Category Archives: Social issues ( be civil ! )

From Banned in Boston to Banned in Berkeley in 55 years

When I arrived in Cambridge for grad school 55 years ago, there were a lot of sore shoulders in people who’d been patting themselves on the back for the blows struck for freedom of expression. Boston was still banning books, and the year before Grove Press had won a suit permitting them to publish Lady Chatterley’s Lover. Hilariously, the same self congratulatory and self-righteous lot is now banning speech in a campus near you. The impetus is always the same, thought control by someone more moral (and now smarter) than you, and always for the noblest and purest of reasons. What happened to irony? Where is George Orwell when you really need him? Well he’s right here

“If liberty means anything at all, it means the right to tell people what they do not want to hear.”

Which brings me to some recent campus disturbances.

Smith, where only members of the media agreeing with the demonstrators were allowed in —

U. Mass — protesting for free tuition —

Princeton — wanting Woodrow Wilson out because of his opinions —

Which brings me to ‘charm school”.

After serving as an army doc for two years in ’68 – ’70, a time when we had 500,000 men in Vietnam, I left with little respect for its leadership. I was stateside at one of the Army’s premier hospitals, which was a plum assignment (because the army was very short of neurologists). This meant that 2 year docs who’d served their first year in Vietnam got their choice of assignment when returning stateside. So I saw plenty of them. NOT ONE thought we were winning over there, despite what the top brass said to the press and the president.

So who would have thought that 25 years later I’d be friendly with a retired Major General, George Baker. Never say never. He was a very intelligent man, an orthopedic surgeon, who’d been chief at Walter Reed and found retirement boring, so he practiced at my hospital. He told me about something he called charm school. It was where newly promoted Generals were sent for training. They were told to toe the straight and narrow sexually and in other matters, and that if a planeload of them went down, the army would have no trouble at all filling their shoes.

I’ve done some alumni interviews for some excellent candidates for Princeton, none of whom were accepted. It would be no problem at all to expel the protestors if physically disruptive or destructive, and replace them. They certainly should NOT be expelled for what they say or think, just how they act. The Princeton acceptance rate is under 10%.

Now that everyone is neatly characterized by racial status, it would be interesting to see the breakdown by race of the occupants of Nassau Hall, also their majors. I seriously doubt that the group most discriminated against in admissions (the Asians) took much part. I doubt that many science majors were involved.

Facilitated communication

Amidst the ads in the Sunday Magazine largely targeted to the 1% that the New York Times claims to hate is an article on facilitated communication. I had a clinical experience with it 30 years ago that you might be interested in.

As a neurologist I was asked to do an Independent Medical Evaluation (IME) on an unfortunate man who was electrocuted at work (he worked on high voltage transmission lines). He went into cardiac arrest and sustained severe brain damage. The issue was not fault, which the power company readily admitted, but whether in what appeared to be a vegetative state, with no visible response to verbal commands, he was in fact conscious but unable to respond. In the latter case the reward to the family would have been substantially larger (for pain and suffering in addition to loss of consortium, etc. etc.). It was claimed that facilitated communication showed that he was able to write the answer to simple calculations given verbally, not visually.

Reviewing the chart before seeing the man, showed that he and his wife were admirable individuals, adopting children that no one else wanted and raising them despite limited income. He was seen at the rehab facility, with attorneys for the insurer for the power compony and his family present. It was apparent that the people caring for him were quite devoted, both to him and his wife and were very sincere, especially one of his young therapists.

The neurologic exam showed that although he did react to deep pain (sternal compression), he did not follow simple commands (e.g. blink). He appeared to be in a coma. Following the neurologic examination the young therapist then demonstrated how when he held the man’s hand to which a pencil was attached, the man could actually perform calculations — add 2 and 2 produce a 4, etc. etc. Several such calculations were produced all with correct answer.

What do you think I did next?

No peeking. Think about it.

I took the first sheet of paper away, placed a clean sheet under the man’s hand and asked for a repeat (this time with the therapist’s eyes closed).

This produced a bunch of random lines, nothing more.  When the therapist opened his eyes and saw the results, he was visibly shaken and close to tears.

Was he faking the whole time? At any time? I seriously doubt it. A faker could have produced a reasonable number with his eyes shut. Try it. He didn’t.

“You can’t con an honest man” —

True, but you certainly can con yourself.

For another example, this time perpetrated by nurses, see how an 11 year old girl (Emily Rosa) put a definitive end to “Therapeutic Touch” and became the youngest co-author ever of an article in the Journal of the American Medical Association —

Just before the battle, mother

This is not a scientific post. Tomorrow I’m going to play piano at a memorial service for the husband of a coworker of my cellist. Wish me luck. I hate playing in public although I love playing chamber music with friends. The fact that one of the pieces I’m going to play is something I wrote is no consolation, since last week my sister in law, an accomplished composer who’s had some of her stuff performed in Carnegie hall, told me that playing something you wrote is no guarantee that you won’t screw up. Thanks a lot.

The distaste for performing in public goes back to grade school when I first started taking lessons. We had to play from memory when the teacher would parade all his pupils at a concert. I never actually screwed up, but was always afraid that I’d get in an endless loop while playing and be unable to get out. I’ve seen this happen once, and even watching it was excruciatingly painful.   In fact that’s how I found that my mother was not omniscient.  Every winter I was told “Close your galoshes and button up or you’ll get sick”. So two weeks before each recital I’d run around with open galoshes and a wide open jacket in the hopes that I’d get sick and miss the recital but I never did.

So wish me luck.  The following fits my current mood

Just before the battle, mother,
I am thinking most of you,
While upon the field we’re watching
With the enemy in view.
Comrades brave are ’round me lying,
Filled with thoughts of home and God
For well they know that on the morrow,
Some will sleep beneath the sod.

Popular song during the American Civil War

Carly’s cancer

Carly Florina had breast cancer surgery (bilateral mastectomy) 2 March 2009 at Stanford University Hospital followed by chemotherapy and radiation. She was given an excellent prognosis for full recovery —

So far so good and it’s coming up on 7 years. But it is reasonable to ask just what her prognosis really is, particularly as she may be our next president. I asked an old friend and colleague who has been involved in research on breast cancer and in many of the clinical trials of therapy over the past 35 years.

So I wrote the following — I’m writing you for some idea what the chances of someone with breast cancer being free for 6+ years (Carly’s surgery was 2/09) will be free for the next 5+? I know that there are all sorts of statistics on survival in breast cancer (because the cohort is so large). If anyone would know them, it would be you.

and got this back

Impossible to answer your question. Too many variables and NO DATA or info. Many people, docs and patients alike call ductal carcinoma in situ,” cancer” but cure rate is 99%. If she was one of those then, of course, she’s likely to be cured . Stage 1 ,luminal A tumors (even though real cancers) have excellent prognoses—probably > 90% cured. For other real cancers Lots depend on stage, hormone receptors ad infinitum. On thin ice lumping anyone into a broad statement without lots more info

just what you’d expect from an circumspect intelligent expert

So I dug a bit more and sent him this

I tried to find out just what type of breast cancer Carly had. No luck, but various newspaper articles show that she did receive postop chemo causing her hair to fall out as well as radiation. Would ductal carcinoma in situ (Dcis) be treated this way? Would stage 1 luminal A tumors be treated this way?

He replied

Dcis definitely no. luminal a probably shouldn’t be. Sounds like a significant cancer. Next issue is did she get antihormonal therapy. Estrogen receptor tumors are the ones that tend to relapse after 5 years. ER neg. tumors while more aggressive overall seldom recur >5 yrs after dx. The radiation part doesn’t mean much unless she had a mastectomy since all lumpectomy patients get radiation. – If she had mastectomy and chemo and radiation it was probably a poorer risk tumor. Even chemo might not be so bad—–we give chemo to node neg tumors which could end up with very good long term prognosis.AMONG RELAPSES in ER pos pts. 15% recur before year 5 and 17% recur after year 5. However overall likelihood of relapse depends on whether or not she had positive or negative nodes and was ER + or Neg. Sorry to be so wordy but prognosis has been improving steadily. I would guestimate that we’re curing about 70% of women with newly diagnosed breast cancer—excluding dcis who are virtually all cured.

I realized that I’d neglected to tell him that she’d had a bilateral mastectomy as well and got the following back after I did.

If she indeed had radiation after a mastectomy as well as chemo it speaks for a more aggressive presentation. Rule of thumb—-post mastectomy xrt reserved for patients with > 4 positive nodes or tumors >5 cm in size. Today, many are giving post mastectomy xrt to 1-3 positive nodes although that was very controversial for years . newer data impies benefit. So, just guessing, but she probably had positive nodes—a poorer prognostic sign for long term—but only if she was estrogen receptor pos. as noted in prior email.

So there you have it — she’s fortunately well presently, but the tumor and prognosis doesn’t sound that good. Still unknown are histologic type of the tumor, presence or absence of spread to lymph nodes (and if so how many), estrogen receptor positivity, which would certainly give us a better idea of her ultimate prognosis (and the country’s should she become president).

I take no pleasure in any of these posts. See Both Carly and Hillary are brilliant women it would be an honor to know and I wish them both the best. FYI Hillary was valedictorian of her class at Wellesley.

So why write about their potential health problems? Look at the sad saga of Hugo Chavez who claimed he was cured in July elected in the fall with death before he could take office in March of the following year — see Also consider the last months in office of Woodrow Wilson and Franklin Roosevelt and the results of the League of Nations and the Yalta conference when they were both impaired.

My wife asked my why I pick on female candidates, and I’ll address Christie’s massive obesity should he rise in the polls.

Hillary’s stroke – II

On 31 July The Clinton campaign released a letter from Hillary’s personal physician Lisa Bardack, MD, a board certified Internist,  basically saying that her health was excellent.

Well it isn’t and her letter essentially proves that she had a stroke in December of 2012. Here’s why.

First: a timeline.

At some time in the week of 9 December 2012 Mrs. Clinton is said to have fainted suffering a concussion. The New York Times reported on this 13 December.

She remained at home until 31 December at which point she was admitted to New York-Presbyterian Hospital when a blood clot was found in a vein draining the brain. (12 August — correction.  She was admitted 30 December).

Subsequently she had double vision due to her eye muscles not working together for a month or so and had to wear special glasses to correct this.

Second: The following explanation for these events was given by Dr. Bardach. You may read the entire letter at but the relevant paragraph is directly quoted below.

“In December of 2012, Mrs. Clinton suffered a stomach virus after traveling, became dehydrated, fainted and sustained a concussion. During follow up evaluations, Mrs. Clinton was found to have a transverse sinus venous thrombosis and began anticoagulation therapy to dissolve the clot. As a result of the concussion, Mrs. Clinton also experienced double vision for a period of time and benefited from wearing glasses with a Fresnel Prism. Her concussion including the double vision, resolved within two months and she discontinued the use of the prism. She had followup testing in 2013, which revealed complete resolution of the effects of the concussion as well as total dissolution of the thrombosis. Mrs. Clinton also tested negative for all clotting disorders. As a precaution, however, it was decided to continue her on daily anticoagulation.”

Third: Why should you believe what yours truly, a neurologist and not a neurosurgeon says about the minimal likelihood of this clot being due to the head trauma she sustained when she fainted? Neurologists rarely deal with acute head trauma although when the smoke clears we see plenty of its long term side effects (post-traumatic epilepsy, cognitive and coordination problems etc. etc.). I saw plenty of it in soldiers when I was in the service ’68 – ’70, but this was after they’d been stabilized and shipped stateside. However, I had an intense 42 month experience managing acute head injuries.

To get my kids through college, I took a job working for two busy neurosurgeons. When I got there, I was informed that I’d be on call every other night and weekend, taking first call with one of the neurosurgeons backing me up.  Fortunately, my neurosurgical backup was excellent, and I learned and now know far more about acute head trauma than any neurologist should. We admitted some of the head trauma cases to our service, but most cases had trauma to other parts of the body, so a general surgeon would run the show with our group as consultants. I was the initial consultant in half the cases. When I saw them initially, I followed the patients until discharge. On weekends I covered all our patients and all our consults, usually well over 20 people.

We are told that Hillary had a clot in one of the large draining veins in the back of her head (the transverse dural venous sinus). I’d guess that I saw over 300 cases of head trauma,but I never saw a clot develop in a dural sinus due to the trauma. I’ve spoken to two neuroradiologists still in practice, and they can’t recall seeing such a clot without a skull fracture over the sinus. Such a fracture has never been mentioned  at any time about Hillary.

Hillary’s neurologic deficit involved a nerve going to the muscles of her left eye. These start in the brainstem, a part of the brain quite near the site where she is said to have had the clot in her vein. The brainstem is crucial in maintaining consciousness, and it is more likely that the faint earlier in December was a warning sign of the stroke she had subsequently.

Why does the letter essentially prove Hillary had a stroke back then ?

I find it impossible to believe that the double vision occurred when she fainted. No MD in their right mind would not immediately hospitalize a case of head trauma with a neurologic deficit such as double vision. This is just as true for the most indigent patient as for the Secretary of State.

My guess was that the double vision came up later — probably after Christmas. Who gets admitted to the hospital the day of New Year’s Eve? Only those with symptoms requiring immediate attention.  Update 9 August — an alert reader asked how I knew she was admitted during the day and not in the evening.  It made me Google this point further — finding this–politics.html — showing that she was admitted 30 December.  Thanks Joe.

Dr. Bardack’s letter states, “As a precaution,however, it was decided to continue her on daily anticoagulation.” I couldn’t agree more. However, this is essentially an admission that she is at significant risk to have more blood clots. While anticoagulation is not without its own risks, it’s a lot safer now than it used to be. Chronic anticoagulation is no walk in the park for the patient (or for the doctor).   The most difficult cases of head trauma we had to treat were those on anticoagulants. They always bled more.

Dr. Bardack’s letter is quite clever.  She never comes out and actually says that the head trauma caused the clot, but by the juxtaposition of the first two sentences, the reader is led to that conclusion.  Suppose, Dr. Bardack was convinced that the trauma did cause the clot.  Then there would be no reason for her to subject Mrs. Clinton to the risks of anticoagulation, given that the causative agent was no longer present.    In all the cases of head trauma we saw, we never prescribed anticoagulants on discharge (unless we had to for non-neurosurgical reasons). I certainly agree with her use of anticoagulation, as I highly doubt that the trauma had anything at all to do with the blood clot in the transverse sinus. It is even possible that the clot was there all the time and caused the faint in early December.

The really important medical data would be Dr. Bardack’s office notes from December and the consultations of the neurosurgeon and admitting physician at Presbyterian 31 December, but I doubt that we’ll ever see them.

Why does this matter? Fortunately, Mrs. Clinton has recovered. However, statistically a person who has had one stroke is far more likely to have another than a person who has never had one. This is particularly true when we don’t know what caused the first (as in this case).

We’ve had two presidents neurologically impaired by stroke in the past century (Woodrow Wilson after World War I and Franklin Delano Roosevelt at Yalta). The decision they made in that state were not happy for the USA or the world.

Lest you regard this as anti-Hillary, concern for the health of future presidents is not confined to Democratic candidates.  Reagan’s age was raised as a legitimate issue by his opponents  as Christie’s near-morbid obesity should be if he gets the Republican nomination.  The resignation of Thomas Eagleton, the first running mate of George McGovern in 1972 because he had a history of electroshock therapy for depression, again shows that these concerns are not limited to any time or  party.

Addendum 14 Aug ’15: Will be away from the net for several weeks.  If you’ve commented after that, you’ve not been ignored or rejected, just held till I get back.

Addendum 13 Oct ’15:  Watching the debate in real time, not videoed and slowed down.  Her mouth moves symmetrically, although her left cheek appears somewhat swollen and distorted.  On close inspection she rarely moves her left eye to the left fully covering the sclera (white) although I did see it once or twice.  It’s very hard to see if her two eyes are working together at this time.  On gaze to the right she fully buries the sclera of her right eye.  So probably she has fully recovered from the stroke of 2012.

I’m not making this up

Docs hate res ipsa loquitur — a favorite of malpractice lawyers — e.g. the thing speaks for itself — If accepted this means that negligence or malpractice requires no proof. So here I am, using it as a rhetorical device in an important malpractice case.

Below are the 7 priority areas set out by Katherine Archuleta, the late unlamented director of the Office of Personnel management. It’s a marvelously politically correct document, with all the appropriate buzzwords to warm the heart (and numb the mind). Unfortunately security wasn’t one of the seven.

OPM has set out seven priority areas:

Honoring the Workforce: OPM will be the champion of the Federal workforce. Through such programs as the OPM Innovation Lab and the Learning Center, we will provide career training and skill development for Federal employees. OPM will serve as the thought leader in research and data-driven human resource management and policy decision-making.

Build a More Diverse and Engaged Workforce: OPM, which by Executive Order is the lead agency on increasing diversity and inclusion in the Federal workforce, will recruit qualified individuals to serve and expand access to the job pipeline from entry and mid-level positions to leadership posts. OPM will provide leadership in helping agencies create work environments where a diverse Federal workforce is fully engaged and energized.

World Class Customer Service: OPM will respond to the interests of its many and diverse customers throughout the lifecycle of an employee. Whether it’s a recent graduate seeking to start a Federal career, a current employee looking for a training opportunity, or a retiree, OPM will provide timely, accurate and responsive service.

IT Improvement: Under the leadership of a new Chief Information Officer and Chief Technology Officer, OPM will implement its IT Strategic Plan to streamline and update IT systems to better serve Federal employees from resume through retirement.

Background Investigations: In partnership with the Office of the Director of National Intelligence, OPM will implement the revised Federal Investigative Standards and will lead efforts to strengthen the background investigations program across government as we maintain the highest standards of quality and timeliness.

Retirement: OPM is closing in on our goal to process 90 percent of cases within 60 days. The agency will continue to update our systems as we continue to transition to a paperless process.

Health Care: OPM will fully implement the Multi-State Plan provision of the Affordable Care Act, provide coverage to Tribal employees and continue providing high quality health insurance benefits to the Federal workforce.

Here’s a link to the original

Res ipsa loquitur

Happy fourth of July

Two encounters in the past 2 days brought home just how fortunate we are to live in the USA, along with the realization that only the immigrants truly appreciate this country. One was with a Greek friend who is a professor of engineering at a local university. His wife is on her way to Greece acting as a money launderer (well not really) bringing US dollars to her family over there. We get his brains for free and probably those of his 15 year old daughter who grew up here.

The other was with our tile man Sergey, a Russian immigrant of 17 years. He describes how his grandfather was sent by Stalin to Siberia, surviving for 14 years. Why? He wasn’t at all active politically, but was a devout Christian. That was all it took. If you find this difficult to accept — look at the following post — Some of the most brilliant mathematicians of the Soviet Union were persecuted for the same reason.

Not convinced? Over 25 years ago, the local paper where we were living at the time had an interview with a Ukrainian woman newly arrived in the states. She was asked what it was she liked best about this country. She said it was being able to have people over to her house for prayer without having the draw the curtains.

Yes, we complain a lot about how things could be better, probably a genetic heritage, as only those who were unsatisfied with their condition where they were had the gumption to get up and come here.

However, as great as we are, tonight’s fireworks pale in comparison to those of the Chinese New Year (they invented fireworks after all). Earlier this year my wife and I viewed a 30 minute display from 3 ships firing away in Hong Kong harbor. Some of them even spelled out Chinese characters according to our daughter in law. If you like loud, go to a Buddist temple for their new year celebrations.

Kuru continues to inform

Neurologists of my generation were fascinated with Kuru, a disease of the (formerly) obscure Fore tribe of New Guinea. Who would have thought they would tell us a good deal about protein structure and dynamics?

It is a fascinating story including a Nobelist pedophile (Carleton Gajdusek) and another (future) Nobelist who I probably ate lunch with when we were both medical students in the same Medical Fraternity but don’t remember –

Kuru is a horrible neurodegeneration starting with incoordination, followed by dementia and death in a vegetative state in 4 months to 2 years. For the cognoscenti — the pathology is neuronal loss, astrocytosis, microglial proliferation, loss of myelinated fibers and the kuru plaque.

It is estimated that it killed 3,000 members of the 30,000 member tribe. The mode of transmission turned out to be ritual cannibalism (flesh of the dead was eaten by the living before burial). Once that stopped the disease disappeared.

It is a prion disease, e.g. a disease due to a protein (called PrP) we all have but in an abnormal conformation (called PrpSc). Like Vonnegut’s Ice-9 ( PrPSc causes normal PrP to assume its conformation, causing it to aggregate and form an insoluble mess. We still don’t know the structure of PrPSc (because it’s an insoluble mess). Even now, “the detailed structure of PrPSc remains unresolved” but ‘it seems to be’ very similar to amyloid [ Nature vol. 512 pp. 32 – 34 ’14]. Not only that, but we don’t know what PrP actually does, and mice with no PrP at all are normal [ Nature vol. 365 p. 386 ’93 ]. For much more on prions please see

Prusiner’s idea that prion diseases were due to a protein, with no DNA or RNA involved met with incredible resistance for several reasons. This was the era of DNA makes RNA makes protein, and Prisoner was asking us to believe that a protein could essentially reproduce without any DNA or RNA. This was also the era in which X-ray crystallography was showing us ‘the’ structure of proteins, and it was hard to accept that there could be more than one.

There are several other prion diseases of humans (all horrible) — mad cow disease, Jakob Creutzfeldt disease, Familial fatal insomnia, etc. etc. and others in animals. All involve the same protein PrP.

One can take brain homogenates for an infected animal, inoculate it into a normal animal and watch progressive formation of PrPSc insoluble aggregates and neurodegeneration. A huge research effort has gone into purifying these homogenates so the possibility of any DNA or RNA causing the problem is very low. There still is one hold out — Laura Manuelidis who would have been a classmate had I gone to Yale Med instead of Penn. n

Enter [ Nature vol. 522 pp. 423 – 424, 478 – 481 ’15 ] which continued to study the genetic makeup of the Fore tribe. In an excellent example of natural selection in action, a new variant of PrP appeared in the tribe. At amino acid #127, valine is substituted for glycine (G127V is how this sort of thing is notated). Don’t be confused if you’re somewhat conversant with the literature — we all have a polymorphism at amino acid #129 of the protein, which can be either methionine or valine. It is thought that people with one methionine and one valine on each gene at 129 were somewhat protected against prion disease (presumably it affects the binding between identical prion proteins required for conformational change to PrPSc.

What’s the big deal? Well, this work shows that mice with one copy of V127 are protected against kuru prions. The really impressive point is that the mice are also protected against variant Creutzfedlt disease prions. Mice with two copies of V127 are completely protected against all forms of human prion disease . So something about V/V at #127 prevents the conformation change to PrPSc. We don’t know what it is as the normal structure of the variant hasn’t been determined as yet.

This is quite exciting, and work is certain to go on to find short peptide sequences mimicking the conformation around #127 to see if they’ll also work against prion diseases.

This won’t be a huge advance for the population at large, as prion diseases, as classically known, are quite rare. Creutzfeldt disease hits 1 person out of a million each year.

There are far bigger fish to fry however. There is some evidence that the neurofibrillary tangles (tau protein) of Alzheimer’s disease and the Lewy bodies (alpha-Synuclein) of Parkinsonism, spread cell to cell by a ‘prionlike’ mechanism [ Nature vol.485 pp. 651 – 655 ’12, Neuron vol. 73 pp. 1204 – 1215 ’12 ]. Could this sort of thing be blocked by a small amino acid change in one of them (or better a small drug like peptide?).

Stay tuned.

Outside information on the Greek financial crisis

Definitely off topic, but I wrote the following to a an international banker friend of 50+ years experience about the Greek financial crisis

“But of more immediate import, what sayeth the banker about shutting the banks in Greece for a week. In this article people were taking Euros out, but if the banks don’t have any and the Europeans won’t give more, what happens then. Gotterdammerung?”

I got the following back

Possibly. Martial law? It happened here in the 30s – the “bank holiday(s)”. Having lived thru 2 bank runs, I can tell you it is a time when rationality is absent. The presumption is the Greek authorities have been planning for this. Greeks are used to violent demonstrations,. I would expect some bank buildings being burned. For a few days the country can function. More and I can not see anything but Grexit. I see a gigantic game of chicken. The Germans have been blinking up until now but the internal political cost to Merkel may be too great. Germany has MUCH to lose if Greece leaves the EU.

The twists and turns of topoisomerase (pun intended)

It is very sad that my late friend Nick Cozzarelli isn’t around to enjoy the latest exploits of the enzyme class he did so much great work on — the topoisomerases. For a social note about him see the end of the post.

We tend to be quite glib about just what goes on inside a nucleus when DNA is opened up and transcribed into mRNA by RNA polymerase II (Pol II). We think of DNA has a linear sequence of 4 different elements (which it is) and stop there. But DNA is a double helix, and the two strands of the helix wind around each other every 10 elements (nucleotides), meaning that within the confines of our nuclei this happens 320,000,000 times.

I’ve written a series of six posts on what we would see if our nuclei were enlarged  by a factor of 100,000 (which is the amount of compaction our DNA must undergo to fit inside the 10 micron (10 millionths of a meter) in diameter nucleus (since if fully extended our DNA would be 1 meter long. So if you compacted the distance from New York to Seattle (2840 miles or 14,995,200 feet) down by this factor you’d get a sphere 150 feet in diameter or half the length of a football (US) field. Now imagine blowing up the diameter and length of the DNA helix by 100,000 and you’d get something looking like a 2,840 mil long strand of linguini which twists on itself  320,000,000 times. The two strands are 3/8th of an inch thick. They twist around each other every 9/16ths of an inch.

For the gory details start at and follow the links.

Well, we know that for DNA to be copied into mRNA it must be untwisted, the strands separated so RNA polymerase II (Pol II) can get to it.  Pol II is enormous — a mass of 500 kiloDaltons and 7 times thicker at 140 Angstroms than the DNA helix of 20 Angstrom thickness.

Consider the fos gene (which we’ll be talking about later). It contains 380 amino acids (meaning that the gene contains at least 1140 nucleotides ). The actual gene is longer because of introns (3,461 nucleotides), which means that the gene contains 346 complete turns of the double helix, all of which must be unwound to transcribe it into mRNA.

So it’s time for an experiment. Get about 3 feet of cord roughly 3/8 of an inch thick. Tie the ends together, loop one end around a hook in your closet, put a pencil in the other end and rotate it about 100 times (or until you get tired). Keeping everything the same, have a friend put another pencil between the two strands in the middle, separating them. Now pull on the strands to make the separation wider and move the middle pencil toward one end. In the direction of motion the stands will coil even tighter (supercoiling) and behind they’ll unwind.

This should make it harder for Pol II to do its work (or for enzymes which copy DNA to more DNA). This is where the various topoisomerase come in. They cut DNA allowing supercoils to unwind. They remain attached to the DNA they cut so that the DNA can be put back together. There are basically two classes of topoisomerase — Type I topoisomerase cuts one strand, leaving the other intact, type II cuts both.

Who would have thought that type II topoisomerase would be involved in the day to day function of our brain.

Neurons are extended things, with information flowing from dendrites on one side of the cell body to much longer axons on the other. The flow involves depolarization of the cell body as impulses travel toward the axon. We know that certain genes are turned on by this activity (e.g. the DNA coding for the protein is transcribed into mRNA which is translated into protein by the ribosome). They are called activity dependent genes.

This is where [ Cell vol. 1496 – 1498, 1592 – 1605 ’15 ] comes in. Prior to neuronal activity, when activity dependent genes are expressed at low levels, the genes still show the hallmarks of highly expressed genes (e.g. binding by transcription factors and RNA polymerase II, Histone H3 trimethylation of lysine #4 {H3K4Me3 } at promoters).

This work shows that such genes are highly negatively supercoiled (see above) preventing RNA polymerase II (Pol II) from extending into the gene body. On depolarization of the cell body in some way Topoisomerase IIB is activated, leading to double strand breaks (dsbs) within promoters allowing the DNA to unwind and Pol II to productively elongate through gene bodies.

There is evidence that neuronal stimulation leads to dsbs ( Nature NeuroScience vol. 16 pp. 613 – 621 ’13 ) throughout the transcription of immediate early genes (e.g. genes turned on by neural activity). The evidence is that there is phosphorylation of serine #139 on histone variant H2AX (gammaH2AX) which is a chromatin mark deposited on adjacent histones by the DNA damage response pathway immediately after DSBs are found.

Etoposide (a topoisomerase inhibitor) traps the enzyme in a state where it remains bound to the DNA of the dsb. On etoposide Rx, there is an increase in activity dependent genes (Fos, FosB, Npas4). Inhibition of topiosomerase IIB (the most prevalent topoisomerase in neurons) by RNA interference (RNAi) leads to blunted activity dependent induction of these genes. This implies that DNA cutting by topoisomerase IIB is required for gene activation in response to neuronal activity.  Other evidence is that knocking down topoisomerase  using RNA interference (RNAi) stops activity dependent gene transcription.

Further supporting this idea, the authors induced dsbs at promoters of activity dependent genes (Fos, fosB, Npas4) using the CRISPR system. A significant increase in transcription was found when the Fos promoter was targeted.

I frankly find this incredible. Double strand breaks are considered bad things for good reason and the cell mounts huge redundant machines to repair them, yet apparently neurons, the longest lived cells in our bodies are doing this day in and day out. The work is so fantastic that it needs to be replicated.

Social Note: Nick Cozzarelli is one of the reasons Princeton was such a great institution back in the 50s (and hopefully still is). Nick’s father was an immigrant shoemaker living in Jersey City, N. J. Princeton recognized his talent, took him in, allowing him to work his way through on scholarship, waiting tables in commons, etc. etc. He obtained a PhD in biochemistry from Harvard and later became a prof at Berkeley, where he edited the Proceedings of the National Academy of Sciences USA for 10 years. He passed away far too soon of Burkitt’s lymphoma in his late 60s. We were friends as undergraduates and in grad school.

I can only wonder what Nick would say about the latest twists of the topoisomerase story


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