TLDR

The difference this time is that the researchers measured changes in gene expression and epigenetics in multiple tissues with the aim of identifying the factors most associated with delayed aging. Once you have that information you could potentially create a drug or gene therapy that replaces the need for vampirism, but of course that takes all the fun out of it.

You got it!

Jargon is unavoidable I'm afraid, but the basic idea is that adding a single methyl group (a carbon with 3 hydrogens) in the case of m1-Psi can block the cell's native recognition machinery, but not interfere with the protein translation machinery. A very clever and elegant biohack!

The new generation of oligonucleotide based therapies including mRNA, siRNA, Antisense Oligo and even several iterations of CRISPR are enabled through medicinal chemistry based modification of everything from the nucleobases (AGTCU), the sugars (deoxyribose, ribose, etc) and the phosphate backbone (replacing Oxygens with Sulfur and other modifications).

For anyone who is interested, I aligned the Pfizer and Moderna sequences as provided in the pdf. The encoded spike proteins are identical, but the mRNAs are different.

Thanks to redundancy in the genetic code, multiple RNA triplets can often encode the same amino acid. The random nature of codon optimization algorithms would lead to the two teams choosing "different' mRNAs that still reflect the codon usage stats of a human mRNA.

There are also notable differences in the 5' (upstream) and 3' (downstream) untranslated regions, or UTRs, that regulate the stability and translation of mRNA molecules. It would be interesting to test them side by side in the lab and see if there is a significant difference in protein production.

A final difference between the two vaccines that is not encoded by the mRNA is in the composition of the lipid nanoparticle that is responsible for delivering the mRNA to the host cells for protein production. Probably the two vaccines use similar but different mixtures of positive charge and lipid. Nanoparticle technology allows mRNA, an enormous highly negatively charged molecule, to be internalized into cellular endosomes and escape to the cytoplasm where it can guide the production of antigenic protein. Without the special mix of positively charged fats (cationic lipids), the mRNA would be dead on injection thanks to serum RNases, and it would never accumulate significantly in the cell.

Another interesting note is that the researchers have posted the sequence of the DNA copy deduced by reverse-transcribing the mRNA, since mRNA doesn't contain "T" bases but instead contains "U" bases. On top of that, therapeutic mRNAs (including Pfizer and Moderna molecules) don't even use U, but instead incorporate 1-methyl pseudouridine (m1-Psi), which avoids activating the innate immune system of cells.

Don't confuse the innate immune system with the adaptive immune system. The job of the innate immune system is to recognize incoming viruses, often in the form of extracellular RNA, and initiate the shutdown of protein synthesis and often cell death. Earlier generation mRNA vaccines that incorporated U instead of m1-Psi exhibited strong activation of the innate immune system and were less effective at hijacking cellular protein producing machinery to manufacture antigen proteins.

All in all it's amazing what has been accomplished in the last year, but it was only possible because of decades of underlying research into this new therapeutic technology. Truly a triumph of chemistry and biology.

https://virginiaproject.com/fi...

SARS-CoV-2 receptor binding domain (RBD) is flanked by EcoRI and BstEII restriction endonuclease sites, used routinely by molecular biologists for cut and paste genetic engineering. These restriction sites are DNA sequences that introduce amino acid point mutations in SC2 that are not found in any other natural coronavirus genomes published prior to the pandemic. They are the equivalent of the fingerprints of the researchers being all over this genome. Furthermore, this region of the spike protein is exactly what has been modified and published by WIV researchers in the past. That's one example. For the rest, see Li Meng Yan et al, 2020 and judge for yourself.

Early estimates from China of SARS-CoV-2 R0, or the number of people an infected person will pass the virus to, was about 2. In other words, the virus is more infections than flu, but it's not out of the realm of possibility that someone drove to the wet market, infected 1 person there, and then infected only 1 other person in the course of their disease.

I would imagine the leadership at the companies doing much of the work to cure/prevent COVID disagree, otherwise they would not come up with their own individual solutions (what we're seeing now) instead of cooperating and sharing the production burden (possible altruistic non-profit scenario?).

Since the US govt. lacks the capacity to produce these kinds of drugs at industrial scale, the only way they could replace the privately owned companies (who possess the knowhow, facilities, workforce, supply chain etc.) would be to do as you suggest. While the govt. may or may not have that right, I respectfully disagree that they should feel free to do so and I don't think that they will. I think a handful of successful companies will develop COVID countermeasures (vaccines much more likely than antibodies) and reap the lion's share of the profits, however much that may be.

Not to forget the bragging rights for winning the race, which loosely translates into a bump in share price as many here have already pointed out.

Monoclonal antibody patents are an important part of many biotech/pharma companies' portfolios and are enforceable. What is challenging is that someone else can develop an antibody with a different sequence that binds to the same target and produces the same effect. Your patent cannot protect you from this, but the hope for many companies is that the barrier to antibody development will allow you to gain mass marketshare before competitors go after your target. While it is a valid concern that the govt may attempt/succeed at confiscation of intellectual property, I think it that the first company to develop a successful COVID-19 prophylactic will probably profit from their initial investment.

Antibodies initially discovered through screening almost always go through a stringent engineering process. Antibody engineering includes but is not limited to humanization (careful substitution of animal host sequence with matching human sequence, but not so much that it *breaks* the antibody, as well as affinity maturation, which involves creating derivative sequences that can be selected for higher affinity to the target. Reduced immunogenicity, pH sensitive binding and the inclusion of other recombinant protein domains or even other antibody binding domains (bispecific antibodies) are other examples of antibody engineering. All of these modifications are absolutely included in your antibody patent and make your molecule much more defensible.

Monoclonal antibodies are big business and the pipeline to discover and produce them is mature. Sorrento has a large human antibody library that they likely screened as phages and selected based on binding of SARS-CoV-2 spike glycoprotein. Winners are easily converted to small format single-chain variable fragment (AKA scFv) antibodies that are relatively inexpensively produced in bacterial cultures.

The downside with scFv is that unlike full-size antibodies (they are 6 times smaller), they are cleared more rapidly from the blood, have only one antigen binding site instead of 2, which makes it harder for them to hold on to their target (imagine doing one-handed pullups instead of two-handed or even just hanging there) and they lack the immune effector functions present on full size antibodies made natively in the body. To convert scFv to full size antibodies is generally straightforward, but production must be switched to mammalian cells (such as CHO) that are capable of handling the more complex protein folding and modification required to make functional antibody molecules.

Overall the strategy to protect front line workers in critical industries is probably the best one. Once a vaccine is available, it will put the monoclonal antibody out of business due to the ability to induce long-term immunity vs. the very short term immunity an antibody would provide.

When my Nexus 5x succumbed to the BLOD earlier this year I dusted off my trusty Nexus 4. Now I can't even remember why I upgraded.

I agree with the sentiment that we can't talk seriously about colonizing other worlds until we learn how to sustainably inhabit our own, but we need to develop the technology to move humans en masse alongside the capability to not ruin whatever place we land on. Not ruining planets is something we should be practicing on earth immediately, but as TFA points out, many people fail to recognize the economic benefits. Some day this world will be come uninhabitable (asteroid? zombies?) and it would be nice for the sake of our species to be able to move at least some of us to a new place and stay alive there. Why not work on this technology and prepare now? I think our descendants would thank us if they didn't have to attempt the long term survival of the human race in a hastily improvised tin can.

One of my favorite stories is Aesop's tale of the boar and the fox:

One day as he moved through the forest the fox came upon his friend the wild boar who was engaged vigorously sharpening his tusks against a large stone.

"My friend," started the fox, "Why do you exert yourself so, seeing there is no hunter about and no other danger from which to defend yourself on this day in the forest?"

To which the boar frankly replied, "The day will come when I have need of sharp tusks. I shall have no time to sharpen them then."

I would add that there are a couple of advantages of the antisense oligonucleotide therapies developed by Ionis and other companies over CRISPR:

1. Delivery. CRISPR currently requires a viral vector to deliver Cas9 protein as well as guide RNA molecules. Antisense oligos (ASOs) have already demonstrated clinical efficacy in delivery to motor neurons to treat spinal muscular atrophy (nusinersen).

2. CRISPR gene editing generates permanent changes in the genome and while accuracy is improving, off-target cutting is still a hurdle. It will be a while before permanent edits make their way into patients' brains, but the CRISPR hype machine may have the momentum to do it. There are RNA targeting varieties of CRISPR, but they face the delivery barrier and don't offer a significant advantage over ASOs.

The story of ASO drugs is actually really inspiring for anyone hoping to develop a brand new class of drugs that target formerly "undruggable" proteins like Huntingin. Ionis (formerly Isis) has been on the brink of collapse many times and had a few clinical flops before finally seeing some success. I think it's amazing that a devastating disease like Huntington's might actually turn into a manageable condition.

Of course, one of the "cheapest" ways to eliminate this disease from future generations is in vitro fertilization followed by genetic screening. Tens of thousands of dollars to ensure your offspring lack the offending gene vs. what will likely amount to hundreds of thousands per year for ASO (or $1 million+ for a one-off CRISPR viral therapy). Still, using genetic disease to understand and master the technology of gene-based drugs (CRISPR, ASOs etc) can help us to better treat genetic disease that arises de novo, especially cancer.

Base Editing is a CRISPR variant where the DNA-cutting activity of Cas9 protein has been modified with a mutation that disables its DNA cutting ability and a fusion to another protein called Cytidine Deaminase which converts "C" bases to "U" bases (which are read as "T"). It is still guided to the precise chromosomal location by a "guide RNA" that is complementary to the region you want to edit.

The CRISPR field is very wild-west like at the moment and everyone is fighting for their share of the spotlight (and the potential wealth) with these minor variants. Whether it's truly safer than vanilla CRISPR will be better demonstrated over time and hopefully by labs without a direct financial interest in the success of one competing platform over another.

I also recently finished Dune (a couple of months ago?) and finished Neuromancer this morning on my walk to work! I agree - the two books are very different, making for a funny sequence of mental space to wander through but well worth the journey. I am also 20% through Jurassic Park - a favorite from my childhood.

Yes! These de-clawed HIV vectors are known more broadly as therapeutic lentivirus. The problem is still efficiency - you have to not only hit every infected cell, but CRISPR editing has to go off without a hitch in those cells. Then there's the issue of turning off the transgene you've just delivered before "off target" cuts can induce chromosomal aberrations that can lead to cancer.

This isn't the first time researchers have used gene editing to tackle HIV infection. There is a clinical trial involving adenovirus delivery of zinc finger nucleases (a prior generation gene editing technology) to patient-derived blood stem cells to inactivate CCR5, an essential HIV receptor, on the surface of immune cells. Importantly, these cells are removed from patients, edited in the lab and returned to the body. This ensures that all NEW blood cells will be HIV resistant, but is also not a total genomic clearance of latent provirus.

I agree that a combination of approaches will probably be required to inactivate latent provirus as well as slow disease transmission. Public health approaches like needle exchanges and safe sex education are probably just as important for eliminating this disease.