Two American (social) tragedies

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they were appalled, describing it to the Grand Jury as ‘filthy,’ ‘deplorable,’ ‘disgusting,’ ‘very unsanitary, very outdated, horrendous,’ and ‘by far, the worst’ that these experienced investigators had ever encountered.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 Equipment was rusty and outdated.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

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

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

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

http://luysii.wordpress.com/2012/05/22/warren-harvard-and-penn-sanctimony-hypocrisy-and-fraud/

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

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

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

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

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

How to spread the new H7N9 flu

People are naturally nervous about the new strain of influenza virus (H7N9) which, as of 5 April had killed 6 people. Eerily the new flu emerged in Asia almost exactly 1 decade after the SARS epidemic. The causative agent of SARS is a Coronavirus, a completely different virus from influenza. To add to the confusion, in the past 9 months a new strain of Coronavirus has emerged in the Middle East, with a high initial case fatality rate (11/16).

My wife and I were in Hong Kong for the past few weeks for a happy family event, and the horror of the SARS epidemic was widely reported on TV and newspaper (interviews with survivors etc. etc.). I’d estimate that, on any given street in Hong Kong, Beijing, Kyoto, Osaka between 1 – 5% of people are wearing masks covering their nose and mouth. This was not a reaction to the news of the new flu (which came out only 6 days ago), but an attempt by those ill with any febrile illness to avoid spreading it.

First, a bit of reassurance. The most severe cases of any epidemic are always the ones by which it announces its presence. So the high case fatality rate (6/16) reported so far almost certainly won’t hold up. Later on, after the causative organism has been identified, and the immune response to it worked out (involving proteins attacking the bug — e.g. the antibodies), we always find that there were hordes of people who had only a mild illness or who weren’t sick at all (except for AIDS, but even there the most severe cases came to light first). However you don’t need a high fatality rate for an epidemic to be lethal — the 1918 flu had a case fatality rate of 10 – 20% yet it killed between 50 and 100 million people.

You couldn’t come up with a better way to spread a respiratory virus that what happened at JFK airport at two midnights ago (it’s the morning of the 6th here in the USA). Two large flights arrived at about the same time — the Cathay Pacific flight we took from Hong Kong had around 200 people. The other flight seemed equally large. Everyone had to go through immigration, showing passports etc. So upwards of several hundred people came off the planes and into a corridor perhaps 15 – 20 feet wide 10 feet high and several hundred feet long. There was one immigration official for US citizens and perhaps 2 more for the non citizens. So there we were, for well over an hour packed cheek by jowl in this space as people were processed through.

If you can think of a better way to spread an infectious virus between a group of unrelated people who will disperse all over New York City, and probably all over America, I’d like to hear it.

Are molecular oncologists looking under the lamppost?

There’s an old joke about a drunk who lost his keys coming home from the bar one night. Daybreak found him still crawling around searching under a lamppost. A passerby asked him why he didn’t look elsewhere. Drunk’s answer: “That’s where the light is”

The molecular biology you need to understand the following can be found in the 5 posts in the “Molecular Biology Survival Guide”. Here’s the link http://luysii.wordpress.com/category/molecular-biology-survival-guide/

The parts of the genome we understand the best are the parts that code for protein. The Cancer Genome Atlas spent a lot of money (1.5 Billion $) looking at genes coding for protein. They started with the most highly curated (translation: hopefully valid) set of genes. There have been tons of papers coming out of the project. Unfortunately, all we know is that every cancer studied so far has lots of mutations in the protein coding genes (the average breast or colon tumor has 90+ such mutations). Many of the mutations found were in previously known cancer causing genes (oncogenes). It would be great if, say, the same few genes were mutated in a given type of cancer. Unfortunately this isn’t the case. There is very little overlap in the mutations between two tumors of the same type. Of course this bears out the well recognized clinical fact not all tumors from organ X (say breast) act the same, even when they are sub classified by the way they look under the microscope (histological type).

This brings us to [ Science vol. 339 pp. 957 - 959 - 961 '13 ]. Once you venture away from the parts of of the genome coding for the amino acids of a protein, the next best understood parts, are those immediately in front (5′ to) the gene itself. The closest element is called the promoter, and is usually within 100 base pairs of the site at which transcription of DNA into RNA begins. Then farther out (sometimes thousands of base pairs out) come the enhancers, which help transcription factors do their work.

TERT is a protein which helps to keep the ends of chromosomes (telomeres) intact. This work looked at the promoter rather than the protein itself, and found two mutations. Together they were found in an astounding 50/70 melanomas, and 24/150 of a variety of cancer cell lines. I think this is much, much higher than any particular oncogene was found mutated in the Cancer Genome Atlas. The net effect of the two mutations was to make binding of a type of transcription factor (ETS) easier, resulting in more TERT being made.

So it’s time to start looking at the 98% of the genome NOT coding for protein. The problem with looking here, is that we really don’t know what it’s doing. The days when it was called junk are mercifully behind us. The second problem, is that we’re going to find changes from the ‘standard’ genome (which really doesn’t exist — the average infant contains 30 mutations not present in either parent) and we have no clue as to how to interpret them.

Everett Koop M. D. RIP

Not many outside medicine know just what he did before becoming surgeon general and famous. He essentially invented the subspecialty of pediatric surgery. Sure, surgeons had been operating on kids from time immemorial, but that’s all Koop did. One of his triumphs was esophageal atresia, meaning that in a newborn part of the esophagus was either absent or too small to pass even fluids, meaning death. The size of the organ in the newborn is a pencil or smaller, and Koop figured out a way to replace or hook up (anastomose) the parts of normal size.

As a med student in Philly, I was lucky enough to make rounds with him at CHOP (Children’s Hospital Of Philadelphia) in the 60′s. He was a typical Pennsylvania Dutchman, very solid, no nonsense, serious, not pompous, rather reserved.

Probably the most accomplished Surgeon General we’ve ever had. I was particularly appalled when Senator Ted Kennedy mau-mau’ed him. Koop was devout and against abortion, and the attacks on his character by the hero of Chappaquiddick were disgusting to those of us who knew him.

Even though Reagan didn’t want him to do it, he was very outspoken about AIDs, and didn’t try to sweep it under the rug as a punishment from God etc. etc. This prominent and early focus probably saved millions of lives, as ignoring it, would have just helped it spread even faster and farther. This is basically the physician’s focus — to deal with the world as it is, not as we wish it to be, and do what we can even for those whose behavior brought misfortune on them. Koop was just being a doc.

To Kennedy’s credit, he later apologized to Koop.

Medical tribulations of politicians — degrees of transparency

Remarkably on the last day of the year, 3 political figures and their medical problems are in the news.  Here they are in order of medical transparency (highest first).

l. George Bush Sr. — the most transparent.  We are told what he has (pneumonia), when he was admitted to hospital when he was in the ICU, when he came out.  Docs call pneumonia ‘the old man’s friend’ not out of cynicism, but because its a mode of death with (relatively) little suffering.  The patient lapses into unconsciousness and usually dies quickly and quietly.  It took my cellist’s father only a day or two to pass away this month.  Clearly it isn’t invariable fatal, and Bush Sr. was now out of the ICU at last count (he’s 88).

2. Hilary Clinton — admitted to the hospital yesterday with a ‘blood clot’ somewhere, said to be a complication of the concussion she suffered a few weeks ago.  Also said to be under treatment with anticoagulants.  Most clots due to head trauma are inside the head and treating them with anticoagulants is a disaster.  The most likely type of clot given the time from the concussion is a subdural hematoma.  It is possible that she’s been so inactive since the concussion that she developed thrombophlebitis in her legs, in which case anticoagulation would be indicated.

More disturbingly, is that her passing out a few weeks ago is a sign of something more serious going on.  Hopefully not.

The powers that be should have told us where the clot actually is.

Update 5:50 PM EST — Well the powers that be did open up and it is a most unusual complication of head injury (and one I’d never seen in nearly 4 decades of practice) — a venous thrombosis in the head.  I’m not even sure it’s due to her head injury.  It might have even caused her syncope, but presumably she had some sort of radiologic study of her head when she fainted, which should have picked it up.  The venous sinuses draining the brain in the back of the head are notoriously asymmetric, so a narrowing attributable to a clot could just be a variant anatomy.  One very bad complication of cerebral venous thrombosis back there (which I saw as a complication of chronic mastoid bone infection — not head trauma) is pseudotumor cerebri.  I really wonder if these guys have the right diagnosis.

3. Hugo Chavez — Yesterday it was announced that he’s had a third complication since his surgery for cancer 3 weeks ago. Naturally, we’re not told just what this complication actually is. This is consistent with the information that has been released about his case.  We know almost nothing about his actual tumor (except that he has one).  He most assuredly is not free of cancer as he stated last fall.  He is said to have have a bleeding problem and a lung infection as the first two complications.

My guess for this third complication is that it is a dehiscence of his abdominal incision, which must have been fairly large for a 6 hour operation.  Dehiscence just means that the wound has spontaneously opened up exposing abdominal contents (which means that peritonitis is not far behind).  Why should this happen?  Two reasons — he’s had radiation to the area which inhibits wound healing, and he’s been on high dose steroids in the past (and perhaps presently) which also inhibits wound healing.

I don’t think he’s going to be able to take office 10 days hence, and doubt that he’ll come back to Venezuela alive.  Transparency has been zilch.  Hopefully the people of Venezuela are beginning to realize just how misleading the information they’ve been fed about his health has been.

This is the sort of thing physicians taking care of really sick people deal with daily, which may explain why your doc friends aren’t as jolly as you are at the New Year’s Eve parties you’re about to attend.

Nonetheless, Happy New Year to all ! ! ! !

Two great men. Hail and Farewell

You probably know that Thomas Jefferson and John Adams both died on July 4, 1826, exactly  50 years after the declaration of independence. Medicine has lost two similar giants E. Donnall Thomas (20 October) and  Joseph Murray  (today) at 92 and 93.  They developed organ transplantation, and received a well deserved Nobel in 1990.   I had the pleasure of seeing neurological consults for his son,  Don Thomas, GP of Lewistown Montana back in the 70s.  The amount of prolonged active life we owe to transplantation medicine is incredible.  RIP.

Carbenes and a defense of Pre-Meds and Docs

Carbenes ! ! ! A whole 25 page chapter in the new Clayden about them ! It wasn’t like this back in the Spring of ’61.  Carbenes were new and exciting. It’s quite different presently in the department, but back then before you could start work on a PhD you had to pass 8 cumulative exams (cumes).  They were given monthly, so once you had 8 under your belt you could start. Until then, you hung around, took courses, went to seminars and made some money as a teaching assistant.  The rumor was that if you passed the first 8 you’d be nominated to be a Junior Fellow (I think Dan Kemp got in this way).  At any rate, I passed 8 of the first 9, and in May ’61 I was ready to begin work. 

The carbene chapter in Clayden is full of all sorts of ways to make carbenes, but back then we weren’t sure if they were involved in ordinary reactions.  I thought they might be involved in the Wolff rearrangement (see p. 1021 of the new edition) and figured out a way to prove it if they were.  Remember this is May ’61.   

Start with cyclopentadiene, do a Diels Alder with acrylic acid (or the acyl chloride, I forget which).   The addition puts the acyl group endo. React the acyl chloride with diazomethane to form the diazoketone.  Photolyze.  Back then we knew that carbenes reacted with olefins to form cyclopropanes.  If so photolysis of this diazoketone should produce a carbene right next to the double bond.  Formation of such a tangled up compound would prove it.

So I took my idea to Woodward, the great man bought it, and let me work on it as my PhD project (rather than one of his ideas).  I never got it to work due to my lousy lab technique, and my fear of blowing my head off with the explosive diazomethane (Tom Lowry had similar fears, but got diazomethane to work on his PhD project with Corey). 

Time for a social note.  When I stop to think of it, the system that got me to Woodward back then was truly remarkable.  I graduated from a 4 year high school of 212 kids which had never sent anyone to the Ivy League.  There were 48 graduates my year of whom half were boys.  None  of the 24 girls went to college and only 6 of the boys.  Yet 4 years later there I was, in a chemistry department which contained 6 nobel future Nobel laureates.

A fellow graduate student back then (now a department chair) grew up on a chicken farm 35 miles away.  A college classmate, the son of an immigrant shoemaker from Italy, later became the editor of PNAS.  Hopefully this country is continuing to do the same for immigrants and the children and grandchildren of immigrants such as ourselves. 

Over the years I’ve read a lot of snarky comments in various chemistry blogs about pre-meds from people attempting to teach them orgo.  Certainly many of them are justified.  Consider what happened when I tried to clean out one rotten apple from such a class —  http://luysii.wordpress.com/2010/08/24/son-of-a-responsibility-you-didnt-know-you-had/.

However, it’s now time for a little pushback.  

As of 5/61 I’d been studying organic chemistry among other things for just over two and a half years.  Yet that’s all it took to get me to the frontier of the field.   Compare that to med school. Starting 9/62 by 5/65 how close was I to knowing enough medicine to take care of a sick person?  Damned far.  Did I find med school harder than grad school?   I certainly did.  No one in our class found it easy, even the future Nobel laureate (although he seemed to spend a lot of his time playing bridge).  Presumably I was just as smart as I was 5/61.

By the summer of ’66 I’d be an intern, with a resident over me and an attending physician over him, to make sure I didn’t screw up.  By the summer of ’67 I’d be a first year resident, with an intern under me, a resident over me andy an attending over him, to make as sure as we could that we didn’t screw up.  By the summer of  ’68 I was in the service, again with an attending.  After finishing that and a residency, by the fall of ’72 I was on my own ready to take care of people with no one checking my work — some 8 years later.

So ease up on the pre-meds (but not academically).  They’ve got a lot longer and harder intellectual road ahead of them than you do.

An incredible paper which may turn diabetes treatment on its head

First off, why should a neurologist be interested in diabetes?  That’s for endocrinologists isn’t it?  Not really.  One of the most serious aspects of diabetes is its acceleration of vascular disease (atherosclerosis), with an increased risk of heart attack and stroke (which is where the neurologist comes in).  So you have a diabetic who has survived a stroke. You want to prevent the next one, and you know that they’re in a much higher risk group for another stroke (1) because they just had one (2) because they’re more likely to have another because of their diabetes.  Also vascular disease makes any neurologic problem worse, dementia, neuropathy you name it.

So I’ve always tried to stay current on diabetes.  Which brings me to Proc. Natl. Acad. Sci. vol. 109 pp. 14972 – 14976 ’12 (11 September issue).  You’d think that nearly a century after Banting and Best’s discovery of Insulin that there were no new wrinkles left.  Not so.

Now for a bit of anatomy and physiology.  In a very simplistic way, you can regard diabetes as not enough insulin.  Insulin lowers blood sugar and is needed after you eat.   It is made in the pancreas, an organ which secretes digestive enzymes into your gastrointestinal tract.  It also secretes insulin, but into the blood rather than the gut.  Insulin is made in relatively small collections of cells (1,000 – 10,0000) called islets dispersed through out the pancreas.  They are .1 – .2 milliMeters in diameter, and even though we have over 1,000,000 of them, they constitute 2% of the mass of the pancreas. 85% of the islet cells make insulin (the beta cells), another cell type (the alpha cells) make another protein (glucagon), also secreted into the blood, making it a hormone by definition.  Glucagon raises blood sugar, by causing the liver to make glucose and then pump it out.

Streptozotocin (a glucose derivative) made by soil bacteria, has the nasty property of selectively killing pancreatic beta cells, leaving everything else alone.  Naturally experimentalists love it and have used it to produce severe diabetes (fatal if untreated) in lab animals, and then try new treatments to see if they can come up with something better.

Amazingly, here’s one they didn’t try until now.  Given our present tools, you can pretty much knock out any gene you want in a mouse embryonic stem cell, implant it in another mouse, and (after a lot of failure), make a strain of mice lacking that particular gene (these are what’s called knockout mice).  What they knocked out was not glucagon (which has effects all over the body, including the brain), but the receptor for glucagon.  So even though there’s plenty of glucagon around, lacking the receptor cells don’t respond to it.  It’s like hearing a language you don’t know — the sound is there all right but you can’t internalize it and react to what’s being said.

It had been known for a while that giving streptozotocin to mice lacking the glucagon receptor doesn’t produce diabetes (or much else).  The finding as been treated with a good deal of skepticism, being blamed on other factors.  The authors of the present paper, found a way to put the glucagon receptor back into the liver (using a virus).  When they did this to a knockout mouse living happily despite being treated with strpetozotocin, their glucose shot up.  The virus didn’t hang around forever, glucagon receptor levels in the liver dropped and blood sugar dropped along with it.   Remember that a normal mouse dies of diabetic complications fairly quickly after receiving streptozotocin.

You couldn’t ask for much better proof, and a new way to treat diabetes may have been found.  Amazing.

As in all of medicine there are caveats.  The glucagon receptor is found in other organs, heart and brain among them, so blocking the action of glucagon this way  may have many other effects.

How fast is your biological clock ticking – II ?? Latest results.

The acceleration in genome sequencing capacity is just incredible.  In May 2010, I posted on the sequencing of the complete genomes of two parents and two of their kids.  Now in August of 2012 we have the results on the complete genomes of 78 parent children trios, along with 1,859 complete sequences from the same population, for comparison.

To get you started here’s the first post:

***

My family breeds about as fast as sequoias.  A cousin had a child at 46 who is presently burning up Columbia.  My brother had a child at 48, also doing OK.  But we do know that the older the parents, the more likely a kid is to have genetic problems (Sarah Palin & Trig).  So what are the odds and how do they change with age?

We don’t really know, but in the next five to ten years, we’ll have a good idea.  The first human genome project sequenced most of the 3,200,000,000 positions in our DNA. It cost billions and took years.  DNA sequencing technology marches on at an incredible pace.   A recent paper rated only 4 pages [ Science vol. 328 pp. 636 - 639 '10 ].  The complete genome sequence of 2 parents and 2 of their children was performed (to 1/100,000 accuracy yet).  There was known genetic disease in the family and the authors were looking for its cause.  The genome sequences of the parents and their children were compared position by position (using computers of course). If the base (adenine, thymine, guanosine, cytosine) at a given position differed from that of the parent supplying the surrounding DNA, a mutation had taken place between the generations.  Since they had looked at the entire genome, they could count the number of mutations they found.  The rate of mutation was 1.1 per 100 million positions, making about 30 new mutations between generations.

So this isn’t by guess and by gosh, but an actual mutation rate and a count.  While medical science marches on,  our biology has not.  We’ll soon be able to give the numbers of the mutations occurring between parents and progeny at a variety of parental ages, when enough of this sort of thing is done. And it definitely will be done as only 10 years separates the incredibly laborious first human genome project from this paper.

Interestingly, the authors didn’t mention anything about this application in their paper, so this may be (gasp) an original idea.

***

This brings us to [ Nature vol. 488 pp. 439, 467 - 468 (editorial) and 471 - 475 (the actual paper) ].  Some 78 trios (momma poppa and baby) had their entire genomes sequenced, looking for changes found in the baby, not present in either parent.  The paper is from Iceland, which has a small population (317,000), and complete genealogical records going back 10 generations (thanks to National Censuses and Parish records).  In addition, to find out what a normal Icelandic genome was, they completely sequenced the genomes of 1,859 more.   The more times a single genome is sequenced, the more accurate it is, and 78 trios were sequenced to 30x coverage — making it quite accurate.  Knowing both the father’s genome and the mothers (which are of course different), any change in the baby from a carbon copy could be definitively linked to the parent providing the mutated sperm or egg.

The bottom line is that mothers contribute 15 mutations to the baby regardless of age, while fathers transmit more (25 to 65).  The most important point, is that the older the father, the greater the number of mutations transmitted.  Why do men transmit more than women — because they are continually producing new sperm, while the eggs each woman possesses were present at birth.  Anyone who has ever played the telephone game knows that messages get distorted when copied.  Nonetheless, the accuracy of the copying is incredible (around 1 error per 100 million bases copied).

Should you be worried about this?  Possibly, but look who they studied – of the 78 children studied 44 had autism spectrum disorder and 21 were schizophrenic.  They don’t say anything about the other 13.

I can’t fault the authors for looking for genetic information to help us all understand autism and schizophrenia, but remember these weren’t normal kids. This work may not generally apply.  The study definitely needs to be repeated with normal progeny before getting too excited.

As usual, even though there 4,933 mutations were discovered in this population, none were found more than once.  This has been discussed before.  For details see http://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/ and

http://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/

The New Clayden pp. 757 — 800

 

Chapter 30: There’s a lot more use of the disconnection approach in the discussions of the synthesis of heterocylic aromatic compounds than there was in the previous edition.  The analysis of the Viagra synthesis pp. 768 –> is particularly fascinating.

The sophistication of the chapter is much higher than what went on previously.  It’s great !  The writer assumes that you have all the previous reactions well under your belt, as well as disconnection and moves rapidly on from there.  

In a sense it’s like the switch from undergraduate math books where proofs are laid out in detail, to the graduate lectures, where proofs are sketched and you are expected to fill in the dots.  I wonder how a neophyte hitting this chapter for the first time would take it. 

One can take the analogy a bit further.  The target molecule can  be considered the theorem and and the synthesis the proof.  This is exactly why math is harder than organic chemistry.  The target molecule is almost telling you (thanks to the disconnection approach) how to make it.  The examples in this chapter are fairly simple.  Yet most accounts of syntheses focus on one or two most difficult steps and the target is far more complex — for an example see ttp://heterocyclist.com/2012/08/24/synthesis-of-kopsia-lapidilecta-alkaloids-the-rcm-approach-takes-a-hit-retraction/.

In medical school, the importance of taking an accurate history was stressed — “The patient is telling you the diagnosis” was said over and over, just as the structure of a synthetic target is telling you how to make it.  Certainly, with each passing year, the MD finds the history more and more valuable, and the physical exam less.  Medicine has one further wrinkle that math and synthetic organic chemistry do not.  The manner in which  the patient gives the history and answers your questions is incredibly important.  It’s not just the words, it’s the tune.  Is the patient depressed, angry, confused, hyped-up etc. etc.  That’s why I always took the history myself, and never had the patient fill out some checklist, it throws away information you can get in no other way

I don’t know enough math to know if proofs break down this way.  But there is another huge difference between math and orgo.  In math the definitions are incredibly precise.  A collection of subsets of a given set either satisfies 3 extremely specific criteria to make them open sets and the containing set into a topology, or they don’t.  Chemical reactions aren’t like that — Anslyn and Dougherty take you through Sn1 and Sn2 and their variants, and then show you how there are reactions that fall between them, containing aspects of both.   The idea of a Diels Alder reaction, is independent of any particular exemplar — so the concepts in chemistry are inherently fuzzy.  If you’re good at reasoning by analogy, then chemistry is your oyster.  Don’t try this in a mathematical proof.  So the zillion mathematical definitions (first countable, compactness, path connected in its varieties) must be memorized exactly as they are, and used in proofs that way, and that way only.   Medical concepts are even fuzzier.  It takes a very different type of mind to do math well, one which, unfortunately, I don’t posses, even though I love the stuff.

 Back to chemistry

p. 772 The example of the tautomer of the thioamide interacting with an alpha haloketone is a great example of hard/hard nucleophile/electrophile and soft/soft nucleophile/electrophile interactions occuring specifically in the same pair of molecules, while quite near to each other.  It should probably be pointed to in the next edition when  hard/soft nucleophiles and electrophiles are first discussed. 

p. 775 — Interesting that they didn’t call the reaction of an alkyne and an azide ‘click chemistry‘ which is what Sharpless calls it.  It has proved extremely useful in linking together molecules of biologic interest — e.g. seeing where a protein is binding to other proteins or to DNA.  The uses are endless and still being discovered. 

Here are a few examples:

       [ Proc. Natl. Acad. Sci. vol. 98 pp. 4740 - 4745 '01 ] Propargyl choline is a choline derivative which can be used to label choline containing phospholipids using Click chemistry  (forming cycloaddition products with a fluorophore containing an azide.  Total lipid analysis of labeled cells shows strong incorporation of propargyl choline into all classes of choline phospholipids — and the fatty acid composition of these lipids is quite normal. 

        [ Proc. Natl. Acad. Sci. vol. 105 pp. 2415 - 2420 '08 ] It was used to quickly label DNA using 5 ethynyl 2′ deoxy uridine — which can be detected using fluorescence. 

       [ Science vol. 320 pp. 868 - 869 '08 ] It is a modification of the Huisgen reaction — the trick was using Copper Iodide as a catalyst.  Polymer scientists love it.

        Another type of click reaction adds a thiol across an olefin using light. 

 

       [ Proc. Natl. Acad. Sci. vol. 107 pp. 15329 - 15334 '10 ] Oligonucleotides can be produced by automated solid phase phosphoramidite synthesis — chains over 100 (deoxy) nucleotides can be formed.  It’s harder with RNA because of the reactivity of the 2′ OH group which requires selective protection.  So the limit here is 50 nucleotides.  This work describes click ligation as a way to put them together. 

p. 793 — A very useful explanation of the nomenclature of heterocyclic ring compounds (which is actually or logical than it first appears). 

p. 794 — Aziridine is less basic than pyroldine and piperidine, because the hybridization of the nitrogen has more s character. But no mention is made of why this should mean less basicity — it’s because the s orbital experiences the positive charge of the nucleus more intensely than a p orbital (which has a node at the nucleus), lowering its energy and making it less likely to share (like a spoiled child). 

p. 796 – While coupling NMR is through bonds rather than throught space (e.g. more coupling between H’s trans to each other on a double bond, than cis — they never explained why this is so, nor do they here. 

p. 796 — It don’t see why the dihedral angle in the bicyclic compound shown is any different from 60 degrees, the axial equatorial bond separation, unless the ring configuration by compressing the C – C – C angle, expands the H – C – H angle.

p. 797 — Why is the shift of the  hydrogen on the carbon containing the OH groups so different between axial (3.5) and equatorial (4.0)? 

p. 799 — Neurologists are excellent at reading MRI scans of patients (or they should be), these vary in appearance depending on whether they use T1 or T2 relaxation.  But the whole issue of relaxation from a higher energy state to a lower one is rarely discussed.  

The text says “So far we have assumed that the drop back down (to a lower energy state) is spontaneous, just like a rock falling off a cliff.  In fact it isn’t — something needs to ‘help’ the protons to drop back again — a process called relaxation”.  Why is this the case? Is it similar to laser action, where something needs to stimulate the drop down to a lower energy state with the emission of laser light.  Perhaps one of the cognoscenti reading this can explain why help is needed for a transition to a lower energy state.  I don’t understand it.

Being able to admit you don’t know something and publicly asking for help is one of the joys of being a non-academic.  I doubt that I’d be able to do this if I were a chemistry department chair, as at least 3 – 4 of my fellow Harvard graduate students 52 years ago became (one of them is still at it and going strong — also to be noted is that he came out of a State University).