The prion battles continue with a historical note at the end

Now that we know proteins don’t have just one shape, and that 30% of them have unstructured parts, it’s hard to remember just how radical that Prusiner’s proposal that a particular conformation (PrPSc) of the normal prion protein (PrPC) caused other prion proteins to adopt it and cause disease was back in the 80s. Actually Kurt Vonnegut got there first with Ice-9 in “Cat’s Cradle ” in 1963. If you’ve never read it, do so, you’ll like it.

There was huge resistance to Prusiner’s idea, but eventually it became accepted except by Laura Manuelidis (about which more later). People kept saying the true infectious agent was a contaminant in the preparations Prusiner used to infect mice and that the prion protein (called PrPC) was irrelevant.

The convincing argument that Prusiner was right (for me at least) was PMCA (Protein Misfolding Cyclic Amplification) in which you start with a seed of PrPSc (the misfolded form of the normal prion protein PrPC), incubate it with a 10,000 fold excess of normal PrPC, which is converted by the evil PrPSC to more of itself. Then you sonicate what you’ve got breaking it into small fragments, and continue the process with another 10,000 fold excess of normal PrPC. Repeat this 20 times. This should certainly dilute out any infectious agent along for the ride (no living tissue is involved at any point). You still get PrPSc at the end. For details see Cell vol. 121 pp. 195 – 206 ’05.

Now comes [ Proc. Natl. Acad. Sci. vol. 117 pp. 23815 – 23822 ’20 ] which claims to be able to separate the infectivity of prions from their toxicity. Highly purified mouse prions show no signs of toxicity (neurite fragmentation, dendritic spine density changes) in cell culture, but are still infectious producing disease when injected into another mouse brain.

Even worse treatment of brain homogenates from prion infected mice with sodium laroylsarcosine destroys the toxicity to cultured neurons without reducing infectivity to the next mouse.

So if this paper can be replicated it implies that the prion protein triggers some reaction in the intact brain which then kills the animals.

Manuelidis thought in 2011 that the prion protein is a reaction to infection, and that we haven’t found the culprit. I think the PCMA pretty much destroyed that idea.

So basically we’re almost back to square one with what causes prion disease. Just to keep you thinking. Consider this. We can knock out the prion protein gene in mice. Guess what? The mice are normal. However, injection of the abnormal prion protein (PrPSc) into their brains (which is what researchers do to transmit the disease) doesn’t cause any disease.

Historical notes: I could have gone to Yale Med when Manuelidis was there, but chose Penn instead. According to Science vol. 332 pp. 1024 – 1027 ’11 she was one of 6 women in the class, and married her professor (Manuelidis) aged 48 when she was 24 graduating in 1967. In today’s rather Victorian standards of consent, power differential between teacher and student, that would probably have gotten both of them bounced out.

So I went to Penn Med. graduating in ’66. Prusiner graduated in ’68. He and I were in the same medical fraternity (Nu Sigma Nu). Don’t think animal house, medical fraternities were a place to get some decent food, play a piano shaped object and very occasionally party. It’s very likely that we shared a meal, but I have no recollection.

Graduating along with me was another Nobel Laureate to be — Mike Brown, he of the statins. Obviously a smart guy, but he didn’t seem outrageously smarter than the rest of us.

Off to the 50th

No posts for a while as I’ll be going to my 50th Med School Reunion (Penn ’66) tomorrow. If there is a creator, he has a fairly sardonic sense of humor

Here’s why.

I arrived in the fall of ’62 having spent 2 years as a grad student in the Harvard Chemistry department (Woodward the last year or so), quite full of myself. The biochemistry (and chemistry) being taught at Penn was quite primitive compared to what I’d been exposed to, and I was a fairly obnoxious prick about it.

How could I have known that classmate (Mike Brown) would win a Nobel for his work on the LDL receptor which led to the statins. The work involved some fairly brilliant chemistry (particularly on regulated intramembrane proteolysis). I hope he doesn’t remember me when we meet, but he probably will.

In defense, although none of us knew it at the time, the Harvard Chemistry department back then was probably one of the greatest in world history. Here’s why. There were 7 future Nobel laureates in the department when I was there from ’60 to ’62 — Woodward, Corey, Lipscomb, Bloch, Herschbach, Gilbert and Karplus. Even better, these guys weren’t sitting on their laurels having already won, but were engaged in doing the work which won them the  Nobels.

But there are far more issues to address at Penn than just this. Here’s a copy of an old post —

Two American (social) tragedies

When the team members entered the clinic, they were appalled, describing it to the Grand Jury as ‘filthy,’ ‘deplorable,’ ‘disgusting,’ ‘very unsanitary, very outdated, horrendous,’ and ‘by far, the worst’ that these experienced investigators had ever encountered. There was blood on the floor. A stench of urine filled the air. A flea-infested cat was wandering through the facility, and there were cat feces on the stairs. Semi-conscious women scheduled for abortions were moaning in the waiting room or the recovery room, where they sat on dirty recliners covered with blood-stained blankets. All the women had been sedated by unlicensed staff – long before Gosnell arrived at the clinic – and staff members could not accurately state what medications or dosages they had administered to the waiting patients. Many of the medications in inventory were past their expiration dates… surgical procedure rooms were filthy and unsanitary… resembling ‘a bad gas station restroom.’ Instruments were not sterile. Equipment was rusty and outdated. Oxygen equipment was covered with dust, and had not been inspected. The same corroded suction tubing used for abortions was the only tubing available for oral airways if assistance for breathing was needed…”[29]
[F]etal remains [were] haphazardly stored throughout the clinic– in bags, milk jugs, orange juice cartons, and even in cat-food containers… Gosnell admitted to Detective Wood that at least 10 to 20 percent… were probably older than 24 weeks [the legal limit]… In some instances, surgical incisions had been made at the base of the fetal skulls. The investigators found a row of jars containing just the severed feet of fetuses. In the basement, they discovered medical waste piled high. The intact 19-week fetus delivered by Mrs. Mongar three months earlier was in a freezer. In all, the remains of 45 fetuses were recovered … at least two of them, and probably three, had been viable.”

A classic back alley abortion mill, except that it was all quite legal.

This wasn’t supposed to happen after Roe vs. Wade. It is so uncanny that the doc (Kermit Gosnell) convicted yesterday of these 3 infanticides graduated from a med school in Philly (Jefferson) the same year (1966) that I graduated from another (Penn). At the time Philly had 3 more (Hahnemahn, Women’s and Temple).

What is so socially tragic about Gosnell, is that he was one of very few blacks in medical school back then. Our class of 125 at Penn had one, but he was a Nigerian Prince. Whether Gosnell liked it or not he was a standard bearer for what we hoped (at the time) was the wave of the future (it was). For just how very few Blacks were being educated at elite institutions back then please see

https://luysii.wordpress.com/2012/05/22/warren-harvard-and-penn-sanctimony-hypocrisy-and-fraud/ — copy to be found below

The second tragedy is a black woman M. D twenty or so years younger (Harvard undergrad, Penn Med followed by an MBA from Wharton) who lost her license to practice in NY State after she went off the deep end and became a holistic practioner (or whatever). She treated a new onset juvenile diabetic with diet and juice after which he came to the ER in diabetic ketoacidosis with a sugar over 300.

My father was an attorney as was my uncle, later a judge. They took it very personally when an attorney was disbarred for some malfeasance or another. I feel the same way when this happens to an M. D. Imagine how the black docs must feel about Gosnell, or the idiot, Conrad Murray, who basically killed Michael Jackson with Diprivan.

If you didn’t follow the link, I’ll close with a more uplifting ending from it.

My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist, having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references her cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents and grandparents of today’s black MDs, Attorneys, teachers etc. etc. were likely just as intelligent as their offspring of today. This country certainly pissed away an awful lot of brains of their generations.

*****

Warren, Harvard and Penn — Sanctimony, Hypocrisy and Fraud

I find the behavior of Elizabeth Warren, Harvard and Penn incredibly disturbing and sad. It’s the perfect storm of sanctimony, hypocrisy and fraud. I imagine that I’m a lot older than the readership, so let’s revisit the bad old days of the 50’s and 60s to see how things were back then and why the behavior of all three besmirches heroic attempts to set things right.

Fall 1956: Enter Princeton along with 725+ others. The cast of characters included about 5 Asians, 1 Indian Asian, no hispanics and/or latinos as I recall, and all of 2 blacks. I was the first to attend from a small (212 kids in 4 grades) NJ High School. I’d never been west of Philly, and immediately appreciated what passed for diversity back then — a roommate from Florida, and 2 guys next door from Wisconsin and Tennessee, the four of us packed like sardines into two miniscule rooms (each of which is now a single).

Although my High School was above the Mason Dixon line, there was only 1 black student in all 4 classes when I was there. A 2nd cousin who graduated 6 years before I entered, noted that there were NO blacks when she was there and asked why, and was told “we don’t encourage them to attend”. To be fair, there were very few black families in the area.

So, because we were musicians, and in the marching band, I got to know one of the blacks. At away games there were postgame parties (what’s the point of having games after all?). Girls would come up to Harvey and tell him that he must meet Virginia, she’s wonderful. etc. etc. Virginia being the black girl at their school, as Harvey was the black boy at ours. There was no condescension involved, and I never saw anyone at Princeton give Harvey a hard time, and we had plenty of southerners. It was the way things were, and we had no idea that things could be different.

Spring 1958: Back at the H. S. The one black girl in the class 2 years behind me was very smart. She graduated as the Salutatorian. However, she should have been the Valedictorian, the powers that be having decided that it wouldn’t do to have a black in that position. That didn’t stop her of course. The high school was so small that it was folded into a regional H. S. the next year. So our little school has reunions every 5 years or so for anyone who ever went there, and I saw her 40 – 50 years later. She’d become a very high powered R. N. with a very responsible position.

Fall 1960: Harvard Chemistry department. Not a black, not a latino, not an Asian to be found in the grad school (there was one Sikh). I don’t recall seeing any as undergraduates. There were a fair number of Japanese, and Asian Indian postdocs however. Fast forward to the present for what it looks like now — https://luysii.wordpress.com/2012/04/19/the-harvard-chemistry-department-reunion-part-i/.

Fall 1962: Entering Penn Med school — 125 students, one black (a Nigerian) no latinos/hispanics, no asians of any sort, under 10 women. They really can’t be blamed for this, the pipeline was empty.

Summer 1963: Visiting my wife to be at her home in Alexandria Virginia. A drive perhaps 10 – 20 miles south toward Richmond finds restaurants with Colored entrances.

2008: My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references the cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents (grandparents) of today’s blacks , are likely just intelligent as their MD, Attorney, teacher etc. etc. offspring today. This country certainly pissed away an awful lot of brains of these generations. So clearly, I’m all for letting the best into our elite institutions whatever they look like.

This is why Warren, and the behavior of Harvard and Penn is such a perversity.

First the sanctimony. Many at Harvard think they are head, neck and groin above you in every sense, intellectual and moral. Do not think for a minute that their previous rejection of a military presence on campus had anything to do with the military’s treatment of gays. It was a cover for their antiwar and antimilitary agenda (present when I was there ’60 -’62 long before Vietnam). They were what my father called “Bible-backed Bastards”, using scripture as cover for what they wanted to do.

Second and Third. That Warren would claim to be Indian and that Penn and Harvard would tout her as evidence of their commitment to diversity, is hypocritical in the extreme and fraudulent as well.

Well, it’s just another scam.like all the rest. Isn’t it? We’ve got State Troopers sitting on their ass in their cars with lights flashing on the Mass. Pike at construction sites. We’ve got politically connected drones handing out tickets on the Pike standing next to machines which do the job when they’re not around. No one seems to mind. It may be one of the reasons unenlightened Florida and Texas grew faster in the last 10 years and acquired one of our representatives (along with 5 more from NY, NJ, Illinois and Pennsylvania).

But it isn’t like the rest. It perverts something the country desperately needed to do and gives arms to those opposing it. Ironic that it wasn’t done by rednecks, but by the very institutions that led the charge.

I hope the powers that be at Penn don’t cluck about diversity at the reunion,  but if they do I plan to find my inner obnoxious prick again.

The prions within us

Head for the hills. All of us have prions within us sayeth [ Cell vol. 156 pp. 1127 – 1129, 1193 – 1206, 1206 – 1222 ’14 ]. They are part of the innate immune system and help us fight infection. But aren’t all sorts of horrible disease (Bovine Spongiform Encephalopathy aka BSE, Jakob Creutzfeldt disease aka JC disease, Familial Fatal Insomnia etc. etc.) due to prions? Yes they are.

If you’re a bit shaky on just what a prion is see the previous post which should get you up to speed — https://luysii.wordpress.com/2014/03/30/a-primer-on-prions/.

Initially there was an enormous amount of contention when Stanley Prusiner proposed that Jakob Creutzfeldt disease was due to a protein forming an unusual conformation, which made other copies of the same protein adopt it. It was heredity without DNA or RNA (although this was hotly contended at the time), but the evidence accumulating over the years has convinced pretty much everyone except Laura Manuelidis (about whom more later). It convinced the Nobel Prize committee at any rate.

JC disease is a rapidly progressive dementia which kills people within a year. Fortunately rare (attack rate 1 per million per year) it is due to misfolded protein called PrP (unfortunately initially called ‘the’ prion protein although we now know of many more). Trust me, the few cases I saw over the years were horrible. Despite decades of study, we have no idea what PrP does, and mice totally lacking a functional Prp gene are normal. It is found on the surface of neurons. Bovine Spongiform Encephalopathy was a real scare for a time, because it was feared that you could get it from eating meat from a cow which had it. Fortunately there have been under 200 cases, and none recently.

If you cut your teeth on the immune system being made of antibodies and white cells and little else, you’re seriously out of date. The innate immune system is really the front line against infection by viruses and bacteria, long before antibodies against them can be made. There are all sorts of receptors inside and outside the cell for chemicals found in bacteria and viruses but not in us. Once the receptors have found something suspicious inside the cell, a large protein aggregate forms which activates an enzyme called caspase1 which cleaves the precursor of a protein called interleukin 1Beta, which is then released from some immune cells (no one ever thought the immune system would be simple given all that it has to do). Interleukin1beta acts on all sorts of cells to cause inflammation.

There are different types of inflammasomes and the nomenclature of their components is maddening. Two of the sensors for bacterial products (AIM, NLRP2) induce a polymerization of an inflammasome adaptor protein called ASC producing a platform for the rest of the inflammasome, which contains other proteins bound to it, along with caspase1 whose binding to the other proteins activates it. (Terrible sentence, but things really are that complicated).

ASC, like most platform proteins (scaffold proteins), is made of many different modules. One module in particular is called pyrin (because one of the cardinal signs of inflammation is fever). Here’s where it gets really interesting — the human pyrin domain in ASC can replace the prion domain of the first yeast prion to be discovered (Sup35 aka [ PSI+ ] — see the above link if you don’t know what these are) and still have it function as a prion in yeast. Even more amazing, is the fact that the yeast prion domain can functionally replace ASC modules in our inflammasomes and have them work (read the references above if you don’t believe this — I agree that it’s paradigm destroying). Evidence for human prions just doesn’t get any better than this. Fortunately, our inflammasome prions are totally unrelated to PrP which can cause such havoc with the nervous system.

Historical note: Stanley Prusiner was a year behind me at Penn Med graduating in ’67. Even worse, he was a member of my med school fraternity (which was more a place to get a decent meal than a social organization). Although I doubtless ate lunch and dinner with him before marrying in my Junior year, I have absolutely no recollection of him. I do remember our class’s medical Nobel — Mike Brown. Had I gone to Yale med instead of Penn, Laura Manuelidis would have been my classmate. Small world