18 ms·

Ctcctcggcgggcacgtag is unique to both SARS-CoV-2 and Moderna's 2015/2016 patents

146 points by Jimmc414 5y ago

thehappypm 5y ago
Odd to see that HN will not tolerate any evidence that the virus may have been designed in a lab.
- efficax 5y ago
  it's not evidence... is the thing...
- erichocean 5y ago
  Not really, the opposite would be true—with the exact same evidence—if it was the government's position that the virus was made in a lab. Then you'd have Substack's talking about how the virus could have been naturally occurring, that there's no reason it had to be made in a lab, that it's just the government blaming China, etc. I wish there was a word for beliefs that supposedly make use of evidence, but can easily use the exact same evidence to argue for the polar opposite belief.
Jimmc414 5y ago
Previous post was taken down within a few minutes by an unhelpful poster causing it getting it flagged with an abusive post. Two good questions were asked there so I will repost them here: >Posted by 'version_five' "This sounds like one of those "bible code" things. As someone who knows nothing about DNA sequences, what is the probability that two codes could be matched? (In a birthday paradox sense where you can go looking anywhere)" >Posted by 'whoomp12342' "isn't it well known that one of the main reasons why we got a vaccine so quickly was because we had done a ton of research when SARS originally broke out?"
- vipa123 5y ago
  Why is it taken down?
  - Jimmc414 5y ago
    Someone with a 3 min old account posted a threatening message unrelated to any ongoing discussions.
    - pwg 5y ago
      3m old accounts can't flag (a certain karma level is needed to be able to flag). An unrelated threatening comment would have gotten the unrelated comment killed, but not the main posting. If the main posting was flagged, that is because some number of users with enough karma to flag clicked the "flag" link on the post.
      - Jimmc414 5y ago
        Maybe that is the case, but they did not flag it, they posted a message with several violent keywords and the post was immediately flagged. It seemed different from normal flagged posts because all of the reply buttons disappeared and as I hit reply on a comment I was in the process of writing, I got the message "You can no longer reply in this post" or something to that effect. I looked at other currently flagged posts and this seemed atypical. You can still reply within the flagged posts comment section. I assumed it was some sort of auto moderation action.
        xiphias2 5y ago
        SARS-CoV2 is in the title, that may be enough for being taken down automatically to avoid flamewars.
        pwg 5y ago
        The reply buttons likely disappeared because it was also made "dead". Looking it up in your profile it shows "[flagged] [dead]". As to why it was made dead, I do not know.
- reindeer76 5y ago
  >This sounds like one of those "bible code" things. As someone who knows nothing about DNA sequences, what is the probability that two codes could be matched? (In a birthday paradox sense where you can go looking anywhere) The genome in question is about 30000 bases long, which isn't nearly long enough for the outcome space size issue to come into play. Assuming independence, the probability is still very remote, effectively zero. However, there is in no way any expectation of independence. SARS-CoV-2 is obviously closely related to SARS-CoV-1, which is obviously closely related to 2015/2016 ongoing vaccine research. (And perhaps gain of function research.)
- dang 5y ago
  https://news.ycombinator.com/item?id=29938340 https://news.ycombinator.com/item?id=29938340 was flagged by other users—quite a few of them. We can only guess why users flag things, but I doubt that it had anything to do with that trollish post. We've banned the latter account now.
Jimmc414 5y ago
To clarify this sequence has not been identified in any other virus in the wild. Additionally it codes for the section pertaining to the furin cleavage site which does not exist in any other observed beta coronavirus.
- etaoins 5y ago
  That’s not correct, furin cleavage sites naturally occur in coronaviruses: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612...
  - moralestapia 5y ago
    >To clarify this sequence has not been identified in any other virus in the wild. >this sequence >this >sequence
  - Jimmc414 5y ago
    You are correct. I should have stated furin cleavage sites have not been observed in another beta coronavirus. (Cold, MERS, SARS) I corrected my statement. Thank you for pointing that out.
    - etaoins 5y ago
      That’s still incorrect. MERS is a Betacoronavirus and has a furin cleavage site: https://www.pnas.org/content/pnas/111/42/15214.full.pdf https://www.pnas.org/content/pnas/111/42/15214.full.pdf Furin clevage sites haven’t been found elsewhere in SARS-Cov-2’s Sarbecovirus subgenus.
  - finite_jest 5y ago
    Not with the same PRRAR sequence of amino acids, right?
    - etaoins 5y ago
      Right, the furin cleavage site seems to have occurred independently in SARS-CoV-2 or one of its undiscovered close relatives.
1MachineElf 5y ago
This substack post is amazing work. I recommend reading the top comments on it for further discussion.
1MachineElf 5y ago
Archive link from today: https://web.archive.org/web/20220114174712/https://arkmedic.substack.com/p/how-to-blast-your-way-to-the-truth https://web.archive.org/web/20220114174712/https://arkmedic....
garbagecoder 5y ago
- Jimmc414 5y ago
  I think the point is that the sequence is searchable within the database of known viruses (virii?) and it is not speculation, it literally does not exist in any sequenced virus in the wild. I'm not sure what you mean with the goalposts comment.
  - garbagecoder 5y ago
    That doesn't prove anything, of course. And by "goalposts" I mean that if you recall, the initial allegation was that COVID was a bioweapon developed by the Chinese. Then it was negligently leaked from a lab doing gain of function research funded by Obama. Then it was just leaked. People seem to want to believe this theory regardless of when facts get in the way. A year ago, there wasn't much evidence against it. Now there are animal finds in Laos that make some of the connection. Not proof, but positive evidence. From the field.[1] Not from cherry-picked database searches. At some point, you have to ask yourself with Ockham's razor: if it really is this simple, then why isn't it widely accepted? Has China gotten to everyone? If so, then why can I post this to my substack? Sometimes the expert opinion is right. I guess sheeple like me will never know. Except in reality, I'm quite open to this hypothesis, I am already a China hawk so I need no motivation there. I just don't think there's as much evidence as people who want to believe this think there is. For what it's worth, using the model of radius->radii for virus->*virii makes sense until you realize radius has an extra 'i' already. Worse, it's a second declension neuter despite the -us and so should be vira just like modicum->modica, whereas radius is second declension masculine. [1] https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2
    - peteradio 5y ago
      I would think someone with domain knowledge would be able to debunk this posts interpretation right?
YXNjaGVyZWdlbgo 5y ago
Humans really are just pattern searching animals.
Maursault 5y ago
Impressive work, but author's logic is unsound because it silently assumes the library or database BLAST uses is complete, yet it likely represents less than 1% of all sequences in the wild. The database BLAST uses only contains sequences that have been found and reported. If every person on the planet was a genetic expert with all necessary resources to find and identify new sequences, in 1000 years we still wouldn't have found all of them. The sequence in question that only matches HIV-1 may very well match a trillion^2 more sequences not in BLAST's database. Anything like this that is engineered likely has a mountain of documentation. Documentary evidence, if found, is a smoking gun in a way the furin cleavage site sequence can't be.
- WanderPanda 5y ago
  It would be interesting to me how likely it is to actually find random sequences in the database. Aka how much correlation there is between natural viruses. In my imagination it is plausible that if you take a particular virus that you will be able to find most of its subsequences (with minor modifications) in other viruses. In that case I think that his analysis is sound. On the other hand, if the other viruses appear to be randomly sampled from the set of all possible sequences than his reasoning does not cut it.
- cuteboy19 5y ago
  Is there any reason to believe that the database isn't a random sample of all possible sequences?
  - etaoins 5y ago
    Genomes are sequenced when they're both accessible and are of scientific/economic interest. This results in an overrepresentation of: - Humans and their pathogens - Economically important organisms (e.g. crops and farm animals) and their pathogens - Model organisms For example, compare the number of Genebank sequences for HIV-1 [1] versus Feline immunodeficiency virus [2]. HIV-1 is additionally problematic because it has an extremely high mutation rate [3], making it more likely for a random sequence to match some sequenced HIV-1 genome. [1]: https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=11676&lvl=3&lin=f&keep=1&srchmode=1&unlock https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mod... [2]: https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=11673&lvl=3&lin=f&keep=1&srchmode=1&unlock https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mod... [3]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574155/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574155/
dnautics 5y ago
Just to be clear, this doesn't imply that moderna released the viruses. Patents are publically visible, after all. It suggests that someone was told to insert a furin cleavage site, then went and "stack overflow copy-pasted" the moderna furin cleavage site, and this became the coronavirus. If we believe that this is what happened, it possible that whoever did this also looked up and copy pasted other furin cleavage sites, and thus the purely random odds of the eye-popping "moderna" aspect of the coincidence would considerably less (let's say, 1 in 100 or less, depending on how much work you think the hypothetical postdoc bothered to do). Do note that the moderna furin cleavage site itself is probably subjected to industrial selection pressures that enhance its delivery, which might also correlate to infectivity, so a non-uniform distribution of infectivity among stack-overflow-ed furin cleavage sites, that favors the infectivity of something like the moderna sequence, should be considered.
- deleted 5y ago
  [deleted]
- hodwik3 5y ago
  Given that this line is from a cell culture, wouldn’t the simpler explanation be that the virus has this sequence because it was replicated in that specific Moderna culture lineage? This would be a particularly useful discovery, because it would dramatically limit the candidates for who did the gain of function research to organizations licensed this Moderna lineage.
ausername42027 5y ago
This is a semi-interesting piece (because of how poorly written it is and how hilariously confident the writer is), but it is embarrassing that the person writing claims to have a PhD in at least something semi-related to molecular biology, yet is trying to convince people that we can use independent probability when dealing with protein amino acid sequences. Certain sequences are seen time and time again in nature, just like certain traits visible to the naked eye have evolved independently. More importantly, this author dismisses natural mixing of SARS and HIV1 as "ridiculous" and provides no other explanation. It is possible that SARS-CoV-2 was created in a lab, but it is also possible that HIV-1 and SARS-CoV-2 co-infected a host. Edit: to elaborate, certain amino acid sequences are seen again and again, and others are practically impossible to see in nature because amino-acids fold into 3D proteins...and each amino acid is like a Lego piece. There is a lot more detail needed to understand fully how tertiary and 4try protein structures form...but it is also possible to understand it decently well after an undergraduate degree in biology, chemistry, biochemistry, etc. A PhD in the field knows this inside and out. If I had to guess, the author of this post has a PhD in something like statistics or computer science, and thinks that they can apply high school level math to two fields (molecular biology and biochemistry) that they do not even have a high school level of understanding of. To make a very stretched analogy (I am a doctoral student in the life sciences and a hobby programmer), this blog post is like saying that some Java source code is stolen because four of the class names are the same between two projects, and then using the number of possible characters in the class names and the length of the name to run some statistics. The problem being that no one has class names like "AeNOQ92bA"...in fact the vast majority of 8 character sequences will never be class names. Just like the vast majority of amino acid sequences (likely) do not exist in nature. And then you dig deeper and find out the class name is something like "MainDashboardSupervisorTree" (I do not know Java so forgive me). Then you also find out that the author of both classes...is the same guy who moved companies and likes particular naming convection, but never meant to copy stuff word for word. Similar to how SARS-CoV-2 could have naturally incorporated HIV-1 RNA into its genome when co-infecting a host.
- dnautics 5y ago
  the HIV-1 protein sequence is the same but not the DNA sequence. The moderna DNA sequence is identical. The odds of HIV-1 mixing with bat coronavirus, and then somehow finding the moderna DNA sequence, while not astronomically low, are pretty low.
efficax 5y ago
This guy appears to also believe that the omicron variant is not a natural mutation but a lab-made version as well. BLAST does not contain all genetic material from all viruses or organisms in all of the natural world. There are countless (really, impossible to count) viruses of all kinds out there dancing around in the bodies of all kinds of creatures. There are literally hundreds of trillions of viruses in your body right now (not different kinds but individual viruses). Each of those hundreds of trillions of replications was an opportunity to mutate. Now multiply that by all of the individual animals human or otherwise who could harbor coronaviruses and you have many hundred billions of trillions of chances to generate the gene sequences in question. If I could get billions of trillions of lottery tickets, I'd win the lottery, and here it looks like SARS-CoV-2 won the "does a gene sequence in the virus exist in a patent by moderna" lottery.
- dnautics 5y ago
  if the mutation rate is that high, then why don't we see a ton of sequence variants around the wobble pairs of the furin cleavage site? (Or for any parts of the coronavirus, for that matter?)
  - efficax 5y ago
    no way to answer such a question without real experimental research, and not even sure what you mean by "see", we dont "see" most virus mutations because most mutations don't survive... and certainly aren't sequenced. And the point isn't that a virus mutates on every replication, but that every replication is a chance for a mutation. The point is everything here hinges on an argument from probability. There are more viruses on earth than there are stars in the universe, the astronomical figures are meet with each other. We're not talking different orders of magnitude between the opportunities for a certain mutation and the probability of a certain mutation occuring.. edit: Further, it looks like the sequence exists in some bacteria, meaning it isn't even a question of a random mutation but possibily the incorporation of the sequence from an existing source (which the author claims doesn't exist, but it does, in mycobacterium smegmatis...). this destroys the entire premise of the claim.
etaoins 5y ago
Using the number of BLAST hits as the basis of an argument is about as reliable as using the number of results when searching for a string on GitHub. Without further analysis of the specific sequence and its biological context it can be highly misleading. See a previous Twitter thread on some other purported HIV inserts: https://twitter.com/trvrb/status/1223666856923291648 https://twitter.com/trvrb/status/1223666856923291648 There also seems to be some circular reasoning the argument. Apparently we can ignore RaTG13 because it’s obviously synthetic, which makes SARS-CoV-2 look even more synthetic. It would be interesting to compare to the BANAL family of SARS-CoV-2-related viruses that are even more closely related to SARS-CoV-2 than RaTG13 [1]. I’m not sure why only viral genomes were searched for the furin cleavage site sequence. Viruses famously exchange genetic material with their host organisms. The “smoking gun” sequence also appears Mycobacterium smegmatis, for example [2]. [1]: https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2 [2]: https://twitter.com/soychicka/status/1243547603746410500 https://twitter.com/soychicka/status/1243547603746410500
- thehappypm 5y ago
  The GitHub example actually is pretty spot on. If you wrote a non trivial piece of code in 2016, then in 2020 it was used verbatim in another program, what would your conclusion be?
  - fastaguy88 5y ago
    For a non-trivial piece of code, the conclusion might be that it was copied (horizontal code transfer??). But the 6 amino acids is not a "non-trivial piece of code" -- it is a trivial short string of letters. So the more relevant question is, how often do we see "dogcat" in GitHub (468 repository names). Or perhaps something more nonsensical: "ifdlog" (6 letters from "goldfish" reversed): 1 repository and 25 code results. "hsifdl" - 1 code result. Random things occur at random.
    - deleted 5y ago
      [deleted]
    - 5y ago
FortDetrickAnon 5y ago
dekhn 5y ago
I ask a question about dna sequences for SWE interviews. It ends up providing some useful signal. For example questions I ask include: if you have a symbol table with 4 symbols, how many bits are required to uniquely identify each symbol (answer: 2 bits). OK, given this ASCII string 'CTCCTCGG', can you compress it a few bits? (answer: without entropy, run length, or backrefs, you can easily compress DNA encoded in 8-bit ASCII from 8 bits/byte to 2 bits/byte). OK, so, how many bits does an 8-long DNA string require encode (answer: 16 bits). Huh, that's a short. The rest of the interview is how to move form using a hash table for counting k-mer frequencies to a vector using a minimal perfect hash, and compute k-mer frequencies quickly using a rolling hash. It's a great question because it always throws the CS people off to hear their questions asked with biological structures involved.
- beebmam 5y ago
  I try to ask questions in software engineering interviews that don't have just a single correct answer, like most real-world engineering problems.
  - dekhn 5y ago
    some of the answers I gave are the only correct answer. if somebody was going to go straight to proposing a probabilistic data structure like a bloom count and could code up a simple example in 20-30 minutes, that is also OK (and would lead almost certainly to an immediate hire).
- vintermann 5y ago
  There's a whole branch of CS, bioinformatics, which would be more confused if you did NOT ask the questions with biological structures involved. The field of string algorithms, or "stringology" as they whimsically call it, is also heavily focused on DNA. I was planning to study bioinformatics in my youth. Life events intervened and I had to do a regular software engineering degree instead, but I still have an unreasonable love for the Burrows-Wheeler transform.
  - dekhn 5y ago
marstall 5y ago
for those with SciAm subs, this June 2020 print article is a profile of the first scientist to encounter Covid. She had spent a decade in caves around China investigating SARS and was therefore called on when early reports of Covid arose. I read this before all the lab leak theories came out, and I'm glad I did because it makes them all seem ridiculous. https://www.scientificamerican.com/article/how-chinas-bat-woman-hunted-down-viruses-from-sars-to-the-new-coronavirus1/ https://www.scientificamerican.com/article/how-chinas-bat-wo...
- rasz 5y ago
  She was "called on" to Wuhan WIV where virus first emerged and where she has been working for at least 7 years and where all of her research was funded by EcoHealth Alliance grants? same EcoHealth Alliance which submitted this gain of function grand proposal in 2018 https://theintercept.com/2021/09/23/coronavirus-research-grant-darpa/ https://theintercept.com/2021/09/23/coronavirus-research-gra... ?
- basch 5y ago
  More about her. "Also, Dr. Shi was trained by Ralph S. Baric of the University of North Carolina in building “chimera” viruses — taking, for example, the spike protein from a new virus and splicing it to the backbone of a known one like SARS. He invented “no-see-um” techniques that left no trace of the splice." source https://donaldgmcneiljr1954.medium.com/how-i-learned-to-stop-worrying-and-love-the-lab-leak-theory-f4f88446b04d https://donaldgmcneiljr1954.medium.com/how-i-learned-to-stop... https://www.researchgate.net/publication/8119695_Development_of_mouse_hepatitis_virus_and_SARS-CoV_infectious_cDNA_constructs https://www.researchgate.net/publication/8119695_Development...
  - akiselev 5y ago
    > the spike protein from a new virus and splicing it to the backbone of a known one like SARS The spike protein was already a defining feature of SARS-CoV when it emerged and became "known" [1]. That's why it was classified as a coronavirus! [2] Edit: Appears I have misread, see reply [1] https://www.science.org/doi/abs/10.1126/science.1086418 https://www.science.org/doi/abs/10.1126/science.1086418 [2] https://en.wikipedia.org/wiki/Coronavirus#Structure https://en.wikipedia.org/wiki/Coronavirus#Structure
lamp987 5y ago
So what does this mean? That covid was made in a lab? Or did covid and moderna independently reach the same "conclusion" through parallel evolutionary pressures (in nature and in research)?
- vintermann 5y ago
  The second possibility is the main objection I have to this post. The lottery arguments may actually be good enough to rule out chance, but ruling out chance isn't the same as ruling out other explanations which can make things extremely non-random.
fastaguy88 5y ago
As other commenters point out, this "analysis" is a joke. An E()-value of 282 says we would expect a match of this short sequence against a completely random library of the same size 282 times. Even with BLASTp's parameter correction for short sequences, NO short sequence will generate a statistically significant score. Let's try a more sensible approach. Let's see how often the sequence occurs in other databases. The author's 1/20^6 (1/64,000,000) probability calculation omits the fact that every database search considers many millions of possible alignments (a crude calculation would be 6 * the database length, or 6 * 1.6E7/20^6 ~ 10000E6/64E6 = 156 times by chance), and we're shown that in a 5,000,000 protein/1.6E7 residue database, 100% matches are seen several dozens of times, as expected. How about other protein sets? Search the human protein set (19,000 proteins), there are no 6 amino acid 100% identical matches. The best matches are 100% of 5 residues, or 83% identity over 6 (with an E()-value of 22). How many proteins do we need to search to find an exact full-length match? (we have dozens of matches in a 5,000,000 viral protein database. and none in 19,000). If you search all the NCBI landmark sequences (~500,000, non-redundant), there are 3 identical matches (E()-value: ~44) in Drosophila, Corn, and Strep. pneumoniae. So this sequence is not very special -- as the E()-value statistics indicate, it happens all the time by chance. (If it happens 3 times in a 500,000 sequence non-redundant database by chance, we would expect it to happen 30-100's of times in a 5,000,000 redundant viral database by chance, which is what we see.) Six amino acid non-significant matches are evidence that properly done statistics are accurate, and pretty much nothing else.
- arisAlexis 5y ago
  It's not only the numbers. 1 out of 282 with the one being Moderna is much more significant. The null hypothesis is important. It's not just the odds reporting. Anybody can pass by your door accidentally Less likely it is someone that threatened you last night. Same odds, different situations.
  - fastaguy88 5y ago
    It is not clear to me why it is much more significant (or how much more). There is confirmation bias here. There would be no "report" if Moderna had not been associated with the sequence. So how many other, perhaps longer, matches were there to other patented sequences with no connection to Moderna? If there were hundreds (which there probably were), it is much less clear what the significance of one of them being in a Moderna patent is, particularly if Moderna was trying to make an HIV vaccine, and the sequence is in HIV (which it is).
im3w1l 5y ago
In my cursory encounters with numerology, I have learned that if you try enough hypotheses, something will always pop out. Could this be the case here too, or is the gun-smoke so thick that no cherry picking can explain it? (eg https://i1.wp.com/www.ghgossip.com/wp-content/uploads/2020/03/coronavirus-666.jpg https://i1.wp.com/www.ghgossip.com/wp-content/uploads/2020/0...)
dpark 5y ago
> *As of writing this those links are still up which at 12 months is pretty good going for any article that dares challenge the drivel propagandised by our beloved “free press [sponsored by pharma]”. Well this is a rough start. “This information is being suppressed, which you can tell by the fact that these linked articles are still available.” The utter lack of critical thinking doesn’t make me expect much from the rest of this.
LorenPechtel 5y ago
Another reason his probabilities are garbage: Nature favors sequences that work. Try a billion variants, keep the one that actually helps. We don't see the 999,999,999 failures.
- dnautics 5y ago
  Why is the native hiv sequence (which has had a lot of convergence potential since hiv mutates, a lot) different, and why did it convergently evolve instead to the nucleotide sequence of moderna's artificial furin site (designed for hiv), which to be fair, is subjected to industrial selection, which would be (I would guess, but don't know) weaker than the natural one due to selection sampling limitations?
feoren 5y ago
Some questions from a layperson: 1. Why do we care so much about a furin cleavage site? The author makes a big deal out of this and I'm not sure why. It seems like he specifically looked at the gene sequence at a furin cleavage site and then said: hey look, this occurs at a furin cleavage site! It must mean something! (Thanks to etaoins for finding at least some evidence that furin cleavage sites are not, in fact, unusual in Coronaviruses, although I have not read the paper: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612...) 2. What does HIV-1 have to do with anything? That is, if these sequences all matched virus XYZ instead, would that also be some sort of smoking gun? The top 3 sequences all seem to be very common among lots of viruses (rotavirus, measles, coronaviruses, and HIV all show up in the top 3 lists). So he seems to have found a single sequence that lots and lots of viruses have (at least variants of), and that one sequence is the first 3 rows of his table. Am I missing something? 3. If we ignore every result entered after Feb 2020, aren't we throwing out a lot of sequences that were entered specifically because people were suddenly all very interested in Coronaviruses? If he's making claims like "these don't appear in any other Coronavirus", the "except those we found after everyone started looking at Coronaviruses much more" somewhat detracts from that, doesn't it? It feels a little bit like finding a passage "He froze, trembling with fear" and saying: the English language has 1 million words, so the probability of finding these 5 words in order is (1 million)^5. Therefore if we find it in two novels, one must have plagiarized the other. But not really though, because "he" and "with" are extremely common words, and "froze", "trembling", and "fear" are very highly correlated to each other. I think it's pretty clear his first 3 examples are all highly correlated. His last example (and the title of this post) seem a little harder to explain to me as a layperson, but I'd note that for a 30-nucleotide sequence, there are 3^30 other sequences that are only a single mutation away. We again see Rotavirus on his list. How far away is that Rotavirus sequence, and do we think it prohibitively unlikely this sequence came from Rotavirus?
- dekhn 5y ago
  For the furin cleavage site, here's some useful evidence. A nobel prize winning geneticist said that was the "smoking gun", but later had to walk it back. https://www.caltech.edu/about/news/the-debate-over-origins-of-sars-cov-2 https://www.caltech.edu/about/news/the-debate-over-origins-o... let's just say some number of scientists love jargon and they love to bandy about "furin cleavage site" and "smoking gun" because it sounds cool. For your second question, HIV-1 doesn't have anything to do with this.
murphyslab 5y ago
A large part of this blog post's ridiculous assertion lies either on ignorance or on the false assumption that horizontal gene transfer [0] does not exist in Nature: > It’s easy enough to change a single nucleotide (a single point mutation or SNP) or even insert or delete nucleotides (less common) but to insert 20 or 30 nucleotides with a code that works? Nope, that has to come from another virus or else it’s been done in a lab. The original preprint which noted similarity of the HIV-1 sequences and those in the COVID spike protein, and on which this blog author's claims rest, was voluntarily withdrawn by its authors. [1] Moreover, the assertions of uniqueness have been thoroughly addressed in the published article, "HIV-1 did not contribute to the 2019-nCoV genome" [2] : > For any virus to obtain additional insert sequences from other organisms, it requires that it has direct interactions with other organisms, most likely through homologous or non-homologous recombination. [...] On the contrary, these motifs are widely present in various mammalian cells and so it will be more likely for bat CoV viruses to gain those motifs from the genomes of their infected cells if recombination indeed occurs. That rebuttal article clearly suggests several feasible sources of the gene in Nature. That surely is more plausible than suggesting that Moderna or some other group nefariously created the COVID genome _in vitro_ before unleashing it upon humanity. I deeply enjoy Hacker News for its ability to surface different ideas and sources of information that I would otherwise never find, but this article is simply ridiculous. [0] https://en.wikipedia.org/wiki/Horizontal_gene_transfer https://en.wikipedia.org/wiki/Horizontal_gene_transfer [1] https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 [2] https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7033698/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7033698/
- dekhn 5y ago
  The really ridiculous thing is that we're expected to "explain it like I'm 5" to smart computer hackers who don't know biology and constantly try to poke holes in mainstream science without taking the time to understand the complexity and subtlety in that field.
  - deleted 5y ago
    [deleted]
empressplay 5y ago
I get that there's a lot of fear around the idea that Covid-19 was engineered, and the potential fallout that could occur if it was proven to be fact. But I expect that almost all governments are now working under the assumption that it was, because they would be extremely foolish not to. So this is all a moot point -- at the top level, the working theory must be the lab-leak theory. And so, fast vaccine production must be a priority. The development of drugs to treat viral infections and their manufacture must also be a priority. The ability to detect carriers and quickly shut down travel must also be a priority. And how do we enforce quarantine in populations that are resistant to it? All of these concerns are, I am certain, at the forefront in the mind of any Western government to be certain, but likely any government anywhere. Because regardless of IF Covid-19 was created in a lab, it COULD HAVE BEEN created in a lab. And we all got caught with our pants down.
- jimmygrapes 5y ago
  Your comment is exactly what I'd write if I believed in a fully competent government. Alas, reality steps in.
- Zerverus 5y ago
  Funnily enough those screaming it was engineered loudest also were the ones saying it’s just the flu and we should react to it by not wearing masks. I propose that what we really see is that humans have a very hard time without someone to blame (hence victim blaming, hence religion and a whole bunch of other coping mechanisms).
yellowapple 5y ago
It doesn't look like that nucleotide sequence is actually unique to both SARS-CoV-2 and Moderna's 2015/2016 patents. Just BLASTed that sequence with the "gss" database and got hits¹ for a bunch of different species of grass (plus some other hits for everything from bacteria to a species of dolphin). Tried again with the "RefSeq_Gene" database (ostensibly the human genome, AFAICT) and got a bunch of hits² for that, too. I ain't a geneticist, so it goes without saying that I don't really know what I'm doing and I'm probably using BLAST wrong, but it seems to me like (EDIT: something very close to) CTCCTCGGCGGGCACGTAG is pretty dang common even within the human genome (let alone other species), and it doesn't seem far-fetched to me that SARS-CoV-2 might've yanked (EDIT: something very close to) that sequence from one of its hosts at some point. EDIT: I forgot to check the completeness of the matches, and it does look like the hits tend to have one or two nucleotides that don't match. Still, it's close enough that the article doesn't seem like it presents much of a smoking gun. ¹: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3TZW9WB01R https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3TZW9W... ²: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3UU86PP013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3UU86P...
- dnautics 5y ago
  Double check the query coverage percentage on your searches.
  - yellowapple 5y ago
    Yep, you're right (and edited above to reflect that). After accounting for that, and after realizing that BLAST only returns the first 100 results, I searched on the "nt" database (where the article found "only" SARS-CoV-2 results) while excluding SARS-CoV-2 (taxid:2697049), "synthetic construct" (taxid:32630), and "other sequences" (taxid:28384). This¹ produced not just a lot of hits, but a lot of exact (i.e. 19/19) hits (mostly various microbes) - further suggesting that even the exact sequence in question ain't unique. I also ran a search on "nt" strictly on SARS-CoV (i.e. the original SARS virus)², and while no single result completely matches the query, there are a lot of results that could be concatenated/combined to produce the query - and while I'm (again) no geneticist, it doesn't seem to me like some sort of impossibility for that concatenation to happen through mutations in the wild. ¹: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3WR4BPX013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3WR4BP... ²: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3YCNK2C013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3YCNK2...
weare138 5y ago
>What this means is that there is no virus known to man that has this particular sequence in its genome prior to the discovery of SARS-Cov-2. So where on earth has it come from? Mutation? The same way we get every new pathogen?
BLanen 5y ago
- WaxedChewbacca 5y ago
lamontcg 5y ago
> It’s interesting because beta coronaviruses likes this don’t have a furin cleavage site, this is the only one. Well that's just entirely false. https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612... I'd draw your attention to section 2.3: > 2.3. Furin cleavage sites are common in Betacoronavirus Oh, also, if you click on Prashant Pradhan's paper it has been withdrawn: https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 > Abstract > This paper has been withdrawn by its authors. They intend to revise it in response to comments received from the research community on their technical approach and their interpretation of the results. If you have any questions, please contact the corresponding author.
justgoigleit 5y ago
From WVI: "...,In this study, we investigated the receptor usage of the SL-CoV S by combining a human immunodeﬁciency virus-based pseudovirus system with cell lines expressing the ACE2 molecules of human, civet, or horseshoe bat... Several important observations were made from this study... Third, the chimeric S covering the previously deﬁned receptor-binding domain *gained its ability to enter cells via human ACE2*, albeit with different efﬁciencies for different constructs. Fourth, a minimal insert region (amino acids 310 to 518) *was found to be sufﬁcient to convert the SL-CoV S from non-ACE2 binding to human ACE2 binding*..." This is *published research*. Specifically observations 3 and 4 https://jvi.asm.org/content/jvi/82/4/1899.full.pdf https://jvi.asm.org/content/jvi/82/4/1899.full.pdf
- justgoigleit 5y ago
  Google search the last author listed
arisAlexis 5y ago
It's very important to investigate these claims. Why dismiss even a low chance of this being the case for something that affected humanity like nothing else for centuries? Why trust a few people to reassure us that their field of expertise and source of funding was not at fault? Let these articles run and investigate everything with an open mind.
jacquesm 5y ago
Another day, another substack disinformation / faulty reasoning / conspiracy piece. The well is endless. Yes, this is a shallow dismissal but 'substack' is beginning to look like a red flag for content quality.
GuB-42 5y ago
It sounds like an algorithmic problem, typical of what you can find in coding competitions. You have two strings, A and B, and a list of strings L. Find the longest substring that appears in both A and B but not in any element of L.
jesse_a_b 5y ago
jesse_a_b 5y ago
CGG-CGG -> just this small sequence is NEVER found in natural viruses. It is typical of gain of function research.

146 points by Jimmc414 5y ago

thehappypm 5y ago

Odd to see that HN will not tolerate any evidence that the virus may have been designed in a lab.

efficax 5y ago
it's not evidence... is the thing...
erichocean 5y ago
Not really, the opposite would be true—with the exact same evidence—if it was the government's position that the virus was made in a lab. Then you'd have Substack's talking about how the virus could have been naturally occurring, that there's no reason it had to be made in a lab, that it's just the government blaming China, etc. I wish there was a word for beliefs that supposedly make use of evidence, but can easily use the exact same evidence to argue for the polar opposite belief.

Jimmc414 5y ago

Previous post was taken down within a few minutes by an unhelpful poster causing it getting it flagged with an abusive post. Two good questions were asked there so I will repost them here: >Posted by 'version_five' "This sounds like one of those "bible code" things. As someone who knows nothing about DNA sequences, what is the probability that two codes could be matched? (In a birthday paradox sense where you can go looking anywhere)" >Posted by 'whoomp12342' "isn't it well known that one of the main reasons why we got a vaccine so quickly was because we had done a ton of research when SARS originally broke out?"

vipa123 5y ago
Why is it taken down?
- Jimmc414 5y ago
  Someone with a 3 min old account posted a threatening message unrelated to any ongoing discussions.
  - pwg 5y ago
    3m old accounts can't flag (a certain karma level is needed to be able to flag). An unrelated threatening comment would have gotten the unrelated comment killed, but not the main posting. If the main posting was flagged, that is because some number of users with enough karma to flag clicked the "flag" link on the post.
    - Jimmc414 5y ago
      Maybe that is the case, but they did not flag it, they posted a message with several violent keywords and the post was immediately flagged. It seemed different from normal flagged posts because all of the reply buttons disappeared and as I hit reply on a comment I was in the process of writing, I got the message "You can no longer reply in this post" or something to that effect. I looked at other currently flagged posts and this seemed atypical. You can still reply within the flagged posts comment section. I assumed it was some sort of auto moderation action.
      - xiphias2 5y ago
        SARS-CoV2 is in the title, that may be enough for being taken down automatically to avoid flamewars.
      - pwg 5y ago
        The reply buttons likely disappeared because it was also made "dead". Looking it up in your profile it shows "[flagged] [dead]". As to why it was made dead, I do not know.
reindeer76 5y ago
>This sounds like one of those "bible code" things. As someone who knows nothing about DNA sequences, what is the probability that two codes could be matched? (In a birthday paradox sense where you can go looking anywhere) The genome in question is about 30000 bases long, which isn't nearly long enough for the outcome space size issue to come into play. Assuming independence, the probability is still very remote, effectively zero. However, there is in no way any expectation of independence. SARS-CoV-2 is obviously closely related to SARS-CoV-1, which is obviously closely related to 2015/2016 ongoing vaccine research. (And perhaps gain of function research.)
dang 5y ago
https://news.ycombinator.com/item?id=29938340 https://news.ycombinator.com/item?id=29938340 was flagged by other users—quite a few of them. We can only guess why users flag things, but I doubt that it had anything to do with that trollish post. We've banned the latter account now.

Jimmc414 5y ago

To clarify this sequence has not been identified in any other virus in the wild. Additionally it codes for the section pertaining to the furin cleavage site which does not exist in any other observed beta coronavirus.

etaoins 5y ago
That’s not correct, furin cleavage sites naturally occur in coronaviruses: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612...
- moralestapia 5y ago
  >To clarify this sequence has not been identified in any other virus in the wild. >this sequence >this >sequence
- Jimmc414 5y ago
  You are correct. I should have stated furin cleavage sites have not been observed in another beta coronavirus. (Cold, MERS, SARS) I corrected my statement. Thank you for pointing that out.
  - etaoins 5y ago
    That’s still incorrect. MERS is a Betacoronavirus and has a furin cleavage site: https://www.pnas.org/content/pnas/111/42/15214.full.pdf https://www.pnas.org/content/pnas/111/42/15214.full.pdf Furin clevage sites haven’t been found elsewhere in SARS-Cov-2’s Sarbecovirus subgenus.
- finite_jest 5y ago
  Not with the same PRRAR sequence of amino acids, right?
  - etaoins 5y ago
    Right, the furin cleavage site seems to have occurred independently in SARS-CoV-2 or one of its undiscovered close relatives.

1MachineElf 5y ago

This substack post is amazing work. I recommend reading the top comments on it for further discussion.

1MachineElf 5y ago

Archive link from today: https://web.archive.org/web/20220114174712/https://arkmedic.substack.com/p/how-to-blast-your-way-to-the-truth https://web.archive.org/web/20220114174712/https://arkmedic....

garbagecoder 5y ago

Jimmc414 5y ago
I think the point is that the sequence is searchable within the database of known viruses (virii?) and it is not speculation, it literally does not exist in any sequenced virus in the wild. I'm not sure what you mean with the goalposts comment.
- garbagecoder 5y ago
  That doesn't prove anything, of course. And by "goalposts" I mean that if you recall, the initial allegation was that COVID was a bioweapon developed by the Chinese. Then it was negligently leaked from a lab doing gain of function research funded by Obama. Then it was just leaked. People seem to want to believe this theory regardless of when facts get in the way. A year ago, there wasn't much evidence against it. Now there are animal finds in Laos that make some of the connection. Not proof, but positive evidence. From the field.[1] Not from cherry-picked database searches. At some point, you have to ask yourself with Ockham's razor: if it really is this simple, then why isn't it widely accepted? Has China gotten to everyone? If so, then why can I post this to my substack? Sometimes the expert opinion is right. I guess sheeple like me will never know. Except in reality, I'm quite open to this hypothesis, I am already a China hawk so I need no motivation there. I just don't think there's as much evidence as people who want to believe this think there is. For what it's worth, using the model of radius->radii for virus->*virii makes sense until you realize radius has an extra 'i' already. Worse, it's a second declension neuter despite the -us and so should be vira just like modicum->modica, whereas radius is second declension masculine. [1] https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2
  - peteradio 5y ago
    I would think someone with domain knowledge would be able to debunk this posts interpretation right?

YXNjaGVyZWdlbgo 5y ago

Humans really are just pattern searching animals.

Maursault 5y ago

Impressive work, but author's logic is unsound because it silently assumes the library or database BLAST uses is complete, yet it likely represents less than 1% of all sequences in the wild. The database BLAST uses only contains sequences that have been found and reported. If every person on the planet was a genetic expert with all necessary resources to find and identify new sequences, in 1000 years we still wouldn't have found all of them. The sequence in question that only matches HIV-1 may very well match a trillion^2 more sequences not in BLAST's database. Anything like this that is engineered likely has a mountain of documentation. Documentary evidence, if found, is a smoking gun in a way the furin cleavage site sequence can't be.

WanderPanda 5y ago
It would be interesting to me how likely it is to actually find random sequences in the database. Aka how much correlation there is between natural viruses. In my imagination it is plausible that if you take a particular virus that you will be able to find most of its subsequences (with minor modifications) in other viruses. In that case I think that his analysis is sound. On the other hand, if the other viruses appear to be randomly sampled from the set of all possible sequences than his reasoning does not cut it.
cuteboy19 5y ago
Is there any reason to believe that the database isn't a random sample of all possible sequences?
- etaoins 5y ago
  Genomes are sequenced when they're both accessible and are of scientific/economic interest. This results in an overrepresentation of: - Humans and their pathogens - Economically important organisms (e.g. crops and farm animals) and their pathogens - Model organisms For example, compare the number of Genebank sequences for HIV-1 [1] versus Feline immunodeficiency virus [2]. HIV-1 is additionally problematic because it has an extremely high mutation rate [3], making it more likely for a random sequence to match some sequenced HIV-1 genome. [1]: https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=11676&lvl=3&lin=f&keep=1&srchmode=1&unlock https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mod... [2]: https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Tree&id=11673&lvl=3&lin=f&keep=1&srchmode=1&unlock https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mod... [3]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574155/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574155/

dnautics 5y ago

Just to be clear, this doesn't imply that moderna released the viruses. Patents are publically visible, after all. It suggests that someone was told to insert a furin cleavage site, then went and "stack overflow copy-pasted" the moderna furin cleavage site, and this became the coronavirus. If we believe that this is what happened, it possible that whoever did this also looked up and copy pasted other furin cleavage sites, and thus the purely random odds of the eye-popping "moderna" aspect of the coincidence would considerably less (let's say, 1 in 100 or less, depending on how much work you think the hypothetical postdoc bothered to do). Do note that the moderna furin cleavage site itself is probably subjected to industrial selection pressures that enhance its delivery, which might also correlate to infectivity, so a non-uniform distribution of infectivity among stack-overflow-ed furin cleavage sites, that favors the infectivity of something like the moderna sequence, should be considered.

deleted 5y ago
[deleted]
hodwik3 5y ago
Given that this line is from a cell culture, wouldn’t the simpler explanation be that the virus has this sequence because it was replicated in that specific Moderna culture lineage? This would be a particularly useful discovery, because it would dramatically limit the candidates for who did the gain of function research to organizations licensed this Moderna lineage.

ausername42027 5y ago

This is a semi-interesting piece (because of how poorly written it is and how hilariously confident the writer is), but it is embarrassing that the person writing claims to have a PhD in at least something semi-related to molecular biology, yet is trying to convince people that we can use independent probability when dealing with protein amino acid sequences. Certain sequences are seen time and time again in nature, just like certain traits visible to the naked eye have evolved independently. More importantly, this author dismisses natural mixing of SARS and HIV1 as "ridiculous" and provides no other explanation. It is possible that SARS-CoV-2 was created in a lab, but it is also possible that HIV-1 and SARS-CoV-2 co-infected a host. Edit: to elaborate, certain amino acid sequences are seen again and again, and others are practically impossible to see in nature because amino-acids fold into 3D proteins...and each amino acid is like a Lego piece. There is a lot more detail needed to understand fully how tertiary and 4try protein structures form...but it is also possible to understand it decently well after an undergraduate degree in biology, chemistry, biochemistry, etc. A PhD in the field knows this inside and out. If I had to guess, the author of this post has a PhD in something like statistics or computer science, and thinks that they can apply high school level math to two fields (molecular biology and biochemistry) that they do not even have a high school level of understanding of. To make a very stretched analogy (I am a doctoral student in the life sciences and a hobby programmer), this blog post is like saying that some Java source code is stolen because four of the class names are the same between two projects, and then using the number of possible characters in the class names and the length of the name to run some statistics. The problem being that no one has class names like "AeNOQ92bA"...in fact the vast majority of 8 character sequences will never be class names. Just like the vast majority of amino acid sequences (likely) do not exist in nature. And then you dig deeper and find out the class name is something like "MainDashboardSupervisorTree" (I do not know Java so forgive me). Then you also find out that the author of both classes...is the same guy who moved companies and likes particular naming convection, but never meant to copy stuff word for word. Similar to how SARS-CoV-2 could have naturally incorporated HIV-1 RNA into its genome when co-infecting a host.

dnautics 5y ago
the HIV-1 protein sequence is the same but not the DNA sequence. The moderna DNA sequence is identical. The odds of HIV-1 mixing with bat coronavirus, and then somehow finding the moderna DNA sequence, while not astronomically low, are pretty low.

efficax 5y ago

This guy appears to also believe that the omicron variant is not a natural mutation but a lab-made version as well. BLAST does not contain all genetic material from all viruses or organisms in all of the natural world. There are countless (really, impossible to count) viruses of all kinds out there dancing around in the bodies of all kinds of creatures. There are literally hundreds of trillions of viruses in your body right now (not different kinds but individual viruses). Each of those hundreds of trillions of replications was an opportunity to mutate. Now multiply that by all of the individual animals human or otherwise who could harbor coronaviruses and you have many hundred billions of trillions of chances to generate the gene sequences in question. If I could get billions of trillions of lottery tickets, I'd win the lottery, and here it looks like SARS-CoV-2 won the "does a gene sequence in the virus exist in a patent by moderna" lottery.

dnautics 5y ago
if the mutation rate is that high, then why don't we see a ton of sequence variants around the wobble pairs of the furin cleavage site? (Or for any parts of the coronavirus, for that matter?)
- efficax 5y ago
  no way to answer such a question without real experimental research, and not even sure what you mean by "see", we dont "see" most virus mutations because most mutations don't survive... and certainly aren't sequenced. And the point isn't that a virus mutates on every replication, but that every replication is a chance for a mutation. The point is everything here hinges on an argument from probability. There are more viruses on earth than there are stars in the universe, the astronomical figures are meet with each other. We're not talking different orders of magnitude between the opportunities for a certain mutation and the probability of a certain mutation occuring.. edit: Further, it looks like the sequence exists in some bacteria, meaning it isn't even a question of a random mutation but possibily the incorporation of the sequence from an existing source (which the author claims doesn't exist, but it does, in mycobacterium smegmatis...). this destroys the entire premise of the claim.

etaoins 5y ago

Using the number of BLAST hits as the basis of an argument is about as reliable as using the number of results when searching for a string on GitHub. Without further analysis of the specific sequence and its biological context it can be highly misleading. See a previous Twitter thread on some other purported HIV inserts: https://twitter.com/trvrb/status/1223666856923291648 https://twitter.com/trvrb/status/1223666856923291648 There also seems to be some circular reasoning the argument. Apparently we can ignore RaTG13 because it’s obviously synthetic, which makes SARS-CoV-2 look even more synthetic. It would be interesting to compare to the BANAL family of SARS-CoV-2-related viruses that are even more closely related to SARS-CoV-2 than RaTG13 [1]. I’m not sure why only viral genomes were searched for the furin cleavage site sequence. Viruses famously exchange genetic material with their host organisms. The “smoking gun” sequence also appears Mycobacterium smegmatis, for example [2]. [1]: https://www.nature.com/articles/d41586-021-02596-2 https://www.nature.com/articles/d41586-021-02596-2 [2]: https://twitter.com/soychicka/status/1243547603746410500 https://twitter.com/soychicka/status/1243547603746410500

thehappypm 5y ago
The GitHub example actually is pretty spot on. If you wrote a non trivial piece of code in 2016, then in 2020 it was used verbatim in another program, what would your conclusion be?
- fastaguy88 5y ago
  For a non-trivial piece of code, the conclusion might be that it was copied (horizontal code transfer??). But the 6 amino acids is not a "non-trivial piece of code" -- it is a trivial short string of letters. So the more relevant question is, how often do we see "dogcat" in GitHub (468 repository names). Or perhaps something more nonsensical: "ifdlog" (6 letters from "goldfish" reversed): 1 repository and 25 code results. "hsifdl" - 1 code result. Random things occur at random.
  - deleted 5y ago
    [deleted]
  - 5y ago

FortDetrickAnon 5y ago

dekhn 5y ago

I ask a question about dna sequences for SWE interviews. It ends up providing some useful signal. For example questions I ask include: if you have a symbol table with 4 symbols, how many bits are required to uniquely identify each symbol (answer: 2 bits). OK, given this ASCII string 'CTCCTCGG', can you compress it a few bits? (answer: without entropy, run length, or backrefs, you can easily compress DNA encoded in 8-bit ASCII from 8 bits/byte to 2 bits/byte). OK, so, how many bits does an 8-long DNA string require encode (answer: 16 bits). Huh, that's a short. The rest of the interview is how to move form using a hash table for counting k-mer frequencies to a vector using a minimal perfect hash, and compute k-mer frequencies quickly using a rolling hash. It's a great question because it always throws the CS people off to hear their questions asked with biological structures involved.

beebmam 5y ago
I try to ask questions in software engineering interviews that don't have just a single correct answer, like most real-world engineering problems.
- dekhn 5y ago
  some of the answers I gave are the only correct answer. if somebody was going to go straight to proposing a probabilistic data structure like a bloom count and could code up a simple example in 20-30 minutes, that is also OK (and would lead almost certainly to an immediate hire).
vintermann 5y ago
There's a whole branch of CS, bioinformatics, which would be more confused if you did NOT ask the questions with biological structures involved. The field of string algorithms, or "stringology" as they whimsically call it, is also heavily focused on DNA. I was planning to study bioinformatics in my youth. Life events intervened and I had to do a regular software engineering degree instead, but I still have an unreasonable love for the Burrows-Wheeler transform.
- dekhn 5y ago

marstall 5y ago

for those with SciAm subs, this June 2020 print article is a profile of the first scientist to encounter Covid. She had spent a decade in caves around China investigating SARS and was therefore called on when early reports of Covid arose. I read this before all the lab leak theories came out, and I'm glad I did because it makes them all seem ridiculous. https://www.scientificamerican.com/article/how-chinas-bat-woman-hunted-down-viruses-from-sars-to-the-new-coronavirus1/ https://www.scientificamerican.com/article/how-chinas-bat-wo...

rasz 5y ago
She was "called on" to Wuhan WIV where virus first emerged and where she has been working for at least 7 years and where all of her research was funded by EcoHealth Alliance grants? same EcoHealth Alliance which submitted this gain of function grand proposal in 2018 https://theintercept.com/2021/09/23/coronavirus-research-grant-darpa/ https://theintercept.com/2021/09/23/coronavirus-research-gra... ?
basch 5y ago
More about her. "Also, Dr. Shi was trained by Ralph S. Baric of the University of North Carolina in building “chimera” viruses — taking, for example, the spike protein from a new virus and splicing it to the backbone of a known one like SARS. He invented “no-see-um” techniques that left no trace of the splice." source https://donaldgmcneiljr1954.medium.com/how-i-learned-to-stop-worrying-and-love-the-lab-leak-theory-f4f88446b04d https://donaldgmcneiljr1954.medium.com/how-i-learned-to-stop... https://www.researchgate.net/publication/8119695_Development_of_mouse_hepatitis_virus_and_SARS-CoV_infectious_cDNA_constructs https://www.researchgate.net/publication/8119695_Development...
- akiselev 5y ago
  > the spike protein from a new virus and splicing it to the backbone of a known one like SARS The spike protein was already a defining feature of SARS-CoV when it emerged and became "known" [1]. That's why it was classified as a coronavirus! [2] Edit: Appears I have misread, see reply [1] https://www.science.org/doi/abs/10.1126/science.1086418 https://www.science.org/doi/abs/10.1126/science.1086418 [2] https://en.wikipedia.org/wiki/Coronavirus#Structure https://en.wikipedia.org/wiki/Coronavirus#Structure

lamp987 5y ago

So what does this mean? That covid was made in a lab? Or did covid and moderna independently reach the same "conclusion" through parallel evolutionary pressures (in nature and in research)?

vintermann 5y ago
The second possibility is the main objection I have to this post. The lottery arguments may actually be good enough to rule out chance, but ruling out chance isn't the same as ruling out other explanations which can make things extremely non-random.

fastaguy88 5y ago

As other commenters point out, this "analysis" is a joke. An E()-value of 282 says we would expect a match of this short sequence against a completely random library of the same size 282 times. Even with BLASTp's parameter correction for short sequences, NO short sequence will generate a statistically significant score. Let's try a more sensible approach. Let's see how often the sequence occurs in other databases. The author's 1/20^6 (1/64,000,000) probability calculation omits the fact that every database search considers many millions of possible alignments (a crude calculation would be 6 * the database length, or 6 * 1.6E7/20^6 ~ 10000E6/64E6 = 156 times by chance), and we're shown that in a 5,000,000 protein/1.6E7 residue database, 100% matches are seen several dozens of times, as expected. How about other protein sets? Search the human protein set (19,000 proteins), there are no 6 amino acid 100% identical matches. The best matches are 100% of 5 residues, or 83% identity over 6 (with an E()-value of 22). How many proteins do we need to search to find an exact full-length match? (we have dozens of matches in a 5,000,000 viral protein database. and none in 19,000). If you search all the NCBI landmark sequences (~500,000, non-redundant), there are 3 identical matches (E()-value: ~44) in Drosophila, Corn, and Strep. pneumoniae. So this sequence is not very special -- as the E()-value statistics indicate, it happens all the time by chance. (If it happens 3 times in a 500,000 sequence non-redundant database by chance, we would expect it to happen 30-100's of times in a 5,000,000 redundant viral database by chance, which is what we see.) Six amino acid non-significant matches are evidence that properly done statistics are accurate, and pretty much nothing else.

arisAlexis 5y ago
It's not only the numbers. 1 out of 282 with the one being Moderna is much more significant. The null hypothesis is important. It's not just the odds reporting. Anybody can pass by your door accidentally Less likely it is someone that threatened you last night. Same odds, different situations.
- fastaguy88 5y ago
  It is not clear to me why it is much more significant (or how much more). There is confirmation bias here. There would be no "report" if Moderna had not been associated with the sequence. So how many other, perhaps longer, matches were there to other patented sequences with no connection to Moderna? If there were hundreds (which there probably were), it is much less clear what the significance of one of them being in a Moderna patent is, particularly if Moderna was trying to make an HIV vaccine, and the sequence is in HIV (which it is).

im3w1l 5y ago

In my cursory encounters with numerology, I have learned that if you try enough hypotheses, something will always pop out. Could this be the case here too, or is the gun-smoke so thick that no cherry picking can explain it? (eg https://i1.wp.com/www.ghgossip.com/wp-content/uploads/2020/03/coronavirus-666.jpg https://i1.wp.com/www.ghgossip.com/wp-content/uploads/2020/0...)

dpark 5y ago

> *As of writing this those links are still up which at 12 months is pretty good going for any article that dares challenge the drivel propagandised by our beloved “free press [sponsored by pharma]”. Well this is a rough start. “This information is being suppressed, which you can tell by the fact that these linked articles are still available.” The utter lack of critical thinking doesn’t make me expect much from the rest of this.

LorenPechtel 5y ago

Another reason his probabilities are garbage: Nature favors sequences that work. Try a billion variants, keep the one that actually helps. We don't see the 999,999,999 failures.

dnautics 5y ago
Why is the native hiv sequence (which has had a lot of convergence potential since hiv mutates, a lot) different, and why did it convergently evolve instead to the nucleotide sequence of moderna's artificial furin site (designed for hiv), which to be fair, is subjected to industrial selection, which would be (I would guess, but don't know) weaker than the natural one due to selection sampling limitations?

feoren 5y ago

Some questions from a layperson: 1. Why do we care so much about a furin cleavage site? The author makes a big deal out of this and I'm not sure why. It seems like he specifically looked at the gene sequence at a furin cleavage site and then said: hey look, this occurs at a furin cleavage site! It must mean something! (Thanks to etaoins for finding at least some evidence that furin cleavage sites are not, in fact, unusual in Coronaviruses, although I have not read the paper: https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612...) 2. What does HIV-1 have to do with anything? That is, if these sequences all matched virus XYZ instead, would that also be some sort of smoking gun? The top 3 sequences all seem to be very common among lots of viruses (rotavirus, measles, coronaviruses, and HIV all show up in the top 3 lists). So he seems to have found a single sequence that lots and lots of viruses have (at least variants of), and that one sequence is the first 3 rows of his table. Am I missing something? 3. If we ignore every result entered after Feb 2020, aren't we throwing out a lot of sequences that were entered specifically because people were suddenly all very interested in Coronaviruses? If he's making claims like "these don't appear in any other Coronavirus", the "except those we found after everyone started looking at Coronaviruses much more" somewhat detracts from that, doesn't it? It feels a little bit like finding a passage "He froze, trembling with fear" and saying: the English language has 1 million words, so the probability of finding these 5 words in order is (1 million)^5. Therefore if we find it in two novels, one must have plagiarized the other. But not really though, because "he" and "with" are extremely common words, and "froze", "trembling", and "fear" are very highly correlated to each other. I think it's pretty clear his first 3 examples are all highly correlated. His last example (and the title of this post) seem a little harder to explain to me as a layperson, but I'd note that for a 30-nucleotide sequence, there are 3^30 other sequences that are only a single mutation away. We again see Rotavirus on his list. How far away is that Rotavirus sequence, and do we think it prohibitively unlikely this sequence came from Rotavirus?

dekhn 5y ago
For the furin cleavage site, here's some useful evidence. A nobel prize winning geneticist said that was the "smoking gun", but later had to walk it back. https://www.caltech.edu/about/news/the-debate-over-origins-of-sars-cov-2 https://www.caltech.edu/about/news/the-debate-over-origins-o... let's just say some number of scientists love jargon and they love to bandy about "furin cleavage site" and "smoking gun" because it sounds cool. For your second question, HIV-1 doesn't have anything to do with this.

murphyslab 5y ago

A large part of this blog post's ridiculous assertion lies either on ignorance or on the false assumption that horizontal gene transfer [0] does not exist in Nature: > It’s easy enough to change a single nucleotide (a single point mutation or SNP) or even insert or delete nucleotides (less common) but to insert 20 or 30 nucleotides with a code that works? Nope, that has to come from another virus or else it’s been done in a lab. The original preprint which noted similarity of the HIV-1 sequences and those in the COVID spike protein, and on which this blog author's claims rest, was voluntarily withdrawn by its authors. [1] Moreover, the assertions of uniqueness have been thoroughly addressed in the published article, "HIV-1 did not contribute to the 2019-nCoV genome" [2] : > For any virus to obtain additional insert sequences from other organisms, it requires that it has direct interactions with other organisms, most likely through homologous or non-homologous recombination. [...] On the contrary, these motifs are widely present in various mammalian cells and so it will be more likely for bat CoV viruses to gain those motifs from the genomes of their infected cells if recombination indeed occurs. That rebuttal article clearly suggests several feasible sources of the gene in Nature. That surely is more plausible than suggesting that Moderna or some other group nefariously created the COVID genome _in vitro_ before unleashing it upon humanity. I deeply enjoy Hacker News for its ability to surface different ideas and sources of information that I would otherwise never find, but this article is simply ridiculous. [0] https://en.wikipedia.org/wiki/Horizontal_gene_transfer https://en.wikipedia.org/wiki/Horizontal_gene_transfer [1] https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 [2] https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7033698/ https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7033698/

dekhn 5y ago
The really ridiculous thing is that we're expected to "explain it like I'm 5" to smart computer hackers who don't know biology and constantly try to poke holes in mainstream science without taking the time to understand the complexity and subtlety in that field.
- deleted 5y ago
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empressplay 5y ago

I get that there's a lot of fear around the idea that Covid-19 was engineered, and the potential fallout that could occur if it was proven to be fact. But I expect that almost all governments are now working under the assumption that it was, because they would be extremely foolish not to. So this is all a moot point -- at the top level, the working theory must be the lab-leak theory. And so, fast vaccine production must be a priority. The development of drugs to treat viral infections and their manufacture must also be a priority. The ability to detect carriers and quickly shut down travel must also be a priority. And how do we enforce quarantine in populations that are resistant to it? All of these concerns are, I am certain, at the forefront in the mind of any Western government to be certain, but likely any government anywhere. Because regardless of IF Covid-19 was created in a lab, it COULD HAVE BEEN created in a lab. And we all got caught with our pants down.

jimmygrapes 5y ago
Your comment is exactly what I'd write if I believed in a fully competent government. Alas, reality steps in.
Zerverus 5y ago
Funnily enough those screaming it was engineered loudest also were the ones saying it’s just the flu and we should react to it by not wearing masks. I propose that what we really see is that humans have a very hard time without someone to blame (hence victim blaming, hence religion and a whole bunch of other coping mechanisms).

yellowapple 5y ago

It doesn't look like that nucleotide sequence is actually unique to both SARS-CoV-2 and Moderna's 2015/2016 patents. Just BLASTed that sequence with the "gss" database and got hits¹ for a bunch of different species of grass (plus some other hits for everything from bacteria to a species of dolphin). Tried again with the "RefSeq_Gene" database (ostensibly the human genome, AFAICT) and got a bunch of hits² for that, too. I ain't a geneticist, so it goes without saying that I don't really know what I'm doing and I'm probably using BLAST wrong, but it seems to me like (EDIT: something very close to) CTCCTCGGCGGGCACGTAG is pretty dang common even within the human genome (let alone other species), and it doesn't seem far-fetched to me that SARS-CoV-2 might've yanked (EDIT: something very close to) that sequence from one of its hosts at some point. EDIT: I forgot to check the completeness of the matches, and it does look like the hits tend to have one or two nucleotides that don't match. Still, it's close enough that the article doesn't seem like it presents much of a smoking gun. ¹: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3TZW9WB01R https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3TZW9W... ²: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3UU86PP013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3UU86P...

dnautics 5y ago
Double check the query coverage percentage on your searches.
- yellowapple 5y ago
  Yep, you're right (and edited above to reflect that). After accounting for that, and after realizing that BLAST only returns the first 100 results, I searched on the "nt" database (where the article found "only" SARS-CoV-2 results) while excluding SARS-CoV-2 (taxid:2697049), "synthetic construct" (taxid:32630), and "other sequences" (taxid:28384). This¹ produced not just a lot of hits, but a lot of exact (i.e. 19/19) hits (mostly various microbes) - further suggesting that even the exact sequence in question ain't unique. I also ran a search on "nt" strictly on SARS-CoV (i.e. the original SARS virus)², and while no single result completely matches the query, there are a lot of results that could be concatenated/combined to produce the query - and while I'm (again) no geneticist, it doesn't seem to me like some sort of impossibility for that concatenation to happen through mutations in the wild. ¹: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3WR4BPX013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3WR4BP... ²: https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3YCNK2C013 https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Get&RID=Y3YCNK2...

weare138 5y ago

>What this means is that there is no virus known to man that has this particular sequence in its genome prior to the discovery of SARS-Cov-2. So where on earth has it come from? Mutation? The same way we get every new pathogen?

BLanen 5y ago

WaxedChewbacca 5y ago

lamontcg 5y ago

> It’s interesting because beta coronaviruses likes this don’t have a furin cleavage site, this is the only one. Well that's just entirely false. https://www.sciencedirect.com/science/article/pii/S1873506120304165 https://www.sciencedirect.com/science/article/pii/S187350612... I'd draw your attention to section 2.3: > 2.3. Furin cleavage sites are common in Betacoronavirus Oh, also, if you click on Prashant Pradhan's paper it has been withdrawn: https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 https://www.biorxiv.org/content/10.1101/2020.01.30.927871v2 > Abstract > This paper has been withdrawn by its authors. They intend to revise it in response to comments received from the research community on their technical approach and their interpretation of the results. If you have any questions, please contact the corresponding author.

justgoigleit 5y ago

From WVI: "...,In this study, we investigated the receptor usage of the SL-CoV S by combining a human immunodeﬁciency virus-based pseudovirus system with cell lines expressing the ACE2 molecules of human, civet, or horseshoe bat... Several important observations were made from this study... Third, the chimeric S covering the previously deﬁned receptor-binding domain *gained its ability to enter cells via human ACE2*, albeit with different efﬁciencies for different constructs. Fourth, a minimal insert region (amino acids 310 to 518) *was found to be sufﬁcient to convert the SL-CoV S from non-ACE2 binding to human ACE2 binding*..." This is *published research*. Specifically observations 3 and 4 https://jvi.asm.org/content/jvi/82/4/1899.full.pdf https://jvi.asm.org/content/jvi/82/4/1899.full.pdf

justgoigleit 5y ago
Google search the last author listed

arisAlexis 5y ago

It's very important to investigate these claims. Why dismiss even a low chance of this being the case for something that affected humanity like nothing else for centuries? Why trust a few people to reassure us that their field of expertise and source of funding was not at fault? Let these articles run and investigate everything with an open mind.

jacquesm 5y ago

Another day, another substack disinformation / faulty reasoning / conspiracy piece. The well is endless. Yes, this is a shallow dismissal but 'substack' is beginning to look like a red flag for content quality.

GuB-42 5y ago

It sounds like an algorithmic problem, typical of what you can find in coding competitions. You have two strings, A and B, and a list of strings L. Find the longest substring that appears in both A and B but not in any element of L.

jesse_a_b 5y ago

CGG-CGG -> just this small sequence is NEVER found in natural viruses. It is typical of gain of function research.