• Allan Dyen-Shapiro

OF PANGOLINS, RECOMBINATION, ACE2, FURIN, ENDANGERED SPECIES, RACISM, AND XENOPHOBIA

"Kung flu," "the Chinese virus," "enormous evidence" that the coronavirus outbreak originated in a Chinese biotech lab—these phrases used by Trump and Pompeo have strained US-China relations and led to attacks against Asian-Americans domestically. When evidence from many different labs ruled out the "evil Chinese biotech" theory for the origin of SARS-CoV-2, the American political establishment next fingered the wet market in Wuhan. In wet markets, live animals, including wild animals, are butchered on-site for customers. According to data presented by George Gao (head of Chinese CDC, the data is not yet published), sequencing of nucleic acids from samples taken from animals at this market all proved negative for the virus. So, yes, this was the site of a superspreading event—humans passing the disease to many other humans—but it was not the place where the virus originated. Similarly, the racist joking in the American media of Chinese people eating bat soup also points in the wrong direction—the first human to get this virus did not get it from a bat.

I live in Florida. One day this week, we had more than 10,000 new cases of COVID-19. A lack of understanding of this virus on the part of both politicians and the general public had a lot to do with this. Getting both to respond intelligently is going to require combatting propaganda. It is worth it for those concerned with racism and xenophobia as well as those concerned with not dying of COVID-19 (as well as science fiction writers who would consider using a virus as a plot device—a whole lot, if not most, of us) to understand where this virus came from.

A new paper in Science Magazine from Feng Gao's lab (at Duke, not at a Chinese lab, for those of you who need that fact to argue with conspiracy theorists), has just established how SARS-CoV-2 evolved into a human pathogen. For those of you adept at reading the scientific literature, here's the link. For those of you who can't or who don't have the time to invest a couple of hours in reading this (it's not a quick read), I'm going to do what I do a lot of on this blog—summarizing and contextualizing.

The typical protocol for understanding the evolution of a virus is to obtain the complete genomic sequence of a family of viruses in many different species. At that point, you have a code consisting of A, T, C, and G. Information of this sort can be compared using computer algorithms and "clustered" into evolutionary trees that show how closely one viral isolate is related to another. In this fashion, a near-identical copy of the virus that causes SARS was found in civets (a feline species). For the MERS virus, it's doppelgänger was found in dromedary camels. Case closed: a civet passed the first disease to humans, and a camel passed the second.

No such near-identical virus has been found for SARS-CoV-2. These studies did, however, identify bat viruses that were approximately 96% identical. Interestingly, however, viruses isolated from pangolins—a spiny anteater—were much closer to SARS-CoV-2 in the part of the virus that codes for production of the S protein. The S protein binds the receptor on human cells (called ACE2), allowing the virus to get in.

Both findings can now be explained by recombination. For those of you having a hard time remembering your high school biology class, recombination occurs when nucleic acids line up with each other (often facilitated by similarity between the sequences) and get tangled up. When this tangle is resolved, pieces of one nucleic acid are swapped out for sequences from the other. It turns out that some parts of the coronavirus genome are hot spots for recombination, showing evidence for many, many recombination events over historical time. The viruses are swapping parts with each other.

One of the parts that was swapping was the section of the S protein responsible for ACE2 binding.

Still with me? A bat infects a pangolin with virus, and a swap occurs to give that bat virus the ACE2-binding site for a pangolin. So, that's still not able to interact with human ACE2, right?

Wrong. Not every amino acid in S protein is critical. The critical ones are those that touch amino acids on ACE2. When biochemists want to know the shape of a protein, they get an X-ray crystal structure. I won't go into how that's done, but the picture that emerges shows where every amino acid is in 3-D space and which ones touch which other ones. It turns out that these important amino acids are identical between the pangolin virus and the human virus. The neat, nickel phrase is "purifying selection." Any change in these amino acids, and the virus can't enter the cells. If it can't replicate, it is lost in future replication cycles.

Natural selection, baby.

There was one other section of S protein in a recombination hotspot, and interestingly, the human virus sequence of this section is not found in any other animal coronavirus. This part is a site that is recognized by furin. Furin is a protease, an enzyme that allows a protein to be cut up into two pieces. Furin is found in all mammalian cells. It resides in compartments (the trans-Golgi Network and late endosomes) that lie at the intersection between the pathway involved in taking in stuff (like viruses) from the outside of the cell and the pathway used to export stuff from the cell.

Allow me to back up a bit. These viruses can be looked at as RNA encased in a shell made of proteins and wrapped in a membrane. The membrane fuses with the cell's membrane to dump the rest of the virus into the cell's cytoplasm. Once there, the protein shell needs to be taken apart in order to free the RNA, because the RNA has the information required for making more virus. Part of taking this protein shell apart is cutting up the individual protein parts, and the enzymes that do the cutting are proteases.

With the SARS virus, the proteases needed to do this job were located only in lung cells. So, SARS is exclusively a respiratory disease—the virus can't get in anywhere else. The COVID-19 virus, uniquely among known coronaviruses, can be cut by furin. Since furin is everywhere, COVID-19 can cause cardiovascular problems, kidney problems, and many other problems because it can infect those cells too.

So, where did the part of S protein that can be cleaved by furin come from? There are somewhat similar (but not cleavable) sites in very distant bat coronaviruses. Could this recombination event have taken place in still a third animal (not a bat and not a pangolin)? At present, nobody knows.

Three big take-home messages:

1. Coronavirus recombination is widespread and how we got this pandemic. Funding should be going to determining the genomic sequence of coronaviruses in wild populations, and this research must be ongoing. Whenever anything new is found, the genomic sequence can be used to make "pseudoviruses"—infectious particles that look to a human cell like a virus but don't contain all of the RNA, so they can't replicate. That makes them much safer to work with in the lab. But they can be assessed for whether they can get into human cells. A novel virus that can infect humans would mean watching very closely for where it shows up in nature and keeping that nature away from humans.

2. Such studies require international collaboration. Xenophobia is antithetical to these goals. Sensible folks need to counter propaganda and spread the word that blaming China for what is a failure of leadership in countries that are currently showing uncontrolled viral spread (the US, Brazil, Mexico, Russia, etc.) is counterproductive.

3. Even though the wet markets had nothing to do with the origin of SARS-CoV-2, they could have. It was plausible. To help avoid future pandemics, humans should be kept away from wild or exotic animals.

The Chinese government is taking steps to do exactly this. After the Wuhan outbreak, the Chinese government banned consumption of wild animals anywhere in the country.

Several species of pangolins are endangered. In 2018, China, the major market, banned importation of pangolins or pangolin products, hoping to save these species. Unfortunately, smuggling still occurs.

There is still better news for one of these species. In June of this year, China's State Forestry and Grassland Bureau gave the Chinese pangolin "first-level protected status." Killing a Chinese pangolin is now as punishable as killing a panda.

Also in June, the Chinese government took what will likely be a much more consequential step. Pangolins were at the wet market in Wuhan because pangolin scales were used in traditional herbal medicine. They have now been removed from the list of approved ingredients in herbal remedies.

However, there may be a loophole. Each year, a new document (the Pharmacopeia) is published listing approved ingredients for both traditional and modern medicines. The 2020 version hasn't come out. In some cases in the past, even though something was removed from the first section of the document (the list of ingredients for herbal remedies), it was not removed from the second section (the list of ingredients in "Western" patented medicines).

I'm betting most of the people reading this had no idea what China was doing on these issues. It wasn't exactly prominent in US media coverage. These are major steps. The US propaganda that the Chinese are not only to blame for our misfortune but aren't doing anything about it is very much a lie.

However, Chinese withholding of information did contribute to the horrendous nature of the pandemic in many European countries. Tight state control of information is dangerous—it resulted in deaths.

I don't envision improvements to this situation without better relations between the US and China. Combatting the misinformation blaming China for this pandemic is a modest step each of us can take toward that goal. Please feel free to discuss/critique/further enlighten as comments on my posting of this blog entry to my Facebook and Twitter profiles.

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© 2016 by Allan Dyen-Shapiro

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