Tag Archives: AAV

Science fiction for the cognoscenti – III — not all the background you need will be explained

Now that every team in the NFL has its own molecular biologist and antiVirologist, you might be interested in knowing how it all started.  Like most technologies affecting our lives it had a military origin.

The escape of the Taiwanese pacifist virus started it all –https://luysii.wordpress.com/2018/11/19/a-science-fiction-story-for-the-cognoscenti-answer-to-the-puzzle-and-a-bit-more.

The technology of infectious gene transfer by recombinant adeno-associated virus  (AAV) was well advanced long before there were garage molecular biologists.

The NFL wars began with the New England Patriots, (who else?), they of deflategate and other nefarious ways to win.

Tom Brady was getting all set to win superbowl LVII in 2023 at age 45 when the first counterattack was successful.

His wife, the beautiful Gisele, hated the idea of him playing so long, being very worried about dementia pugilista from all the head trauma.  Tom had agreed to yearly PET scans with Pittsburgh compound B, an uncharged derivative of thioflavin T which gets through the blood brain barrier and which stains senile plaques.  They showed no evidence of plaques (although plenty of demented people don’t have them) so he kept on playing behind Belichick’s not so secret weapon — 400 pound linemen.  Even though he’d lost a step or two, his eye and arm were still good and the linemen gave him plenty of time to throw.

Football players have always been bulking up.  Even the early experience with extra testosterone (which causes testicular atrophy in high doses) didn’t dissuade them.  Newer anabolic steroids had somewhat fewer testicular effects.  Eventually players took to using HCG to help normalize things, but some testicular atrophy was a price they were willing to pay.  The cheerleaders felt a lot safer around those using them.

So how did the Patriots have 400 pound linemen when no one else did?  The answer goes back to Piedmontese and Belgian Blue cattle which were bred for their large muscles.  They turned out to have inactivating mutations in the gene for myostatin, a protein which causes muscles to stop growing.

Boston isn’t known as the home of biotech for nothing, and Belichick contracted with an as yet un-named biotech firm (their depositions having been sealed by the court) to come up with a small molecule (compound M) absorbable through the skin which inhibited myostatin.

No one caught on why Belicheck had separate showers installed for the lineman and defensive backs, but they had to use them and got  dosed that way.  Testing for performance enhancing drugs was always negative. The linemen loved it, as their testicles grew back to normal size.  The cheerleaders didn’t.

So there the Patriots were, about to play the Arizona Cardinals, a team only winning 3 games in 2018 in superbowl LVII. No one understood how the Cardinals turned around and how they got those very slippery running backs.

No one, except the molecular biologist they hired.  But that’s for next time.

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The Impeachment Trial of President Tester 2027

It’s almost Christmas. Time for some R&R. Here’s another science fiction story for the cognoscenti, which assumes you have some scientific chops.  Not all will be explained.

After the Taiwanese biologic agent turned the world’s armed forces into pacifists, you’d think that the end of history had arrived. For how this happened see the first story — https://luysii.wordpress.com/2018/11/19/a-science-fiction-story-for-the-cognoscenti-answer-to-the-puzzle-and-a-bit-morea-science-fiction-story-for-the-cognoscenti/.

Well, thought all sorts of garage molecular biologists, maybe humanity could be further improved, or those not of the right sort eliminated.   The Syrians learned this the hard way creating a biologic agent which attacked Jews, not realizing that Syrians were closer genetically to them than anyone else [ Proc. Natl. Acad. Sci. vol. 97 pp. 6769 – 6774 ’00 ].  The Israeli’s saw this coming and had a defense ready.   The midEast became a lot quieter.

The touchy feely types thought of other ways to improve humanity, particularly a group of vegetarian molecular biologists at Montana State University.

You probably thought of Montana State in Bozeman as Moo U, where the sons of the soil achieved a rudimentary education.  After Jon Tester was elected president in 2024, a lot of money was poured in.  Sophisticates were appalled that Tester made it after Trump.  They should have known better– the US has elected a peanut farmer, someone from Dogpatch, a broken down actor making movies with a chimp, and the ever appalling Donald Trump.

Actually as far back as the 70s Montana had a state legislator (Kenneth Nortvedt) Junior Fellow at Harvard writing papers on alternate theories of gravity.  Biologic research was alive in Montana since 1928 at Rocky Mountain Labs in Hamilton and still kicking with prion work as of 2015 — http://klyq.com/prion-disease-study-at-hamilton-lab-is-published-youtube/.

So what happened?  Have you ever heard of the Lone Star Tick?  https://acaai.org/allergies/types/food-allergies/types-food-allergy/meat-allergy.  A single bite can make you allergic to meat.  Your body’s immune response to a tick antigen, must also in some way react with meat, the same way that the response to strep infection can sometimes cross react with the heart causing rheumatic fever.

At first it was thought that the tick injected galactose linked (alpha 1 –> 3 )to galactose, but that was quickly debunked when taking alpha-galactosidase (available at your friendly local health food store) didn’t work.

Montana attracts all sorts of people, ranging from rugged individualists to touchy feely types and points between.  There’s plenty of room out there (more cows than people at last count) so the dominant zeitgeist is live and let live.  The one unforgivable sin is putting on airs or bragging.

Thus it came to pass in the year 2025 (anno Tester #1) when the federal funding spigot was turned full force on MSU that a group of smart vegetarians from Portland Oregon overcame their scruples about living in a land whose major function was producing meat, and wound up in the newly formed Mike Mansfield department of molecular genetics at MSU.

Basically they knocked out gene after gene in the tick and looked at what disappeared in the secretions of the tick as it bit.  There were plenty of glycoproteins some of which had galactose.  It was child’s play to isolate and sequence the gene.

By this time the technology to put any protein coding gene in adeno-associated virus (AAV) and infect people was well advanced.  So they experimented on themselves, injecting virus after virus, forcing themselves to swallow their scruples as well as meat and seeing which of the tick’s proteins made them ill when they did.

The rest is history.  The virus spread quickly and suddenly no one could eat beef or pork.  The ranching industry in Montana and elsewhere died.  Ecologists rejoiced that the prairie was no longer grazed.

A group of bankrupt ranchers from all over the state (and a few from Wyoming) invaded the lab and killed every scientist there.

They were not tried in Montana, as no one would convict them, instead being tried in Vermont (Birkenstock country) and sent to prison for life.

Which brings us to the Impeachment trial of President Tester.

Can you guess what it was for?  Answer next year.

In the meantime, a very Merry Christmas and Happy New Year to all

 

A science fiction story (for the cognoscenti) — answer to the puzzle and a bit more

Comrade Chen we have a serious problem.

Don’t tell me one of our bugs escaped confinement.

Worse.  One of theirs did.  And it’s affecting the PLA (People’s Liberation Army).  Some are turning into pacifists.

It doesn’t kill them?

No. But for our purposes it might as well.

It’s a typical adenoassociated virus (AAV) like we use.

Well, what does the genome look like?

We’ve sequenced it and among other things, it codes for a protein which enters the brain and alters behavior.

What?

Well, the enemy has some excellent biologists, one of whom works on Wolbachia.

What’s that?

It’s a rickettsial organism which changes the sex life of some insects.

I don’t believe that.

Do you have a cat?

Yes.

Well many cats contain another organism (toxoplasma gondi).

So what.

Rats infected by the organism become less afraid of cats.

Another example please.

A fungus infecting carpenter ants causes the ant to leave its colony, climb a tree, chomp down on the underside of a leaf and die, freeing fungal spores to fall on the ground where they can reinfect new ants.

Well what is the genome of the virus?

It has some very unusual sequences, and one which proves that the Wolbachia biologist on the other side has a very large ego.

How so.

Well in addition to the brain infecting protein, there is a very unusual triplet of peptides all in a row.

Methionine Alanine Aspartic Acid Glutamic acid, then a stop codon, then Isoleucine Asparagine, than a stop codon, then Threonine Alanine Isoleucine Tryptophan Alanine Asparagine.  We think that the first two in some way cause readthrough of the stop codons so the protein following the short peptides is made.

Where does the big ego come in?

Sir, proteins can have hundreds and hundreds of amino acids.  People got tired of writing their full names out, so each of the 20 amino acids was given a single letter to stand for it.

M – Methionine

A – Alanine

D – Aspartic acid

What does D have to do with Aspartic acid?

Nothing sir, look on the letters as Chinese characters.

E -Glutamic Acid

I – isoleucine

What about the stop codon between Glutamic acid and Isoleucine

Just regard it as a space.

N – Asparagine

Nooo! ! ! I I’m beginning to get the picture.

Yes sir, it stands for MADE IN TAIWAN

—-

A few years later

Well the Taiwanese biologist outsmarted himself (or herself).   The Taiwanese soldiers wouldn’t fight either as the virus spread.  Most conflicts between nation states pretty much ended (Russia/Ukraine, North Korea/South Korea) etc. etc.  The Taiwanese biologist was nominated for the Nobel Peace Prize, and did receive it in absentia, as every military type in the world was looking for him (or  her), so he (or she) went into hiding, and is believed to be living in an Ashram near Boulder, Colorado.

Unfortunately, the idea of using viruses to change human behavior spread past nation states, and private groups with their own agendas began using it.

The ‘new soviet man’ of the previous century looked rather benign compared to what subsequently happened.

The next story for the scientific cognoscenti will describe the events leading up to the impeachment trial of President Jon Tester in 2028.

 

A science fiction story (for the cognoscenti)

Comrade Chen we have a serious problem.

Don’t tell me one of our bugs escaped confinement.

Worse.  One of theirs did.  And it’s affecting the PLA (People’s Liberation Army).  Some are turning into pacifists.

It doesn’t kill them?

No. But for our purposes it might as well.

It’s a typical adenoassociated virus (AAV) like we use.

Well, what does the genome look like?

We’ve sequenced it and among other things, it codes for a protein which enters the brain and alters behavior.

What?

Well, the enemy has some excellent biologists, one of whom works on Wolbachia.

What’s that?

It’s a rickettsial organism which changes the sex life of some insects.

I don’t believe that.

Do you have a cat?

Yes.

Well many cats contain another organism (toxoplasma gondi).

So what.

Rats infected by the organism become less afraid of cats.

Another example please.

A fungus infecting carpenter ants causes the ant to leave its colony, climb a tree, chomp down on the underside of a leaf and die, freeing fungal spores to fall on the ground where they can reinfect new ants.

Well what is the genome of the virus?

It has some very unusual sequences, and one which proves that the Wolbachia biologist on the other side has a very large ego.

How so.

Well in addition to the brain infecting protein, there is a very unusual triplet of peptides all in a row.

Methionine Alanine Aspartic Acid Glutamic acid, then a stop codon, then Isoleucine Asparagine, than a stop codon, then Threonine Alanine Isoleucine Tryptophan Alanine Asparagine.  We think that the first two in some way cause readthrough of the stop codons so the protein following the short peptides is made.

Where does the big ego come in?

Figure it out.

 

Answer next week.

18 at one blow said the molecular biologist

With apologies to the brothers Grimm, molecular biologists may have found a way to treat 18 genetic diseases at one blow [ Cell vol. 170 pp. 899 – 912 ’17 ]. They use adeno-associated virus (AAV) packing a modified enzyme and an RNA to remove repeat expansions from RNA.   The paper give a list of the 18, all but one of which are neurologic.  They include such horrors as Huntington’s chorea, the most common form of familial ALS, 3 forms of spinocerebellar ataxia and 6 forms of spinocerebellar atrophy.

They use Cas9 from Streptococcus Pyogenes, part of the CRISPR system (https://en.wikipedia.org/wiki/CRISPR)  bacteria use to defend themselves against viruses, with a single guide RNA.  Even more interestingly, Cas9 is an enzyme which breaks up RNA, but the Cas9 they used is catalytically dead.  They think that just binding to the aggregated RNA containing the repeats is enough to break up the aggregate.  This is the way antiSense oligoNucleotides are thought to work.

The problem with getting a bacterial enzyme into a human cell is avoided here by using a virus to infect them (AAV).  It did get rid of RNA aggregates in patients’ cells from 4 of the diseases (two myotonic dystrophies, and the familial ALS).

It is almost too fantastic to be true.

Why almost all of these repeat expansion diseases affect the nervous system is anyone’s guess.  As you can image theories abound.  So all we have to do is figure out how to get the therapy into the brain (hardly a small task).