Viral–A Review
A Review of Viral: The Search for the Origin of COVID-19 by Alina Chan and Matt Ridley, Harper (November 16, 2021), 416 pages
This review was originally commissioned and written one year ago, around the time that Viral was released. The person who commissioned the article did not feel they could get adequate confirmation from another scientist with regards to the claims I make around codon usage and chose not to publish it. Please feel free to message me if you notice anything that is incorrect.
It is late November, 2021, and the holidays are approaching. The year is coming to a close. In contrast, for those concerned with finding the origin of the devastating COVID-19 pandemic that has upended and ended so many lives, the investigation feels like it is still very much open-ended. Among those closest to this pursuit is an unexpected leader and co-author of Viral: The Search For The Origin of COVID-19, Dr. Alina Chan.
Alina is one of an estimated 64,000 postdocs in the United States. Her research at the Broad Institute of MIT and Harvard is currently focused on finding better ways to deliver gene therapy treatments. It is the kind of tinkering work that involves combing through data, mixing and matching the parts of how we (human beings and viruses) express genes and applying them to treat genetic diseases. I understand this work because I am also a genetic engineer, combining pieces of proteins to try to find cures for devastating illnesses.
Towards the start of the pandemic, Alina’s interest was drawn into understanding the evolution of SARS-CoV-2. In particular, she co-wrote a preprint (an unreviewed scientific paper) on the platform biorxiv, describing the observation that SARS-CoV-2 was well-adapted for human transmission very early in the pandemic. This was the first red flag for Dr. Chan in what would become a series of concerns revealed over the course of the next eighteen months. The preprint caught the eye of author Matt Ridley (Genome, The Red Queen, The Rational Optimist) and became the gateway to a collaborative authorship for Viral.
As the story goes, Matt approached Alina about writing this book, but she didn’t agree to write it until late spring of 2020, when they signed the deal with HarperCollins and went public with the announcement. From that point forward, the two worked in tandem in different time zones. As Matt went to sleep in the UK, Alina would pick up the writing from Boston. They finished the book in record time but with little sleep. Alina was still working in the lab, conducting her research, and often stayed up late after work (often until 2 or 3 in the morning) to push forward with writing. Having a deadline helped.
The basis of Viral was not an easy story to tell. It spans continents, global investigations, powerful organizations, teeth-gritting conflicts-of-interest, Twitter debates and internet sleuths. On the more technical side, it covers everything from codon usage to sample naming in sequencing databases. It unearths student theses found by anonymous Twitter user The Seeker which were then translated and interpreted by the ad hoc organization DRASTIC and other independent investigators. It is complex territory to cover, and to make that accessible to the average reader is a heavy lift. Matt and Alina move through the space gracefully, keeping the reader engaged from start to finish.
My own introduction to the hypothesis that COVID-19 might have been caused by the leak of a virus in a lab came through my husband, who spends a lot of time on Twitter and warned me about the pandemic before it started. We were living in downtown Seattle, navigating early pandemic life. After a stint of working from home, I had resumed walking to the lab of the biotech company I was working for to develop cell therapy treatments for cancer. We were all trying to find the safest path forward between contradictory information about masks and route of transmission. A lab-leak hypothesis did not sit well with me, a laboratory scientist working during a pandemic. My own tribalism around science blinded me early on to what might be the reality of the origin of the virus.
Despite those biases, I started following some of the organic conversations happening on Twitter around the origin of COVID-19, including observations by Alina, questions posed by accounts such as @lab_leak, and responses from folks like @pathogenetics on aspects of genetic engineering. For background, I was actively working to engineer genes so that immune cells could attack cancer. These immune cells (T cells) don’t always like to express the genes we put into them, so we use a method called codon optimization to find an optimally expressed version. I often had half a dozen different codon optimization methods employed at a given time to find the best approach, and if I aligned these different versions in the software I used to do my work, they looked like individual sequences due to variable codon usage.
It was this knowledge about codons that piqued my interest in the genetic basis of SARS-CoV-2. Couldn’t one simply use the finger-print-like codon usage to find out if it had been engineered, as compared to natural viruses? The answer is still murky, partly because we now know that the Wuhan Institute of Virology had been sampling natural viruses in the tens of thousands. But there is one region of the viral genome that presents concern for the case of this pandemic coming from a potentially engineered virus: the furin cleavage site and in particular, the codon usage of this oddity in SARS-CoV-2. The “CGG-CGG”; which receives valid coverage in Viral and which virologist Dr. David Baltimore called, “the smoking gun for the origin of the virus.”
Why was the CGG-CGG so concerning? Life itself is determined by the central dogma of biology: DNA is transcribed into RNA which gets translated into protein; the trinucleotides or codons that make up each subunit of a protein (an amino acid) are favored differently depending on the species. In the lab, they are so divergent that if you want Protein X to be expressed in bacteria or in a human cell line, you synthesize different pieces of DNA for each.
The same is true for viruses. The way that we, the genetic engineers, optimize expression in a given type of cell is by studying the general codon usage within a species and optimizing the design for each.
There are various sources for codon usage, but my go-to is Genscript: https://www.genscript.com/tools/codon-frequency-table which I use to check for any hangups I might have in expressing a given gene in a given species. Let’s take a look at the options for Arginine, the amino acid encoded by the “CGG” codon. In humans, the frequency (or fraction) of the six codons that make Arginine (R) are:
You’ll notice that nominally, the CGG triplet is the most frequent codon for arginine in human cells, which we assume might be slightly easier to express. If one were to engineer a furin cleavage site into a viral backbone and wanted it to express best in human cells, they might select CGG-CGG over other options. Now the important comparison is, how frequent is that codon in coronaviruses related to SARS-CoV-2? One analysis suggests that CGG is present at a much lower frequency: 0.03 or 3%.
Viral covers this in greater detail, highlighting some of the sleuthing and literature mining done by the DRASTIC community, made up of scientists and citizen scientists.
Beyond the technicality of writing on a complex topic like the fraught and yet-unclear origin of COVID-19 comes the hardship of becoming a target for those who disagree with the information presented. Alina has been advised by friends and family to consider changing her name for her own personal safety. She’s become the target of smears on Twitter and elsewhere. As a sample of this, The Boston Globe quoted a state-run Chinese publication (Global Times) which stated that her “filthy behavior and lack of basic academic ethics have also aroused the disgust of many international experts.” It isn’t an easy lens for anyone to be under, much less a scientist. I ask her where her strength comes from, to stand solidly in the eye of such a storm. She doesn’t know, but she tells me that she does know, assuredly, that she must continue to disseminate information gathered on this topic.
Among the important points made in Viral is a call to action towards the end of the book. The authors recall a meeting held in 1975 in Asilomar, included as one of Nature’s ‘Meetings That Changed The World.’ Scientists gathered and set standards for the ethical boundaries of genetics and recombinant DNA work. Another Asilomar is necessary and vital, the authors argue in Viral. But has something like this been planned or even whispered about, I ask Alina. Not yet.
Reading Viral revitalized in me the power of books; the power of taking the time to lay out a complex story, to communicate it to a broader audience in a way that pours more data and background into a narrative that was largely swept under the rug by our mainstream media. Viral is one of the most important books that has been published on the pandemic. I encourage everyone to read this story, absorb its information; information I have only touched on in this review but which Matt and Alina so beautifully aggregated for all.
I admire Alina’s dedication to her dual missions; to both build awareness around the origin of the pandemic, and to advance the art of genetic engineering and gene therapy for the treatment of human disease.
Ultimately, I hope that her voice and words on the topic of viral origins can help make scientific research more safe for all.
You can listen to my interview with Alina for Lady Scientist Podcast.