I feel very thankful to have been chosen to be a participant in Virtual Explorations in Cancer Research. I learned quite a lot, not just about cancer and treatments, but also about possible career pathways from listening to and asking questions of many amazing scientists and doctors.
One guest speaker that I really appreciated having was Dr. Keith Eaton. His talk was very interesting because he was both a cancer doctor and a cancer survivor. His mindset must be so different from other doctors’ because he went through what all his patients are going through, and he knows firsthand the struggles of cancer and how to go about treating it. His story was also interesting because he practically diagnosed himself and was accepted into two groundbreaking clinical trials including CAR-T cell treatment. I thought his story was incredible, and I really appreciated his talk.
I choose to research and understand the article, “What happens if the coronavirus’s spikes mutate?” by Jake Siegel because when I first heard about the coronavirus, this was one of my largest concerns. What happens if it mutates?
Currently, coronavirus has relatively low mortality rates, which is still not great. However, it would be so much worse if the virus mutates to have a much higher mortality rate. Additionally, I was skeptical if someone who had coronavirus and then recovered would have antibodies to protect them from getting sick again, or if the virus would mutate too fast for this to happen.
The article summarized a study that was conducted by the Bloom lab which specializes in studying the evolution of proteins and viruses, specifically influenza. The leader of this particular study was Tyler Starr, who has a BA in biology and biochemistry, and a PhD in biology and biochemistry and molecular biophysics.
The study modelled possible mutations of the protein RBD (the receptor binding domain), part of the spikes on the outside of the virus, and the effect that this would have on the virus’s ability to bind with ACE2, a protein on the outside of human cells, which allows it to get inside. They model the protein folding using a technique called deep mutational scanning, or computer modelling, by changing individual amino acids to see what the end structure is. This technique is also being used to develop the yearly flu vaccine, as that is a virus that is constantly mutating.
As can be seen above, protein folding has up to four main steps, determining the final shape of the protein. Original illustration by Fiona Willmer.
Protein folding is a very complex process where the final shape is dependent on the original order of the amino acids, coded by the DNA. There are many attractions and repulsions that cause the final shape to be what it is. As you can probably imagine, even a single mutation can result in a completely different structure and function. The function that this particular study was focused on was the ability to bind to the molecule ACE2. Currently, the coronavirus binds well to this protein, allowing it to get inside. The researchers mapped some likely scenarios of mutation and found some very surprising results.
While most of the mutations made the bind between RBD and ACE2 weaker, there were quite a few that had the same amount of bind or an even tighter bind. While this doesn’t necessarily mean a more deadly virus, the results are surprising. The data from these simulations was presented in the form of heat maps and visualizations.
I reached out to Dr. Starr to ask why a stronger bind doesn’t mean a more powerful virus, and he replied, letting me know that although there is much that we still have to learn about coronavirus, the hypothesized reason (based on findings in influenza) is that the binding power is sufficient. He said that if the bond was too weak, the virus would clearly not bind well and be weaker, but if it was too strong, it would possibly even hinder the ability of the virus to replicate. If the virus had an extremely high RBD and ACE2 attraction, and was released to take over other healthy cells aside from the one it was coming from, it would have a lot of difficulty even overcoming the attraction of the ACE2- RBD bond from its own cell or those near it, weakening the virus by impeding its ability to spread.
RBM (a part of RBD) binding coronavirus to the ACE2 human protein. Illustration from “Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor”
I also asked Dr. Starr what his team’s original hypotheses were and what actually happened. He told me that because this was more of an “exploratory study” there were no hypotheses, but that they did see some surprising results. He said that the number of mutations which enhanced the ability of RBD to bind with ACE2 was quite unusual. He also said that the number of “stable” proteins that they were able to identify with mutations was a large amount, which could aid with vaccine development. The article added that many vaccines are using RBD, and the results from this study can help find a form of the protein that is stable and able to be mass produced for the public.
The article also mentioned that researchers hope that the results of this study will help them figure out where the virus’s origins lie and better understand how they evolved to infect humans. I asked Dr. Starr about how this data can help us understand the spread to humans as well as if we could backtrack the virus to find its origins. He let me know that the findings have a lot of information that they can use to help watch for early signs if the virus is mutating in unexpected ways by serving as a database to compare to samples in patients. This can help us determine which outside forces are causing these mutations to occur. The data from this study can also help us understand which mutations were involved in coronavirus being able to jump from other species to humans.
Sources:
“Instructions.” SARS-CoV-2 RBD DMS, 2020, jbloomlab.github.io/SARS-CoV-2-RBD_DMS/.
“Lab Members.” Fred Hutch, research.fhcrc.org/bloom/en/members.html.
Lan, Jun, et al. “Structure of the SARS-CoV-2 Spike Receptor-Binding Domain Bound to the ACE2 Receptor.” Nature News, Nature Publishing Group, 30 Mar. 2020,
Siegel, Jake. “What Happens If the Coronavirus's Spikes Mutate?” Fred Hutch, 29 June 2020, www.fredhutch.org/en/news/center-news/2020/06/coronavirus-spike-protein-mutations.html.
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