By Dr Heiko Khoo, PublicSafety.org.uk
Microbiology is concerned with microbes, organisms that are invisible to the naked eye. They include bacteria, archaea, viruses, fungi, prions, protozoa and algae. Our bodies are full of microbes.
Microbes that cause infectious diseases kill about 16 million people every year. Many of these deaths are preventable.  They account for about a quarter of all deaths, and half of those in under 45yr olds.  However, most viruses and bacteria are harmless to people, or are of benefit to us.
Viruses are the smallest type of microbes. You can fit 500 million rhinoviruses (a common cold virus) on a pin head. Viruses are not living organisms. They only come to ‘life’ by multiplying inside the living cells of a host.
A virus is made of genetic material, either DNA or RNA, which is covered in a protective coat made of protein. They latch onto host cells to get inside and reproduce themselves. Once inside, the host cell’s machinery is used to replicate the genetic material of the virus. These virus particles burst out of the host cell to penetrate others.
It is estimated that there are 100 million more viruses on earth than there are stars in the universe. If they were all lined up in a row, they would stretch for 200 light years. 
It is believed that mammals are host to about 320,000 undiscovered viruses.  We currently know of more than 220 virus species that can infect humans. We find a few more every year. More than two thirds of human viruses also infect other animals, mainly mammals.
Pathogens, Transmission and Epidemics
Pathogens are disease causing organisms. Newly emergent pathogens get more attention than other widespread and treatable killer diseases like TB, Malaria and measles. The WHO and the pharmaceutical industry maintain that effective intervention can halt the spread of new diseases provided they are discovered in a timely fashion.
We know that about 1400 pathogens can infect man, 87 of them were discovered since 1980. Of course, the discovery of a pathogen is not the same as its emergence. Exposure to pathogens comes through various forms of transmission. Droplets, aerosol, contaminated food, bites by animals or intermediate arthropods (insects, spiders and their relatives). Any pathogen that can infect a person and cause a disease has to overcome species barriers, so most infections come from mammals, then birds, and a few from reptiles and invertebrates. About 500 of the pathogenic ‘species’ that can infect man can also transmit between us.
An epidemic is the transmission of an infection between people, where each infects more than one other.  Many factors can play a significant role in accelerating or decelerating the so-called R number – which measures the average number of secondary infections that come from those infected. This depends on the character of the pathogen. With respiratory agents like SARS-COV-2 and similar droplet transmitted infections this is determined by the density of people, proximity, time spent, ventilation, and other environmental conditions.
The Search for Origins
It is the traditional view that many human pathogens emerged with the growth of stable agricultural settlements about 12,000 years ago, during the Neolithic revolution. The birth of fixed agricultural settlements changed our proximity to animals and other people. It is believed that this increased our exposure to pathogens compared to nomadic life. However, this thesis seems to be blind to the quantity of pathogens that infect apes.  Surely, jungles are a natural environment for interspecies encounters?
Two methods are used to determine the origin of viruses
Knowledge of the evolutionary speed of pathogenic viruses is fundamental to virus surveillance, control measures, and any possible vaccines. If we know the origin of a virus, we can tell how fast it has evolved. Two methods are used to determine the age and origin of viruses, molecular clock theory, and co-evolution theory. Attempts to apply them produce radically different and contradictory results.
The Molecular Clock
The dominant method used to search for the origin of viruses is to map samples on a molecular clock. This helps to estimate the age of a virus, and its ancestors, by looking at the equivalent of the leaves from a tree. These leaves are examined, like the samples of SARS-COV-2 taken from swabs since 2020. The results are used to trace their genesis in time and place and to plot a map of the tree’s evolution.
An alternative historical method is co-evolution. This examines the leaves, as well as the twigs, the branches, and the trunk, in order to sketch an evolutionary tree for the virus and identify its ancestral roots. The evidence for points of divergence can be used as date markers. Such examples are found in people and animals separated during their evolution by migration or by the isolation of landmasses. This approach changes our perspective on historical origins. Now we find that some viruses have co-evolved with humans and primates for tens of thousands or many millions of years. 
The Origins of HIV
The first AIDS patient was diagnosed in 1981 and the HIV virus was discovered in 1983, but the origins of human immune deficiency viruses predate this, but by how long?
Using the molecular clock method, the origin of HIV has been traced to Kinshasa in the Congo in the 1920s. The speed of mutations to the genetic code of HIV were measured using blood samples dating back to 1959.  In the research paper that first made this claim, the authors speculate that post-colonial changes to sexual behaviour may have played a significant role in the emergence of the AIDs pandemic. 
HIV originated from the transmission from ape to man of Simian Immunodeficiency Viruses (SIVs) which are found in 40 types of African apes. Co-evolutionary theory has been used to examine the origin of these viruses by looking at four types of African green monkey. Each is host to slightly different SIVs. If susceptibility to SIVs is derived from a common ancestor, they may have originated 3 million years ago. 
In humans, sexual intercourse is one of the main HIV transmission routes. So, it is an intriguing fact that the most promiscuous apes, the bonobos, appear to be free from SIVs in the wild.  Bonobos spend much of their time having sex for pleasure. They are rarely kept in zoos because their sexual antics are so shocking. Wouldn’t it be ironic if it was this sexual behaviour that produced immunity?
Coronaviruses are a group of single-stranded RNA viruses that have common ancestors in nidoviruses. Nidoviruses replicate in a huge range of living hosts; from molluscs to mammals, insects to reptiles, and birds to leaches.
“Coronaviruses are capable of adapting quickly to new hosts through the processes of genetic recombination and mutation in vivo. Point mutations alone are not sufficient to create a new virus. However, this may occur when the same host is simultaneously infected with two coronavirus strains, enabling recombination of genomic fragments of hundreds or thousands of base pairs long and thus making a new virus”. 
If you keep these conflicting dating methods for origins in mind, the molecular clock locates the date of origin of coronaviruses about 10,000 years ago. However, Co-evolutionary theorists provide convincing arguments to hypothesize that coronaviruses originate in birds and bats tens of millions of years ago or even earlier, in the carboniferous period over 300 million years ago.  Studies using molecular clocks locate the genesis of SARS in recent history. This is an automatic result of the method.
The SARS epidemic 2002-2004
The 2002-2004 SARS epidemic spread to 29 countries infecting 8098 people and killing 774 in 2003. A few more cases were reported in 2004. The disease mainly affected China and East Asia.
The SARS virus was linked to Horseshoe bats from the Rhinolophus affinis species. These are small insect eating bats. Coronaviruses in some insect eating mammals may originate from ancient mutations to nidoviruses carried by insects.  Bats were found to be the main reservoirs of coronaviruses but other animals that have closer proximity to man may act as intermediate hosts for zoonotic spill-over events to humans.
Fine perfumes, delicious coffee and exotic dishes
“Give me an ounce of civet, good apothecary; sweeten my imagination. There’s money for thee.” -King Lear Shakespeare
Civets are nocturnal mammals found in Asia and Africa. They release a strong musky odour used for centuries in the perfume industry. The harvesting of civetone for perfumes continues despite the development of synthetic alternatives.  The animals are also farmed in Indonesia for the coffee industry, as Civets add a unique flavour to the coffee beans when digested and excreted.
A “SARS-CoV-like virus was isolated from a few Himalayan palm civets and a raccoon dog at a Shenzhen food market during the SARS epidemic of 2002–2003. Their genomic sequences displayed 99.8% identity with that of the human SARS-CoV.”  In early 2004, after the first epidemic passed, a few people came down with SARS in Guangzhou at a restaurant where they kept live Civets and had them on the menu.
The US Centers for Disease Control (CDC) noted that “viruses very similar to SARS-CoV” have been found in civets and that some civet handlers have “evidence of infection with SARS-CoV or a very similar virus.” The Guangzhou Respiratory Disease Research Institute reported a survey in which 70% of civets were found to carry the SARS virus and 40% of game traders carried SARS antibodies. 
Did SARS really disappear?
“I can understand perfectly how the report of my illness got about. I have even heard on good authority that I was dead.” -Mark Twain
The overwhelming majority of scientists seem to believe that SARS “disappeared” in 2004 as a consequence of public health measures  or because of some evolutionary quirk. 
Analysis based on the rate of mutations detected in SARS samples locates an original animal to human spill-over date at some time in 2002.. This predates the SARS outbreak by only a few months. And a common bat ancestor virus is presumed to have emerged at some time between 1996 and 2002. 
This date is highly suspect, as a Hong Kong study of blood serum taken in 2001- two years before the SARS outbreak – detected antibodies to SARS in 1.8% of 938 samples. The donors were healthy adults taking part in a hepatitis survey.  And in two Chinese studies reported on the website of the National Health Commission of the Peoples Republic of China, SARS antibodies were detected in more than 40% of blood samples collected from hospitalised children in 2001. This points to widespread and undetected SARS infections in China two years before the outbreak was noticed. Similar antibody levels were found in hospitalised children in Beijing in 2003. 
An eminent team of Chinese experts including Prof. Nanshan Zhong, the hero of China’s campaign against SARS in 2003-4 and SARS-COV-2 in 2020, suggested that SARS was transmitted directly from bats to humans in 1991 and became adapted to humans in 1998, but this only led to an epidemic when climatic conditions facilitated the spread of a more virulent strain – grounds for “sounding a global alarm on the possibility of the re-emergence of SARS” . The report shows that SARS did not simply disappear, because:
“Anti-SARS-CoV sero-positivity was detected in 20% of all the samples tested from Guangzhou children who were born after 2005, suggesting that weakly virulent huSARS-CoVs might still exist in humans.” 
So, antibody prevalence to the SARS virus was common long before the SARS epidemic and remained present long after.
Inside China, after 2004, SARS testing was rare. Outside China, no one was testing for SARS anyway. The myth of the disappearing SARS virus is resolved. Its circulation in humans simply fell off the radar.
SARS or HCoV 043?
Consider the case of a Canadian nursing home in Surrey, British Columbia in 2003. An outbreak of respiratory illness infected 142 lodge residents and 53 health workers, and 8 residents died. Initially, no causative agent was found. When more people became ill, some samples were sent to the National Microbiology Laboratory where they were found to be a mutant SARS virus. Experts at the Centers for Disease Control and Prevention in Atlanta disputed these findings.
A bemused New York Times reporter asked how such uncertainty could arise:
“One of the most glaring problems uncovered by the nursing home outbreak was the absence of a formal agreement among scientists about precisely what steps and laboratory methods should be used to make a definitive diagnosis of SARS.
For example, many test results remain in dispute, largely because the scientists involved in different laboratories did not use the same methods to test each specimen to try to identify the virus and to determine whether the patients’ immune systems had produced antibodies against it.” 
Eventually, a 2006 study in the Canadian Journal of Infectious Diseases and Medical Microbiology rejected SARS as the causative agent and maintained that this was an outbreak of respiratory illness due to HCoV-OC43. HCoV 043 is a coronavirus in general circulation. It causes some of the common colds that everyone gets as a child. New mutations circulate every year, some will make you mildly ill, others will pass without being noticed. It can have a relatively high fatality rate in vulnerable groups. 
HCoV-NL63 the one that got away
Just as the affected countries struggled to contain SARS, along came another human coronavirus, HCoV-NL63. Few people have ever heard of it.
HCoV-NL63 was first discovered in 2003, in a 7-month-old child in hospital in the Netherlands.  It mainly affects children and less commonly elderly immunocompromised people. It generally appears as a mild upper respiratory tract infection, but can also cause a serious lower respiratory tract infection.
Subsequent research indicated that the virus was in general circulation all around the world.  For example, a study of 854,575 PCR tests for human coronaviruses conducted in the United States between 2014-2017 showed a positivity rate of 2.2% for HCoV-OC43, 0.8% for HCoV-229E, 0.6% for HCoV-HKU1, and 1.0% for HCoV-NL63.
The above chart shows the number of tests per week in thousands and the percentage testing positive for four human coronaviruses. The viruses compete with each other for dominance in their human hosts. In 2016 NL63 was dominant, in 2015 and 2017 it was OC43. The study also detected other viruses in 30% of those infected with any of these coronaviruses.  Counter-intuitively, the interaction between a variety of influenza and cold viruses in hosts can generate positive outcomes, possibly due to the mutual stimulation of immune responses. 
Half of all Pneumonia cases are of Unknown Origin
Pneumonia, which is the main clinical feature of COVID-19, affects about 2% of elderly people each year. However, despite new techniques and intensive searches – in three sophisticated studies conducted after 2010 in the Netherlands and the United States – the cause of pneumonia could not be identified in more than 50% of cases. Viruses were found in 25% but in a third of these cases simultaneous bacterial infection of the lower respiratory tract was also identified. 
So, what was the cause of the 50% of pneumonias of unknown origin after 2010?
Perhaps the search for the origins of SARS-COV-2 should have started with this question?
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