The Pangolin Paper

On reading Lethal infection of human ACE2-transgenic mice caused by SARS-CoV-2-related pangolin coronavirus GX_P2V(short_3’UTR) by Lai Wei, Shuiqing Liu, Shanshan Lu, Shengdong Luo, Xiaoping An, Huahao Fan, Weiwei Chen, Erguang Li, Yigang Ton and Lihua Song.

Bouquet of flowers by Marie-Anne Camax-Zoegger (1881-1952)

A slight detour today, although some will recognize a few familiar symptoms. On reading will fully on track next week.

This study has made international news, even though it’s not yet been peer-reviewed, that is to say examined by several scientists up front of publication in a scientific journal. Just one example; the French TV news channel LCI featured a 30-minute late night discussion where nobody disputed it was part of a Chinese biological warfare program. One journalist said the pangolin virus was mutated by Gain of Function research.

It’s a manuscript where the details matter. The paper says what it does, everything is clear, although it is hard core molecular virology which is essentially a language unto itself. So let’s have a go translating it.

This group has previously worked with two coronaviruses derived from pangolins none of which caused disease in lab mice. For one isolate, what virologists call a virus grown in the lab, they noticed 114 building blocks were missing from its genome compared to other pangolin viruses. It was a no brainer to want to work out the consequences of these missing blocks.

As coronaviruses are RNA viruses that mutate fast, so much so that even genomes in a virus isolate are heterogeneous, they derived seven clones. As anticipated, all seven were genetically distinct. They worked up clone #7 in detail.

They injected clone 7 virus into mice carrying the gene for human ACE2 protein that COVID-19 pandemic viruses need to get into cells. 100% of these mice died rapidly compared to the parental virus.

As these results differ to those of a group from the Wuhan Institute of Virology, as well as a previous study of their own, they did the work up and determined the amounts of pangolin virus in various tissues.

They noticed more than ten thousand times more clone 7 virus in the brains of these ACE2 transgenic mice at day 6 compared to parental virus. By contrast, the amounts in the lung were no different. This is unusual to say the least.

The group went on to say that their humanized ACE2 mice had huge quantities of the ACE2 protein in the brain which probably explains why they found so much virus there. The singularity of this research hinges around this atypical ACE2 mouse. A simple conclusion suggested by the authors was that the mice were dying of brain disease as opposed to lung disease.

It’s worth remembering that the missing building blocks in the pangolin virus genome showed up in a lab virus isolate. Virology is full of examples where viruses change subtly upon adaptation to lab culture.

In short, 1) we have no idea such a virus would survive in the wild; 2) we have no idea what would happen if this virus was injected into pangolins; 3) we have even less idea if ever such a virus spilt over into humans; 4) there is no information for public health officials in this work.

If the missing genome blocks had been identified in biopsies from one or more pangolins, something that could easily have been done by a PCR analysis, then it would have been more interesting. You could have started wondering.

Why was the manuscript misconstrued? The authors talk up a little their work; just look at the title, Lethal infection of… However, this is par for the course and journalists should have seen through it.

That 100% of animals died was caught by the press although you can find this in umpteen virology papers. Others noted that no biosafety level was mentioned for the work, but this is a detail that might well have been fixed during peer-review.

Under the ethics statement we learn that the work was approved by the Institutional Animal Care and Use Committee of the Fifth Medical Center, General Hospital of the Chinese People’s Liberation Army. Could it be this? If so, it’s a bit thin, but along with omission of the biosafety level, maybe it was enough for some.

We have seen that the US Defense Advanced Research Projects Agency (DARPA) reviewed a joint collaboration involving American and Chinese researchers at the Wuhan Institute of Virology involving engineering of bat coronaviruses. As is well known, DARPA is an agency of the Department of Defense. It is equally well known that this research proposal was refused.

It is a small step for a not too rich imagination to conclude that DARPA was interested in biological warfare involving bat coronaviruses. This makes no sense of course as it was a collaborative effort between two nations. But then reason and rumor are often unlinked.

The manuscript is first and foremost a classical piece of virology that doesn’t shock. No exaggeration is merited.

What we have learnt post-COVID is that there is a group of bat coronaviruses, distinct from SARS1 viruses, that can also grow on human cells. It is easy to say with hindsight, but how did virologists not know this before the COVID pandemic? After all, we’ve been looking for a while. We were blindsided. Add to this, natural pangolin coronaviruses with a capacity to infect human cells. Who knows what else is out there?

What we see is that any virology manuscript can be misconstrued and provoke ire so long as there are enough key words. Pangolin, coronavirus and China were apparently enough. The details don’t seem to matter. Virology will have to live with this new normal, as unwarranted and tiring as it is, although some journalists and their expert commentators could have done a better job.

Details matter, words have meaning. They always did.