Archive for the ‘Rip Van Winkle’ Category

Miles Monroe and Synthesis Bashing — RVW #7

Monday, September 10th, 2007

Without further ado, here is Retread’s latest Rip Van Winkle installment, in which Rip feels much like Miles Monroe. My apologies for not posting it earlier; I’ve been occupied with other things. In fact, the apparent hectic state from which Retread was emerging when he wrote this post strikes me as similar to how I feel in coming back to this blog after not even checking it for so long: a little weird. — Paul

Sleeper is one of the great Woody Allen movies from the 70s. Woody plays Miles Monroe, the owner of (what else?) a health food store who through some medical mishap is frozen in nitrogen and is awakened 200 years later. He finds that scientific research has shown that cigarettes and fats are good for you. A McDonald’s restaurant is shown with a sign “Over 795 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 Served”.

Rip returned from the 100-year birthday blowout and band camp and began attacking a giant pile of accumulated unread journals. In the 9 August Nature (p. 630 – 631) he was amazed to read criticism of a 64-step, 22-year synthesis of an exquisitely complex molecule (azadirachtin) — a molecule for which it is easier to count the number of optically inactive carbons than the optically active ones. Back in the 60s, we were all impressed with how Woodward got the five asymmetric centers in one of the six-membered rings of reserpine (which was in use as an antihypertensive at the time, and whose fairly common side effect of depression was one of the clues leading to the amine theory of affect). Rip was surprised to find that the criticism was not that the synthesis was incorrect, but that the project shouldn’t have been done at all. Apparently, a significant body of organic chemists think this way.

Political correctness has left us with few groups that are safe to disparage. With apologies to one of them (Christians) I’ve got to ask, “What would Woodward do?”

Rip’s father went into the hospital shortly after his 100th, and is getting out 1 Sep, so it may be a while before he can respond to what this post brings forth.

Retread

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Serendipity — RVW #6

Saturday, July 28th, 2007

The wrap up is on its way. In the meantime, Retread has come to the rescue with the next installment of his Rip Van Winkle series. Enjoy.

I think Jones’ book is terrific. It’s just a leisurely discourse on organic chemistry, with plenty of examples, hints, exhortations, warnings, opinions etc. etc. It’s always friendly and never turgid or pompous. I’ve now (20 July) made it halfway through, doing most of the problems (as suggested by Paul and Excimer).

A series of comments on the first half would be rather disjointed, so I’ll put just one in now and then. Here’s today’s: I wrote my Junior paper on the Grignard reagent, and it seemed obvious that no one knew what was going on back then. From the discussion on p. 236, it seems like not much has changed. Any comments?

——

There wasn’t much response to the request for examples of chemical serendipity in the last post, so here are two from medicine to get the discussion going.

Interns don’t get much sleep. On a three-month surgery rotation, it was 36 hours on/12 off, but to get a weekend off, call was bunched so that in one 7-day stretch, it was 5 nights on/2 nights off, making 24 of 168 hours off call. Most nights we got 3-4 hours of crummy sleep. According to legend, Mary Walker was one such intern who in 1934, fell asleep during a lecture on myasthenia gravis (a disease characterized by muscle weakness, which can affect the ability to breathe, hence the “gravis”) for which there was no known treatment. She woke up after the lecture, walked up to the great man and asked how to treat myasthenia. The great man, irritated, said — “It’s just like curare poisoning”, so she went off to the library, looked up curare poisoning, found the treatment (physostigmine), administered it to a myasthenic and became famous.

Few of the drugs first used to treat neurological disease were discovered rationally. The first drug for epilepsy (bromide ion) was thought to work by decreasing libido, as epileptics were thought to be sexually overwrought. Things improved in the 30s with the discovery that seizures could be induced by electric shocks administered to the brain. Zillions of hapless rabbits were shocked while pumped full of various drugs. If the drug increased the current required for seizures, it was a potential anticonvulsant. This is exactly how Dilantin was discovered. Cruel, but at least rational.

Science marches on, and it was soon discovered that drugs getting into the brain (which is mostly fat) had to be soluble in lipids (which meant they weren’t too soluble in water). So potential drugs were first put into amphipathic (soluble in water and lipids) solvents, like soap. Soap is basically a bunch of long chain (12-18 carbons) carboxylic acids. One such solvent was 2-propylpentanoic acid (valproic acid).  Many drugs put into it seemed to work pretty well. Fortunately, someone had the brains to do a control, and found that the actual anticonvulsant was valproic acid (and a very useful one it was — although like everything else in medicine, not without side effects). A case of not throwing out the bathwater. Anything similar in chemistry?

Retread

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From Vietnam to Proteins — RVW #5

Monday, July 16th, 2007

In 1968, the USA had half a million men in Vietnam.  The Army needed lots of docs to take care of them and their motto was “If you can practice medicine outside the army, you can practice it inside the army”.  There was no 4F for docs, nor were there medical excuses.  There were excuses for individuals of exceptional value, and as chemists, you should know where this arose (see the starred footnote at the end of this post if you don’t). This meant that all newly minted MDs would spend two years during or after residency training in the service.

Fortunately (for me) the Army was short of neurologists in 1968, so with just one year of residency (instead of the usual three) under my belt, I was sent to one of their best hospitals (Fitzsimons) to work under an excellent and seasoned neurologist (Col. Halbert Herman Schwamb — whose name alone scared the hell out of me).

The tour of duty in Vietnam was one year for everyone, so docs who had been there for their first of two years got their pick of where to go for their final year.  Naturally, Fitzsimons was one of their top picks, so the place was full of them.

What in the world does this have to do with molecular biology?  The army had something called the ‘body count’ which meant the number of Viet Cong (and possibly civilian) bodies they could find.  It gave a number, which was increasing with each passing month.  It showed we were winning.  However, not one of the returning two-year docs I talked to (and I talked to a lot of them) thought we were winning.  Most thought we were losing, and badly.  They were, of course, right.  The point is that what we could not measure was far more important than what we could.

Consider the following terms from molecular biology: nonsense codon, noncoding DNA, Junk DNA.  Two of them are downright pejorative.  All imply that anything in our DNA not coding for an amino acid going into a protein is unimportant.  As most of you probably know, the four bases of DNA (A, T, G, and C) are read in groups of three (these are the codons) giving 64 possibilities.  The 3/64 not coding for an amino acid are called nonsense codons.  They tell the protein making machinery (the ribosome) to stop and start on another protein.  The 3 codons are just as vital for life as the other 61, or we’d just be one big protein.  Calling them nonsense always seemed peculiar to me.

Noncoding DNA means DNA which doesn’t code for an amino acid going into a protein.  The implication is that it doesn’t code for anything else.  Of our 3.2 billion positions in DNA, perhaps 2% codes for amino acids going into proteins.  The rest has been called ‘junk DNA’ — again the implication is that it does nothing.

You have doubtless heard that we are 98.5% chimpanzee.  What this means is that our proteins are 98.5% similar (e.g. they have the same sequence of amino acids in 98.5% of positions).  Again, the proteincentric view is dominant here—proteins are all that you have to know.

Now, we all love chemistry or we wouldn’t be here reading this.  Consider Independence Hall and Monticello from the chemical point of view.  They’re both made of bricks, and a chemical analysis of them could certainly figure out that one set of bricks came from South Jersey and the other came from the Virginia piedmont.  However, the most sophisticated chemical analysis can not tell us why the two buildings look so different.

Why not?  Chemistry can’t deal with the way the bricks are put together.  You can do a lot with bricks if you stack them just right (and the chemical nature of the bricks doesn’t matter very much for this).

However, for at least 30 years, minor differences in proteins were thought to determine the differences between a man and chimp.  In fact, it was seriously stated at one point, that chemically man and chimp weren’t different enough (as far as their proteins were concerned) to be considered separate species.

Well, we are, and the determining difference lies in the 98% of the DNA which does NOT code for protein.  In some way (which we are just beginning to find out) it determines which protein is made where, how much of it is made, and when it is made.  Molecular biology is definitely still in the hunter gatherer stage at this point.

That’s enough for now.  The details are emerging and including things like epigenetics, microRNAs, RNA interference, and even in bacteria metabolite control of mRNA translation into protein (look up the work of Breaker at Yale if you’re interested).

**The answer is Henry Mosely who died at age 27 in the battle of Gallipoli in 1915.  Moseley used X-ray diffraction to show that each element has an atomic number. With this tool he was able to fill the six remaining gaps in the periodic table (at the time) and to put some order into the rare earths.  After that, the British (and everyone else) decided that brains like that shouldn’t be used as cannon fodder.

At my father’s recent 79th Rutgers reunion ( yes his 79th ! ) I met an 87 year old graduate.  I asked him where he served in the war (because just about every male in his generation did).  He said that he didn’t.  I asked him how come. The answer — “I was making penicillin for Merck.”

Retread

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Drugs and More — RVW #4

Monday, July 2nd, 2007

This is the fourth part in Retread’s Rip Van Winkle series.

There’s a lot to say about just the introduction to Jones. First a mistake — on p. xxxii he implies that heroin is addictive while morphine (described as a pain killer) is not. Unfortunately not true. Both can be addictive and I saw plenty of narcotic addiction as a neurologist (notice I said “can be” not “is”). When I was an Army Doc from ‘68 – ‘70, we had half a million men in Vietnam, and really pure heroin was readily available from Thailand next door. The tour of duty over there was one year. It was estimated that 20 – 30% of the troops used narcotics while there. We were braced for a giant expansion of the addict population over here. It didn’t happen. When shipped back to the states, some mild withdrawal occurred and I saw a few seizures when withdrawal was more severe. Most vets gave it up without much difficultly (assuming that the 20 – 30% figure is close to accurate).

Having used lots of morphine (postoperative pain, auto accidents etc. etc.) I would say that 95% of people receiving morphine or one of its synthetic cousins do NOT like the way it makes them feel (although they are all grateful for the pain relief). What is truly fascinating is that those liking the stuff and those not liking it describe the experience exactly the same way. “I was out of control. I didn’t care about anything. I couldn’t concentrate—I hated it” or “I didn’t have a care in the world. I was just floating, and forgot my troubles—I loved it”. I don’t think neurochemistry—or even chemistry—can explain this. It is the province of novelists and psychiatrists.

Second (still on p. xxxii) although structure determination is easy now, it wasn’t back then (as Jones mentions). However, structure determination taught a lot of chemistry to chemists and certainly sharpened their analytic skills.

A chemist (David Ginsburg from Israel) gave us a series of lectures on the opium alkaloids (I think in the fall of ‘60). I’m not sure just how many but my retranscribed notes on them go for 46 pages of which the first 32 were on the determination of the structure of morphine, and the last 14 concerned its synthesis. As I recall, Woodward
attended all of them.

Parenthetically, it is always a good idea to retranscribe your notes (assuming people still take notes) so that you can understand them years later.

The most interesting statement (again p. xxxii) is “Chemists began the transformation from the hunter-gatherer stage to modern times, in which we routinely seek to use what we know to generate new knowledge.” While certainly true, I think that chemists have always done this. We certainly thought so in the 60s. The further implication is that there is no role for just ‘messing about’ to find new chemistry. I don’t know enough chemical history to say how many surprises there have been, but no one anticipated Buckyballs and nanotubes (as I recall). What about the metathesis reaction? Was that figured out beforehand? In the next installment, I’ll argue that molecular biology is still in the hunter gatherer stage, even though up to a few years ago most molecular biologists didn’t think so.

Retread

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Math, Physics, and Chemistry — RVW #3

Thursday, June 14th, 2007

In his third post, Retread looks at some of the physics and math needed and used by chemists.

Now that the answer book to Jones has arrived (23 May) I’m going to start over from the beginning, this time doing all the problems.  Mathematicians are fond of saying that it isn’t a spectator sport, and that problems must be done to really grasp the material.  I’m not so sure that is true for chemistry, but I’ll take excimer’s advice.

I’d gone through the first 300 or so pages of Jones and it’s apparent the two textbooks are wildly different in the way they approach the beginner.

English & Cassidy start out with hydrocarbon structures.  Molecular orbitals make their appearance on p. 63 (remember the book only has 442 pages of text). They are introduced as follows: “A somewhat more easily visualized physical picture of a double bond is given by a relatively recent theoretical development known as the molecular orbital theory.”  Recall that there are only six three dimensional drawings in the first 100 pages of E&C.  Four of them involve orbitals.

Jones drenches the reader in atomic and molecular orbitals using all the graphics at his disposal.  One needs to step back in time to realize the mathematical armor the high school graduate possessed in ‘56 entering college.  Outside a few of the great academic high schools in the USA (Central High in Philly, Bronx High School of Science) calculus was simply not taught in US public high schools.  The thinking was that is was so hard that it would destroy the brain of anyone under 18.  There was a giant dose of anxiety on taking it for the first time.  Just about all the undergraduates in the math courses I audited had a year or two of calculus in high school and some were exposed to it in the 8th grade.

So junior chem majors back then didn’t have the apparatus to tackle the Schrodinger equation etc.  Formal quantum mechanics wasn’t taught to us back then.  Even though the department had Walter Kauzmann, who wrote the influential “Quantum Chemistry” in ‘57, and who taught physical chemistry (which we all took), quantum mechanics wasn’t really discussed in the course.

The department did introduce us to quantum mechanical thought.  As juniors we were required to read a book “The Logic of Modern Physics” by P. W. Bridgman, written in 1927 in the early heyday of quantum mechanics.  I found it extremely irritating.  It argued that all we could know was numbers on a dial reporting the results of a measurement.  The notion of particle trajectory was to be abandoned, etc. etc. Jones skirts the issue on p. 10 where he talks about the node in the 2S orbital, a place where an electron is NEVER found.  An electron following a trajectory as we know it macroscopically could never pass through the node.  If you like thinking about such things, I recommend just about anything a physicist named Mark P. Silverman writes.  In particular, Ch. 5 “And Yet It Moves: Exotic Atoms and the Invariance of Charge” in his book “A Universe of Atoms, An Atom in the Universe” deals with the issue of the ‘motion’ of an electron in an atom.

I have a friend, a retired philosophy prof from Columbia, who dismisses all biology and chemistry as ‘anecdotal’.  The only thing he regards as solid is Godel’s proof.  I told him he better hope he’s wrong if he ever gets sick.  In a similar vein, Bridgman is as wrong as he can be when it comes to chemistry.  Why?  Because the theory behind chemistry may have its origin in numbers on a dial, but it gives rise to gazillions of successful predictions about reactions, structure and spectra.  Theory is immaterial, but it guides chemists (it’s the old Cartesian dichotomy between flesh and spirit).   Following chemistry in a peripheral fashion during my years in medicine by reading what appeared in Nature and Science (on a superficial level), it seemed that the work in gas phase kinetics was just confirming (always good) what we ‘knew’ back from ‘58 – ‘62.  The one surprise was the reversal (p. 245) of the acidity of primary, secondary and tertiary alcohols in the gas phase.

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A Tale of Two Textbooks, Then & Now — RVW #2

Wednesday, June 6th, 2007

In the second part of his series, Retread lays out his first impressions of Jones vis-à-vis his previous orgo text in grad school, English & Cassidy.

The book for my first Organic Chemistry course (’58 – ‘59) was English and Cassidy, 2nd edition, ‘56.  Jones is the 2004 edition.

………………………………………English & Cassidy            Jones

Pages (text only)                442                          1323
Page size  (inches)            9 x 6                         10 x 8
Text width                          4.5                           5.25
Text height                         7.0                           8.50

The most striking difference is the graphics.  There were only six 3-dimensional representations in the first 100 pages of Cassidy, while Jones has TNTC (too numerous to count).  It is hard to find a page in Jones without one.

The tone is completely different.  Jones is chatty and conversational.  “Remarks for the Student” in E&C begins as follows:   ”It is usually taken for granted that the student who  takes up the study of organic chemistry has a thorough knowledge of first-year college chemistry.”  Not too warm and fuzzy.

One of the very best things about Jones, is that he tells you what is hard, and what you must learn. “The (R, S) convention looks a bit complicated.  It is easier than it appears right now, but it just must be learned and cannot be reasoned out.”   Repeat this advice 50,000 times and you’re through med school.  There is no reason the appendix is on the right, the heart is on the left, speech is usually in the left hemisphere  etc. etc.  Jones also tells you what looks  hard but really isn’t — drawing cyclohexane in the chair form for instance.

Another very good thing about Jones (which may seem rather trivial) is that when he points you back, he gives you a page number to go to.  On retirement from medicine, I indulged a lifelong taste for math by auditing some math courses (number theory, abstract algebra,  algebraic geometry) at the local colleges.   Math books almost never repeat anything.  You are referred back to theorem 10.3 (and have to hunt for it).   There are hundreds of theorems, corollaries etc. in the average upper level math book.  It gets irritating unless you have a completely flawless memory.

Also, math books don’t usually tell you what’s really important, and what will be used later.  Not all results are equally crucial for the argument.  On reading it for the first time, you can’t tell the wheat from the chaff.  Jones is excellent at this.

In one sense, the two books can’t be compared, just as stereos back then and now can’t be.  I worked all summer as a supermarket checker at $1/hour before entering college in ‘56 and bought an RCA Victor record player to take with me for $140.  The richest man in the world back then could not buy sound of today’s quality no matter what he was prepared to spend.

However today’s convenience store worker would have to work considerably more hours to buy Jones (167.74) and the answer book (80.59) than I would have had to for English & Cassidy back then.  I asked the student checking me out how anyone could afford books like
these.  He said that often students bought a single textbook and shared it.  Shades of the 19th century Ghetto.  My grandfather told me how there were people who could only read Hebrew upside down, or at a 45 degree angle, because 4 – 6 students would sit around the  same table and study the same page at the same time.

One final point.  Despite the dryness, formality, lack of graphics etc. etc. not much harm was done.  I liked the book back then as did most of us.  This includes Jones himself (Yale ‘59), who almost certainly used the book, as English and Cassidy were Yale professors and the first edition came out in ‘49.

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