry is formed, maintained, and destroyed in cellular populations, which vaccine developers might use to better understand the deceptive strategies that SARS-CoV-2 could employ, says Mishra.

Mishra was also co-author on a 2013 paper in the same publication (DOI: 10.1098/rsif.2013.0614) where the signaling game theory was used to explain why cellularity emerged 3.5 billion years ago.

The simulations most recently presented by Mishra and his colleagues show that invasion by Batesian mimics will make Müllerian mimicry unstable in a “coevolutionary chase.” Using the technique, SARS-CoV-2 makes changes to its spike protein so it can stay in the mimicry ring to wreak havoc, they theorize.

Mishra says he has no clue how this adversarial chase will end. People who received the original COVID-19 vaccine may need a booster shot to protect against new variants. It is also possible that scientists will learn the stranger-danger combinations vary in people depending on the haplotype structure of their genomes.

The perspective of game theory enthusiasts is that players who are strangers may or may not be dangerous to one another, and that friends can be mistook for foes—and vice versa, says Mishra. The sheer number of players and ploys make this a complicated mathematical puzzle requiring tools to simplify.

Balancing Act

The notion that mimicry is a problem for both biology and social structures emerged from a collaboration between Mishra (a computer scientist and mathematician with experience in biology and cancer research), Massey, and Will Casey, professor of cyber science at the U.S. Naval Academy. Game theory is the unifier, says Mishra, whether the mission is to eliminate a virus, a cybercriminal, or fake news.

Mimicry and deception are major considerations in cybersecurity, says Casey, whose teaching and research are focused on game theory and bio-inspired technologies for enhancing cybersecurity. “Some technologies focus on identifying the stealthy deception of malware hiding itself and its actions within a backdrop of mundane system software code and tasks, [while others]… such as honeypots, are deceptive by nature and are designed to confuse, delay, or capture cyber attacker identities.”

The effects of deception in cyber systems have become “more tangible and visible” in recent years, Casey says. During the 2016 presidential election, for example, what started as a social engineering email attack on Hillary Clinton’s campaign chairman led to the WikiLeaks disclosure “intended to embarrass the Democratic party candidate and further feed information games played out on social media.” The role of “fake personae influence campaigns” targeting special interest social media groups has since become better understood, he adds.

Well-known earlier examples following a related pattern include the malicious computer worm Stuxnet that employed “multiple clever goal-seeking deceptions,” including socially engineered emails and “zero-day attacks” involving hackers hiding malicious code in fonts to infiltrate systems.

Players in the game all process information and act on it, but they are not all rational and may be working in circumstances where they do not have all the facts (“information asymmetry”), Mishra explains. Migrant children at the border are strangers but not dangers, and neither are some microbes after we have been infected and recovered. Cancer cells and insurrectionists, on the other hand, are dangers but not strangers.

Finding the right balance between the stranger and the danger is the hard part of the problem, Mishra continues. COVID-19 is a stranger but not a danger unless it jumpstarts a cytokine storm and turns deadly. “Understanding those lines is where game theory comes in.”

In the case of COVID-19, a vaccine is a way of teaching the mimicry ring (via the immune system) to eject the virus when it comes in later, he explains. Once the virus gets thrown out, it will mutate to change its charge or shape so that the stimulated antibodies no longer work. 

Answers In the Genome

With COVID-19, the researchers believe, the SARS-CoV-2 virus mimics healthy cells to infect the host organism and vaccines against it mimic the virus so the immune system mounts an attack. Signaling tactics will get repeated until they no longer work.

In the case of mRNA and tRNA, biology made sure they could not deceive each other by putting them in the same cell and coding their behavior in DNA, says Mishra. But outside RNA, including the COVID-19 virus, can still employ dishonest tactics to get inside and “screw up the system.”

The next step for Mishra and his colleagues is to obtain the “right quality” data to understand how different genomic structures affect individuals’ response to being infected—and then start teasing out strategies for outwitting this formidable viral opponent. It is a big job that requires engineering, technology, big data, and data analysis, he says.

The enabling mathematics and algorithms are available, says Mishra, and he has a team working on assembling a solution. “It can’t be black-box AI [artificial intelligence] because I want to be able to understand what is happening. It has to be systems biology.”

Finding Equilibrium

Ultimately, the signaling game could be used to help inform the design of vaccines, Mishra says. “There are two ways to do vaccines—one is the plug-and-play [aka ‘Whack-a-mole’] model where you wait for new mutations to emerge and then create a booster, and the other is to create a universal vaccine where you predict all the strategies that the virus can use and put them together in one place and stop it. Both [approaches] are hard and can be disastrously expensive and if you make a mistake… we could go extinct.”

It is not as if humanity has not confronted this existential threat before, he quickly adds, referencing the nuclear arms race with Russia. That game ended with the signing of treaties, a verification system, and the doctrine of “mutually assured destruction” that put the two sides in equilibrium. It was a “beautiful application” of the game theory, which might similarly provide an answer to the vaccine question.

At the virus and vaccine level, many different games are being played at multiple levels over questions such as when to reopen schools and businesses, the size of stimulus checks, how many vaccines to make, how to mix them, and whether to get vaccinated or take the first vaccine that becomes available, Mishra adds. The games are structured in part by how people deal with each other, and the utilities involved—beyond the primary one of staying alive—include the ability to go to work and engage with one another.

Social distancing and wearing masks solve one problem but are unrealistic answers because they go against people’s rational understanding of utilities, he says. A game-theory approach would not assume everyone will understand the science and follow the rules but incorporate the decision-making rationale of many individuals into the design of solutions. It would then send out signals (information) “so we come to an equilibrium that is attractive... [and] allows people to behave in the right way.”