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. “

Progress has been slow but not for want of trying

Progress in the sense of therapy for Alzheimer’s disease and Glioblastoma multiforme is essentially nonexistent, and we could use better therapy for Parkinsonism. This doesn’t mean that researchers have given up. Far from it. Three papers all in last week’s issue of PNAS came up with new understanding and possibly new therapeutic approaches for all three.

You’ll need some serious molecular biological and cell physiological chops to get through the following.

l. Glioblastoma multiforme — they aren’t living much longer than they were when I started pracice 45 years ago (about 2 years — although of course there are exceptions).

The human ZBTB family of genes consists of 49 members coding for transcription factors. BCL6 is also known as ZBTB27 and is a master regulator of lymph node germinal responses. To execute its transcriptional activity, BCL6 requires homodimerization and formation of a complex with a variety of cofactors including BCL6 corerpressor (BCoR), nuclear receptor corepressor 1 (NCoR) and Silencing Mediator of Retinoic acid and Thyroid hormone receptor (SMRT). BCL6 inhibitors block the interaction between BCL6 and its friends, selectively killing BCL6 addicted cancer cells.

The present paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3981 – 3986 ’17 ] shows that BCL6 is required for glioblastoma cell viability. One transcriptional target of BCL6 is AXL, a tyrosine kinase. Depletion of AXL also decreases proliferation of glioblastoma cells in vitro and in vivo (in a mouse model of course).

So here are two new lines of attack on a very bad disease.

2. Alzheimer’s disease — the best we can do is slow it down, certainly not improve mental function and not keep mental function from getting worse. ErbB2 is a member of the Epidermal Growth Factor Receptor (EGFR) family. It is tightly associated with neuritic plaques in Alzheimer’s. Ras GTPase activation mediates EGF induced stimulation of gamma secretase to increase the nuclear function of the amyloid precursor protein (APP) intracellular domain (AICD). ErbB2 suppresses the autophagic destruction of AICD, physically dissociating Beclin1 vrom the VPS34/VPS15 complex independently of its kinase activity.

So the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. E3129 – E3138 ’17 ] Used a compound downregulating ErbB2 function (CL-387,785) in mouse models of Alzheimer’s (which have notoriously NOT led to useful therapy). Levels of AICD declined along with beta amyloid, and the animals appeared smarter (but how smart can a mouse be?).

3.Parkinson’s disease — here we really thought we had a cure back in 1972 when L-DOPA was first released for use in the USA. Some patients looked so good that it was impossible to tell if they had the disease. Unfortunately, the basic problem (death of dopaminergic neurons) continued despite L-DOPA pills supplying what they no longer could.

Nurr1 is a protein which causes the development of dopamine neurons in the embryo. Expression of Nurr1 continues throughout life. Nurr1 appears to be a constitutively active nuclear hormone receptor. Why? Because the place where ligands (such as thyroid hormone, steroid hormones) bind to the protein is closed. A few mutations in the Nurr1 gene have been associated with familial parkinsonism.

Nurr1 functions by forming a heterodimer with the Retinoid X Receptor alpha (RXRalpha), another nuclear hormone receptor, but one which does have an open binding pocket. A compound called BRF110 was shown by the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3795 – 3797, 3999 – 4004 ’17 ] to bind to the ligand pocked of RXRalpha increasing its activity. The net effect is to enhance expression of dopamine neuron specific genes.

More to the point MPP+ is a toxin pretty selective for dopamine neurons (it kills them). BRF110 helps survival against MPP+ (but only if given before toxin administration). This wouldn’t be so bad because something is causing dopamine neurons to die (perhaps its a toxin), so BRF110 may fight the decline in dopamine neuron numbers, rather than treating the symptoms of dopamine deficiency.

So there you have it 3 possible new approaches to therapy for 3 bad disease all in one weeks issue of PNAS. Not easy reading, perhaps, but this is where therapy is going to come from (hopefully soon).

At the 55th

This is a mostly nonscientific post concerning the 55th reunion of the Princeton Class of 1960 last weekend. First the Science. Nick Cozzarelli was one of the most distinguished members of our class — great work on Topoisomerase, editor of PNAS for 10 years which established a prize named for him for the best paper each year. No one I’ve ever talked to in the class knew of him or his work. Shirley Tilghman, president of Princeton certainly did, and was shocked to hear of his untimely passing from Burkitt’s lymphoma when I told her of it at our 50th, saying he was a great scientist. However, he’s one of the reasons Princeton back then was a great institution (and hopefully still is). The son of an immigrant shoemaker in Newark NJ, he was taken in, given a scholarship, and worked his way through, serving meals in commons etc. etc. I made sure the undergraduates picking up a little cash by pouring drinks and serving meals at reunions heard about him. He was a good friend.  R. I. P. Nick.

Another friend, an emeritus prof of chemical engineering, referees a lot of papers. He estimates that 80% of the papers in his field, quantum chemistry, coming from China are absolute trash. According to him China gives bonuses to people getting published in high impact journals. What he finds particularly appalling is that he writes up a detailed list of corrections and improvements for the paper, and then finds it published totally unchanged in another journal.

He and I reminisced about our great undergraduate advisor Paul Schleyer with the department chair (who of course knew of him since he is one of the most cited and prolific (1,400 papers) chemists of the 20th century). He’s another reason Princeton was such a great institution back then (and hopefully still is). For details please see https://luysii.wordpress.com/2014/12/15/paul-schleyer-1930-2014-a-remembrance/ and https://luysii.wordpress.com/2014/12/14/paul-schleyer-1930-2014-r-i-p/

I finally saw the new Chemistry building (under construction at the 50th) and it is gorgeous. The NMR set up is particularly impressive, with the megaHertz of the machinery a factor of 15 greater than those we first started using in the 60s. Alas Varian is no more. It was bought a few years ago by another company which terminated the business. For where the money came from see https://luysii.wordpress.com/2011/05/16/princeton-chemistry-department-the-new-oberlin/.

In a remarkable coincidence, my wife an I were able to chat with the son of a neurologist in my call group, just finishing up his PhD in Chemistry there. How improbable is that?

Now for the nonScientific part.

For those undergraduates reading this at similar institutions, some advice — get to know as many of your classmates as you can. Premeds at Princeton back then had to take a lot of the same courses — biology, basic chemistry, organic chemistry, calculus, physics etc. etc. So we got to know each other. The rest of the class, not so much unless we were in other organizations (in my case, the marching band, Triangle club, and the eating club). At reunions I always meet classmates that I wish I knew back then and form new friendships.

Sometimes that isn’t always easy, with everyone working out the various important issues present from 18 to 22. A classmate’s wife described the men of the class at their 25th reunion as ‘roosters’, crowing and impressing each other. Not the case 30 years later. Everyone glad just to be there and catch up.

Princeton was all male back then. The current wives (some being #2, #3, #5) are an impressive bunch. They were uniformly intelligent and interesting. Not a bimbo in the lot of them, although most were very attractive physically. So the class may have slept with bimbos, but they were no longer in evidence.

Various seminars were held. I went to one about America’s relation to food. The panelists were 6 trim females with a fair amount of pseudoscience and touchy feely crap emitted, but at least the cautionary tale of the trash in the popular press about diet was mentioned (e.g. the paper about eat chocolate lose weight). What was fascinating was that the incidence of obesity (BMI over 29) in the group of several hundred listeners was at most 5%, proving, once again, that obesity in the USA is largely a class phenomenon. Also noted, is that I only saw one or two undergraduates and graduates smoking, again a class phenomenon, something Americans don’t like to talk about, but there nonetheless.

A memorial service for classmates was held in the chapel (built in 1929 but designed to appear that it was built in 1299). The organ is magnificent as were the acoustics, the sound surrounding you rather than coming at you. Bach and Vidor were performed by the organist. Apparently there was quite a battle about which to do first — refurbish the organ or the chapel acoustics. The stone had roughened distorting the sound so it didn’t echo properly. Clear plastic was applied to smooth the stone and then the organ was fixed. If you can hear a concert there please do so. Great composers write for the space their music will be performed in as well as the instruments it will be performed on, certainly true of Gabrielli, Bach and Vidor.

On a sadder note. I know of 4 suicides of class members (we started with around 725). Probably there are more. Also a good friend and classmate’s wife and daughter appeared to accept an award in his name. Although still alive he is incontinent, unable to walk and demented from Alzheimer’s. Despite degrees from Princeton, Harvard and Penn, Board examiner in Neurology blah blah blah, I was totally unable to help him. All I could do was offer emotional chicken soup to his wife, something my immigrant grandmother did with her 4th grade education in the dry goods store she ran. That’s why it’s good to be retired from neurology and not see this day after day.

Finally the P-rade. It is a great emotional lift for the psyche to march a mile or so to the reviewing stand being cheered by probably 1,000 – 2,000 younger graduates the whole time. The younger they got the louder the cheers and the drunker they were. It’s pretty hard not to feel good after that. I have heard that the only weekend event where more beer is consumed than Princeton reunions is the Indianapolis 500.  Along those lines, I only saw one truly drunk individuals among the 250 or so classmates and significant others although just about everyone had alcohol.  The alcoholics are no longer around for the 55th.