"Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest. For real. [...] The really clever bit is that although this replacement Ψ placates (calms) our immune system, it is accepted as a normal U by relevant parts of the cell."
This sounds like a serious backdoor or attack vector to me - would there be any risk in introducing this Ψ, allowing some natural occuring permutations to turn wild or dangerous?
"There are 11 pseudouridines in the Escherichia coli rRNA, 30 in yeast cytoplasmic rRNA and a single modification in mitochondrial 21S rRNA and about 100 pseudouridines in human rRNA indicating that the extent of pseudouridylation increases with the complexity of an organism."
So at first it shows, that Pseudouridine is not something completely new in nature. It exist for a long time already.
And it seems a higher amount signals to the immune system, that this RNA is more human like and not coming from a virus. Since this mechanism seems to be established in nature I think one can assume it is safe. If it wouldn't be safe, viruses would probably already exist, which would make use of this "backdoor".
Now that we are producing and injecting industrial quantities of Ψ, any chance this will get incorporated in actual viruses or maybe teach the immune system not to ignore it (or maybe even go crazy about it)?
But the broader concern about advances in biotech being potentially very dangerous is I think a very good one..
Pseudouridine is the most common RNA modification in cells, actually. They produce it all the time.
> and probaby Ψ is not super durable as a chemical.
Quite the opposite. Pseudouridine usually increases the stability of the RNA molecule it modifies.
Many people have asked, could viruses also use the Ψ technique to beat our immune systems? In short, this is extremely unlikely. Life simply does not have the machinery to build 1-methyl-3’-pseudouridylyl nucleotides. Viruses rely on the machinery of life to reproduce themselves, and this facility is simply not there. The mRNA vaccines quickly degrade in the human body, and there is no possibility of the Ψ-modified RNA replicating with the Ψ still in there. “No, Really, mRNA Vaccines Are Not Going To Affect Your DNA“ is also a good read.
Wetware: A Computer in Every Living Cell
(the second for systems biology)
'In addition, I’ve been maintaining a page on ‘DNA for programmers’ since 2001.'
So, you break it up every so often with some other nucleotides.
It’s really an amazing system
Countdown to see this in vivo. For real.
> Many people have asked, could viruses also use the Ψ technique to beat our immune systems? In short, this is extremely unlikely. Life simply does not have the machinery to build 1-methyl-3’-pseudouridylyl nucleotides. Viruses rely on the machinery of life to reproduce themselves, and this facility is simply not there. The mRNA vaccines quickly degrade in the human body, and there is no possibility of the Ψ-modified RNA replicating with the Ψ still in there.
A non-technical detail that the post misses is the human story here. Katalin Kariko, the biochemist that pioneered the idea of delivering vaccines in mRNA form, got nothing but rejections for her grant applications for this very idea and was eventually demoted from tenure track at U Penn.
Whatever you think of this, it's a misleading understatement to describe it as:
> As with other fundamental scientific research we are now reaping the benefits of, the discoverers of this technique had to fight to get their work funded and then accepted.
From the article the post itself cites:
> By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.
While not an entirely false picture, the real situation is far from that clear and scientific struggles of Katalin Karikó, who finally left the academia for private sector (she is now a vice president in BioNTech, one of the vaccine-producing corporations) is an illustration of the perils of the contemporary grant systems.
Truly revolutionary concepts are often indistingushable from bullshit. At least from the grant committee point of view. Your best chance to snap up a grant is to come with a project of marginal improvement that produces one or two papers in a reliable timeframe.
Marginal improvements have their indisputable value, but they mostly appeal to risk-averse people; whoever wants to work on something really outlandish, must rely on other sources of financing, often private. After all, there is a risk of utter failure = not producing even that one paper that is, these days, a basic unit of wealth in the Publish-or-Perish world. Or of a delay that breaks the original time plan.
Well, in the modern world we have both a greedy private sector and a greedy academia...
It might be an "understatement" but it's hardly misleading. You make it sound like the author intentionally dissed them by downplaying the story.
The technique eventually did end up funded and accepted. And she still made millions (from the license), will get a Nobel soon (I predict - there's alredy pressure for that), plus, her story will 99% be made into a movie sometime in the next 20-30 years (I also predict).
The way the CS and genetics concepts map with each other is really fascinating and thought-provoking.
How would a curious engineer go about learning more about this particular "computer architecture" ?
Going further, is there a realistic career path for someone with a software engineering background to retrain, pivot and meaningfully contribute to research in this area ?
By meaningful I don't just mean the obvious role of building software tools for genetics engineering & research, but actually writing those RNA bits and designing vaccines or other similar items.
Would you need to basically start from scratch as a biology or medical undergrad before working your way up to a PhD, or are there interesting jobs at the crossroads where a previous career as an engineer might be an asset ?
Just seems like he reads the manufacturer's instructions!
For the ones with the knowlegde I have the following question: how long in days (hours?), does it take for this mRna to degrade and stop functioning and restoring the normal working of the host cells?
Poets say science takes away from the beauty of the stars - mere globs of gas atoms. I too can see the stars on a desert night, and feel them. But do I see less or more?
This article was fascinating to read. The deep understanding in genetics, biology, engineering, etc..., and all the work from thousands of people that ultimately culminated in the production of this vaccine, illustrates how beautiful science is.
I was curious about a part that I haven't found a lot of writing on so far - namely, what happens with the artificial spike protein after the cell assembled it.
Does it, like, keep floating around inside the cell? Does it attach to the cell membrane like it would to the viroid? Does it leave the cell and enter the bloodstream or does it something altogether different?
I figure it can't really stay inside the cell as it has to interact with the immune system at some point.
However, if it attaches to the cell wall, wouldn't this cause risk that the immune system considers the whole cell a pathogen and attacks it? After all, teaching the immune system to destroy anything the spike is attached to is sort of the whole point of the exercise.
Finally, if the spike enters the bloodstream, could it wreak havoc with ACE2 receptors?
Any suggestions where I could go to learn more specifically about this sort of genetic engineering and more generally about biology (University level and above).
Many people also recommend the book „Cell”.
You will also want to start with a first few chapters of Organic Chemistry from any course/book
I would be happy to devote 10 years (or a lifetime for that matter) to bring the fields to bear on one another, sounds super interesting.
As others have already noted, most work at the "intersection" of the domains is currently superficial, say designing support software as opposed to actually hacking on the genetic code.
Could you go into more detail about the structural reasons that prevent a clean mapping? Can you think of ways to lower the barrier so as to engage more people? Do you see problems that are relatively easy to export?
An example of exporting problems, in this case from digital pathology, is the Camelyon challenge, which brought machine learning to bear on cancer detection. Hype aside, the important aspect is that researchers working to segment images and train neural networks did not have to have a biochemistry background, nor understand cellular functions and provenance, nor understand staining protocols. A clean export.
I am basically looking for a "biocrackme" that is relatively self contained.
The question about the one base change that did _not_ lead to an additional C or G, the CCA -> CCU modification?
(Note to myself: I think the question is: Why CCA -> CCU and not CCA -> CCG)
How far we have come, as a species, by looking at what this vaccine is, is both inspiring and scary
The futurologist in me imagines prescriptions containing RNA sequences which you get to the nearest pharmacy to 3D print the drug. Future of the medicine looks more exciting than ever.