Snake Venom Phosphodiesterase in the Karikó–Weissman Papers

Table of Contents

1. What Dr. Ardis Says
2. Where the Words Appear
3. The Sentences, Word for Word
4. What the Sentences Mean
5. What Snake Venom Phosphodiesterase Is
6. Seventy Years in the Laboratory
7. A Laboratory Tool Is Not an Ingredient
8. What the Vaccine Documents List
9. “To Cut RNA or DNA to Insert the mRNA”
10. Questions Readers Ask
11. Key Research Papers
12. Connections
13. Featured Videos

1. What Dr. Ardis Says

Dr. Ardis has made this argument in at least two places. In a 2025 podcast interview he said:

“Their names are Katalin Karikó and Drew Weissman. And when you go look at their research studies, they were funded by the NIH starting in 2009 to develop these COVID-19 mRNA vaccines. Strange. And in every one of those research studies, they state snake venom phosphodiesterase, snake venom…”

That passage is from Culture Apothecary with Alex Clark, the episode “Nicotine Is NOT the Villain: What Big Pharma Hides From Parents” (May 2025). It comes at 29:03 in the episode’s auto-generated transcript, which spells her name “Cataline Carico”.

In the film Watch the Water 2 he set out the same argument at greater length:

“Every study since 2009, 2011, 2012, 2015…every single one of their … studies says that in order to cleave…cut RNA or DNA, they use snake venom phosphodiesterase… to cleave the RNA or DNA to insert the mRNA for our gene therapy. … when I say I am worried that there is snake venom in the shots…why don’t you go look at the recipes of the researchers who created the shots. Stew, the … words ‘snake venom’ is in the paper.”

His own show later posted a clip naming the papers he means: “Covid Vax Synthetic Snake Venom Research Funded by NIH Grant to mRNA Scientists Katalin Kariko and Drew Weissman 2008 & 2011.”

In his telling, he came to these papers from a blood test. A Canadian physician, Dr. Charles Hoffe, had reported raised D-dimer results in patients after vaccination. A medical reference listed “snake venom poisoning” among the uses of the D-dimer test. That sent Dr. Ardis to find out who had created the shots. That part of his argument has its own page: D-Dimer and Snake Venom.

His statement contains three separate claims, and each can be checked against a document:

1. The funding — that the NIH paid for their studies from 2009 to develop COVID-19 vaccines. The grant-by-grant public record is on The NIH Grants Behind the Karikó–Weissman Research.
2. The words — that every one of their studies names snake venom phosphodiesterase. Sections 2–4 below.
3. The use — that the enzyme cuts RNA or DNA to insert the mRNA, so that venom could be in the shots. Sections 5–9 below.

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2. Where the Words Appear

On 3 October 2026 we asked PubMed, the US National Library of Medicine’s index of medical research, for every paper that lists both Karikó K and Weissman D as authors. It returned 34 papers, from 2000 to 2022. 22 of them date from 2008 onward, and 20 of those 22 are stored whole in PubMed Central, the library’s free full-text archive, so every word of them can be searched. The other two are 2013 laboratory-protocol chapters in the book series Methods in Molecular Biology, which are not openly available. PubMed holds no paper by the two of them dated 2009.

Searched word by word, the 20 full texts contain the word “venom” in exactly two papers, three times in all:

• once in the 2008 Molecular Therapy paper on pseudouridine mRNA;
• twice in a 2011 Nucleic Acids Research paper on two of the cell’s antiviral enzymes, OAS and RNase L.

The other 18 contain it zero times:

• the 2010 Nucleic Acids Research paper on the enzyme PKR, one of the three papers the Nobel committee named;
• the 2011 Nucleic Acids Research paper on purifying mRNA by HPLC;
• the 2012 Molecular Therapy erythropoietin paper;
• two from 2013, in Gene Therapy and the Journal of Photochemistry and Photobiology B;
• three from 2015: PLoS One, the Journal of Controlled Release and a Molecular Therapy commentary;
• two from 2017: the Zika vaccine paper in Nature and a Nature Communications paper;
• two from 2018, in the Journal of Experimental Medicine and Nature Communications;
• two from 2019, in Human Gene Therapy and Molecular Therapy Nucleic Acids;
• the 2020 SARS-CoV-2 vaccine paper in Immunity;
• two from 2021, in Nature Communications and Immunity;
• and a 2022 correction notice.

The 12 joint papers from 2000–2007 are not in the open full-text archive, so they could not be searched the same way. That group includes the famous 2005 Immunity paper. The patent filed on that discovery is fully public, though. It is US Patent 8,278,036, “RNA containing modified nucleosides and methods of use thereof”, with Karikó and Weissman as the inventors (priority date 23 August 2005, granted 2 October 2012). Its full text contains no “venom”, no “snake” and no “phosphodiesterase”. The RNA-cutting enzyme named in its experiments is a bacterial nuclease (Benzonase).

Read the picture from left to right: two tiles out of twenty carry the word, and none of the documents on the right carries it at all.

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3. The Sentences, Word for Word

Here is every sentence in their joint papers that mentions snake venom, in full and in context.

The 2008 paper (Molecular Therapy)

This paper showed that mRNA built with pseudouridine (Ψ) in place of uridine made far more protein, in cells and in mice, without setting off the immune alarm. In its Discussion section the authors suggest reasons why. The snake-venom sentence is the second one here:

“A likely contributing factor to the enhanced translation observed with Ψ modification is an increase in biological stability of the mRNAs (Figure 4d). Indeed, higher resistance to hydrolysis by phosphodiesterases from snake venom and spleen has been reported when uridine was replaced with Ψ in dinucleotide substrates. [19]”

Reference 19 is a two-page 1965 chemistry report by Naylor, Ho and Gilham in the Journal of the American Chemical Society.

The 2011 paper (Nucleic Acids Research)

This paper asked whether Ψ also protects mRNA from RNase L, an enzyme the body switches on to shred viral RNA during an infection. Its Discussion first sums up what was already known:

“The presence of Ψ has been shown to enhance the stability of RNA secondary structures, but has not previously been demonstrated to cause resistance to nucleases. RNA containing Ψ was cleaved efficiently by RNase A, RNase H (36), RNase T1, RNase T2, nuclease P1 and snake venom phosphodiesterase, although there is some indication that pancreatic diesterase and snake venom phosphodiesterase may cleave Ψ-RNA with reduced efficiency (37).”

Reference 36 is a 2004 laboratory-methods paper by Zhao and Yu in the journal RNA. Reference 37 is the same 1965 report.

An earlier paper: Temple University, 1988

Before her mRNA work, Karikó was a postdoctoral researcher at Temple University in Philadelphia, studying an antiviral signalling molecule called 2-5A. A 1988 paper from that laboratory, with her as second author, names the enzyme in its summary. This time it is a tool the researchers actually used:

“Identification and structural determination of the 2- and 8-azido adenylate trimer 5′-triphosphates were accomplished by enzymatic hydrolyses with T2 RNase, snake venom phosphodiesterase, and bacterial alkaline phosphatase. Hydrolysis products were identified by HPLC and PEI-cellulose TLC analyses.”

That is the classic laboratory use of the enzyme. Researchers cut a small sample into pieces, then identify the pieces to confirm what the molecule was. The 1988 paper is not one of the joint Karikó–Weissman papers, since the two met in the late 1990s, and it is not about mRNA.

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4. What the Sentences Mean

Both joint-paper sentences make the same small point, and neither describes an experiment the authors did.

In 2008 the authors had a puzzle: their pseudouridine mRNA produced much more protein than ordinary mRNA. One reason, they suggested, might be that it lasts longer before the cell breaks it down. As support they pointed to a 1965 test-tube result. When uridine was replaced by pseudouridine in tiny two-letter pieces of RNA, two RNA-cutting enzymes cut them more slowly. One enzyme was purified from snake venom, the other from spleen.

The 2011 sentence revisits the same old result more cautiously. RNA containing pseudouridine is still cut efficiently by six different enzymes, the snake venom one included. There is only “some indication” that two of them work a little more slowly on it.

Picture a report on a new kind of rope that notes, “an earlier test found this fibre resists a standard hacksaw slightly better than ordinary rope.” The hacksaw is the yardstick for toughness. It is not part of the rope, and nobody who uses the rope ever meets the hacksaw. In these two sentences the snake venom enzyme plays the hacksaw’s part.

We checked this against both full texts. In both papers the word “venom” appears only in these Discussion sentences, and “phosphodiesterase” appears elsewhere only in the title of the 1965 report in the reference list. Neither paper’s Methods section names the enzyme.

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5. What Snake Venom Phosphodiesterase Is

An enzyme is a protein that speeds up one chemical job. This one has a single job: it chews RNA or DNA from one end, one letter (nucleotide) at a time. In chemists’ terms it is an exonuclease that works from the 3′ end of the chain and releases single 5′-nucleotides. Its other names are phosphodiesterase I and venom exonuclease. “Phosphodiesterase” simply names the bond it breaks: the phosphodiester bond that links each letter of RNA or DNA to the next.

It occurs in small amounts in the venom of many snakes. For laboratory use it is classically purified from rattlesnake venom, for example that of the eastern diamondback, Crotalus adamanteus. In the venom it is a minor ingredient, not one of the main toxins. A 2023 genetic study in eLife traced its origin. Snakes adapted it from an older gene, ENPP3, which belongs to a family of enzymes that our own bodies also make. The snake version shares that family’s basic chemistry, and in a bite it may disturb the prey’s ATP-based chemical signalling (Pan 2023; on the human family, Stefan 2005).

Same word, different enzyme. The “phosphodiesterases” you may have read about in medicine are unrelated proteins that break a similar bond inside small signalling molecules. Examples are PDE5, the target of erectile-dysfunction drugs, and the enzymes that end the cyclic-AMP signal discovered by Earl Sutherland. They are not snake venom enzymes.

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6. Seventy Years in the Laboratory

Biochemists first turned to venom for a practical reason. Venoms are concentrated mixtures of digestive enzymes, and in the 1950s they were one of the richest sources of enzymes that cut nucleic acids in a predictable way. Once purified, this enzyme became a standard tool:

• 1952 — Sinsheimer and Koerner publish a method for purifying venom phosphodiesterase.
• 1959 — Razzell and Khorana describe exactly which bonds it cuts, and show that it works stepwise, one nucleotide at a time from one end. Har Gobind Khorana went on to share the 1968 Nobel Prize for deciphering the genetic code (Nirenberg, Khorana & Holley).
• 1965 — Robert Holley’s team publishes the first complete sequence of any nucleic acid, a transfer RNA. In his Nobel lecture Holley described one of the methods that made it possible: “One new method that was especially useful is outlined in Figs. 5 and 6. As indicated in Fig. 5, partial digestion of an oligonucleotide with snake venom phosphodiesterase gives a mixture of degradation products.” Nibbling a fragment back letter by letter, and identifying what was left at each step, revealed the order of the letters.
• 1965 — Naylor, Ho and Gilham test how pseudouridine changes the way RNA-cutting enzymes behave. This is the report the Karikó–Weissman papers cite.
• 1988 — Karikó’s Temple University group uses it, with two other enzymes, to confirm the structure of molecules they had made.
• Today — the exact phrase “snake venom phosphodiesterase” appears in 423 PubMed records and in the full text of 1,965 papers in PubMed Central (searched 3 October 2026). It is an ordinary item in a biochemistry laboratory’s freezer.

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7. A Laboratory Tool Is Not an Ingredient

When a laboratory uses this enzyme, it is almost always to analyse a sample: take a small portion, cut it into pieces, identify the pieces. The portion that is tested is used up. Nothing from that test tube goes back into anything that is made, sold or injected.

A food laboratory that dissolves a spoonful of soup in acid to measure its salt has not put acid in the soup. The spoonful was sacrificed so that the rest could be described.

The same holds for an animal-derived test that really is used on medicines meant for injection: the endotoxin test made from horseshoe-crab blood (Limulus amebocyte lysate). The Karikó–Weissman patent reports using it to check their RNA samples for bacterial endotoxin. The European regulator’s report on the vaccine lists it among its abbreviations and says endotoxin testing “is performed at different stages of the manufacturing process.” Testing a sample does not make the test part of the product.

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8. What the Vaccine Documents List

If an enzyme were part of a vaccine, or part of how its mRNA is made, two kinds of official document would show it. One is the label, which lists every ingredient. The other is the regulator’s assessment of the manufacturing process.

The FDA labels (2026–2027 formula)

The current US label for COMIRNATY (published 7 September 2026) lists, for each 0.3 mL dose given to adults and teenagers:

“30 mcg nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2 JN.1-descendent variant XFG. … lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.19 mg cholesterol), 0.06 mg tromethamine, 0.4 mg tromethamine hydrochloride, and 31 mg sucrose. … COMIRNATY does not contain preservatives.”

The current SPIKEVAX label (published 31 August 2026) lists, for each 0.5 mL dose:

“50 mcg nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized spike glycoprotein (S) of the SARS-CoV-2 JN.1-descendent variant XFG. … a total lipid content of 1.01 mg (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), 0.25 mg tromethamine, 1.2 mg tromethamine hydrochloride, 0.021 mg acetic acid, 0.10 mg sodium acetate trihydrate, and 43.5 mg sucrose.”

Neither label contains the words “venom”, “snake” or “phosphodiesterase”. What each of these ingredients does is explained in plain words on From Pseudouridine to the COVID-19 Vaccines.

The European manufacturing record

The European Medicines Agency’s public assessment report on COMIRNATY (19 February 2021, 140 pages) describes how its mRNA is made:

“The BNT162b2 active substance is manufactured by in vitro transcription using a linear DNA template, produced via plasmid DNA from transformed Escherichia coli cells.”

In plain words, the process runs like this:

1. Bacteria grow copies of a ring of DNA that carries the spike-protein gene.
2. The ring is cut open into a straight template.
3. In a tube with no cells, an enzyme (an RNA polymerase) reads the template and writes out the mRNA.
4. A DNA-destroying enzyme (DNase) removes the template, and the mRNA is purified.

The report names a “DNase digestion step”, “proteinase K digestion” and filtration steps. It says the materials used to make the DNA template are “animal origin free”, and that “reagents used in active substance manufacturing and in the establishment of the MCB and WCB are the only materials of animal origin used in the manufacture of BNT162b2” (the MCB and WCB are the banks of bacterial cells). It names the theoretical risk from those reagents as prion-type agents, “deemed of minimal risk”, and does not name the animals. The words “venom” and “phosphodiesterase” do not appear anywhere in its 140 pages.

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9. “To Cut RNA or DNA to Insert the mRNA”

Dr. Ardis describes the enzyme’s use as cutting RNA or DNA “to insert the mRNA for our gene therapy”. The documents describe a different sequence of events.

• Making the mRNA. The mRNA is written out in a tube from a DNA template, and the template is then destroyed (Section 8). No step in the published process inserts anything into DNA.
• Inside the body. The mRNA is read in the cell’s cytoplasm, outside the nucleus where DNA is kept. The cell makes the protein and then breaks the mRNA down. The questions people ask about DNA are answered on the hub page, in its safety record.
• “Gene therapy”. The phrase comes from the papers themselves. Their conflict-of-interest notes say that the two scientists formed “a small biotech company RNARx that receives funding from the National Institutes of Health to explore the use of nucleoside-modified mRNA for gene therapy.” In those statements the phrase describes RNARx’s work: delivering mRNA so that cells make a useful protein for a while. The company’s one NIH project was an mRNA for erythropoietin, to treat anemia, and the mRNA does not become part of anyone’s genes. Weissman’s later NIH grant on gene editing for hemophilia A (from 2017) is a separate line of work, in which mRNA carries an editing enzyme. Both are on the NIH grants page.
• The enzyme. In the joint papers the snake venom enzyme appears only in the two Discussion sentences above. It is not in their Methods, in the patent, on the labels or in the manufacturing report.

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10. Questions Readers Ask

Is there snake venom in the mRNA COVID-19 vaccines?

Neither current FDA label lists any snake-derived ingredient. The European regulator’s 140-page manufacturing record does not mention snake venom or phosphodiesterase. Those are the documents in which an ingredient or a manufacturing enzyme would appear.

Did Karikó and Weissman use snake venom in their experiments?

None of their 20 searchable joint papers describes using it. The three mentions sit in two Discussion sections, and all of them point to a 1965 study. Karikó’s 1988 Temple University paper used the enzyme in its routine way, as a laboratory reagent to identify molecules. That was about a decade before she met Weissman.

Why does the phrase turn up in so many papers?

Because it is a standard laboratory reagent. The exact phrase appears in 423 PubMed records and in 1,965 full-text papers.

What about Dr. Ardis’s other venom claims?

His argument that the spike protein resembles snake neurotoxins is set out, as he states it, on The Synthetic-Venom-Peptide Hypothesis and Cobra Venom and Nicotine. His D-dimer argument is on D-Dimer and Snake Venom.

How can I check this myself?

Open the two papers’ full texts in PubMed Central (links below) and use your browser’s find function to search for “venom”. Do the same with the patent on Google Patents and with the two labels on DailyMed.

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Key Research Papers

1. Karikó K, Muramatsu H, Welsh FA, et al. (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. — PubMed PMID: 18797453
2. Anderson BR, Muramatsu H, Jha BK, et al. (2011). Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res. — PubMed PMID: 21813458
3. Naylor R, Ho NW, Gilham PT (1965). Selective chemical modifications of uridine and pseudouridine in polynucleotides and their effect on the specificities of ribonuclease and phosphodiesterases. J Am Chem Soc. — PubMed PMID: 4284810
4. Zhao X, Yu YT (2004). Detection and quantitation of RNA base modifications. RNA. — PubMed PMID: 15146083
5. Suhadolnik RJ, Karikó K, Sobol RW Jr, et al. (1988). 2- and 8-azido photoaffinity probes. 1. Enzymatic synthesis, characterization, and biological properties of 2- and 8-azido photoprobes of 2-5A and photolabeling of 2-5A binding proteins. Biochemistry. — PubMed PMID: 3242613
6. Karikó K, Buckstein M, Ni H, Weissman D (2005). Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. — PubMed PMID: 16111635
7. Anderson BR, Muramatsu H, Nallagatla SR, et al. (2010). Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. — PubMed PMID: 20457754
8. Sinsheimer RL, Koerner JF (1952). A purification of venom phosphodiesterase. J Biol Chem. — PubMed PMID: 12999743
9. Razzell WE, Khorana HG (1959). Studies on polynucleotides. III. Enzymic degradation; substrate specificity and properties of snake venom phosphodiesterase. J Biol Chem. — PubMed PMID: 13673021
10. Razzell WE, Khorana HG (1959). Studies on polynucleotides. IV. Enzymic degradation; the stepwise action of venom phosphodiesterase on deoxyribo-oligonucleotides. J Biol Chem. — PubMed PMID: 13673022
11. Holley RW, Apgar J, Everett GA, et al. (1965). Structure of a ribonucleic acid. Science. — PubMed PMID: 14263761
12. Pan CT, Lin CC, Lin IJ, et al. (2023). The evolution and structure of snake venom phosphodiesterase (svPDE) highlight its importance in venom actions. Elife. — PubMed PMID: 37067034
13. Stefan C, Jansen S, Bollen M (2005). NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci. — PubMed PMID: 16125936

PubMed Topic Searches

1. PubMed: Snake venom phosphodiesterase
2. PubMed: Every paper by Karikó and Weissman together
3. PubMed: Pseudouridine and mRNA stability

External Authoritative Resources

• The 2008 Molecular Therapy paper, full text (PubMed Central) — the snake-venom sentence is in the Discussion.
• The 2011 Nucleic Acids Research paper, full text (PubMed Central) — the two mentions are in the Discussion.
• US Patent 8,278,036 B2, “RNA containing modified nucleosides and methods of use thereof” — full text.
• COMIRNATY prescribing information (DailyMed) — section 11, Description, lists the ingredients.
• SPIKEVAX prescribing information (DailyMed) — section 11, Description, lists the ingredients.
• European Medicines Agency: COMIRNATY public assessment report (2021) — the manufacturing description.
• Robert W. Holley, Nobel lecture “Alanine Transfer RNA” (1968) — the sequencing method that used the enzyme.
• Transcript of Dr. Ardis’s interview in Watch the Water 2 — the full passage quoted in Section 1.

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Connections

• All Notable Doctors
• Karikó & Weissman — the hub: the discovery, the vaccines and the full benefit-and-harm record
• The NIH Grants — every grant on the public record, and what each one paid for
• Research, Paper by Paper — the papers in order, and the obstacle each one removed
• From Pseudouridine to the COVID-19 Vaccines — how the discovery became the vaccines, and every ingredient explained
• The 2023 Nobel Prize — what the prize was awarded for, in the committee’s words
• D-Dimer and Snake Venom — the blood-test argument that led Dr. Ardis to these papers
• Dr. Bryan Ardis — the site’s documentation of his work, as he states it
• The Synthetic-Venom-Peptide Hypothesis — his reading of the spike protein
• Cobra Venom and Nicotine — the receptor he says cobra toxins and nicotine share
• Nirenberg, Khorana & Holley — the 1968 Nobel; Khorana described this enzyme and Holley used it to read the first RNA sequence
• Earl Sutherland — cyclic AMP and the other, unrelated “phosphodiesterases”
• Beutler, Hoffmann & Steinman — Toll-like receptors and dendritic cells, the sensors and cells of the 2005 discovery

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