The spike protein is the dangerous bit of the virus; without it, the virus is harmless. If we could somehow get our immune system to recognize the spike protein, it could then glom onto and destroy the viruses before they start reproducing in our cells. And that\u2019s what the Pfizer and Moderna vaccines do.<\/p>\n\n\n\n
The vaccine is in fact composed not of spike protein itself, but of artificially synthesized instructions<\/em> for making the spike protein. Those instructions, coded in mRNA, are packed in lipid nanoparticles and injected into our arms. The mRNA, engineered to evade our body\u2019s many defenses against foreign genetic material, goes into our cells and instructs our own protein-synthesizing material to make many copies of the spike protein itself. <\/em> Since these copies aren\u2019t attached to a virus, they aren\u2019t dangerous, but they prime the immune system to destroy any later-attacking viruses by zeroing in on the spike proteins on the viral surface.<\/p>\n\n\n\n Thus the vaccine uses our own bodies in several ways: to make copies of just the spike protein, and then to provoke our immune system to recognize them, which the body \u201cremembers\u201d by storing the instructions to fabricate antibodies against real viral spike proteins. The part of this story that amazes me is the years of molecular-genetic studies that went into our ability to design an injectable mRNA, studies that weren\u2019t done to help make vaccines, but simply to understand how the genetic material makes proteins. In other words, pure research undergirded this whole enterprise.<\/p>\n\n\n\n You can read a longish but fascinating account of how the mRNA vaccine was made at the link below at science maven and engineer Bert Hubert\u2019s website (click on the screenshot). Hubert doesn\u2019t go into the details about packaging the engineered mRNA into lipid nanoparticles, which is a tale in itself, so there\u2019s a lot more to learn. At the end, I\u2019ll link to a story about how quickly this vaccine was made\u2014less than a week<\/em> to both sequence the virus\u2019s RNA, including the spike protein, and<\/em> then use that sequence to design a vaccine based on the spike protein. What I\u2019ll do here is try to condense Hubert\u2019s narrative even more. <\/p>\n\n\n\n Before China even admitted that the viral infection was dangerous and spreading, Yong-Zhen Zhang, a professor in Shanghai, had already sequenced its RNA (the genetic material of this virus is RNA, not DNA), and then deposited the sequence on a public website (a dangerous thing to do in China). The entire viral genome is about 29,000 bases long (four \u201cbases\u201d, G, A, C, and U, are the components of RNA), and makes 6-10 proteins, including the spike protein.<\/p>\n\n\n\n Within only two days after that sequence was published,<\/em> researchers already knew which bit coded for the spike protein (this was known from previous work on coronaviruses) and then, tweaking that sequence, designed mRNA that could serve as the basis of a vaccine. Once you\u2019ve designed a sequence, it\u2019s child\u2019s play these days to turn it into actual RNA.<\/p>\n\n\n\n The final mRNA used in the Pfizer vaccine is 4282 bases long (if you remember your biology, each three bases code for a single amino acid, and a string of amino acids is known as a protein). But the vaccine mRNA does a lot more than just code for a protein. Here are the first 500 bases of the Pfizer mRNA as given by Bert Hubert, and below you\u2019ll see a diagram of the whole mRNA used in the vaccine:<\/p>\n\n\n\n If you remember your genetics, this sequence looks odd, for mRNA sequences usually contain the bases A, G, C, and U (uracil). Where are the Us? In this vaccine, the Us have been changed into a slightly different base denoted by \u03a8 (psi), which stands for 1-methyl-3\u2032-pseudouridylyl. I\u2019ll give the reason they did this in a second.<\/p>\n\n\n\n But what you see above is less than one-eighth of the whole mRNA used in the vaccine. I won\u2019t give the whole sequence, as it\u2019s not important here, but the structure<\/em> of the mRNA is. Remember, this was engineered by people using previous knowledge and their brains, and then entering the sequence into a \u201cDNA printer\u201d that can fabricate DNA that itself can be turned into virus-like RNA. Isn\u2019t that cool? Here\u2019s a picture of the Codex DNA BioXp3200 DNA printer used to make the DNA corresponding to the vaccine\u2019s RNA (photo from Hubert\u2019s site):<\/p>\n\n\n\n And here\u2019s the heart of this post: the structure of the 4282-nucleotide string of RNA that is the nuts and bolts of the vaccine (also from Hubert):<\/p>\n\n\n\n You can see that it\u2019s complicated. The heart of this<\/em> is the \u201cS protein__mut\u201d, which is the engineered code for the spike protein. But all that other stuff is needed to get that bit into the cell without it being destroyed by the body, get it to start making lots of spike protein to act as a stimulus (antigen) to our immune system, and to get the spike protein made quickly and copiously. The more innocuous spike protein we can get into our body, the greater the subsequent immune response when the virus attacks. Each bit of the mRNA shown in the diagram above has been engineered to optimize the vaccine. I\u2019ll take it bit by bit:<\/p>\n\n\n\n Cap<\/strong>: Underlined in the diagram above, this is a two nucleotide sequence (GA) that tells the cell that the mRNA comes from the nucleus, where it\u2019s normally made as a transcript from our DNA. These bases protect the engineered RNA from being attacked and destroyed by our body, as it makes it look like \u201cnormal\u201d RNA.<\/p>\n\n\n\n Five prime (5\u2032) untranslated region (\u201c5\u2032-UTR\u201d) in the diagram. <\/strong>This 51-base bit isn\u2019t made into spike protein, but is essential in helping the mRNA attach to the small bodies called ribosomes where it is turned into proteins\u2014three-base \u201ccodon\u201d by three-base \u201ccodon\u201d\u2014with the help of smaller RNA molecules called \u201ctransfer RNAs\u201d (tRNAs). Without the 5\u2032-UTR, the protein won\u2019t get made. Besides helping get the engineered mRNA to the ribosomes, this region has been further engineered. First, the Us have been engineered into \u03a8s, which keeps the immune system from attacking the mRNA without impairing its ability to attach to the ribosomes and make protein. And the sequence has been further tweaked to give it information for making a LOT of protein. To do this, the designers used sequence from our alpha-globin gene\u2019s UTR, for that region makes a lot of protein. (Alpha globin is one half of our hemoglobin molecules, one of the most copious and quickly made proteins in the body.)<\/p>\n\n\n\n S glycoprotein signal peptide (\u201csig\u201d) in the diagram<\/strong>. This 48-base bit, which does<\/em> become part of the protein, is crucial in telling the cell where to send the protein after it\u2019s made. In this case, it tells it to leave the cell via the \u201cendoplasmic reticulum\u201d, a network of small tubules that pervades the cell. Even this short bit was engineered by the vaccine designers, who changed 13 of the 48 bases. Why did they do this? Well, they changed the bases that don\u2019t make a difference in the sequence of the protein (these are usually bases in the third position, whose nature isn\u2019t important in protein sequence). But these bases do affect the speed<\/em> at which a protein is made. Hubert doesn\u2019t explain why this happens, but I suspect that the engineered changes were designed to fit with more common transfer-RNA molecules (tRNAs), which are the small bits of RNA that attach to amino acids in the cytoplasm and then carry them to the mRNA to be assembled into proteins. While there are 64 three-base sequences (4\u00b3), there are only 20 amino acids that normally go into proteins. That means that some tRNAs code for the same amino acids. Since these \u201credundant\u201d tRNAs are not present in equal quantities in the cell, you can make proteins faster if you design an mRNA sequence that matches with the most common tRNAs. I\u2019m guessing that this is what these 13 changes were about.<\/p>\n\n\n\n Spike protein (\u201cS protein__mut\u201d) in the diagram. <\/strong>This is the heart of the mRNA, containing 3777 bases that code for the spike protein. In this code, too, they\u2019ve \u201coptimized\u201d it by changing the \u201credundant\u201d bases to allow protein to be made faster. The \u03a8s are now gone, as they\u2019re not needed to evade the body\u2019s defenses. But there\u2019s one bit that puzzled me until I read Hubert\u2019s explanation. The spike protein made by the body after vaccination differs from the viral spike protein in just two of the 1259 amino acids. The engineered sequence substitutes two amino acids\u2014both prolines\u2014for amino acids in the viral spikes. Why? Because it was known from previous work that these prolines stabilize the spike protein, keeping it from folding up. It thus retains the same shape it has in the native virus. A folded-up spike protein may induce antibodies, but they won\u2019t readily go after the virus\u2019s own spike proteins because their shape is different. This is just one of the many bits of prior knowledge that came to bear on the vaccine\u2019s design.<\/p>\n\n\n\n The 3\u2032 untranslated region (\u201c3\u2032-UTR\u201d) in the diagram<\/strong>: mRNA\u2019s have these, but we\u2019re not quite sure what they do, except, as Hubert says, the region is \u201cvery successful at promoting protein expression.\u201d How this happens is as yet unclear. This bit, too, was engineered by the vaccine designers to make the mRNA more stable and boost protein expression.<\/p>\n\n\n\n The poly-A tail (\u201cpoly[A]\u201d in the diagram)<\/strong>. This is the 140-base end of the message. All mRNAs made into proteins contain a repeat of the adenine base at the butt (3\u2032) end, so we get an AAAAAAAAAAAAA. . . sequence. It turns out that these A\u2019s are used up when an mRNA molecule makes protein over and over again (they\u2019re like telomeres that get shorter as we age!). When all the As are gone, the mRNA is useless and falls off the ribosomes. Again, previous knowledge told the designers how many As<\/em> to put at the end of the sequence. It was known that around 120 As gave the best result in terms of protein production; the designers used 100 As split up with a 10-base \u201clinker\u201d sequence. Hubert doesn\u2019t explain the linker, and I don\u2019t know why it\u2019s there.<\/p>\n\n\n\n Nevertheless, you can see the complexity of this vaccine, whose design rests on an exact knowledge of the spike protein\u2019s sequence (recent mutations in the sequence don\u2019t seem to affect the efficacy of the vaccine, as they probably don\u2019t affect the spike\u2019s shape), as well as on previous research about stuff like the \u03a8 bases helping evade mRNA destruction, the optimum sequences for high production of protein, the number of As at the end that are most efficacious, and then those two proline substitutions in the vaccine\u2019s spike protein. It\u2019s all marvelous, a combination of new and old, and a testament to the value of pure research, which sometimes comes in mighty handy.<\/p>\n\n\n\n This prior knowledge, combined with fast sequencing of RNA and the development of machines to turn code into RNA, help explain why the vaccine was designed so quickly. Of course it had to be tested and distributed as well, and this Guardian<\/em> article<\/a> tells you ten additional reasons why it took only ten months to go from the onset of the pandemic to a usable vaccine.<\/p>\n\n\n\n Finally, a bit of history of science is recounted by \u201czeynep\u201d at Substack, <\/em>showing additional reasons why the vaccine came out so quickly (click on screenshot). It\u2019s largely about Yong-Zhen Zhang, the Chinese scientist who published the genetic code of the Covid-19 virus. Zeynep sees him as a hero who took risks with that publication. What\u2019s clear is that without that code (and of course sequencing of DNA and RNA has been done for a long time\u2014another benefit of pure research), we wouldn\u2019t be near as far along as we are in battling the pandemic.<\/p>\n\n\n\n When you think about all this, and realize that only one species has both the brains and the means to make a designer vaccine to battle a devastating virus, and then think about the many scientists whose work contributed over many years to the knowledge involved in designing these vaccines, it should make you proud of humanity\u2014and of the human enterprise of science. Yeah, we screw up all the time, and are xenophobic and selfish, but this time we overcame all that and used the best in us to help all of us.<\/p>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":"![\"\"](\"https:\/\/whyevolutionistrue.com\/wp-content\/uploads\/2020\/12\/bnt162b2.png\")
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