Category Archives: Neurology & Psychiatry

The elegance of metabolism control in the cell.

The current two pronged research effort on the possible use of Gemfibrozil (Lopid) to treat Alzheimer’s disease now has far wider implications than Alzheimer’s disease alone. As far as I’m aware, the combination of mechanisms described below to control a cellular pathway as never been reported before.

A previous post has the story up to 3 August — https://luysii.wordpress.com/2015/08/03/takes-me-right-back-to-grad-school/ — you can read it for the details, but here’s some background and the rest of the story.

Background: One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. A paper in the 7 July PNAS (vol. 112 pp. 8445 – 8450 ’15 7 July ’15) essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

I wrote the author (Dr. Pahan) to ask how they came up with Gemfibrozil (Lopid). He told me that a transcription factor (PPARalpha) helps transcribe the ADAM10 gene into mRNA, and that Gemfibrozil makes PPARalpha a better transcription factor.

I told him to datamine from HMOs to find out if people on Lopid had less Alzheimer’s, he said it would be hard to get such as grant to do this as a basic researcher.

A commenter on the first post gave me a name to contact to try out the idea, but I’ve been unable to reach her. So on 3 August, I wrote an Alzheimer’s researcher at Yale about it. He responded nearly immediately with a link to an ongoing clinical study in progress in Kentucky, actually using Gemfibrozil.

Both researchers (Dr. Jicha and Nelson) were extremely helpful and cooperative. What is so fascinating is that they got to Gemfibrozil by an entirely different route. There are degrees of Alzheimer’s disease, and there is a pathologic grading scheme for it. They studied postmortem brain of 4 classes of individuals — normal nondemented elderly with minimal plaque, non demented elderly with incipient plaque, mild cognitive impairment and full flown Alzheimer’s. They had studied the microRNA #107 (miR-107) in another context. Why this one of the thousand or so microRNAs in the human genome? Because it binds to the mRNA of BACE1 and prevents it from being made. Why is this good? Because BACE1 chops up APP at a different site so the Abeta peptide is formed.

How did Gemfibrozil get into the act? Just as Dr. Pahan did, they looked to see what transcription factors were involved in making miR-107, and found PPARalpha. So to make less BACE1 they give people Gemfibrozil which turns on PPARalpha which turns on miR-107, which causes the mRNA for BACE1 to be destroyed, hopefully making less Abeta. The study is in progress and will last a year, far too short with far too few people to see a meaningful cognitive effect, but not so short that they won’t see changes in the biologic markers  they are studying in the spinal fluids (yes 72 plucky individuals have agreed to take Gemfibrozil (or not) and have two spinal taps one year apart.

The elegance of all this is simply astounding. One transcription factor turns on a gene for a chopper which inhibits Abeta formation, and turns on a microRNA which stops an APP chopper producing Abeta from being made.

So there’s a whole research program for you. Take a given transcription factor, look at the protein genes it turns on. Then look at the microRNA genes it turns on and then see what protein mRNAs they turn off. Then see they affect the same biochemical pathway as do ADAM10 and BACE1.

The mechanism is so elegant (although hardly simple) that I’ll bet the cell uses it again, in completely different pathways.

One problem with PPARalpha is that it is said to affect HUNDREDS of genes (Mol. Metab vol. 3 pp. 354 371 ’14).  So Gemfibrozil is a nice story, but even if it works, we won’t really be sure it’s doing so by ADAM10 and microRNA-107.

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 http://online.wsj.com/public/resources/documents/clintonhealth2015.pdf 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 http://news.yahoo.com/blogs/ticket/clinton-admitted-hospital-blood-clot-015548623–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.

Takes me right back to grad school

How many times in grad school did you or your friends come up with a good idea, only to see it appear in the literature a few months later by someone who’d been working on it for much longer. We’d console ourselves with the knowledge that at least we were thinking well and move on.

Exactly that happened to what I thought was an original idea in my last post — e.g. that Gemfibrozil (Lopid) might slow down (or even treat) Alzheimer’s disease. I considered the post the most significant one I’d ever written, and didn’t post anything else for a week or two, so anyone coming to the blog for any reason would see it first.

A commenter on the first post gave me a name to contact to try out the idea, but I’ve been unable to reach her. Derek Lowe was quite helpful in letting me link to the post, so presently the post has had over 200 hits. Today I wrote an Alzheimer’s researcher at Yale about it. He responded nearly immediately with a link to an ongoing clinical study in progress in Kentucky

On Aug 3, 2015, at 3:04 PM, Christopher van Dyck wrote:

Dear Dr. xxxxx

Thanks for your email. I agree that this is a promising mechanism.
My colleague Greg Jicha at U.Kentucky is already working on this:
https://www.nia.nih.gov/alzheimers/clinical-trials/gemfibrozil-predementia-alzheimers-disease

Our current efforts at Yale are on other mechanisms:
http://www.adcs.org/studies/Connect.aspx

We can’t all test every mechanism, but hopefully we can collectively test the important ones.

-best regards,
Christopher H. van Dyck, MD
Professor of Psychiatry, Neurology, and Neurobiology
Director, Alzheimers Disease Research Unit

Am I unhappy about losing fame and glory being the first to think of it?  Not in the slightest.  Alzheimer’s is a terrible disease and it’s great to see the idea being tested.

Even more interestingly, a look at the website for the study shows, that somehow they got to Gemfibrozil by a different mechanism — microRNAs rather than PPARalpha.

I plan to get in touch with Dr. Jicha to see how he found his way to Gemfibrozil. The study is only 1 year in duration, and hopefully is well enough powered to find an effect. These studies are incredibly expensive (and an excellent use of my taxes). I never been involved in anything like this, but data mining existing HMO data simply has to be cheaper. How much cheaper I don’t know.

Here’s the previous post —

Could Gemfibrozil (Lopid) be used to slow down (or even treat) Alzheimer’s disease?

Is a treatment of Alzheimer’s disease at hand with a drug in clinical use for nearly 40 years? A paper in this week’s PNAS implies that it might (vol. 112 pp. 8445 – 8450 ’15 7 July ’15). First a lot more background than I usually provide, because some family members of the afflicted read everything they can get their hands on, and few of them have medical or biochemical training. The cognoscenti can skip past this to the text marked ***

One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. The paper essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

The authors didn’t artificially increase the amount of ADAM10 to see if the animals got fewer plaques (that’s probably their next paper).

So there you have it. Should your loved one get Gemfibrozil? It’s a very long shot and the drug has significant side effects. For just how long a shot and the chain of inferences why this is so look at the text marked @@@@

****

How does Gemfibrozil increase the amount of ADAM10 around? It binds to a protein called PPARalpha which is a type of nuclear hormone receptor. PPARalpha binds to another protein called RXR, and together they turn on the transcription of a variety of genes, most of which are related to lipid metabolism. One of the genes turned on is ADAM10, which really has never been mentioned in the context of lipid metabolism. In any event Gemfibrozil binds to PPARalpha which binds more effectively to RAR which binds more effectively to the promoter of the ADAM10 gene which makes more ADAM10 which chops of APP in such fashion that Abeta isn’t made.

How in the world the authors got to PPARalpha from ADAM10 is unknown — but I’ve written the following to the lead author just before writing this post.

Dr. Pahan;

Great paper. People have been focused on ADAM10 for years. It isn’t clear to me how you were led to PPARgamma from reading your paper. I’m not sure how many people are still on Gemfibrozil. Probably most of them have some form of vascular disease, which increases the risk of dementia of all sorts (including Alzheimer’s). Nonetheless large HMOs have prescription data which can be mined to see if the incidence of Alzheimer’s is less on Gemfibrozil than those taking other lipid lowering agents, or the population at large. One such example (involving another class of drugs) is JAMA Intern Med. 2015;175(3):401-407, where the prescriptions of 3,434 individuals 65 years or older in Group Health, an integrated health care delivery system in Seattle, Washington. I thought the conclusions were totally unwarranted, but it shows what can be done with data already out there. Did you look at other fibrates (such as Atromid)?

Update: 22 July ’15

I received the following back from the author

Dear Dr.

Wonderful suggestion. However, here, we have focused on the basic science part because the NIH supports basic science discovery. It is very difficult to compete for NIH R01 grants using data mining approach.

It is PPARα, but not PPARγ, that is involved in the regulation of ADAM10. We searched ADAM10 gene promoter and found a site where PPAR can bind. Then using knockout cells and ChIP assay, we confirmed the participation of PPARα, the protein that controls fatty acid metabolism in the liver, suggesting that plaque formation is controlled by a lipid-lowering protein. Therefore, many colleagues are sending kudos for this publication.

Thank you.

Kalipada Pahan, Ph.D.

The Floyd A. Davis, M.D., Endowed Chair of Neurology

Professor

Departments of Neurological Sciences, Biochemistry and Pharmacology

So there you have it. An idea worth pursuing according to Dr. Pahan, but one which he can’t (or won’t). So, dear reader, take it upon yourself (if you can) to mine the data on people given Gemfibrozil to see if their risk of Alzheimer’s is lower. I won’t stand in your way or compete with you as I’m a retired clinical neurologist with no academic affiliation. The data is certainly out there, just as it was for the JAMA Intern Med. 2015;175(3):401-407 study. Bon voyage.

@@@@

There are side effects, one of which is a severe muscle disease, and as a neurologist I saw someone so severely weakened by drugs of this class that they were on a respirator being too weak to breathe (they recovered). The use of Gemfibrozil rests on the assumption that the senile plaque and Abeta peptide are causative of Alzheimer’s. A huge amount of money has been spent and lost on drugs (antibodies mostly) trying to get rid of the plaques. None have helped clinically. It is possible that the plaque is the last gasp of a neuron dying of something else (e.g. a tombstone rather than a smoking gun). It is also possible that the plaque is actually a way the neuron was defending itself against what was trying to kill it (e.g. the plaque as a pile of spent bullets).

Could Gemfibrozil (Lopid) be used to slow down (or even treat) Alzheimer’s disease?

Is a treatment of Alzheimer’s disease at hand with a drug in clinical use for nearly 40 years? A paper in this week’s PNAS implies that it might (vol. 112 pp. 8445 – 8450 ’15 7 July ’15). First a lot more background than I usually provide, because some family members of the afflicted read everything they can get their hands on, and few of them have medical or biochemical training. The cognoscenti can skip past this to the text marked ***

One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. The paper essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

The authors didn’t artificially increase the amount of ADAM10 to see if the animals got fewer plaques (that’s probably their next paper).

So there you have it. Should your loved one get Gemfibrozil? It’s a very long shot and the drug has significant side effects. For just how long a shot and the chain of inferences why this is so look at the text marked @@@@

****

How does Gemfibrozil increase the amount of ADAM10 around? It binds to a protein called PPARalpha which is a type of nuclear hormone receptor. PPARalpha binds to another protein called RXR, and together they turn on the transcription of a variety of genes, most of which are related to lipid metabolism. One of the genes turned on is ADAM10, which really has never been mentioned in the context of lipid metabolism. In any event Gemfibrozil binds to PPARalpha which binds more effectively to RAR which binds more effectively to the promoter of the ADAM10 gene which makes more ADAM10 which chops of APP in such fashion that Abeta isn’t made.

How in the world the authors got to PPARalpha from ADAM10 is unknown — but I’ve written the following to the lead author just before writing this post.

Dr. Pahan;

Great paper. People have been focused on ADAM10 for years. It isn’t clear to me how you were led to PPARgamma from reading your paper. I’m not sure how many people are still on Gemfibrozil. Probably most of them have some form of vascular disease, which increases the risk of dementia of all sorts (including Alzheimer’s). Nonetheless large HMOs have prescription data which can be mined to see if the incidence of Alzheimer’s is less on Gemfibrozil than those taking other lipid lowering agents, or the population at large. One such example (involving another class of drugs) is JAMA Intern Med. 2015;175(3):401-407, where the prescriptions of 3,434 individuals 65 years or older in Group Health, an integrated health care delivery system in Seattle, Washington. I thought the conclusions were totally unwarranted, but it shows what can be done with data already out there. Did you look at other fibrates (such as Atromid)?

Update: 22 July ’15

I received the following back from the author

Dear Dr.

Wonderful suggestion. However, here, we have focused on the basic science part because the NIH supports basic science discovery. It is very difficult to compete for NIH R01 grants using data mining approach.

It is PPARα, but not PPARγ, that is involved in the regulation of ADAM10. We searched ADAM10 gene promoter and found a site where PPAR can bind. Then using knockout cells and ChIP assay, we confirmed the participation of PPARα, the protein that controls fatty acid metabolism in the liver, suggesting that plaque formation is controlled by a lipid-lowering protein. Therefore, many colleagues are sending kudos for this publication.

Thank you.

Kalipada Pahan, Ph.D.

The Floyd A. Davis, M.D., Endowed Chair of Neurology

Professor

Departments of Neurological Sciences, Biochemistry and Pharmacology

So there you have it.  An idea worth pursuing according to Dr. Pahan, but one which he can’t (or won’t).  So, dear reader, take it upon yourself (if you can) to mine the data on people given Gemfibrozil to see if their risk of Alzheimer’s is lower.  I won’t stand in your way or compete with you as I’m a retired clinical neurologist with no academic affiliation. The data is certainly out there, just as it was for the JAMA Intern Med. 2015;175(3):401-407 study.  Bon voyage.

@@@@

There are side effects, one of which is a severe muscle disease, and as a neurologist I saw someone so severely weakened by drugs of this class that they were on a respirator being too weak to breathe (they recovered). The use of Gemfibrozil rests on the assumption that the senile plaque and Abeta peptide are causative of Alzheimer’s. A huge amount of money has been spent and lost on drugs (antibodies mostly) trying to get rid of the plaques. None have helped clinically. It is possible that the plaque is the last gasp of a neuron dying of something else (e.g. a tombstone rather than a smoking gun). It is also possible that the plaque is actually a way the neuron was defending itself against what was trying to kill it (e.g. the plaque as a pile of spent bullets).

Why drug discovery is so hard (particularly in the brain): Reason #28: The brain processes its introns very differently

Useful drug discovery for neurologic and psychiatric disease is nearly at a standstill. It isn’t for want of trying by basic researchers and big and small pharma. A recent excellent review [ Neuron vol. 87 pp. 14 – 27 ’15 ] helps explain why. In short, the brain processes its protein coding genes rather differently.

This post assumes you know what introns, exons and alternate splicing are. For pretty much all the needed background see the following.

First: https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/
Second:https://luysii.wordpress.com/2010/07/11/molecular-biology-survival-guide-for-chemists-ii-what-dna-is-transcribed-into/

When splicing first came out I started making a list of proteins which were alternatively spliced. It is now safe to assume that any gene containing introns (95% of all protein coding genes [ Proc. Natl. Acad. Sci. vol. 112 pp. 17985 – 17990 ’08 ]) results in several protein products due to alternative splicing. The products produced vary from tissue to tissue, probably because most tissues express different splicing regulators.

Here are a few. A2BP1 (aka Rbfox1, aka FOX1) is a brain specific RNA splicing factor found only in postmitotic terminally differentiated neurons. It is deleted in 10% of glioblastomas. Another is nSR100 (neural Specific Related protein of 100 kiloDaltons) — see later.

To show how crucial alternative splicing is for the every existence of the brain, consider this. The neuronal splicing regulator PTBP2 is barely expressed in most tissues. It is upregulated in neurons. Both PTBP1 and PTBP2 are repressors of neural alternative splicing (but some genes are actually enhanced). In a given region of the brain either PTPB1 or PTBP2 is expressed (but not both). PTBP1 promotes skiping of a neural specific exon (exon #10) in PTBP2 transcripts. This exposes a premature termination codon in PTBP2 leading to nonsense mediated decay (NMD). PTPB1 is expressed in most nonNeural tissues and neural precursor cells, but is silenced in developing neurons by the microRNA miR-124. The mRNA for PTBP2 contains an alternative exon which triggers nonsense mediated decay (NMD) when skipped. Inclusion of the exon requires positive transacting factors such as nSR100 in neurons. Repression is mediated by PTBP1 in undifferentiation. microRNAs (which ones?) downregulate PTBP1 during neuronal differentiation, relieving the negative regulation of PTBP2. Depletion of PTBP1 in fibroblasts is enough for PTBP2 induction and neuronal transdifferentiation.

It gets more complicated still. PTBP1 inhibits splicing of introns at the 3′ end of some genes involved in presynaptic function. This results in nuclear retention and turnover via components of the nuclear RNA surveillance machinery. As PTBP1 is downregulated during neuronal differentiation, the target introns are spliced out and the mature mRNAs are found.

Now we get to microExons, something unknown until 2014. For more details see — https://luysii.wordpress.com/2015/01/04/microexons-great-new-drugable-targets/.
Briefly, microexons are defined as exons containing 50 nucleotides or less (the paper says 3 – 27 nucleotides). They have been overlooked, partially because their short length makes them computationally difficult to find. Also few bothered to look for them as they were thought to be unfavorable for splicing because they were too short to contain exonic splicing enhancers. They are so short that it was thought that the splicing machinery (which is huge) couldn’t physically assemble at both the 3′ and 5′ splice sites. So much for theory, they’re out there.

The inclusion in the final transcript of most identified neural microExons is regulated by a brain specific factor nSR100 (neural specific SR related protein of 100 kiloDaltons)/SRRM4 which binds to intronic enhancer UGC motifs close to the 3′ splice sites, resulting in their inclusion. They are ‘enhanced’ by tissue specific RBFox proteins. nSR100 is said to be reduced in Autism Spectrum Disorder (really? all? some?). nSR100 is strongly coexpressed in the developing human brain in a gene network module M2 which is enriched for rare de novo ASD assciated mutations.

MicroExons are enriched for lengths which are multiples of 3 nucleotides. Recall that every 3 nucleotides in mRNA codes for an amino acid. This implies strong selection pressure was used to preserve reading frames as 3n+1 and 3n+2 produce a frameshift. The microExons are enriched in charged amino acids. Most microExons show high inclusion at late stages of neuronal differentiation in genes associated with axon formation and synapse function. A neural specific microExon in Protrudin/Zfyve27 increases its interation with Vessicale Associated membrane protein associated Protein VAP) and to promote neurite outgrowth.

[ Proc. Natl. Acad. Sci. vol. 112 pp. 3445 – 3450 ’15 ] Deep mRNA sequencing of mouse cerebral cortex expanded the list of alternative splicing events TENfold and showed that 72% of multiexon genes express multiple splice variants. Among the newly discovered alternatively spliced exon are 1,104 exons involved in nonsense mediated decay (NMD). THey are enriched in RNA binding proteins including splicing factors. Another set of alternatively spliced NMD exons is found in genes coding for chromatin regulators. Conservation of NMD exons is found in lower vertebrates, but those involving chromatin regulators are found later into the mammalian lineage. So the transcriptome in the brain is even more complicated.

A bit more about the actual effects on protein structure of alternate splicing. The sites chosen for this aren’t random. Cell and tissue differentially regulated alternative splicing events are significantly UNDERrepresented in functionally defined folded domains in proteins, they are enriched in regions of protein disorder that typically are surface accessible and embed short linear interaction motifs (with other proteins and ligands). Among a set of analyzed neural specific exons enriched in disordered regions, 1/3 promoted or disrupted interactions with partner proteins. So regulated exon splicing might specify tissue and cell type specific protein interaction networks. They regard their inclusion/exclusion as protein surface microsurgery.

How much can a little microexon do to protein function? Here’s an example of a 6 nucleotide microexon (two amino acids). Insertion of the microExon in the nuclear adaptor protein Apbb1 enhances its interaction with Kat5/Tip60 a histone deacetylase. The microExon adds Arginine and Glutamic acid to a phosphotyrosine binding domain (PTB domain) which binds Kat4. This enhances binding.

Had enough? The complexity is staggering and I haven’t even talked about recursive splicing — that’s for another post, but here’s a reference if you can’t wait — [ Nature vol. 521 pp. 300 – 301, 371 – 375, 376 – 379 ’15 ]. Pity the drug chemist figuring out which alternatively spliced form of a brain protein to attack (particularly if it hasn’t been studied for microExons).

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) https://en.wikipedia.org/wiki/Daniel_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 –https://en.wikipedia.org/wiki/Stanley_B._Prusiner

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 (https://en.wikipedia.org/wiki/Ice-nine) 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 https://luysii.wordpress.com/2014/03/30/a-primer-on-prions/

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.

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 https://luysii.wordpress.com/2010/03/22/the-cell-nucleus-and-its-dna-on-a-human-scale-i/ 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

The uses of disorder

There was a lot of shock and awe about a report showing how seemingly minor changes in an aliphatic group on benzene led to markedly different conformations in its protein target (lysozyme from bacteriophage T4) http://pipeline.corante.com/archives/2015/06/18/tiny_and_not_so_tiny_changes.php.

Our noses are being rubbed in just how floppy proteins are, in contrast to the first glimpses of protein structure obtained by Xray crystallography. Back then we knew so little about proteins, that seeing all the atoms laid out in alpha helices and beta sheets was incredibly compelling. We talked about the structure of a protein rather than a structure. Even back then, with hemoglobin (one of the first solved proteins) it was obvious that proteins had to have more than one structure. The porphyrin ring in heme that oxygen binds to is buried deep in hemoglobin, and the initial structure had to move in some way to allow oxygen to find its way in (because the initial structure showed no obvious channel for oxygen). So hemoglobin had to breathe.

We now know that many proteins have intrinsically disordered segments. Amazingly, the most recent estimate I could find in my notes (or in Wikipedia) is this — It is estimated that over 30% of eukaryotic proteins have stretches of over 30 amino acids that are intrinsically disordered [ J. Mol. Biol. vol. 337 pp. 635 – 645 ’04 ]. Does anyone out there know of more recent data?

We’re a lot smarter now — here’s a comment on Derek’s post — “I have always thought crystal structures of proteins/enzymes are more a guide than actually useful. You are crystallizing a protein first-proteins don’t pack like that in vivo. Then you are settling on the conformation that freezes out- is this the lowest energy form? Then you are ignoring hte fact that these are highly dynamic structures that are constantly moving, sliding, shaking, adjusting. Then if you put a ligand in there you get the lowest energy form-which is what it would look like after reaction and before ligand dissociation- this is quite different from what it can look like at other stages of the reaction.”

Here is an interesting example of the uses of protein disorder going on right now in just about every neuron in your body. Most neurons have long processes, far too long for diffusion to move a needed protein to their ends. For that purpose we have microtubules (aka neurotubules in neurons) stretching the length of the processes, onto which two types of motors attach (dyneins which moves things to negative end of the microtubule and kinesins which move things to the positive end).

The microtubule is built from a heterodimer of two proteins (alpha and beta tubulin). Each contains about 450 amino acids and forms a globule 40 Angstroms (4 nanoMeters) in diameter. The heterodimers pack end to end to form a protofilament. 13 protofilaments line up side by side to form the microtubule, a hollow structure about 250 Angstroms in diameter. In cells microtubules are 1 to 10 microns long, but in nerve process they can be ‘up to’ 100 microns in length. Even at 1 micron (1,000 nanoMeters) that’s 13 * 250 heterodimers in a microtubule.

Any protein structure this important has a lot of modifications imposed on it to alter structure and function. Examples include phosphorylation and the addition of glutamic acid chains (polyglutamylation). The carboxy terminal tails of alpha and beta tubulin are flexible and stick out from the tubulin rod (which is why they aren’t seen on Xray crystallography). The carboxy terminal tail is the site of post-translational glutamylation. The enzyme polyglutamylating the carboxy terminal tail of beta tubular is TTLL7 (you don’t want to know what the acronym stands for). It binds to the alpha/beta tubular heterodimer by an intrinsically disordered region of its own (becoming structured in the process), then it binds to the intrinsically disordered carboxyl terminal tails, structuring them and modifying them. It’s basically a mating dance. There is a precedent for this — see https://luysii.wordpress.com/2013/12/29/the-mating-dance-of-a-promiscuous-protein/

So disordered regions of proteins although structureless are far from functionless

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.

What is schizophrenia really like ?

The recent tragic death of John Nash and his wife warrants reposting the following written 11 October 2009

“I feel that writing to you there I am writing to the source of a ray of light from within a pit of semi-darkness. It is a strange place where you live, where administration is heaped upon administration, and all tremble with fear or abhorrence (in spite of pious phrases) at symptoms of actual non-local thinking. Up the river, slightly better, but still very strange in a certain area with which we are both familiar. And yet, to see this strangeness, the viewer must be strange.”

“I observed the local Romans show a considerable interest in getting into telephone booths and talking on the telephone and one of their favorite words was pronto. So it’s like ping-pong, pinging back again the bell pinged to me.”

Could you paraphrase this? Neither can I, and when, as a neurologist I had occasion to see schizophrenics, the only way to capture their speech was to transcribe it verbatim. It can’t be paraphrased, because it makes no sense, even though it’s reasonably gramatical.

What is a neurologist doing seeing schizophrenics? That’s for shrinks isn’t it? Sometimes in the early stages, the symptoms suggest something neurological. Epilepsy for example. One lady with funny spells was sent to me with her husband. Family history is important in just about all neurological disorders, particularly epilepsy. I asked if anyone in her family had epilepsy. She thought her nephew might have it. Her husband looked puzzled and asked her why. She said she thought so because they had the same birthday.

It’s time for a little history. The board which certifies neurologists, is called the American Board of Psychiatry and Neurology. This is not an accident as the two fields are joined at the hip. Freud himself started out as a neurologist, wrote papers on cerebral palsy, and studied with a great neurologist of the time, Charcot at la Salpetriere in Paris. 6 months of my 3 year residency were spent in Psychiatry, just as psychiatrists spend time learning neurology (and are tested on it when they take their Boards).

Once a month, a psychiatrist friend and I would go to lunch, discussing cases that were neither psychiatric nor neurologic but a mixture of both. We never lacked for new material.

Mental illness is scary as hell. Society deals with it the same way that kids deal with their fears, by romanticizing it, making it somehow more human and less horrible in the process. My kids were always talking about good monsters and bad monsters when they were little. Look at Sesame street. There are some fairly horrible looking characters on it which turn out actually to be pretty nice. Adults have books like “One flew over the Cuckoo’s nest” etc. etc.

The first quote above is from a letter John Nash wrote to Norbert Weiner in 1959. All this, and much much more, can be found in “A Beatiful Mind” by Sylvia Nasar. It is absolutely the best description of schizophrenia I’ve ever come across. No, I haven’t seen the movie, but there’s no way it can be more accurate than the book.

Unfortunately, the book is about a mathematician, which immediately turns off 95% of the populace. But that is exactly its strength. Nash became ill much later than most schizophrenics — around 30 when he had already done great work. So people saved what he wrote, and could describe what went on decades later. Even better, the mathematicians had no theoretical axe to grind (Freudian or otherwise). So there’s no ego, id, superego or penis envy in the book, just page after page of description from well over 100 people interviewed for the book, who just talked about what they saw. The description of Nash at his sickest covers 120 pages or so in the middle of the book. It’s extremely depressing reading, but you’ll never find a better description of what schizophrenia is actually like — e.g. (p. 242) She recalled that “he kept shifting from station to station. We thought he was just being pesky. But he thought that they were broadcasting messages to him. The things he did were mad, but we didn’t really know it.”

Because of his previous mathematical achievments, people saved what he wrote — the second quote above being from a letter written in 1971 and kept by the recipient for decades, the first quote from a letter written in 12 years before that.

There are a few heartening aspects of the book. His wife Alicia is a true saint, and stood by him and tried to help as best she could. The mathematicians also come off very well, in their attempts to shelter him and to get him treatment (they even took up a collection for this at one point).

I was also very pleased to see rather sympathetic portraits of the docs who took care of him. No 20/20 hindsight is to be found. They are described as doing the best for him that they could given the limited knowledge (and therapies) of the time. This is the way medicine has been and always will be practiced — we never really know enough about the diseases we’re treating, and the therapies are almost never optimal. We just try to do our best with what we know and what we have.

I actually ran into Nash shortly after the book came out. The Princeton University Store had a fabulous collection of math books back then — several hundred at least, most of them over $50, so it was a great place to browse, which I did whenever I was in the area. Afterwards, I stopped in a coffee shop in Nassau Square and there he was, carrying a large disheveled bunch of papers with what appeared to be scribbling on them. I couldn’t bring myself to speak to him. He had the eyes of a hunted animal.

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