The viruses in our brains

PNMA2 (ParaNeoplastic antigen MA2) is a protein initially found as the target of the immune response (autoantibodies) producing a nasty dementing neurologic disease (Paraneoplastic encephalitis).  The PNMA2 protein is exclusively expressed in neurons which implies that neurons are using it for something.   This is teleological thinking, usually looked down on, but always needed in molecular biology and cellular physiology.

What PNMA2 does is amazing.  It forms icosahedral viral capsids which are released from cells (in culture) as nonEnveloped capsids.  It isn’t clear if this normally happens in our  brains.    Probably it doesn’t, and when the capsid somehow gets out of the producing cell or neuron immunological hell breaks loose and autoimmune encephalitis is the result.

PNMA2 is derived from one of the long terminal repeat retrotransposons (LTR retrotransposons), viral remnants that make up 8% of the human genome (https://en.wikipedia.org/wiki/LTR_retrotransposon). This explains why it makes particles that look like viruses.  Such particles can contain RNA, so big pharma is interested in them as a way of delivering mRNA drugs.

Totally off topic but yesterday I read a paper about E. Coli DNA gyrase, an amazing enzyme which untangles DNA ( Science vol. 384 pp. 227 – 232 ’24 ).

Here is what it does.   If you’ve got some venetian blinds in your home twist it 20 or so times (keeping the ends fixed, and you have the DNA double helix, with two strands winding around each other.  Now to read or copy a single strand, you must grab both strands where you want this to happen  and pull them apart keeping the ends of the venetian blind fixed.  This immediately increases the coiling elsewhere. Since there are only 10 nucleotides/turn of the double helix, copying a gene for a 100 amino acid protein means you are removing 33 twists from the separated strands (and producing new ones elsewhere).   The cords of the venetian blind quickly become a tangled mess when this happens.  This is where DNA gyrase comes in.  It cuts both strands of the DNA double helix, holding on to the cut ends, and slides an intact double helix of the twisted DNA through the cut.   Sounds fantastic doesn’t it?  Hard to see how evolution could come up with something like this but it did.

The paper contains the following passage toward the end

“A second model based on a sign-inversion reaction wassuggested to describe introduction of (–)SC by this enzyme (28). This model proposed that the enzyme binds to a positive crossover followedby a DNA strand passage through a DNA double-strand break that results in a sign inversion.”

(28) is 28. P. O. Brown, N. R. Cozzarelli,Science206, 1081–1083 (1979).

The paper is 45 years old and has now been shown to be correct.  N. R.  Cozzarelli is my late good friend and Princeton classmate Nick, and it is very nice to see him honored here.

A few words about Nick.  Although Princeton was full of rich kids, they still had the brains to take in someone like Nick whose father was an immigrant shoemaker in Jersey City.  Nick worked his way through Princeton waiting on tables in commons (where all Freshmen ate).  I can still see the time that some rich preppie jerk gave him a hard time about the service.

Nick got his PhD at Harvard and later became a professor at Berkeley where he did his great work.  Nick later edited the Proceedings of the National Academy of Sciences (USA) for 10 years before his very untimely death over 20 years ago from Burkitt’s lymphoma.  R. I. P. Nick.

A letter to the PNAS editor which will never be published

“Starting out the year 2021 by looking back at the year 2020 might seem like an exercise in masochism, given the horrific loss of life, the untold economic hardships, the resurgence of white supremacy across the country“

As a good friend and college and grad school classmate of Nick Cozzarelli who edited PNAS for 10 years, I find this statement by the current PNAS editor — May Berenbaum, unhelpful, unscientific and frankly appalling. Had Nick not been taken from us far too soon in 2006 by Burkitt’s lymphoma, he’d likely be editing PNAS still. Does the editor’s statement rank with any of Nick’s work on DNA gyrase or DNA topology?

It is an exercise in the religion of political correctness, showing adherence to its current catechism, for political correctness and wokeness is nothing but a religion for the secular.  In our town expressions of faith abound on front lawns complete with statues of the virgin and signs proclaiming “we believe in science’. There really is no difference.

How a hack like Berenbaum got to be editor is beyond me, given the women scientists of great stature around (Doudna, Ghez, Randall).

Is Nick — https://en.wikipedia.org/wiki/Nicholas_R._Cozzarelli — an example of white supremacy? Nick’s father was an immigrant shoemaker from Jersey City and Nick worked his way through Princeton waiting on tables in commons.

Sad

Very sad — Nature vol. 557 p. 144 ’18 (10 May) “PNAS resignation On 1 May, Inder Verma, a cancer researcher at the Salk Institute for Biological Sciences in La Jolla, California, resigned as editor-in-chief of the journal Proceedings of the National Academy of Sciences. The move comes after the publication of an investigation by Science, in which several female researchers who were either at the institute or had ties to it between 1976 and 2016 allege that Verma harassed them. Verma, who served on powerful committees at the institute, vehemently denied the allegations in a statement to Nature. The Salk Institute suspended him on 21 April while it investigates the claims.”

Why sad?  Because my late Princeton classmate and good friend Nick Cozzarelli edited PNAS for 10 years.  He died far too soon at 68 of Burkitt’s lymphoma after doing great work on DNA gyrase.  From the Wiki about him ” In 1995, Cozzarelli was invited to become the editor-in-chief of the Proceedings of the National Academy of Sciences. He took the position because felt that the journal had great unrealized potential as a scientific publication.^[3] During his tenure, he expanded the editorial board from 26 to more than 140 and created a second track to allow scientists to submit manuscripts directly.”

Nick was credited for strongly increasing the quality and influence of PNAS.  This was recognized by the journal in the form of the Cozzarelli prizes established a year after his death.  There are 6 chosen from the more than 3,200 research articles appearing in the journal each year, representing the six broadly defined classes under which the National Academy of Sciences is organized.

A social note:  Although Princeton University was the home of many bluebloods in the late 50s, this was not true of all.  Nick went through Princeton on scholarship (waiting on tables in commons etc. etc.).  He was the son of an immigrant shoemaker from Jersey City.  Hopefully Princeton is still doing this.

Addendum 10 May — a friend said  ”

Your blog post seems to be one big non sequitur.

I doubt that harassment victims are “sad” that their complaints are finally getting heard and acted on. The fact that Verma’s behavior was allowed to continue all these years reflects poorly on the Salk Institute, but I don’t see how it reflects poorly on PNAS, where he was simply an editor and has now resigned. Essentially, Verma received PNAS submissions while sitting at his desk (at the Salk Institute) and declared “yes” or “no.”  I don’t see how your late friend Nick’s PNAS legacy has been sullied by any of that. “

To which I replied

”

No it’s sad because of what Verma’s behavior (at Salk and likely as PNAS editor) would have meant to Nick (and how he loved PNAS), given the type of guy Nick was.  My late father (an attorney) and uncle (a judge) took things the same way when a lawyer got disbarred for some malfeasance or other, e.g. as a reflection on the institution of the legal profession.   They took it personally as a reflection on them.  Perhaps illogically, but that’s the way they and Nick were. “