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.

Advice for first time high school students entering the Ivy League in the fall

The Ivy league can be and was very intimidating for students from small high schools, particularly if they are the first from their school or family to ever go there.  Here are a few stories about similar Freshmen entering Princeton in 1956.  We all wondered if we were smart enough.

First yours truly.  The first intimidation was the guy next door who built a tesseract, a 3 dimensional model of a 4 dimensional cube.  The second was his story about another guy in the class so smart that he looked at the Freshmen Herald with 700+ pictures and names, and knew everyone in the class by name by the next day.  He wound up in the top 7 members of the class (Junior Phi Beta Kappa).

Fortunately at an assembly during orientation, a dean told us not to worry, that they knew we would be able to do the work, and that only emotional trouble or misbehavior would get us out.  This happened to a member of the class, schizophrenia often presents in late adolescence (one name for it used to be dementia praecox), and another member was expelled for stealing stuff from other rooms.  Then there were the preppies (about 50% of the class back then) who basically had the first month of classes and appeared to know it all.   After a month or two I knew I would make it, but the first few months were scary.

Then there was the guy who was recruited because of his character.  He went to a small high school in New Jersey and played on their basketball team, which was getting creamed by an affluent suburban school.  At nearly the end of the game, they slacked off and he ran through the whole team and scored a basket.  An alum came up to him and asked him why he did it.  He said he wanted to show the other team that while they beat his team, but they didn’t beat him.  The alum promptly recruited him to Princeton.  His father was a factory worker, and took him down, and my friend was impressed, saying to his father that he didn’t think he belonged there.  The father said something to the effect of give it a shot and don’t tell them.  Subsequently he got a PhD in ceramics and worked at Los Alamos.

Then there was a guy from a little town in Maine, whose school was so proud when he got in, that they announced it over the intercom (as did my high school).  Similarly intimidated at the time, he became an endocrinologist and was involved in drug development writing 45 papers in the process.

Another guy was recruited by an alum from a larger school in western New York, and went through on a ROTC scholarship, becoming a naval officer, joining the state department and becoming an ambassador to a central American country.

None of us knew any of this at the time.  It came out 50 years later as we gathered after Princeton football games.  Although we were intimidated we didn’t let on and did fine — and you will too.

Addendum 5 June:  From a classmate

Learned some good lessons about life and about myself at P.U. First, I wasn’t the science wunderkind I thought I was, but that I was a much better writer than I thought.

 

One life lesson highlights my artistic judgment shortcomings. I took a painting class with the painter in residence (Stephan Greene), held in the loft of the architecture building. On my left was a guy named Frank ‘59, and on my right xxxx ‘60, whom I was convinced would be one of the world’s great artists. He wore 3-piece suits from a thrift store, a cravat, and used a pouch rather than a wallet. He also had a very large and very illegal ’38 Buick sedan convertible. What’s not to like. So, with my meager funds I bought 2 of his paintings, one for $5 and another for $10. I still have one. Frank was painting goofy stuff of which I made fun. Stephan Greene asked me to hang the Spring student/faculty art show in the Student Center, which I did. I resisted hanging Frank’s so-called paintings.

 

As I understand it, Pete dropped out of Princeton in his senior year (? due to a paternity issue), and ended up somewhere being a librarian. Frank, whose art I made fun of……..was FRANK STELLA!!! So much for my art judgment.