Is Gain-of-Function Responsible for the Bird Flu Jump to Cows and Humans?

In the past six months, bird flu has surprised scientists at least twice.
Since bird flu infections in humans are rare, these incidents have raised significant concern among scientists.
Why is this happening, and how concerned should we be?
Certain types of flu viruses typically infect specific hosts and do not usually jump from one host to another.
There is a wide variety of bird flu viruses, ranging from H1 to H19, but they have mostly remained in birds and animals, rarely affecting humans.
This changed with the H5N1 clade 2.3.4.4b.
The December USDA preprint reveals that the same viral strain was found in dairy cows that have no known connection to the infected herds. This suggests that the transmission in cows has already started quietly, and asymptomatic cows likely contributed to the rapid spread of the virus.
Since these cases are mostly scattered throughout Asia, they haven’t received much public attention in Western countries until recently.
However, this person reported no contact with sick or dead birds but had close exposure to sick dairy cows. The cows showed decreased milk production, reduced appetite, fever, and dehydration, suggesting H5N1 infection.
This was the first report in the United States of the highly pathogenic avian influenza H5N1 virus suspected of transmitting from a mammalian animal species to a human.
These cases have alerted scientists, as they suggest that the virus may have acquired the ability to spread between mammals and potentially infect humans.
If a highly pathogenic H5N1 virus were to develop the ability to spread easily among humans, including through human-to-human transmission, it could have a significant impact on the human population, given the high mortality rate observed in previous cases.
The spillover from one species to another typically happens naturally through the food chain. For instance, it can happen when infected birds are eaten by another species. These events generally occur on a small scale, unlike the widespread occurrences seen in U.S. cattle.
The process was complex. For example, a mutant H5N1 virus was created carrying the specific gene mutation PB2 E627K. It was then passed through ferrets 10 times. After gaining a total of five mutations, the mutant H5N1 virus gained the ability to be transmitted via aerosols or respiratory droplets.
Publishing these key mutations enables others to replicate the work in their own labs and marks the beginning of the unsettling H5N1 narrative.
The actual experiments are conducted in China’s CAS lab. There might be a specific reason for choosing this location.
The project, as we’ll explain later, is also a gain-of-function (GOF) study.
GOF studies on the bird flu virus have triggered broad criticism by the U.S. scientific community since 2011. Richard Ebright, a molecular biologist and laboratory director at the Waksman Institute of Microbiology, also told Science, “This work should never have been done.” From a biosafety perspective, scientists have expressed concern that a new virus generated through research could escape from the lab or that bioterrorists could leverage the published results into a bioweapon for malignant purposes.
Serial passage involves growing and reproducing the virus from one cell to another or from one animal to another. These studies have high risks of generating mutations that can lead to greater transmissibility, pathogenicity, and zoonotic transmission. The more potent mutants can be selected for the next passage.
As written in their proposal, CAS scientists are responsible for measuring “fitness,” which indicates the outcome of a viral infection—whether it develops faster or slower and whether it results in a severe or mild illness. Samples are collected before and after each round of passages to identify patterns of transmission and pathogenicity. This increases the likelihood of creating mutant H5N1 strains that can cause more severe diseases with faster transmission.
The second clue is linked to the animal models they carefully selected to reproduce the virus—mallard ducks, Chinese geese, and Japanese quail.
The mallard duck is the most abundant migratory and wide-ranging duck on Earth and can crossbreed with 63 other species. It is an asymptomatic carrier harboring many bird flu viruses, potentially allowing more mutated viruses to recombine.
Furthermore, the Japanese quail has a dual expression of two bird flu virus receptors on both avian and mammalian species. It is such an ideal host that after a series of passage trials, people can identify those strains that are more adaptive to mammalian receptors but not bird receptors.
Therefore, this study design favors the selection of a mutated H5N1 virus that has enhanced tropism for mammalian hosts with a higher pathogenicity or transmissibility.
This is a technologically well-designed study setting to achieve the gain-of-function purpose, in which the study objective appears to be about enhanced surveillance, monitoring, fitness, and vaccine studies.
In addition, this study plans to use live viruses to challenge mallard ducks with low-pathogenic bird flu viruses first, followed by a high-pathogenic virus.
Because the bird flu virus is highly prone to recombination, a genome reassortment among high- and low-pathogenic bird flu viruses could generate new recombinant influenza viruses with unpredictable host tropism or pathogenicity.
Therefore, this creates an even higher potential of generating new gain-of-function mutants.
“We are disturbed by recent reports about the U.S. Department of Agriculture’s (USDA) collaboration with the Chinese Communist Party (CCP)-linked Chinese Academy of Sciences (CAS) on bird flu research,” they wrote in an April 12 letter.
“This research, funded by American taxpayers, could potentially generate dangerous new lab-created virus strains that threaten our national security and public health,” they added.
In this study, an inhaled aerosol dose of 5.1 log10 plaque-forming units (PFU) caused a strong fever and acute respiratory disease in four out of six macaques, resulting in their deaths. PFU is a method of measuring the amount of the virus.
In comparison, in studies conducted from 2001 to 2014 with cynomolgus macaques, when these monkeys were given high doses of H5N1 (6.5–7.8 log10 PFU) through various routes (nose, throat, mouth, and eyes), they usually developed mild illness, and only 2 out of 49 monkeys died from the infection, based on previous reports.
This research on the bird flu viruses and current outbreaks in birds and cows should also remind us of the fiercely debated origin of SARS-CoV-2.
It’s particularly important to consider the current focus of scientific research after experiencing an unprecedented, challenging period due to COVID-19. Some Chinese government-controlled labs are still creating more dangerous viruses and enabling them to spread on a large scale in the name of pandemic preparedness. This raises the question of whether they are truly helping people or creating more diseases.
These alarming facts and circumstances should prompt immediate, thorough investigations into Chinese labs and their potential connection to the H5N1 bird flu outbreak.
In the pursuit of advancing science and researching more effective ways to protect people, such as developing vaccines, the underlying driving force behind such endeavors is often technological competition. However, scientists may have created more problems than solutions for humanity.
Editing the virus to enhance its transmissibility and pathogenicity, and researching its pandemic potential, only fuels more fear, rather than resolving the issue.
Ironically, some modern technology can have an extensive negative impact on society. The ability of scientists to conduct GOF research does not justify its necessity.
Influenza A viruses are classified into dozens of subtypes according to two types of glycoproteins on the surface of the virus.
The “H5Nx” nomenclature indicates different neuraminidase types (such as N1, N2, N6, N8) are paired with the H5 protein.
Five subtypes of avian influenza A viruses, H5, H6, H7, H9, and H10 are known to have caused human infections.
Bird flu viruses are classified as either low or highly pathogenic avian influenza based on the disease severity they trigger.
The H5 and H7 subtypes are highly pathogenic. Specifically, A(H5N1) and A(H7N9) viruses have caused most of the avian influenza A viral infections reported in people.
HPAI A(H5N6) and LPAI A(H9N2) viruses have also caused human infections in recent years.