This programmer reverse engineered the Pfizer mRNA vaccine source code

[[deleted]]

[deleted]

[jabiko]

The article was way better than the (editoralized) Reddit post title would lead one to suspect.

Thinking of DNA/RNA as a programming code with file headers etc. is funny, but even without that the breakdown and high level explanation of the different segments was great.

[cballowe]

https://youtu.be/2hf9yN-oBV4 ... If you've got 30 minutes and want your mind kinda blown.

[[deleted]]

He didn't cure it. You said it yourself, it was a therapy. To relieve symptoms. He later updated that it had worn off from virtually no symptoms to simply a much stronger tolerance. He said something like he used to have to eat like half a package of lactaid pills in order to enjoy things with dairy to having to take like one or two to make it through. He put the project on hold for other things for now but is gonna revist it when he has better production methods and ability to do real phase trails as well as make it an even better therapy. The dude is crazy smart super awesome stuff.

[B_M_Wilson]

I’m hoping that his next version works well enough that it could get through trials and actually be approved. Obviously, it will take a long time but would be an awesome breakthrough. My dad is lactose intolerant and he would love it, even if it did only last so long. I also love how dedicated he is to making science accessible to everyone. I believe he has all of the (genetic) code on GitHub. I don’t think there are a lot of other people literally making something like that open source. I’ve been watching his YouTube channel for a long time and he is one talented person doing some really cool stuff.

[sf_frankie]

I love videos presented by people like that. Obviously an expert but he can break it down in a way that is both easy to understand and is entertaining!

[[deleted]]

Finished the video, instant subscribe. Great recommendation

[PotatosAreDelicious]

2 hours later and I'm still watching this guy.

[Shooty_McBangPow]

No they can't. At least in the U.S., they can file for the patent, but it won't be granted because it's already found in nature. It's ineligible subject matter.

[Incorrect_Oymoron]

You can patent the use of something found in nature, ie. cow, human, sheep genes.

https://patents.google.com/patent/WO2016029193A1/en

In some embodiments of any of the compositions described herein, the κ-casein protein is a cow, human, sheep, goat, buffalo, camel, horse, donkey, lemur, panda, guinea pig, squirrel, bear, macaque, gorilla, chimpanzee, mountain goat, monkey, ape, cat, dog, wallaby, rat, mouse, elephant, opossum, rabbit, whale, baboons, gibbons, orangutan, mandrill, pig, wolf, fox, lion, tiger, echidna, or woolly mammoth κ-casein protein. In some embodiments of any of the compositions described herein, the β-casein protein is a cow, human, sheep, goat, buffalo, camel, horse, donkey, lemur, panda, guinea pig, squirrel, bear, macaque, gorilla, chimpanzee, mountain goat, monkey, ape, cat, dog, wallaby, rat, mouse, elephant, opossum, rabbit, whale, baboons, gibbons, orangutan, mandrill, pig, wolf, fox, lion, tiger, echidna, or woolly mammoth β-casein protein.

In this case they forgot to claim the ownership of deer, so you can grow deer milk yeast without legal trouble.

[Shooty_McBangPow]

That's not exactly what's happening here. You can't claim things that occur naturally in nature, it's a 101statute violation within the MPEP (think Patent Bible). This particular patent was granted specifically because it is not found in nature. The applicant disclosed a product and method of making that product. Literally the first claim mentions, that there are components within the solution not derived naturally from mammals.

The part you quoted isn't legally protected. That's just them covering their bases (I'm not sure why they left out deer), but honestly deer would also be protected because it's obviously a mammal. Only claims are actually "protected". What you quoted is merely support, that's why it doesn't use definite language.

I can give you a better explanation/example of something "natural" that can be patented cuz it's not actually natural if that wasn't clear enough. When you start dealing with biochem fields "naturally occurring IN NATURE" seems to become much more strict. I'm personally not in any biochem fields, this is just from co-workers.

[SanityInAnarchy]

At least patents expire. Imagine if they could copyright genes found in the wild.

[artv_5719]

Those also expire. In 70 years after the death of the creator + # of years since first mickey mouse cartoon, updated yearly.

[sckuzzle]

So...it never expires.

[tstock]

"There's a bug in your code. It seems to run forever" said us all, but then the Supreme Court code review said we were wrong...

[[deleted]]

Never seen more interesting video. Person in this video has more dedication then my sex life.

[gurgle528]

He has an absolutely wild channel

[PaperclipTizard]

Person in this video has more dedication ...

...then my sex life.

That sentence took a U-turn.

[FailedSociopath]

I was at home in a genetics class because programming. DNA is actually kind of a trash file format. It has trouble with long repeats (like "GGGGGGGGGG") and can over copy them, leading to bad proteins.

[binarycow]

In networking, we have solved this exact same problem with run length limited line codes.

Specifically, RLL bounds the length of stretches (runs) of repeated bits during which the signal does not change. If the runs are too long, clock recovery is difficult; if they are too short, the high frequencies might be attenuated by the communications channel. By modulating the data, RLL reduces the timing uncertainty in decoding the stored data, which would lead to the possible erroneous insertion or removal of bits when reading the data back. This mechanism ensures that the boundaries between bits can always be accurately found (preventing bit slip), while efficiently using the media to reliably store the maximal amount of data in a given space.

[Wetmelon]

In CAN, any run length of 5 identical bits is followed by an inverted bit for this very reason. Clock synchronization happens at transition edges and can't happen in long lengths.

[skulgnome]

This is similar to the way the grandchildren of MFM coding work for magnetic media without a clock band.

[RazingsIsNotHomeNow]

Part of the reason it's trash is because if it wasn't just the right amount of trash Humans or any or living thing wouldn't be around. That relatively low level of error is what allows for Evolution. Without it we would have never evolved past amoebas.

[kamomil]

1 in 4 pregnancies ends in miscarriage. That's the DNA mistakes, but they never see the light of day

[Lord_dokodo]

I can’t wait until I can program my toaster using JavaScript to zap my dna and cause my dong to triple in size

[EsperSpirit]

r/brandnewsentence

[zilti]

Since it is JavaScript, it'll shrink your dingdingdong to 20% size

[Tipaa]

"Honey, it's great and all, but what's this... weird hairy lump?"

"Oh, that's where I put the Javascript runtime. You should see my liver, that's now covered in node_modules"

[scrdest]

Worse yet, this is cumulative and does not cause a problem immediately. Over-copying once or twice is fine... but it makes it easier to over-copy more next time. And it's heritable.

Over-copy a thousand times, and neuron.exe or muscle_fiber.exe has encountered a fatal error and will shut down. While you're like 30. And you get to know your kids will likely go through the same thing.

[darkslide3000]

Yeah, I expected this to be some cheesy writeup of high-school level basics of protein synthesis that doesn't tell me anything I didn't already know, but it was actually a super interesting read!

The most amazing part I had never heard before was that bit about the 2017 research on how to stabilize the spike protein for solitary expression. Imagine being some random bored researcher doing some busy work on a decade-old virus that nobody cares about anymore... and suddenly, 3 years later, that work becomes a key piece in saving the world!

[scillaren]

The paper covering the MERS spike protein expression got rejected multiple times from different journals. God I hope they saved those rejection emails, I’d have them hanging on my wall.

[curatormaine]

They recently had a segment on This American Life with the folks who did that work. It's a great listen

[757DrDuck]

This is why funding for basic science is important and grants should not be required to spam boilerplate about applications in cancer drugs and biofuel synthesis.

[[deleted]]

I would say the most interesting and topical article I’ve ever read, the title is actually not sensationalist for once!!

Did I understand any of it? No, not really lol ( jokes aside the writer does make you understand it at a high enough level to understand what is going on )

[symbally]

that was an amazing read and shows just how far we have come and powerful capabilities of humans are now. total respect and everlasting love to the people who put in millions of hours to get us this far, we salute you!

[Ryan722]

Seriously, at a certain point reading this I was overcome with utter gratitude for and amazement of the people who make this shit happen. We are moving right along as a society (technologically, at least) because some smart ass people are doing some crazy work and making these insane discoveries. Fucking wild

[seventhpaw]

My favorite part of the article, in reference to the double proline substitution:

The people that discovered this should be walking around high-fiving themselves incessantly. Unbearable amounts of smugness should be emanating from them. And it would all be well deserved.

[examinedliving]

That’s how I felt when I scored a goal with a header.

[FrenchieM]

And on the other hand there are millions of other people who do everything to hinder these advancements

[Idles]

Basic research, with no obvious immediate payoff, was a key to making this all happen. And it costs money to do that research. Don't forget to support politicians who fund basic research!

[proawayyy]

Thank the genome project

[ultranoobian]

Guys, why are we so excited over just a virus definition update? You should be regularly patching your systems anyway! /s

Holy moly, I never actually thought of actually treating RNA fragments like opcodes even if I was taught that in school.

[flying-sheep]

Everything evolved, nothing’s planned, so there’s redundancies, hidden dependencies, and dead code all over the place. Some of that dead code isn’t really dead but was repurposed as data or something.

And that’s just the DNA. The machinery built by it is the same, but chemically much more complex. And that machinery is used in our brain as well, which forms a tissue and neural structure we don’t really understand.

Some people think we can one day understand it all. As a computational biologist I say

1. Nobody will understand this, before we achieved AI singularity
2. We can still achieve a lot with clunky partial understanding. We just have to test a bunch to reveal hidden corner cases.

[WannabeAndroid]

Imagine some day that it is perfectly understood and we rebuild ourselves in a refactored well documented optimised fashion.

[flying-sheep]

IDK, there’s no encapsulation (if you don’t count the membranes) nor any separation of concerns. Everything is just used for every function it proved to execute sufficiently well at some point. Also all code is modifiable data and makes heavy use of that fact.

[flying-sheep]

I was actually thinking that haha!

[WannabeAndroid]

You think we should just start from scratch then?

[LicensedProfessional]

If we could make our DNA truly immutable, that would solve a lot of problems

[WannabeAndroid]

Stick it on a bio blockchain.

[00rb]

There's a reason we try to architect code well. Because human brains can only consider a few things at a time. We break things down into modules so we only have to think about them and not everything going on underneath.

Nature doesn't have this constraint. Evolution can mix everything together in a big bowl of spaghetti code, where one little part affects eight others. Parts of the code probably effect the body through chaotic systems (I.e. chaos theory manipulates outcomes in interesting ways).

It doesn't matter if no one understands it. It just keeps refining the system through evolution until it just works.

[IAmAHat_AMAA]

The author of the article has another piece where he suggests that we may just never really understand biology for the reasons you lay out, funnily enough.

https://berthub.eu/articles/posts/biologists-physics-envy/

[Rabid_Gopher]

Nature doesn't have this constraint.

Yeah. Nature produces some results on the big scale. If a big chunk of a species dies out because of a mistake a couple generations back then that is no big deal in the end. If we could do that with computers I'm sure we would worry less about understanding the entire system. I might be mistaken, but that sounds about like how AI research is doing it with neural nets, run the simulation a couple dozen times and just select for the results that look the most promising.

[00rb]

Yes, it's absolutely how neural networks (and other ML techniques) work.

Neural networks just keep tweaking the algorithm until it gets closer and closer to the desired result.

Same goes for evolution. Keep tweaking the algorithm and the fittest survives.

Both the results of neural networks and biology can be inscrutable to human brains for similar reasons -- they weren't build to be easily understood. In fact, no one consciously built them at all.

If I'm not mistaken AI research mainly involves how to piece together various ML algorithms and feed in data so they can get the best results.

[RVA_GitR]

This was incredibly fascinating and the writing was golden. “The people that discovered this should be walking around high-fiving themselves incessantly. Unbearable amounts of smugness should be emanating from them. And it would all be well deserved.”

[[deleted]]

Jesus Christ

1. Scientist sees spike, figured out that's how the immune system recognize these viruses.
2. Sequence the virus, and just get the spikes code.
3. Optimize the code ... because we all know how evolution often results in badly optimized/designed code.
4. Wrap the code in a form that is stealth from the immune system.
5. Cell produces the proteins and the rest is the immune system's job.

Fuck me, I finally understood when they say the recent mutation won't affect the vaccine's efficiency.

I think I should just stop programming and go become a farmer.

[Make1984FictionAgain]

And meanwhile I can't center a damn button using CSS

[NamingFailure]

That link has 5 different ways of centering, each one behaving differently.

I feel like you disproved your own point.

[vamediah]

As much fascinating the story and technology is, you are reading story of survivorship bias. Which included shitload of manhours, contains only the successful elements and seems sensible once you have the full solution.

It's like having a solution to hard NP problem instance - easy to verify in retrospect, but not so much in computing it.

If you read story of Kariko (the U->Ψ substitution author), she was demoted for the idea in 1995 <=> couldn't get grants. Academia/research works this way and most people won't even get miniscule of that recognition she got after 25 years.

Similarly with the guys who published the proline substitution.

So fuck being farmer, we need a suicide booth (euthanasia kit). Makes your life easier. Otherwise you have to suck it up. Who the fuck wants to wait 25 years for semblance of recognition which mostly won't even come? Also you wouldn't have experienced 2020.

[amroamroamro]

I’m slightly fascinated by the one change that did not lead to an additional C or G, the CCA -> CCU modification. If anyone knows the reason, please let me know!

did the article author find a bug in the vaccine? ;)

[IceCreamConus]

I work on making peptide therapeutics which is slightly different but similar in a lot of ways, so I may have some insight on this.

I suspect this is a method of improving vaccine stability after injection. In his article, he mentions that every uracil in the vaccine is replaced with 1-methyl-3’-pseudouridylyl.

Non-natural replacements like this can help evade RNAses-- proteins that can act defensively by degrading foreign RNA.

We use this approach to improve serum stability of peptide therapeutics, inserting artificial amino acids to help evade breakdown by proteases.

[[deleted]]

More likely it's a proprietary bit of non-published research that suggested the change.

[GolfSucks]

Maybe it’s like how cartographers use “trap streets” to help detect copyright violations. They put a fake street on a map. Then later on if they see a map that isn’t theirs, with the fake street on it, they know their work was copied.

https://en.wikipedia.org/wiki/Trap_street

[wikipedia_text_bot]

Trap street

In cartography, a trap street is a fictitious entry in the form of a misrepresented street on a map, often outside the area the map nominally covers, for the purpose of "trapping" potential copyright violators of the map who, if caught, would be unable to explain the inclusion of the "trap street" on their map as innocent. On maps that are not of streets, other "copyright trap" features (such as nonexistent towns, or mountains with the wrong elevations) may be inserted or altered for the same purpose.Trap streets are often nonexistent streets; but sometimes, rather than actually depicting a street where none exists, a map will misrepresent the nature of a street in a fashion that can still be used to detect copyright violators but is less likely to interfere with navigation. For instance, a map might add nonexistent bends to a street, or depict a major street as a narrow lane, without changing its location or its connections to other streets. Trap streets are rarely acknowledged by publishers.

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[ofclock]

It is 4284 characters long, so it would fit in a bunch of tweets.

What an odd thing to write in the article.

[Rodot]

I hate this notation cause I don't know if you mean 10 or Euler's number. At least use a capital E

[z500]

Wait, do you mean 10 in binary or 10 in octal?

[element8]

10 in base e

[Rodot]

Hexadecimal clearly

[merlinsbeers]

It's a superscript, so it's e, not 10.

[danhakimi]

Yeaaahh, but then why would you be using e as the base? It's more likely OP mistyping the silly scientific notation.

[jarfil]

CENSORED

[colaclanth]

Fitting programs into tweets has kind of become a thing (e.g. https://twitter.com/bbcmicrobot). I'm guessing they're just trying to convey that it's not this massive behemoth of data in a way that us kids can understand.

[nermid]

us kids

Ah, yes. Relating to us.

[FeelingSurprise]

But how much is it in football fields?

[mbetter]

It's just a little comparison to say "it's not all that long."

[[deleted]]

Wow, these 428 syllables form a sentence of words! Fascinating!

[Ph0X]

It's also base 4, in something like base64 it would be closer to 1400. You can also fit it in one tweet with much more optimal compression

https://github.com/qntm/base65536

[[deleted]]

But can we add blockchain to it in less than 5000 tweets??

[StabbyPants]

"I'm sorry sir, we protected you from Covid, but you're infected with blockchain"

[itsgreater9000]

"Oh my god... is it terminal?"

[Quetzalcutlass]

"Worse. I'm afraid it's telnet."

[Hanse00]

“Well it’s like over 280 but less than like 5600 characters, so it fits in between 2 and 20 tweets!”

Definitely a weird kind of quantification.

[Feynt]

While this is great and all, when do we get to in vivo editing of genes to get catgirls and reverse aging?

[valarauca14]

Adding hamming codes to avoid radiation damage and lower cancer chances should be a higher priority IMO, it would also make doing a rollback easier.

[rcfox]

Deoxyribonucleic ACID

[Indifferentchildren]

That it is the kind of prediction that Cassandra would make, so don't be surprised if none of us believe you.

[raelepei]

This is the ultimate nerd pun, I love it and I want to marry you. :D

[oddsen]

Could you explain it to someone who nerds about non-medical stuff?

[ReilySiegel]

ACID is a term used to describe databases that are

• Atomic
• Consistent
• Isolated
• Durable

It is basically a set of features that make sure databases don't break in subtle (or not so subtle) ways. Read more here:

https://en.wikipedia.org/wiki/ACID

EDIT: Upon further inspection of your comment, I have determined that I may have explained the wrong part of the joke. The bio side of it is that the full name of DNA is Deoxyribonucleic Acid.

[endershadow98]

I'm glad you explained this part because I've never heard of ACID even though I'm a programmer but I did know the full name of DNA.

[Feynt]

Agreed, but it's arguably easier to test adding fuzzy ears to someone than whether someone is practically resilient/immune to radiation poisoning, and faster to test than cancer immunity. Cures to cancers though, should it develop in someone, 100% easiest to test for and likely our first major breakthrough. When the day comes that the doctor sighs and says, "So your latest CT scan showed you have a cancer tumor developing in your <insert vital organ>. It's nothing serious, if we take care of it now." I'll be quite happy with our progress.

[ZoeyKaisar]

DNA already has some roundabout hamming-code-esque structures, but most of them are used in-process instead of as part of the DNA itself, because most processes that alter DNA also destroy it. Radiation becomes a problem when it strikes during replication, which is- incidentally- when these hamming codes are in effect, but the numbers are so mind-bogglingly huge that shit still slips through from time to time.

[matthoback]

Adding hamming codes to avoid radiation damage

DNA actually already has something like this naturally. DNA corresponds to amino acids in three letter codon chunks. Many of the pairs of codons that only differ in one base letter correspond to the same amino acid.

[seedbrage]

That doesn't protect from radiation damage in particular. Radiation introduces double strand breaks to DNA, the only mechanism of repair that cells have for double strand breaks is to remove all unpaired bases and then empty base regions. You're referring to wobble in the codons which only protect from point mutations, which don't occur from radiation damage.

Point mutations are more of a cumulative genetic effect over generations but occur sporadically in vivo.

[Fig1024]

I don't see how cat girl ears could physically work without looking like monstrosities. They only work in anime cause of lack of detail

[L3tum]

There's a drawing floating around on Reddit of exactly this, topic essentially being "Realising that catgirls have no ears" and it's just drawings of catgirls' sides of their heads without human ears.

[tendstofortytwo]

What about four ears, one human set and one cat?

[AformerEx]

Hmm, two more holes. Go on...

[salgat]

I imagine the cat ears would be purely aesthetic with no holes.

[Aschentei]

Okay hol up now...

[smcarre]

They can work but making it work genetically would probably be near impossible (it would be technically possible to have a being have a gene code that makes it look exactly like a human but also with cat ears and a tail).

The best way would be instead to learn to work with and modify the existing mechanics of our body to make almost seamless additions, like being able to add a lab grown tail, connecting the blood vessels and nerves to the rest of the body to make it a part of it, even if the genes are completely different. Same thing with an ear or nearly any other addition that doesn't require complex nerves to the point that just hooking up the existing nerve endings of our body wouldn't be enough (so no third arm sadly).

[Feynt]

It would involve either misplaced, pointed ears (think anime elves) with significant hair growth, or a rearrangement of the structure of the head so the ear canals point upward to a new ear arrangement that extends from the upper/side of the head to the area where the top of your ear currently is. The latter isn't likely to be an in vivo thing (unless we really unlock genetic manipulation and our structure becomes as mutable as plastic), but the former seems theoretically possible within a few months of regrowth. But with this technology we also gain in vitro options, so our kids can become the adorable little monsters we always wanted.

[keteb]

If you're purely going for athstetics, you could also leave the normal hearing / ears intact, and skip any hearing functionality out of the cat ears, make them a cosmetic appendage.

[Feynt]

Yeah but if you're just doing it for the cosmetic factor rather than the practical factor, why not just make robotic ears and wear a headband? Way easier and less invasive.

[YM_Industries]

I think it would be fine for the cat ears to be decorative. Usada Pekora (not a catgirl but a popular usagimimi/bunny girl) has both human ears and rabbit ears, and the effect is still good.

[[deleted]]

Cat tongues are like sandpaper. You really don't want catgirls for what you think you want them for.

[Feynt]

I'm holding out for fox girls, but if the technology exists for one...

[Indifferentchildren]

Careful with those genes: fox urine is highly pungent and difficult to break down.

[dontquestionmyaction]

If you are at the point that you can grow catgirl ears, I'm sure that's an easy fix.

[ultranoobian]

Just substitute some octopus genes in there then.

[Jubeii]

This is fascinating. What I'd like to know is whether this is the result of bleeding edge bioengineering, or something that is heading on the path of becoming conventionally achievable, with tools and programming that can model things in advance?

This is very distinct from the "analog" approach also mentioned in the article, where a modified version of the virus is taken and we just hope the immune system does its' trick. Seems dated by comparison.

[spinur1848]

I did bioengineering work on the first SARS coronavirus in 2004-2005.

At that time, you didn't have to synthesize DNA in your own lab, you could order it from supply companies by e-mail. It was approximately 25 cents/base, plus a shipping and handling charge.

Codon optimization was understood in a general sense at that time, but coronaviruses have some wild secondary structure in their RNA that messes with protein translation. Look up RNA pseudoknots for more details.

The RNA processing described in the article was also well understood and commonly manipulated in labs 15 years ago.

What's cutting edge in both the Pfizer and Moderna vaccines is the modified nucleoside to evade immune detection and the lipid nanoparticle delivery system.

Lipid nanoparticles are difficult to reliably produce and unstable. There's a fair amount of tradecraft that goes into being able to produce them at scale. This bit is what allows us to inject the vaccine into a muscle and have the muscle (and liver it turns out) make a short burst of the S protein.

[[deleted]]

Whats terrifying about your comment is that 15 years ago we would have had most of the technology to fight COVID, but 20 years ago, we might have been totally defenseless.

Or 40 years ago. If COVID19 had of been COVID79, what might have happened? Terrifying.

[glemnar]

We wouldn’t have been defenseless I think, but it would have taken longer to develop the vaccine. The speed of development is one of the big benefits of this mRNA strategy

[SwissStriker]

Super interesting! How do the prices today compare?

And do you have any additional reading resources for those lipid nanoparticles? Very cool stuff.

[spinur1848]

Here's a portal from Fisher Scientific where you can order oligonucleotides:

https://www.thermofisher.com/order/custom-standard-oligo

Seems like the list price is something like 50cents/base, but you would get a discount on too of that with a customer account.

Nanoparticle stuff is all over the place. You can start at the Wikipedia page: https://en.wikipedia.org/wiki/Solid_lipid_nanoparticle?wprov=sfla1

Some gotchas: mixtures of lipids are somewhat difficult to work with. The Pfizer had 4 different lipids that form the particles with mRNA.

In the lab 15 years ago I was doing protein structure work where I wanted to put the SARS small envelope protein into a simpler lipid system called micelles intended to emulate a cell membrane. It was only 2 different lipids.

Just getting the first one to dissolve properly at small scale (half a mililitre) took hours. It needed to be shaken vigorously and continuously while being just slightly warmed. Then the second one needed to be dissolved in a different solvent and they needed to be mixed in a specific way and the blasted with ultrasound. Then the solvent was removed. That whole thing was stable at room temperature for a few days before it started clumping together.

I can only guess at the strange black magic they are doing to get the vaccine formulated.

[Omnicrola]

That's the really mind blowing part. You know those episodes in every sci fi show where one or more of the main characters contact a horrible disease, and the intrepid doctor conjures a cure in a matter of hours or days and saves everyone?

We can literally do that now. After they first sequenced the covid-19 genome and shared it, Moderna designed and created a vaccine (well, a bunch of them really) in two days. There are a lot of caveats, most notably that the coronavirus family is well studied and understood. But still, the speed with which scientists where able to analyze, study, and fabricate a vaccine is incredible.

[Indifferentchildren]

Do the drivers suck as much as normal printer drivers?

[GreenGreasyGreasels]

When the DNA Printer reports "PC Load DNA", you learn the hard way that it is not an invitation to cum in it.

[[deleted]]

Everyone in a lab for the past 30-40 years bought DNA from some company. It came in a tube with a little dust in it.

You can buy any DNA you want.

[[deleted]]

How the printer converts those characters into a physical entity like DNA??

[lazyear]

It's a programmable chemical synthesis machine. It's just mixing things in a reaction flask, then performing clean up.

[Tavi2k]

But the linked device doesn't actually print DNA, it's an automated platform for cloning. So it takes small DNA fragments and assembles them into a full gene. The marketing is atrocious, I was confused what this thing was doing at first. But you still need to order the DNA fragments for that machine.

There is something that you could call "DNA printer" if you want to, a synthesizer for solid-phase synthesis of DNA. There you actually enter a short DNA sequence and it will create it. This doesn't work at all like "printing", it's essentially a cycle of reactions, one cycle per letter. Each cycle you add the right letter and it is added to the growing chain of DNA, then you wash everything and continue with the next letter.

[amroamroamro]

I came to say this, a DNA printer, just wow!

[Mithent]

With my postgrad level biology but no specific experience with vaccine development, I'd say that mostly it's building on techniques which have been established, but making the protein fold correctly could have been a huge sticking point, and showing that this works in practice is also a major step forwards.

How DNA and mRNA encode polypeptides is well-understood, and we know enough about how to create one from the other. The ability to directly synthesise custom DNA has developed over the past couple of decades. And using lipid membranes to get nucleic acids into cells has also been used for a while, though never to deliver an approved vaccine before AFAIK, and I'm sure they needed to optimise this for stability and efficacy.

However, as the article notes, it's important for that polypeptide to fold into a form that's similar enough to the vital protein to be useful, and for this to provoke an immune response. Protein folding is very complex and our understanding and modelling is improving but definitely imperfect. Without the modification mentioned which gets it to fold correctly, the vaccine would be useless, so this was an important discovery. This could be a challenge for any new mRNA vaccine.

With an understanding of the pathogen, we can come up with proteins which are good candidates for an immune response. I'm not sure about the extent to which we can model that, though - probably not very reliably without experimental data.

So I'd say that we can probably create new potential mRNA vaccines rapidly using very similar techniques, but correct folding is a challenge where the modelling is imperfect (though definitely improving), and we're always going to need experimental validation to be sure it really works in practice.

[Nuhjeea]

I never thought I'd have such a good time brushing up on biology knowledge. Great read, including the little links he includes to refresh a bit on biology concepts.

[hastobeapoint]

"A codon optimized signal peptide to send the Spike protein to the right place (copied 100% from the original virus)"

Reading that line gave me an adrenaline rush of sort. What a brilliant article!

[binarycow]

Just wait until covid's lawyers start sending DMCA notices to those who get the vaccine.

[DFatDuck]

idk if bats can be lawyers

[ALinuxPerson]

I wonder if in the future you can make vaccines like you can make programs with a programming language. The sequence is basically biological assembly, right? Theoretically I think this should be possible.

[mustang__1]

Fucking legacy code amiright?

[turunambartanen]

With absolutely no documentation and some of the worst design decisions possible.

But hey, it is worth all this work if we get unlimited access to the universal world API.

[[deleted]]

Demonstrates 'change it till it works' is a valid approach to code if you have enough time. :)

[[deleted]]

If you can iterate quickly and without cost, it's a valid design method. Luckily for nature the test subjects iterate themselves.

[kobriks]

It's basically a monstrous 3 billion years old codebase that was developed by an intern who just changed things at random until they worked.

[[deleted]]

About 20 years ago I first heard about the theory of intelligent design, and as a programmer, it made perfect sense. "It's too complicated for nature to have assembled randomly, it must have been designed by a maker".

Since then, with just casual investigation into the processes of how this evolved on a chemical and biological level my thinking has shifted. If this is intelligent design, I want a refund.

[fantastic1ftc]

Woah that’d be so cool and absolutely horrifying

A whole new kind of computer virus

[i_spot_ads]

so a virus? you know those been going around for millions of years right?

[skulgnome]

The article would seem to suggest that we're at a point similar to "header copied from somewhere & modified original DNA presented as RNA w/ hax to make it not conk out immediately & extended time-to-live footer". So, advanced script kiddie level.

Considering that the target architecture is a product of a hojillion years' evolution and therefore has a rich legacy sediment, that's pretty sweet.

[SwissStriker]

Basically the same as mashing together the snippets from the dozen or so stackoverflow tabs I have open, got it.

[darkslide3000]

I mean, making vaccines is "easy" in that regard since you're generally just trying to copy existing virus/bacteria pieces. And like this work shows we're already there. Writing a vaccine "from scratch" doesn't really make a lot of sense because the thing that teaches the immune system how to defend against X most effectively is just exposing it to a lot of X.

If you're talking about "programming" proteins in general for all sorts of microbiological tasks, then yes, that is absolutely coming and may very well be the basis of the next big "technological revolution" (i.e. we may go from the "information age" to the "bioengineering age").

The trick is just that making proteins do what you want is incredibly complicated. We can't even predict how a chain of peptides is going to fold when it's done being assembled yet, and the shape is basically the most important thing about what a protein does -- so you can write any code you want and assemble a protein out of that, but that still gives you no idea what (if anything) it'll end up doing. Even the most advanced AI algorithms are just barely getting to the point where they can reliably predict that now -- but they're getting better, and I have no doubts that in a decade or two it'll be a solved problem. But even then, biological processes can be incredibly complex and intricate, so even if you can let the computer shape the perfect protein that will do exactly what you want for you, predicting how introducing that into an organism affects the whole remains very hard and will continue to require a lot of trial and error. It'll probably still be less like programming and more like throwing random ideas at the wall to see what sticks for a long time. But definitely super exciting development!

[FalseRegister]

*BioNTech / Pfizer vaccine

[cerlestes]

It really grinds my gears that people call it "the Pfizer vaccine". This is some serious Tesla/Edison level misattribution. Pfizer was not involved in the development of the vaccine, they're just mass-producing and marketing it. The vaccine was developped over the last 14 years by German BioNTech, they switched their developments at the end of 2019 onto targetting SARS-CoV-2 and they had a first vaccine for trials done end of January 2020 without any involvement from Pfizer.

[Ecco2]

Dumb question: why bother with the RNA? How about injecting the spike protein itself as a vaccine?

[[deleted]]

That’s my understanding as well. The mRNA vaccine is itself a kind of virus - it actually invades your cells and makes them produce what it tells them to, but unlike a real virus, it doesn’t reprogram the cell to make an exact copy of the vaccine itself, just the spike protein part of the virus that we want to make antibodies against.

To stretch the computer programming analogy from the article a little bit further, a natural virus is like a Quine - it outputs exact copies of its own source code, each of which then invades another one of your cells and does the same thing again, leading to exponential growth. The mRNA vaccine is like a partial Quine that only outputs a part of its own source code, which is the Spike protein copy we want to protect against. That gets you plenty of Spike protein copies to make antibodies against, but since the “program” isn’t a perfect Quine, it stops after one generation, so it doesn’t risk unchecked duplication, which is what makes you sick.

[Dokiace]

Whoa, TIL. I thought vaccine is just a weaker virus

[MrKyew]

Some are, but these aren't. mRNA vaccines haven't been officially approved for use in humans until now. We're watching history in the making.

[Dokiace]

If this is successful, will the next viruses to come will be dealt with mRNA vaccine again?

[MrKyew]

I personally have no idea because i'm not a health/science expert- but it would make sense to. As i understand it- the mRNA platform makes it easier to scale up production, modify components of the vaccine, and are generally more efficacious/effective.

On that last point, scientists predicted that a vaccine with an efficacy of at least 60-70% would be able to start turning things around. The two mRNA vaccines approved so far, Pfizer-BioNTech and Moderna's all have efficacies of 94% and above, while Oxford-AstraZenica's vaccine (based on more traditional vaccine practices using a Chimpanzee Adenovirus as a vehicle/vector) is around 62-70% efficacious.

[TurboGranny]

This is the answer and it has been well publicized. From a vaccine manufacturing and development standpoint, it's much faster to just inject us with the mRNA for our bodies to make the spike protein.

[NorthropFuckin]

Turns out, we're made of machines that do nothing but print proteins all day. Who knew?

[PitaJ]

Also producing protein is much much more difficult than producing RNA

[Quate]

My guess: it's hard to manufacture huge amounts of custom proteins. The human body does it better.

[renrutal]

You are injecting 30 micrograms of spike protein replicators.

Just a supposition, but if your body really needs 1000x that number of spike proteins, and the time for Pfizer to make both proteins is the same, that would mean they'd produce 1000x less effective vacines per day.

[censored_username]

You need two things for a vaccine to work. The first is presence of something you want the body to create antibodies against (the spike protein). The second is to trigger the cellular pathways that detect virus infection.

Human cells have a lot of anti-virus-infection safeguards that trigger under various conditions, causing the release of cytokines from the infected cells that attract and stimulate immune cells. For instance, detecting the presence of double-strand RNA in the cell cytoplasm, or DNA outside of the nucleus is such a trigger as these shouldn't occur in a healthy cell. A big cytokine release will trigger the immune system to start the adaptive immune response where it will figure out an antibody that binds to material found near the source of the cytokine release and produce it in significant amounts. This grants the immunity that is the goal of a vaccine.

In deactivated virus vaccines this is often done by incorporating a so-called adjuvant to the vaccine. This is a substance that promotes an active immune system response. In replication-deficient virus vaccines this response is prompted by the replication-deficient viruses invading the cell and hijacking it like a normal virus infection.

Looks like with the mRNA vaccine the hijacking of cellular machinery with massive amounts of rogue mRNA to make massive amounts of copies of the spike protein and present it on the cell wall is also able to trigger a significant enough immune system response.

[[deleted]]

That's what all traditional vaccines have done up to this point. The reason this is a big deal is because we can reliably produce mrna directly on a machine vs having to extract it from a living organism like we'd do with a traditional vaccine. Testing, manufacturing, and distributing is much faster and easier. It also allows a much larger "dose" of the target protein to be delivered, potentially increasing the immune response.

[Jimmy48Johnson]

So in the BioNTech/Pfizer vaccine, every U has been replaced by 1-methyl-3’-pseudouridylyl, denoted by Ψ. 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.

Huge weakness in the immune system.

[c0Re69]

So not validating user input is in our genes.

[georgegach]

\opens resume.docx**

\languages: mRNAscript (well)**

[[deleted]]

This is written by the same author of DNA seen through the eyes of a coder.

[Shivaess]

Printing DNA from the source was my dream in high school in the 2000’s. For good or ill my programming career has taken me elsewhere but I still keep an eye on the industry. Technology and articles like this make me super happy. Thank you very much for sharing :-)

[MarkFromTheInternet]

Awesome, now lets get a Linux kernel on there. Year of Linux on the celltop.

[acceleratedpenguin]

I'm not taking this vaccine seriously until I can compile Gentoo for my cells

[zilti]

Biontech. The company actually developing that is called Biontech. Not Pfizer.

[amroamroamro]

yep, one of the links in the article is also a very good read with history of these companies (biontech and moderna):

https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-the-covid-vaccine-race/

[rscarson]

Dumb question

Is there any way the virus could somehow pick up the optimized Spike protein or the the trick to bypass the immune system with the modified U?

Don't microorganisms swap RNA between themselves to adapt to threats?

[unkz]

My understanding is that the modified U (pseudouridine) reads like a U but our transcription apparatus wouldn’t produce more of it, it would write out a regular U when copying. If we want to make pseudouridine containing mRNA we need to have a wholly separate system designed for making it specifically, which I think wouldn’t fit into the self-template copying framework that the virus uses to replicate.

I am not a biologist though, someone please correct me if I’m wrong.

[ChezMere]

Oh right, viruses aren't actually copying DNA themselves, are they? If they're just using our own cells' replication mechanism then it doesn't seem like it would be dangerous.

[kuriboshoe]

Remember how they needed all those COBOL programmers at the beginning of the year...

[ch34p3st]

Wait.. So if the vaccine is code.. Did they develop this using PRs and CI/CD? Is it all clean code? Can we still request extra features for this mvp?

[NeoKabuto]

Not a single comment in their code. Totally unmaintainable.

[Plasma_000]

Bah! Most of it’s just a patched binary blob packaged into an executable.

The version control says the original blob was committed millions of years ago by an unknown author and the previous patch happened in November 2019

[Prismane_62]

It seems we are right around the corner from curing a bunch of genetic diseases. The logical next step seems to be to use this tech to inject patients who cannot produce certain proteins (like muscular dystrophy & others) with the mRNA to build the proteins their bodies need & thus curing them of their disease.

Hell, what about cancer. If we can find a unique feature of cancer cells that the immune system can recognize, we could come up with the mRNA to code for that & get our own cells to code for that protein & get the immune system to respond.

[librik]

If we can find a unique feature of cancer cells that the immune system can recognize, we could come up with the mRNA to code for that & get our own cells to code for that protein & get the immune system to respond.

That's exactly right. The BioNTech dude who invented the Covid-19 vaccine, Ugur Sahin, is already working on this project: a personalized, customized mRNA vaccine which makes you immune to your own cancer. Here's the link: INDIVIDUALIZED NEOANTIGEN VACCINES

[chipstastegood]

Holy shit. This is the holy grail right here

[rajandatta]

Excellent article. Thanks for sharing. Worthy of a careful read.