Here's a fascinating new research study: Evidence for a mouse origin of the SARS-CoV-2 Omicron variant.
The study starts with a mystery. Omicron has 45 mutations. That's a huge genetic leap from previous versions of COVID. How did that happen?
Three theories have been put forward for how this could have happened. The most common theory is that COVID infected an HIV-positive person for months and gradually accumulated all 45 mutations. A second possibility is that COVID gradually metamorphized in some part of Africa where testing was minimal over the past year, and only took off when a late mutation made it extremely contagious.
The third possibility is that COVID entered another species some time in the past year, mutated to be well-adapted to that new species, and then jumped back into humans. This research paper is by a group of scientists who looked carefully at that third option.
When viruses go into different species, they tend to mutate in slightly different ways. Certain nucleotide replacement mutations are more common in some species than others.
When this group of researchers looked at the mutation pattern in Omicron's 45 mutations, they found a lot of individual mutations which would occur only rarely in a virus in a human host, but which would be quite common in a virus in a mouse host. This was strong evidence that the mutations had taken place in mice. (No other species fit the pattern of mutations nearly as well.)
When they looked at how well omicron bound to the ACE2 receptor in different species, that was the clincher. Omicron bound to the ACE2 receptor in mice very, very strongly - much more strongly than it bound to the human ACE2 receptor. The odds of there being this good a match by chance was one in 100,000:
Dr. John Campbell has just done an excellent summary of this research paper.
There's a precedent for a human virus mutating in mice in ways that make that virus more benign.
Yellow fever is a viral disease. It gives people a high fever. And, if it damages the liver, it makes the skin go yellow, hence the name, yellow fever. It was once a killer, especially for Europeans, who had little or no immunity.
Dr. Max Theiler was a South African virologist in the 1930's. Max Theiler came up with a brilliant plan to weaken the yellow fever virus.
Most viruses are adapted to infect a specific host. Theiler had this idea that, if he could find a variant that would reproduce in an animal host with a physiology quite different from humans, and breed it again and again in that non-human host, eventually it would be so well adapted to that new host it could only barely infect humans.
Theiler was able, with difficulty, to infect a mouse with yellow fever. He then let the virus reproduce and evolve in that mouse. Then he took a sample from that mouse and infected a second mouse. He did that a hundred times. By that time he had a virus that was really adept at infecting mice, and terrible at infecting humans.
If you gave the mouse version of yellow fever to a human, the human would not get sick at all. BUT, anyone infected with the mouse version of yellow fever developed a long-lasting immunity to human yellow fever.
It took him years, but by 1937, Max Theiler had developed the very first live-virus vaccine that was engineered by humans. Theiler eventually got the Nobel Prize for Medicine.
The best guess of the authors of the research paper cited above is that, roughly a year ago, COVID must have infected a population of mice somewhere. After a year of adapting to be ideally suited to mice, it has now re-entered the human population as the Omicron variant - highly infectious, but much less virulent in its ability to sicken or kill people; a natural vaccine, if you will.
When I heard about this research, I almost fell over. Why? Because in the Spring of 2021 I wrote a novel with an eerily similar plot.
In my novel, Dr. Jaime Morales - a public health doctor in Ecuador - finds a new variant of COVID so mild it could be suitable for use as a live-virus vaccine. He works together with his Canadian friend, Dr. Jayjay Walker, to try to locate enough cases of this mild variant to prove that it is weak enough for use in a vaccine.
At first, the two assume this very mild variant has occurred by chance. Eventually Jaime challenges Jayjay on the extreme unlikelihood of that. Jayjay has a flash of insight, and remembers how Max Theiler had bred the yellow fever vaccine in mice. To their great disappointment, it's not in mice.
It is somewhere else though. The following is all of Chapter 31 from my (still-unpublished) novel The Almost Forever War. Anything in italics is the narrator, science journalist Maggie King, who is interviewing Jaime and Jayjay together:
Chapter 31: Max Theiler's Ghost
Two days later. Today I will finally get to find out what Jaime's breakthrough was. I'm no longer willing to be patient, so I just outright ask Jaime: 'What was it that you had figured out?'
Jaime: I was sure there was something we had missed. I was racking my brain, trying to come up with possible answers. We weren't sure, but the pattern of Cuenca Variant cases suggested a spike on the August long weekend, when we celebrate Ecuador's Independence. We'd always assumed it was because people were more social over the holidays, and broke more of the social distancing rules. This was almost certainly part of the reason. I'm asking myself what else is different at holidays. Well, the food is different: more desserts, more wine. People had special meals. In my head, I am going through the special meals that people have, when the answer hit me, just like that.
Jayjay: The day after Katie's call, Jaime emails me to set up a Skype call. When Jaime appears he is beaming. I ask him if he's sure enough now to tell me his mystery brainwave.
Jaime: I can't resist taunting him. I give him two good clues. First, I say that Max Theiler's ghost has come to haunt Ecuador. Then I say, Jayjay in the time you lived in Ecuador, you must have gone to a number of holiday meals at people's homes. What special meals are served? Jaime looks at me like I'm crazy for a full thirty seconds. Then he gets it. He starts hitting himself in the head with his fists so hard I was afraid he might hurt himself.
Jaime pantomimes Jayjay hitting himself in the head.
Jayjay: I can not believe I didn't didn't think of it. Cuy, of course, it had to be cuy.
At this point, I break in and ask 'What is cooey ?'
Jaime: Cuy is the Spanish word for guinea pig. I know in North America guinea pigs are kept as pets, but in Ecuador, they're food. Barbecued guinea pig is not just food, but expensive, special occasion food. The varieties of guinea pig grown for food are bigger than the varieties used for pets, so a single roasted guinea pig is an ample portion of meat for one person for dinner.
Jayjay: They roast cuy over charcoal. They gut the cuy and put a wooden dowel about two inches in diameter through the center of the animal from one end to the other, so the body of the cuy is wrapped around the dowel, which fits into a rotisserie. The cuy's skin goes all brown and crispy as it cooks. It's really no different from the rotisserie chicken you see cooking in the deli section of a grocery store. But for me it was always weird to see this little animal, that still looks like a guinea pig while it's being cooked. It was delicious, though. I can see why it's considered a delicacy.
Jaime: Remember viandas, the daily catering service I told you about? Most days everyone gets the same meal, which changes over a rotation. For important holidays, viandas providers usually offer a choice of main courses. I ask our viandas provider if her customers can do that, she says they can. I ask her if cuy is one of the special order options. It is. I ask if she has a record of what people special ordered for the Ecuador’s Independence Day long weekend, which was August 7th to 10th . She says, yes, it's still on the computer. She offers to send it to me.
Jayjay: You were lucky she was young and did everything on the computer.
Jaime: I was. She sends me a spreadsheet with all her customers showing what each customer ordered for that weekend. Out of the 200 some odd families the viandas service provided meals to, less than a third had special ordered cuy. But, every one of our Cuenca variant cases except one had ordered cuy for the Independence Day Weekend. Even the two staff at the viandas provider who had tested positive for the Cuenca Variant had special ordered cuy. Cuy was the source of the Cuenca Variant.
Jayjay: My first reaction was to ask: 'How could that be?' After all, the cuy were cooked; that should have destroyed the virus.
Jaime: That confused me too. I asked the viandas provider how the cuys were prepared. She said cuy is a bit of a specialty meal. The provider hired two grandmothers who prepared the cuy at one of their homes. These women picked up live guinea pigs, slaughtered and gutted them, cooked them, wrapped them in paper and brought them down to the viandas provider. So they had no contact with any of the other food the viandas provider sent out. I'm sure these two grandmothers did their best to keep themselves clean, but when they spent the first part of the day up to their elbows in guinea pig guts, it would have been very easy to contaminate either the cooked cuy or its wrapping paper.
Jayjay: I said we couldn’t call it the Cuenca Variant any more; we should call it cuyvid - or better yet cuypox! I was the one who came up with the name for the cuy equivalent of cowpox!
I ask: 'How is Max Theiler important in all this?'
Jaime: Remember we told you Max Theiler deliberately infected mice through multiple generations so that the yellow fever virus became so well adapted to mice that the adapted virus could only barely reproduce in humans.
Jayjay: We have to guess that some form of COVID had gotten into guinea pigs, and had adapted so well to guinea pigs, this adapted virus was now too weak to make people sick. Nature had done accidentally what Theiler did deliberately.
Jaime: I also suspected that cuy having cuypox would enable us to find more cases, but I wanted to be sure before we broke out the champagne. I found out which farm supplied the two grandmothers with cuy. I went to visit that farm. We tested three young cuy for COVID. The tests all came back positive. I risked my bosses wrath by having one more genome sequencing done on a sample from one of the cuy that had tested positive. It was identical to our other Cuenca variant sequences.
Jayjay: I went to a cuy farm once. It was basically just a barn and a couple of outbuildings filled with pens that each had hundreds of cuy in them. And acres of alfalfa grass they'd cut and feed to the cuy. Cuy are Ecuador's equivalent of broiler chickens. Twelve weeks old and they're someone's dinner.
Jaime: Individual families can order live cuy delivered to their homes, or cuy that has already been prepared to cook. I asked the cuy farmer to give me the names and addresses of such individuals ten days previous. Of the six customers that had received prepared cuy, two had tested positive. Of the eight families who had received live cuy, we found a total of nine positives, spread over four families.
Jayjay: I was thrilled. We could find tons of cases just tracking the cuy farm's customers!
Jaime: I was curious how COVID had got into the cuy population. I asked the grower if there had been any strange outbreaks of disease among cuy. She said in the Spring of 2019 there had been cases of whole farms of cuy getting sick down in Bolivar province, diarrhea mostly, a few deaths, but it stopped after a few weeks. At the time, COVID was out of control in Guayas. More than 10,000 people had died of COVID. When things started to get bad in Guayas, a lot of people had fled the city for the high country, including Bolivar Province.
Jayjay: If 10,000 people on the coast died of COVID, you have to assume at least 50,000 people got somewhat sick and another 150,000 were asymptomatic. With that many people infected there would have been lots of different COVID mutations, lots of different variants. If a person was infected with a very weak variant of COVID they wouldn’t get sick; they wouldn’t even know they had been infected. You have to assume one of those people got a job on a cuy farm.
Jaime: I asked the farmer if there had been any sickness in the Cuenca cuy farms, and she said, yes, there was. She blamed it on the stud cuy. Cuy farmers liked to keep genetic diversity in their herds so they would trade male guinea pigs between farms to keep stock from getting inbred. She figured that's how whatever made cuy in Bolivar sick had worked its way up to Cuenca.
Jayjay: I have to think our original theory was half right. Let's imagine the physiology of guinea pigs is different enough from that of human beings that guinea pigs can't catch normal COVID. Random chance might not produce a virus so extremely weak it could be used as a live vaccine. But it could produce a variety of moderately weak variants. Maybe there are a hundred moderately weak variants out there. You just need one that has mutated away from being able to affect humans and towards being able to infect guinea pigs. Once that gets into cuy, this already weak variant keeps adapting and evolving to be better and better suited to guinea pigs, enough so by the end it can barely infect humans.
Jaime: I very strongly suspected you were right that guinea pigs could not catch normal COVID. Cuy live in very close quarters in small pens. If one got infected, it seems likely it would have spread like wildfire. I have to think that if whole herds of guinea pigs were being infected with normal COVID, there would be enough people getting sick and/or dying that case tracking would have pointed the finger at guinea pigs as the source.
Jayjay: But you wanted to be sure, I remember. Discovering that any form of COVID had spread through a livestock animal had you a little freaked.
Jaime: I told Jayjay, as soon as the WHO gives us your money, (I can see he is taunting Jayjay here!) I want to find a cuy herd that isn't infected with cuypox, send half a dozen of those cuy to the main government lab in Quito, and ask researchers to try to infect them with normal COVID any way they can. Inject them with COVID, put it in their food, spritz it up their noses. Then wait and see if any of the cuy have been infected with normal COVID. If guinea pig can be a vector to spread COVID, it's really important to know that.
Jayjay: COVID did seem to infect a lot of animals. So you were right to be a little worried.
Jaime: Next I say to Jayjay there are three things I want to tie down before we end our call. First I asked if had he sent the money to the WHO.
Jayjay: I replied that I was waiting to see if you had come up with a new way to find cases. Clearly you have. I promised I would instruct my bank to do so, as soon we were done our call.
Jaime: Then, I ask Jayjay if he has contacted Ting Ting. He says he now feels comfortable involving Ting Ting and will do so.
Jayjay: The last thing Jamie asks is that I fill Katie in on the existence of cuypox, and explain how it will enable us to find lots of cases. And to ask WHO send money as soon as possible so his boss doesn't burst a blood vessel.
I say Gawd, things were really taking off! They both nod.
I think you should blog your whole novel.
Bruce, you can see the future. You are a magical man. Any idea if you have the ability to time travel?